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Veterans and Agent Orange: Update 2010 (2012)

Chapter: 7 Cancer

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Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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7

Cancer

Cancer is the second-leading cause of death in the United States. Among men 50–64 years old, the group that includes most Vietnam veterans (see Table 7-1), however, the risk of dying from cancer exceeds the risk of dying from heart disease, the leading cause of death in the United States, and does not fall to second place until after the age of 75 years (Heron et al., 2009). About 570,000 Americans of all ages were expected to die from cancer in 2010—more than 1,500 per day. In the United States, one-fourth of all deaths are from cancer (Jemal et al., 2010).

This chapter summarizes and presents conclusions about the strength of the evidence from epidemiologic studies regarding associations between exposure to

TABLE 7-1 Age Distribution of Vietnam-Era and Vietnam-Theater Male Veterans, 2009–2010 (numbers in thousands)


Vietnam Era Vietnam Theater


Age Group (Years) n (%) n (%)

All ages 7,805 3,816
≤ 54 133 (1.8) 32 (0.9)
55-59 1,109 (15.1) 369 (10.4)
60-64 3,031 (41.3) 1,676 (47.0)
65-69 2,301 (31.3) 1,090 (30.6)
70-74 675 (9.2) 280 (7.9)
75-84 511 (6.9) 322 (9.0)
≥ 85 178 (2.4) 83 (2.4)

SOURCE: IOM, 1994, Table 3-3, updated by 20 years.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

the chemicals of interest—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), picloram, and cacodylic acid—and various types of cancer. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals (DLCs) informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners of DLCs. If a new study reported on only a single type of cancer and did not revisit a previously studied population, its design information is summarized here with its results; design information on all other new studies can be found in Chapter 5.

The objective of this chapter is assessment of whether the occurrence of various cancers in Vietnam veterans themselves may be associated with exposure they may have received during military service. Therefore, studies of childhood cancers in relation to parental exposure to the chemicals of interest are discussed in Chapter 8, which addresses possible adverse effects in the veterans’ offspring. Studies that consider only childhood exposure are not considered relevant to the committee’s charge.

In an evaluation of a possible connection between herbicide exposure and risk of cancer, the approach used to assess the exposure of study subjects is of critical importance in determining the overall relevance and usefulness of findings. As noted in Chapters 3 and 5, there is great variety in detail and accuracy of exposure assessment among studies. A few studies used biologic markers of exposure, such as the presence of a chemical in serum or tissues; some developed an index of exposure from employment or activity records; and some used other surrogate measures of exposure, such as presence in a locale when herbicides were used. As noted in Chapter 2, inaccurate assessment of exposure can obscure the relationship between exposure and disease.

Each section on a type of cancer opens with background information, including data on its incidence in the general US population and known or suspected risk factors. Cancer-incidence data on the general US population are included in the background material to provide a context for consideration of cancer risk in Vietnam veterans; the figures presented are estimates of incidence in the entire US population, not predictions for the Vietnam-veteran cohort. The data reported are for 2004–2008 and are from the most recent dataset available (NCI, 2010). Incidence data are given for all races combined and separately for blacks and whites. The age range of 55–69 years now includes about 80% of Vietnam-era veterans, and incidences are presented for three 5-year age groups: 55–59 years, 60–64 years, and 65–69 years. The data were collected for the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute and are categorized by sex, age, and race, all of which can have profound effects on risk. For example, the incidence of prostate cancer is about 2.6 times as high in men who are 65–69 years old as in men 55–59 years old and almost twice as high in blacks 55–64 years old as in whites in the same age group (NCI, 2010).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Many other factors can influence cancer incidence, including screening methods, tobacco and alcohol use, diet, genetic predisposition, and medical history. Those factors can make someone more or less likely than the average to contract a given kind of cancer; they also need to be taken into account in epidemiologic studies of the possible contributions of the chemicals of interest.

Each section of this chapter pertaining to a specific type of cancer includes a summary of the findings described in the previous Agent Orange reports: Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994); Veterans and Agent Orange: Update 1996, referred to as Update 1996 (IOM, 1996); Update 1998 (IOM, 1999); Update 2000 (IOM, 2001); Update 2002 (IOM, 2003); Update 2004 (IOM, 2005); Update 2006 (IOM, 2007); and Update 2008 (IOM, 2009). That is followed by a discussion of the most recent scientific literature, a discussion of biologic plausibility, and a synthesis of the material reviewed. When it is appropriate, the literature is discussed by exposure type (service in Vietnam, occupational exposure, or environmental exposure). Each section ends with the committee’s conclusion regarding the strength of the evidence from epidemiologic studies. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

Biologic plausibility corresponds to the third element of the committee’s congressionally mandated statement of task. In fact, the degree of biologic plausibility itself influences whether the committee perceives positive findings to be indicative of an association or the product of statistical fluctuations (chance) or bias.

Information on biologic mechanisms by which exposure to TCDD could contribute to the generic (rather than tissue-specific or organ-specific) carcinogenic potential of the chemicals of interest is summarized in Chapter 4. It distills toxicologic information concerning the mechanisms by which TCDD affects the basic process of carcinogenesis; such information, of course, applies to all the cancer sites discussed individually in this chapter. When biologic plausibility is discussed in this chapter’s sections on particular cancer types, the generic information is implicit, and only experimental data peculiar to carcinogenesis at the site in question are presented. It is of note that in this update we have explicitly included an examination of the contribution of epigenetic mechanisms in assessing the carcinogenicity of TCDD. A large literature indicates that carcinogenesis is a process that involves not only genetic changes but also epigenetic changes (Johnstone and Baylin, 2010). There is emerging evidence that TCDD and the chemicals of interest may disturb epigenetic processes (see Chapter 4), and reference to this evidence, as it applies to cancers is included where it exists, by cancer site.

Considerable uncertainty remains about the magnitude of risk posed by exposure to the chemicals of interest. Many of the veteran, occupational, and environmental studies reviewed by the committee did not control fully for important

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

confounders. There is not enough information about the exposure experience of individual Vietnam veterans to permit combining exposure estimates for them with any potency estimates that might be derived from scientific research studies to quantify risk. The committee therefore cannot accurately estimate the risk to Vietnam veterans that is attributable to exposure to the chemicals of interest. The (at least currently) insurmountable problems in deriving useful quantitative estimates of the risks of various health outcomes in Vietnam veterans are explained in Chapter 1 and the summary of this report, but the point is not reiterated for every health outcome addressed.

ORGANIZATION OF CANCER GROUPS

For Update 2006, a system for addressing cancer types was described to clarify how specific cancer diagnoses were grouped for evaluation by the committee and to ensure that the full array of cancer types would be considered. The organization of cancer groups follows major and minor categories of cause of death related to cancer sites established by the National Institute for Occupational Safety and Health (NIOSH). The NIOSH groups map the full range of International Classification of Diseases, Revision 9 (ICD-9) codes for malignant neoplasms (140–208). The ICD system is used by physicians and researchers to group related diseases and procedures in a standard form for statistical evaluation. Revision 10 (ICD-10) came into use in 1999 and constitutes a marked change from the previous four revisions that evolved into the ninth ICD-9. ICD-9 was in effect from 1979 to 1998; because ICD-9 is the version most prominent in the research reviewed in this series, it has been used when codes are given for a specific health outcome. Appendix B describes the correspondence between the NIOSH cause-of-death groupings and ICD-9 codes (Table B-1); the groupings for mortality are largely congruent with those of the SEER program for cancer incidence (see Table B-2, which presents equivalences between the ICD-9 and ICD-10 systems). For the present update, the committee gave more attention to the World Health Organization’s classification for lymphohematopoietic neoplasms (WHO, 2008), which stresses partitioning of these disorders first according to the lymphoid or myeloid lineage of the transformed cells rather than into lymphomas and leukemias.

The system of organization used by the committee simplifies the process for locating a particular cancer for readers and facilitated the committee’s identification of ICD codes for malignancies that had not been explicitly addressed in previous updates. VAO reports’ default category for any health outcome on which no epidemiologic research findings have been recovered has always been “inadequate evidence” of association, which in principle is applicable to specific cancers. Failure to review a specific cancer or other condition separately reflects the paucity of information, so there is indeed inadequate or insufficient information to categorize such a disease outcome.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

BIOLOGIC PLAUSIBILITY

The studies considered with respect to the biologic plausibility of associations between exposure to the chemicals of interest and human cancers have been performed primarily in laboratory animals (rats, mice, hamsters, and monkeys) or cultured cells. Collectively, the evidence obtained from studies of TCDD indicates that a connection between human exposure to this chemical and cancers is biologically plausible, as will be discussed more fully in a generic sense below and more specifically in the biologic-plausibility sections on individual cancers. Recent reviews have affirmed the now well-established mechanistic roles of the aryl hydrocarbon receptor (AHR) in cancer (Androutsopoulos et al., 2009; Barouki and Coumoul, 2010; Dietrich and Kaina, 2010; Ray and Swanson, 2009), and the data have firmly established the biologic plausibility of an association between TCDD exposure and cancer.

With respect to 2,4-D, 2,4,5-T, and picloram, several studies have been performed in laboratory animals. In general, the results were negative although some would not meet current standards for cancer bioassays; for instance, there is some question of whether the highest doses (generally 30–50 mg/kg) in some of these studies reached a maximum tolerated dose (MTD). It is not possible to have absolute confidence that these chemicals have no carcinogenic potential. Further evidence of a lack of carcinogenic potential is provided, however, by negative findings on genotoxic effects in assays conducted primarily in vitro. The evidence indicates that 2,4-D is genotoxic only at very high concentrations. Although 2,4,5-T was shown to increase the formation of DNA adducts by cytochrome P450–derived metabolites of benzo[a]pyrene, most available evidence indicates that 2,4,5-T is genotoxic only at high concentrations. Recently, Hernández et al. (2009) have reviewed the mechanisms of action of nongenotoxic carcinogens, including TCDD in this category

There is some evidence that cacodylic acid is carcinogenic. Studies performed in laboratory animals have shown that it can induce neoplasms of the kidney (Yamamoto et al., 1995) and bladder (Arnold et al., 2006; Wei et al., 2002). In the lung, treatment with cacodylic acid induced formation of neoplasms when administered to mouse strains that are genetically susceptible to them (Hayashi et al., 1998). Other studies have used the two-stage model of carcinogenesis in which animals are exposed first to a known genotoxic agent and then to a suspected tumor-promoting agent. With that model, cacodylic acid has been shown to act as a tumor-promoter with respect to lung cancer (Yamanaka et al., 1996).

Studies in laboratory animals in which only TCDD has been administered have reported that it can increase the incidence of a number of neoplasms, most notably of the liver, lungs, thyroid, and oral mucosa (Kociba et al., 1978; NTP, 2006). Some studies have used the two-stage model of carcinogenesis and shown that TCDD can act as a tumor-promoter and increase the incidence of ovarian cancer (Davis et al., 2000), liver cancer (Beebe et al., 1995), and skin cancers

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

(Wyde et al., 2004). As to the mechanisms by which TCDD exerts its carcinogenic effects, it is thought to act primarily as a tumor-promoter. In many of the animal studies reviewed, treatment with TCDD has resulted in hyperplasia or metaplasia of epithelial tissues. In addition, in both laboratory animals and cultured cells, TCDD has been shown to exhibit a wide array of effects on growth regulation, hormone systems, and other factors associated with the regulation of cellular processes that involve growth, maturation, and differentiation. Thus, it may be that TCDD increases the incidence or progression of human cancers through an interplay between multiple cellular factors. Tissue-specific protective cellular mechanisms may also affect the response to TCDD and complicate our understanding of its site-specific carcinogenic effects.

As shown with long-term bioassays in both sexes of several strains of rats, mice, hamsters, and fish, there is adequate evidence that TCDD is a carcinogen in laboratory animals, increasing the incidence of tumors at sites distant from the site of treatment at doses well below the maximum tolerated. On the basis of animal studies, TCDD has been characterized as a nongenotoxic carcinogen because it does not have obvious DNA-damaging potential, but it is a potent “promoter” and a weak initiator in two-stage initiation–promotion models for liver, skin, and lung. Early studies demonstrated that TCDD is 2 orders of magnitude more potent than the “classic” promoter tetradecanoyl phorbol acetate and that TCDD skin-tumor promotion depends on the AHR. For many years, it has been known that TCDD is a potent tumor-promoter. Recent evidence has shown that AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the interleukin-6 (IL-6) cytokine, which has tumor-promoting effects in numerous tissues—including breast, prostate, ovary, and malignant cholangiocytes—and opens up the possibility that TCDD would promote carcinogenesis in these and possibly other tissues (Hollingshead et al., 2008). TCDD has been shown to downregulate reduced folate carrier (Rfc1) mRNA and protein in rat liver, which is essential in maintaining folate homeostasis (Halwachs et al., 2010). Reduced Rfc1 activity and a functional folate deficiency may contribute to the risk of carcinogenesis posed by TCDD exposure.

Mechanisms by which TCDD induces G1 arrest in hepatic cells (Mitchell et al., 2006; Weiss et al., 2008) and decreases viability of endometrial endothelial cells (Bredhult et al., 2007), insulinsecreting beta cells (Piaggi et al., 2007), peripheral T cells (Singh et al., 2008), and neuronal cells (Bredhult et al., 2007) have recently been identified, and these results suggest possible carcinogenic mechanisms. TCDD may contribute to tumor progression by inhibiting p53 regulation (phosphorylation and acetylation) triggered by genotoxicants via the increased expression of the metastasis marker AGR2 (Ambolet-Camoit et al., 2010) and through a functional interaction between the AHR and FHL2 (“four and a half LIM protein 2,” where the LIM domain is a highly conserved protein structure) (Kollara and Brown, 2009). Borlak and Jenke (2008) demonstrated that the AHR is a major regulator of c-raf and proposed that there is cross-talk

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

between the AHR and the mitogen-activated protein kinase signaling pathway in chemically induced hepatocarcinogenesis. TCDD inhibits ultraviolet-C (UV-C) radiation-induced apoptosis in primary rat hepatocytes and Huh-7 human hepatoma cells, and this supports the hypothesis that TCDD acts as a tumor-promoter by preventing initiated cells from undergoing apoptosis (Chopra et al., 2009). Additional in vitro work with mouse hepatoma cells has shown that activation of the AHR results in increased concentrations of 8-hydroxy-2’-deoxyguanosine (8-OHdG), a product of DNA-base oxidation and later excision repair and a marker of DNA damage. Induction of cytochrome P4501A1 (CYP1A1) by TCDD or indolo(3,2-b)carbazole is associated with oxidative DNA damage (Park et al., 1996). In vivo experiments in mice corroborated those findings by showing that TCDD caused a sustained oxidative stress, as determined by measurements of urinary 8-hydroxydeoxyguanosine (Shertzer et al., 2002), involving AHR-dependent uncoupling of mitochondrial respiration (Senft et al., 2002). Mitochondrial reactive-oxygen production depends on the AHR.

Electronics-dismantling workers, experiencing complex exposures including polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), had elevated levels of urinary 8-OHdG indicative of oxidative stress and genotoxicity; this cannot, however, be ascribed directly to the dioxin-like chemicals (DLCs) (Wen et al., 2008). In a study of New Zealand Vietnam War veterans (Rowland et al., 2007), clastogenic genetic disturbances arising as a consequence of confirmed exposure to Agent Orange were determined by analyzing sister-chromatid exchanges (SCEs) in lymphocytes from a group of 24 New Zealand Vietnam War veterans and 23 control volunteers. The results showed a highly significant difference (p < 0.001) in mean SCE frequency between the experimental group and the control group. The Vietnam War veterans also had a much higher proportion of cells with SCE frequencies above the 95th percentile than the controls (11.0 and 0.07%, respectively).

The weight of evidence that TCDD and dioxin-like PCBs make up a group of chemicals with carcinogenic potential includes unequivocal animal carcinogenesis and biologic plausibility based on mode-of-action data. Although the specific mechanisms by which dioxin causes cancer remain to be established, the intracellular factors and mechanistic pathways involved in dioxin’s cancer-promotion mode of action all have parallels in animals and humans. No qualitative differences have been reported to indicate that humans should be considered as fundamentally different from the multiple animal species in which bioassays have demonstrated dioxin-induced neoplasia.

Thus, the toxicologic evidence indicates that a connection of TCDD and perhaps cacodylic acid with cancer in humans is, in general, biologically plausible, but (as discussed below) it must be determined case by case whether such potential is realized in a given tissue. Experiments with 2,4-D, 2,4,5-T, and picloram in animals and cells have not provided a strong biologic basis of the presence or absence of carcinogenic effects.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

THE COMMITTEE’S VIEW OF “GENERAL” HUMAN CARCINOGENS

To address its charge, the committee weighed the scientific evidence linking the chemicals of interest to specific individual cancer sites. That was appropriate given the different susceptibilities of various tissues and organs to cancer and the various genetic and environmental factors that can influence the occurrence of a particular type of cancer. Before considering each site in turn, however, it is important to address the concept that cancers share some characteristics among organ sites and to clarify the committee’s view regarding the implications of a chemical’s being a “general” human carcinogen. All cancers share phenotypic characteristics: uncontrolled cell proliferation, increased cell survival, invasion outside normal tissue boundaries, and eventually metastasis. The current understanding of cancer development holds that a cell or group of cells must acquire a series of sufficient genetic mutations to progress and that particular epigenetic events (events that affect gene function but do not involve a change in gene coding sequence) must occur to accelerate the mutational process and provide growth advantages for the more aggressive clones of cells. That means that a carcinogen can stimulate the process of cancer development by either genetic (mutational) or epigenetic (nonmutational) activities.

In classic experiments based on the induction of cancer in mouse skin that were conducted over 40 years ago, carcinogens were categorized as initiators, those capable of causing an initial genetic insult to the target tissue, and promoters, those capable of promoting the growth of initiated tumor cells, generally through nonmutational events. Some carcinogens, such as those found in tobacco smoke, were considered “whole carcinogens;” that is, they were capable of both initiation and promotion. Today, cancer researchers recognize that the acquisition of important mutations is a continuing process in tumors and that promoters, or epigenetic processes that favor cancer growth, enhance the accumulation of genotoxic damage, which traditionally would be regarded as initiating activity.

As discussed above and in Chapter 4, 2,4-D, 2,4,5-T, and picloram have shown little evidence of genotoxicity in laboratory studies, except at very high doses, and little ability to facilitate cancer growth in laboratory animals. However, cacodylic acid and TCDD have shown the capacity to increase cancer development in animal experiments, particularly as promoters rather than as pure genotoxic agents. Extrapolating organ-specific results from animal experiments to humans is problematic because of important differences between species in overall susceptibility of various organs to cancer development and in organ-specific responses to particular putative carcinogens. Therefore, judgments about the “general” carcinogenicity of a compound in humans are based heavily on the results of epidemiologic studies, particularly on the question of whether there is evidence of excess cancer risk at multiple organ sites. As the evaluations of particular types of cancer in the remainder of this chapter indicate, the committee finds that TCDD in particular appears to be

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

a multisite carcinogen. That finding is in agreement with the International Agency for Research on Cancer (IARC), which has determined that TCDD is a category 1 “known human carcinogen,” and with the US Environmental Protection Agency (EPA), which has concluded that TCDD is “likely to be carcinogenic to humans.” It is important to emphasize that the goals and methods of IARC and EPA in making their determinations were different from those of the present committee; the missions of those organizations focus on evaluating risk to minimize future exposure, whereas this committee focuses on risk after exposure. Furthermore, recognition that TCDD and cacodylic acid are multisite carcinogens does not imply that they cause human cancer at every organ site.

The distinction between general carcinogen and site-specific carcinogen is more difficult to grasp in light of the common practice of beginning analyses of epidemiologic cohorts with a category of “all malignant neoplasms,” which is a routine first screen for any unusual cancer activity in the study population rather than a test of a biologically based hypothesis. When the distribution of cancers among anatomic sites is lacking in the report of a cohort study, a statistical test for an increase in all cancers is not meaningless, but it is usually less scientifically supportable than analyses based on specific sites, for which more substantial biologically based hypotheses can be developed. The size of a cohort and the length of the observation period often constrain the number of cases of cancer types observed and the extent to which specific types can be analyzed. For instance, the present update includes an analysis of cumulative results on diabetes and cancer from a report of the prospective Air Force Health Study (Michalek and Pavuk, 2008). For the fairly common condition of diabetes, that publication presents important information summarizing previous findings, but the cancer analysis does not go beyond “all cancers.” The committee does not accept those findings as an indication that exposure to Agent Orange increases the risk of every variety of cancer. It acknowledges that the highly stratified analyses conducted suggest that some increase in the incidence of some cancers did occur in the Ranch Hand subjects, but it views the “all cancers” results as a conglomeration of information on specific cancers—most important, melanoma and prostate cancer, on which provocative results have been published (Akhtar et al., 2004; Pavuk et al., 2006) and which merit individual longitudinal analysis to resolve outstanding questions.

The remainder of this chapter deals with the committee’s review of the evidence on each individual cancer site in accordance with its charge to evaluate the statistical association between exposure and cancer occurrence, the biologic plausibility and potential causal nature of the association, and the relevance to US veterans of the Vietnam War.

ORAL, NASAL, AND PHARYNGEAL CANCER

Oral, nasal, and pharyngeal cancers are found in many anatomic sites, including the structures of the mouth (inside lining of the lips, cheeks, gums, tongue,

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

and hard and soft palate) (ICD-9 140–145), oropharynx (ICD-9 146), nasopharynx (ICD-9 147), hypopharynx (ICD-9 148), other buccal cavity and pharynx (ICD-9 149), and nasal cavity and paranasal sinuses (ICD-9 160). Until recently, cancers that occur in the oral cavity and pharynx have been thought to be similar in descriptive epidemiology and risk factors, whereas cancer of the nasopharynx is known to have a different epidemiologic profile. However, we now recognize that human papilloma virus (HPV) is an important risk factor for squamous-cell carcinoma of the head and neck, with the risk estimates being highest for the base of the tongue and tonsils (Marur et al., 2010).

The American Cancer Society (ACS) estimated that about 36,540 men and women would receive diagnoses of oral, nasal, or pharyngeal cancer in the United States in 2010 and that 7,880 men and women would die from these diseases (Jemal et al., 2010). Almost 91% of those cancers originate in the oral cavity or oropharynx. Most oral, nasal, and pharyngeal cancers are squamous-cell carcinomas. Nasopharyngeal carcinoma (NPC) is the most common malignant epithelial tumor of the nasopharynx although it is relatively rare in the United States. There are three types of NPC: keratinizing squamous-cell carcinoma, nonkeratinizing carcinoma, and undifferentiated carcinoma.

The average annual incidences reported in Table 7-2 show that men are at greater risk than women for those cancers and that the incidences increase with age—although there are few cases, and care should be exercised in interpreting the numbers. Tobacco and alcohol use are established risk factors for oral and pharyngeal cancers. Reported risk factors for nasal cancer include occupational exposure to nickel and chromium compounds (d’Errico et al., 2009; Feron et al., 2001; Grimsrud and Peto, 2000), wood dust (d’Errico et al., 2009), leather dust (Bonneterre et al., 2007), and high doses of formaldehyde (Nielsen and Wolkoff, 2010).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and oral, nasal, and pharyngeal cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion.

In Update 2006 at the request of the the Department of Veterans Affairs (VA), the committee attempted to evaluate tonsil-cancer cases separately, but it was able to identify only three cohort studies that provided the number of tonsil-cancer cases in their study populations and concluded that these studies did not provide sufficient evidence to determine whether an association existed between exposure to the chemicals of interest and tonsil cancer. Since then, no studies have offered any important additional insight into this question. The committee

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-2 Average Annual Incidence (per 100,000) of Nasal, Nasopharyngeal, Oral-Cavity and Pharyngeal, and Oropharyngeal Cancers in United Statesa

55-59 Years Old 60-64 Years Old 65-69 Years Old
  All Races While Black All Races While Black All Races While Black
Nose, Nasal Caviiy, and Middle Ear:
  Men 1.3 2.4 2.2 1.8 4.0 2.7 2.4 3.5 4.3
  Women I.I 0.9 1.0 1.0 1.6 2.0 2.3 1.3
Nasopharynx:
  Men 25 1.4 2.6 1.9 1.3 0.8 3.2 I.S 2.3
  Women 1.1 0.6 0.4 0.8 0.7 0.3 1.1 1.0 0.4
Oral Caviiy and Pharynx:
  Men 42.1 42.7 44.9 50.2 52.1 46.8 55.9 55.9 64.5
  Women 12.7 12.8 11.9 15.1 15.8 14.2 20.7 21.8 18.2
Oropharynx:
  Men 1.9 1.7 4.2 1.9 1.8 4.0 2.4 2.2 3.5
  Women 0.3 0.3 0.2 0.6 0.6 1.0 0.4 0.5 0.0

   aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2004–2008 (NCI, 2010).

responsible for Update 2006 recommended that VA evaluate the possibility of studying health outcomes, including tonsil cancer, in Vietnam-era veterans by using existing administrative and health-services databases. Anecdotal evidence provided to that committee suggested a potential association between the exposures in Vietnam and tonsil cancer. The new evidence indicating that cancer of the tonsils can have a viral (HPV) etiology underscores a reasonable mechanistic hypothesis for an excess of cancers in Vietnam-era veterans exposed to Agent Orange; as a result of immune alterations associated with exposure, veterans may be susceptible to HPV infection in the oral cavity and tonsils. The present committee strongly reiterates the 2006 and 2008 recommendation that VA develop a strategy that uses existing databases to evaluate tonsil cancer in Vietnam-era veterans.

Studies evaluated previously and in the present report are summarized in Table 7-3.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Cypel and Kang (2010) updated the study of Vietnam-era Army Chemical Corps (ACC) veterans, comparing mortality through 2005 among ACC veterans by Vietnam service. They reported six cases of oral-cavity and pharyngeal cancer in the deployed cohort compared with two cases in the nondeployed cohort for an

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-3 Selected Epidemiologic Studies—Oral, Nasal, and Pharyngeal Cancer

Reference Study Populationa (Exposed
Casesb
Exposure of Interest/Estimated Risk
(95% CI)b
VIETNAM VETERANS
United States
Air Force Health Study—Ranch Hand veterans vs SEA veterans
(unless otherwise noted)
  All COIs
Akhtar et al., 2004 While AMIS subjects vs national rates (buccal cavity)    
  Ranch Hand veterans    
  Incidence 6 0.9 (0.4-1.9)
  With tours in 1966-1970 6 1.1 (0.5-2.3)
  Mortality 0 0.0 (nr)
  Comparison veterans    
  Incidence 5 0.6 (0.2-1.2)
  With tours in 1966-1970 4 0.6 (0.2-1.4)
  Mortality 1 0.5 (nr)
AFHS, 2000 Participants in 1997 examination cycle. Ranch 4 0.6 (0.2-2.4)
  Hands vs comparisons (oral cavity, pharynx, and
larynx), incidence
   
US Cohort of Army Chemical Corp   All COIs
Cypel and Kang et al., 2010 ACC—deployed vs nondeployed and vs US men
(Vietnam-service status through 2005)
   
  Oral cavity and pharyngeal cancer    
  Deployed vs nondeployed 6 vs 2 17 (0.3-8.7)
  ACC vs US men    
  Vietnam cohort 6 1.5 (0.6-3.3)
  Non-Vietnam cohort 2 0.8 (0.1-2.8)
US CDC Vietnam Experience Study   All COIs
Boehmer et al., 2004 Follow-up of CDC VIS cohort (ICD-9 140-149) 6 nr
US Centers for Disease Control and Prevention   All COIs
CDC, 1990a Case-control study of US males born 1929-1953
89 nasopharyngeal carcinomas
   
  Vietnam service 3 0.5 (0.2-1.8)
  62 nasal carcinomas    
  Vietnam service 2 0.7 (0.2-2.9)
State Studies of US Vietnam Veterans   All COIs
Visintainer et al., 1995 PM study of deaths (1974-1989) of Michigan
Vietnam-era veterans—deployed vs nondeployed
   
  Lip, oral cavity, and pharynx 12 1.0 (0.5-1.8)
Australian Vietnam Veterans vs Australian Population   All COIs
ADVA, 2005a Follow-up 1982-2000—incidence
  Head and neck 247 1.5 (1.3-1.6)
  Navy 56 1.6 (1.1-2.0)
  Army 174 1.6 (1.3-1.8)
  Air Force 17 0.9 (0.5-1.5)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa (Exposed
Casesb
Exposure of Interest/Estimated Risk
(95% CI)b
ADVA, 2005b Follow-up through 2001    
  Head and neck 101 1.4 (1.2-1.7)
  Navy 22 1.5 (0.9-2.1)
  Army 69 1.5 (1.1-1.8)
  Air Force 9 1.1 (0.5-2.0)
  Nasal 3 0.8 (0.2-2.2)
CDVA, 1997a Follow-up 1980-1994    
  Lip (ICD-9 140) 0 nr
  Nasopharyngeal cancer (ICD-9 147) 2 0.5 (0.1-1.7)
  Nasal cavities (ICD-9 160) 2 1.2 (0.1-4.1)
Australian Conscripted Army National Service Vietnam-EraVeterans deployed vs nondeployed) All COIs
ADVA, 2005c Follow-up    
  Head and neck    
  Incidence (1982-2000) u 2.0 (1.2-3.4)
  Mortality (1966-2001) 16 1.8 (0.8-4.3)
  Nasal    
  Mortality (1966-2001) 0 0.0 (0.0-48.2)
CDVA, 1997b Follow-up (1980-1994)    
  Nasopharyngeal cancer (ICD-9 147) 1 1.3 (0.0- > 10)
  Nasal cavities (ICD-9 160) 0 0.0 (0.0- > 10)
OCCUPATIONAL
IARC Phenoxy Herbicide Cohorl (mortality vs national mortality rates)   Dioxin, phenoxy herbicides
Kogevinas IARC cohort, male and female workers exposed    
  Oral cavity, pharynx cancer (ICD-9 140-149) 26 1.1 (0.7-1.6)
  Exposed to highly chlorinated PCDDs 22 1.3 (0.8-2.0)
  Not exposed to highly chlorinated PCDDs 3 0.5 (0.1-1.3)
  Nose, nasal sinus cancer (ICD-9 160) 3 1.6 (0.3-4.7)
  Exposed to highly chlorinated PCDDs 0 0.0 (0.0-3.5)
  Not exposed to highly chlorinated PCDDs 3 3.8 (0.8-11.1)
Saracci et al., 1991 IARC cohort—exposed subcohort (males.    
  females)—updated to 1987    
  Buccal cavity, pharynx HCD-8 140-149) 11 1.2 (0.6-2.1)
  Nose, nasal cavities (ICD-8 160) 3 2.9 (0.6-8.5)
BASF Production Workers (included in IARC cohort)   Dioxin, phenoxy herbicides
Zober et al., 1990 BASF Aktiengesellschaft accident cohort—33    
  cancers in 247 workers at 34-yr follow-up    
  Squamous-cell carcinoma of tonsil 1 nr
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa (Exposed
Casesb
Exposure of Interest/Estimated Risk
(95% CI)b
Dutch Production Workers (included in IARC cohort)   Dioxin, Phenoxy Herbicides
Hooiveld et al., 1998 Dutch chemical production workers (lip, oral cavity, pharynx)    
  All working any time in 1955-1985 1 2.3 (0.1-12.4)
  Cleaned up 1963 explosion 1 7.1 (0.2-39.6)
German Production Workers (included in IARC cohort)   Dioxin, Phenoxy Herbicides
Becher et al., 1996 German phenoxy herbicide or chlorophenol production workers    
  Buccal cavity, pharynx (ICD-9 140-149) 9 3.0 (1.4-5.6)
  Tongue 3 nr
  Moor of mouth 2 nr
  Tonsil 2 nr
  Pharynx 2 nr
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort)   Dioxin, Phenoxy Herbicides
McBride et al., 2009a 1,599 production workers (male and female) vs national rates—mortality 1969 through 2004    
  Buccal cavity and pharynx    
  Ever-ex posed workers 3 2.6 (0.5-7.6)
't Mannetje et al., 2005 New Zealand phenoxy herbicide producers (men and women) (ICD-9 140-149) 2 2.8 (0.3-9.9)
  Lip (ICD-9 140) 0 nr
  Mouth (ICD-9 141-145) 2 5.4 (0.7-20)
  Oropharynx (ICD-9 146) 0 nr
  Nasopharynx I ICD-9 147) 0 0.0 (0.0-42)
  Hypopharynx, other (ICD-9 148-149) 0 nr
  Phenoxy herbicide sprayers (> 99,& men)    
  (ICD-9 140-149) 1 1.0 (0.0-5.7)
  Lip (ICD-9 140) 0 nr
  Mouth (ICD-9 141-145) 0 0.0 (0.0-7.5)
  Oropharynx (ICD-9 146) 0 nr
  Nasopharynx I ICD-9 147) 1 8.3 (0.2-46)
  Hypopharynx, other (ICD-9 148-149) 0 nr
United Kingdom Production Workers (included in IARC cohort   Dioxin, Phenoxy Herbicides
Coggon et al., 1986 British MCPA production workers    
  Lip (ICD-9 140) 0 nr
  Tongue (ICD-9 141) 1 1.1 (0.0-6.2)
  Pharynx (ICD-9 146-149) 1 0.5 (0.0-3.0)
  Nose (ICD-9 160) 3 4.9 (1.0-14.4)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa (Exposed
Casesb
Exposure of Interest/Estimated Risk
(95% CI)b
Agricultural Health Study   Herbicides
Alavanja et al., 2005 US AHS—incidence (buccal cavity)    
  Private applicators (men and women) 66 0.7 (0.5-0.8)
  Lip 25 1.4 (0.9-2.1)
  Spouses of private applicators (> 99% women) 14 0.7 (0.4-1.2)
  Lip 2 1.4 (0.2-5.1)
  Commercial applicators (men and women) 5 0.9 (0.3-2.2)
  Lip 3 2.7 (0.6-8.0)
Blair et al., 2005a US AHS (buccal caviiy and pharynx)    
  Private applicators (men and women) 5 0.3 (0.1-0.7)
  Spouses of private applicators (> 99% women) 0 0.0 (0.0-25.4)
Other Agricultural Workers   Herbicides
Hansen et al., 2007 Danish gardeners—incidence    
  (buccal caviiy and pharynx, ICD-7 140-148)    
  10-year follow-up (1975-1984) reported in 6 1.1 (0.4-2.5)
  Hansen et al. (1992)    
  25-year follow-up (1975-2001)    
  Born before 1915 (high exposure) 3 0.7 (0.2-2.3)
  Born 1915-1934 (medium exposure) 6 0.7 (0.3-1.4)
  Born after 1934 (low exposure) 0 0.0 (0.0-1.0)
Nordby et al., 2004 Norwegian farmers born 1925–1971—incidence,    
  lip    
  Reported pesticide use nr 0.7 (0.4-1.0)
Blair et al., 1993 White male farmers in 23 states—deaths    
  1984-1988    
  Lip 21 2.3 (1.4-3.5)
Ronco et al., 1992 Italian farmers (lip. tongue, salivary glands. mouth, pharynx)—mortality    
  Self-employed 13 0.9 (nr)
  Employees
Danish self-employed farmers—incidence
4 0.5 (nr)
  Lip 182 1.8 (p 0.05)
  Tongue 9 0.6 (nr)
  Salivary glands 13 0.9 (nr)
  Mouth 14 (0.5 < p 0.05)
  Pharynx 13 (0.3 p < 0.05)
  Nasal cavities, sinuses
Danish farming employees—incidence
11 0.6 (nr)
  Lip 43 (2. Lip < 0.05)
  Tongue 2 0.6 (nr)
  Salivary glands 0 0.0 (nr)
  Mouth 0 0.0 (p < 0.05)
  Pharynx 9 1.1 (nr)
  Nasal cavities and sinuses 5 1.3 (nr)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa (Exposed
Casesb
Exposure of Interest/Estimated Risk
(95% CI)b
Wiklund, 1983 Swedish male and female agricultural workers—incidence   99% CI
  Lip 508 1.8 (1.6-2.1)
  Tongue 32 0.4 (0.2-0.6)
  Salivary glands 68 1.0 (0.7-1.4)
  Mouth 70 0.6 (0.5-0.8)
  Throat 84 0.5 (0.4-0.7)
  Nose, nasal sinuses 64 0.8 (0.6-1.2)
Burmeisler, 1981 Iowa farmers—deaths in 1971-1978    
  Lip 20 2.1 (p<0.0l)
Forestry Workers   Herbicides
Reif et al., 1989 New Zealand forestry workers—incidence    
  Buccal cavity 3 0.7 (0.2-2.2)
  Nasopharynx 2 5.6 (1.6-19.5)
Other Herbicide and Pesticide Applicators   Herbicides
Swaen et al., 2004 Dutch licensed herbicide applicators    
  Nose 0
  Mouth, pharynx 0
Caplan et al., 2000 Case-control study of US males born 1929-    
  1953, all 70 nasal cancers (carcinomas, 11 lymphomas, 5 sarcomas) in CDC (1990a) study population    
  Selected landscaping, forestry occupations 26 1.8 (1.1-3.1)
  Living, working on farm 23 0.5 (0.3-0.8)
  Herbicides, pesticides 19 0.7 (0.4-1.3)
  Phenoxy herbicides 5 1.2 (0.4-3.3)
Asp et al., 1994 Finnish herbicide applicators    
  Buccal, pharynx (ICD-8 140-149)    
  Incidence 5 1.0 (0.3-2.3)
  Mortality 0 0.0 (0.0-3.0)
  "Other respiratory" (ICD-8 160, 161,163)—    
  Incidence 4 1.1 (0.3-2.7)
  Mortality 1 0.5 (0.0-2.9)
Torchio et al., 1994Wiklund et al., 1989a Italian licensed pesticide users    
  Buccal cavity, pharynx
Licensed Swedish pesticide applicators—incidence
18 0.3 (0.2-0.5)
  Lip 14 1.8 (1.0-2.9)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa (Exposed
Casesb
Exposure of Interest/Estimated Risk
(95% CI)b
Paper and Pulp Workers   Dioxin
McLean et al., 2006 (Includes cohort studied in Rix et al., 1998) IARC cohort of pulp and paper workers Exposure to nonvolatile organochlorine    
  compounds (oral cavity, and pharynx)    
  Never 33 0.9 (0.6-1.3)
  Ever 15 0.5 (0.3-0.9)
Rix et al., 1998 Danish male, female paper-mill workers    
  Buccal cavity (ICD-7 140-144)    
  Men 24 1.0 (0.7-1.5)
  Women 4 1.5 (0.4-3.8)
  Pharynx (ICD-7 145-149)    
  Men 15 2.0 (1.1-3.3)
  Women 2 2.1 (0.2-7.6)
  Tonsil cancers among pharyngeal cancers 11 nr
Robinson et al., 1986 Northwestern US paper and pulp workers   90%CI
  Buccal cavity, pharynx (ICD-7 140-148) 1 0.1 (0.0-0.7)
  Nasal (ICD-7 160) 0 nr
ENVIRONMENTAL
Seveso, Italy Residential Cohort   TCDD
Bertazzi et al., 1993 Seveso residents—10-yr follow-up—incidence    
  Buccal cavity (ICD-9 140-149)    
  Zone B—Men 6 1.7 (0.8-3.9)
  Women 0 nr
  Zone R—Men 28 1.2 (0.8-1.7)
  Women 0 nr
  Nose, nasal cavities (ICD-9 160)    
  Zone R—Men 0 nr
  Women 2 2.6 (0.5-13.3)
Other Environmental Studies
Hardell et al., 1982 Residents of northern Sweden (44 nasal, 27   Phenoxy acid,
  nasopharyngeal cancers)   chlorophenols
  Phenoxy acid exposure 8 2.1 (0.9-4.7)
  Chlorophenol exposure 9 6.7 (2.8-16.2)

ABBREVIATIONS: ACC, Army Chemical Corps; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2 methyl-4-chlorophenoxyacetic acid; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PM, proportionate mortality; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VES, Vietnam Experience Study.

aSubjects are male, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

increased but nonsignificant adjusted relative risk (RR) of 1.68 (95% confidence interval [CI] 0.33–8.73). In the prior report on mortality through 1991 (Dalager and Kang, 1997), they had observed three cases in the Vietnam cohort and no cases in the non-Vietnam cohort.

Occupational Studies

McBride et al. (2009a,b) reported on the mortality experience through 2004 of the New Zealand cohort of 1,599 workers who had been employed in manufacturing phenoxy herbicides from trichlorophenol (TCP); picloram was also produced in the plant. In their analysis (McBride et al., 2009a), there were three deaths from buccal cavity and pharyngeal cancer in the ever-exposed group and no deaths in the smaller never-exposed group, for a nonsignificant excess standardized mortality ratio (SMR) of 2.6 (95% CI 0.5–7.6). No deaths from nasopharyngeal cancer were observed in either group. The small numbers of cases limit interpretation of the data. The results in McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no possible opportunity for TCDD exposure and no observed deaths.

Environmental Studies

There have been no environmental studies of oral, nasal, or pharyngeal cancers and exposure to the chemicals of interest since Update 2008.

Biologic Plausibility

As noted above, there is now accepted evidence that HPV contributes causally to cancers of the head and neck (Marur et al., 2010; Szentirmay et al., 2005) and to tonsil cancers in particular (Gillison and Shah, 2001). It is unknown whether Agent Orange exposure contributes to a susceptibility to viral infection or action, but it warrants further exploration. The sparseness of data on the specific tumor site and a general lack of information on smoking, drinking, and viral exposure status in the few available epidemiologic studies preclude exploration of this hypothesis in the literature today.

Long-term animal studies have examined the effect of exposure to the chemicals of interest on tumor incidences (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). The National Toxicology Program study (Yoshizawa et al., 2005a) has also reported an increase in the incidence of gingival squamous-cell carcinoma in female rats treated orally (by gavage) with TCDD at 100 ng/kg 5 days/week for 104 weeks. The incidences of gingival squamous-cell hyperplasia was significantly increased in all groups treated at 3–46 ng/kg. In addition, squamous-cell carcinoma of the oral mucosa of the palate was increased. Increased neoplasms of the oral mucosa were previously

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

observed and described as carcinomas of the hard palate and nasal turbinates (Kociba et al., 1978). Kociba et al. (1978) also reported a small increase in the incidence of tongue squamous-cell carcinoma. A similar 2-year study performed in female rats failed to reveal a pathologic effect of TCDD on nasal tissues (Nyska et al., 2005).

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

The new studies of oral, nasal, and pharyngeal cancers reported small, nonsignificant excesses in mortality from oral and pharyngeal cancers with very small numbers of cases. These data are not sufficient, taken in combination with the previously reviewed literature, to suggest an association with the herbicides sprayed in Vietnam.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and oral, nasal, or pharyngeal cancers.

CANCERS OF THE DIGESTIVE ORGANS

Until Update 2006, VAO committees had reviewed “gastrointestinal tract tumors” as a group consisting of stomach, colorectal, and pancreatic cancers, with esophageal cancer being formally factored in only since Update 2002. With more evidence from occupational studies available, VAO updates now address cancers of the digestive organs individually. Findings on cancers of the digestive organs as a group (ICD-9 150–159) are too broad for useful etiologic analysis and will no longer be considered.

Esophageal cancer (ICD-9 150), stomach cancer (ICD-9 151), colon cancer (ICD-9 153), rectal cancer (ICD-9 154), and pancreatic cancer (ICD-9 157) are among the most common cancers. ACS estimated that about 223,350 people would receive diagnoses of those cancers in the United States in 2010 and that 113,240 people would die from them (Jemal et al., 2010). When other digestive cancers (for example, small intestine, anal, and hepatobiliary cancers) were included, the 2010 estimates for the United States were about 274,330 new diagnoses and 139,580 deaths (Jemal et al., 2010). Collectively, tumors of the digestive organs were expected to account for 19% of new cancer diagnoses and 24% of cancer deaths in 2010. The average annual incidences of gastrointestinal cancers are presented in Table 7-4.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-4 Average Annual Incidence (per 100,000) of Selected Gastrointestinal Cancers in United Statesa

55-59 Years Old 60-64 Years Old 65-69 Years Old
All Races White Black All Races White Black All Races White Black
Stomach:
   Men 153 13.7 22.4 23.3 21.2 38.5 37.9 32.6 72.7
   Women 7.1 5.5 11.7 8.9 7.1 14.5 15.5 12.8 23.1
Esophagus:
   Men 16.5 16.5 21.4 24.6 25.0 31.0 343 36.1 36.0
   Women 3.0 2.7 6.4 3.8 3.7 7.0 83 7.5 14.6
Colon (excluding rectum):
   Men 53.5 50.2 85.1 81.7 77.9 128.6 129.6 126.0 1813
   Women 41.5 37.6 66.4 61.7 57.8 95.1 104.2 101.6 140.1
Rectum and rectosigmoid junction:
   Men 32.1 30.2 34.7 42.7 41.4 41.3 62.0 59.7 67.4
   Women 19.3 IS.2 22.1 23.5 23.1 28.4 31.8 29.9 39.9
Liver and intrahepatic bile duct:
   Men 32.6 25.2 78.8 31.6 24.8 67.1 34.5 263 48.8
   Women 8.1 6.4 14.5 8.1 6.0 13.6 12.7 103 13.6
Pancreas:
   Men 22.6 21.7 33.9 36.5 35.2 58.4 53.6 52.7 79.6
   Women 15.6 15.1 21.7 25.0 23.8 40.1 36.7 34.7 563
Small intestine:
   Men 53 5.4 6.8 6.6 6.6 9.9 9.2 8.8 14.5
   Women 3.6 3.4 7.0 4.2 3.9 8.5 6.1 6.1 II.1
Anus, anal canal, and anorectum:
   Men 33 3.4 4.7 3.2 3.5 2.8 4.0 4.4 4.1
   Women 4.5 4.8 4.9 4.6 5.0 3.5 5.4 5.8 6.2
Other digestive organs:
   Men 1.1 0.8 3.4 1.3 1.4 1.6 2.2 2.4 1.2
   Women 0.6 0.5 0.9 1.4 1.4 1.3 1.4 1.2 3.1
Gallbladder
   Men 1.0 0.8 1.6 1.4 13 2.0 2.9 2.4 3.5
   Women 2.2 1.8 4.9 2.5 23 3.5 4.9 4.6 6.2
Other biliary:
   Men 25 2.1 5.0 5.4 5.1 5.2 7.0 6.8 4.7
   Women 1.8 1.8 0.9 2.7 2.5 4.1 5.1 4.8 4.9

   aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2004–2008 (NCI, 2010).

The incidences of stomach, colon, rectal, and pancreatic cancers increase with age. In general, the incidences are higher in men than in women and higher in blacks than in whites. Other risk factors for the cancers vary but always include family history of the same form of cancer, some diseases of the affected organ, and diet. Tobacco use is a risk factor for pancreatic cancer and possibly stomach cancer (Miller et al., 1996). Infection with the bacterium Helicobacter

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

pylori increases the risk of stomach cancer. Type 2 diabetes is associated with an increased risk of cancers of the colon and pancreas (ACS, 2006).

It is noteworthy that there has been one report of Vietnam veterans that included all gastrointestinal cancers collectively. Cypel and Kang (2010) published an update on the disease-related mortality experience of ACC veterans who handled or sprayed herbicides in Vietnam in comparison with their non-Vietnam veteran peers or US men. Vital status was determined through December 31, 2005. In the analyses, the site-specific rates for digestive cancers were not examined. No statistically significant excess mortality from all cancers of the digestive tract was found in ACC Vietnam veterans compared with non-Vietnam veterans (adjusted RR = 1.01, 95% CI 0.56–1.83).

Esophageal Cancer

Epithelial tumors of the esophagus (squamous-cell carcinomas and adeno-carcinomas) are responsible for more than 95% of all esophageal cancers (ICD-9 150); 16,640 newly diagnosed cases and 14,500 deaths were estimated for 2010 (Jemal et al., 2010). The considerable geographic variation in the incidence of esophageal tumors suggests a multifactorial etiology. Rates of esophageal cancer have been increasing in the last 2 decades. Adenocarcinoma of the esophagus has slowly replaced squamous-cell carcinoma as the most common type of esophageal malignancy in the United States and western Europe (Blot and McLaughlin, 1999). Squamous-cell esophageal carcinoma rates are higher in blacks than in whites and higher in men than in women. Smoking and alcohol ingestion are associated with the development of squamous-cell carcinoma; these risk factors have been less thoroughly studied for esophageal adenocarcinoma, but they appear to be associated. The rapid increase in obesity in the United States has been linked to increasing rates of gastroesophageal reflux disease (GERD), and the resulting rise in chronic inflammation has been hypothesized as explaining the link between GERD and esophageal adenocarcinoma. The average annual incidence of esophageal cancers is shown in Table 7-4.

Conclusions from VAO and Previous Updates

The committee responsible for VAO explicitly excluded esophageal cancer from the group of gastrointestinal tract tumors, for which it was concluded that there was limited or suggestive evidence of no association with exposure to the herbicides used by the US military in Vietnam. Esophageal cancers were not separately evaluated and were not categorized with this group until Update 2004. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the chemicals of interest to sustain that negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

on each should be evaluated separately. Esophageal cancer was thus reclassified into the default category of inadequate or insufficient evidence to determine whether there is an association. No additional studies reporting on esophageal cancer were reviewed in Update 2008. Table 7-5 summarizes the results of the relevant studies concerning esophageal cancer.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies There have been no published studies of esophageal cancer in Vietnam veterans since the last VAO update in 2008.

Occupational Studies Four occupational cohort studies have been published since the last VAO update in 2008. Collins et al. (2008, 2009a,b) published a series of papers examining the mortality experience of TCP and pentachlorophenol (PCP) workers employed in a Dow Chemical Company in Midland, Michigan, from 1937 to 1980. The TCP workers constitute the Dow cohort in the NIOSH cohort. Serum dioxin evaluation to estimate exposures to five dioxins was used in a subgroup of 98 workers (Collins et al., 2008). Although the serum dioxin, furan, and PCB concentrations were measured many years after exposure, distinct patterns of dioxin congeners among workers with different chlorophenol exposures were found.

The mortality experience of Dow chemical TCP workers in Midland potentially exposed to TCDD was reported by Collins et al. (2009a). Their study followed 1,615 workers who worked at least 1 day in a department with potential TCDD exposure. Follow-up ended on December 31, 2003, and the mean duration of follow-up was 36.4 years. Cause of death was determined by death certificates and SMRs were calculated by using national mortality figures. Some 17% of the sample (280) had serum TCDD evaluations that indicated higher concentrations than those of unexposed workers (Collins et al., 2007). Five esophageal-cancer deaths were observed, for an SMR of 1.0 (95% CI 0.3–2.2). None of the five people had had concurrent PCP exposure.

The second report on the Dow Midland cohort (Collins et al., 2009b) described the mortality experience of 773 PCP workers who were exposed to chlorinated dioxins not including TCDD. Of the cohort, 75% had been followed for more than 27 years. SMRs were calculated by comparing the PCP workers with the general US population and with that of Michigan. There were two observed deaths from esophageal cancer (SMR = 0.8, 95% CI 0.1–2.9).

McBride et al. (2009a,b) published two reports on a mortality follow-up of the workers in the Dow AgroSciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD. In McBride et al. (2009a), the SMR of ever-exposed workers was compared with that of never-exposed workers. The SMR for esophageal-cancer deaths in exposed workers was 2.5 (95% CI 0.7–6.4) compared with an SMR of 2.1 (95% CI 0.1–12.2) in the never-exposed group. The

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-5 Selected Epidemiologic Studies—Esophageal Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS
US Centers for Disease Control and Prevention All COIs
Boehmer et al., 2004 Follow-up of CDC VES cohort ICD-9 140-149) 6 1.2 (0.4-4.0)
State Studies of US Vietnam Veterans All COIs
Visintainer et al., 1995 PM study of deaths (1974-1989) of Michigan 9 0.9 (0.4-1.6)
  Vietnam-era veterans—deployed vs nondeployed    
Australian Vietnam Veterans vs Australian Population All COIs
ADVA, 2005a Australian male Vietnam veterans vs Australian 70 1.2 (0.9-1.5)
  population—incidence    
  Navy 19 1.6 (0.9-2.4)
  Army 40 1.1 (0.7-1.4)
  Air Force 11 1.5 (0.8-2.8)
ADVA, 2005b Australian male Vietnam veterans vs Australian 67 1.1 (0.8-1.3)
  population—mortality    
  Navy 13 1.0 (0.5-1.7)
  Army 42 1.0 (0.7-1.3)
  Air Force 12 1.5 (0.8-2.6)
CDVA, 1997a Australian military Vietnam veterans 23 1.2 (0.7-1.7)
Australian Conscripted Army National Service Vietnam-Era (deployed vs nondeployed) Veterans All COIs
ADVA, 2005c Australian male conscripted Army National    
  Service Vietnam-era veterans: deployed vs nondeployed    
  Incidence 9 1.9 (0.6-6.6)
  Mortality 10 1.3 (0.5-3.6)
CDVA, 1997b Australian National Service Vietnam veterans 1 1.3 (0.0- > 10)
OCCUPATIONAL
IARC Phenoxy Herbicide Cohort(mortality vs national mortalityrates) Dioxin, Phenoxy Herbicides
Kogevinas et al., 1997 IARC cohort, male and female workers exposed 28 1.010.7-1.4)
  to any phenoxy herbicide or chlorophenol    
  Exposed to highly chlorinated PCDDs 20 1.3 (0.8-1.9)
  Not exposed to highly chlorinated PCDDs 6 0.5 (0.2-1.1)
Saracci et al., 1991 IARC cohort—exposed subcohort (men and 8 0.6 (0.3-1.2)
  (women)    
Dow Chemical Company—Midland. MI (included in IARC and (NIOSH cohorts) Dioxin, Phenoxy Herbicides
Collins et al., 2009a,b Trichlorophenol workers 5 1.0 (0.3-2.2)
  Pentachlorophenol workers 2 0.8 (0.1-2.9)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
New Zealand Production Workers—Dow plant in Plymouth, NZ (included ini IARC cohort) Dioxin. Phenoxy
Herbicides
Mc Bride et al, 2009a 1,599 production workers (male and female) vs national rates—mortality 1969 through 2004
Ever exposed 4 2.5 (0.7-6.4)
Never exposed 1 2.1(0.1-12.2)
’t Mannetje et aL, 2005 New Zealand phenoxy herbicide producers (men and women) 2 2.0(0.2-7.0)
Phenoxy herbicide sprayers (> 99% men) 1 0.7 (0.0-4.0)
United Kingdom Production Workers (included in IARC cohort Dioxin. Phenoxy
Herbicides
Coggon et al., 1986 British MCPA production workers 8 0.9(0.4-1.9)
Agricultural Health Study Herbicides
Blair et al.. US AHS
2005a Private applicators (men and women) 16 0.5 (0.3-0.9)
Spouses of private applicators (> 99% women) 1 0.3(0.1-1.9)
Other Agricultural Workers Herbicides
Lee et al.. Population-based case-control—agricultural 137
2004a pesticide use and adenocarcinoma of the esophagus
Insecticides 0.7(0.4-1.1)
Herbicides 0.7(0.4-1.2)
Ronco Danish farm workers—incidence
etal.. 1992 Male—Self-employed 32 0.4 (p <0.05)
Employee 13 0.9 (nr)
Female—Self-employed 1 1.4 (nr)
Family worker 2 0.4 (nr)
Wiklund, Swedish male and female agricultural 99% a
1983 workers—incidence 169 0.6 (0.5-0.7)
Other Studies of Herbicide and Pesticide Applicators Herbicides
Magnani UK case—control
etal.. 1987 Herbicides nr 1.6(0.7-3.6)
Chlorophenols nr 1.2(0.7-2.2)
Asp et al.. Finnish herbicide applicators—incidence 3 1.6(0.3-4.6)
1994 Finnish herbicide applicators—mortality 2 1.3(0.2-4.7)
Forestry Workers
Reif et al.. New Zealand forestry workers—nested case- 4 1.8(0.7-4.8)
1989 control (incidence) correspondence
Paper and Pulp Workers Dioxins
McLean IARC cohort of pulp and paper workers
Et al.. 2006 Never 27 0.7(0.4-1.0)
Ever 26 0.8(0.5-1.2)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
ENVIRONMENTAL
Seveso, Italy Residential Cohort

TCDD
Pesalori
el al, 2009
Seveso—20-yr follow-up to 19%—incidence
(men and women, combined)
Zone A 0
ZoneB 1 0.3(0.0-1.9)
ZoneR 35 1.3(0.9-1.9)

ABBREVIATIONS: AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PM, proportionate mortality; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VES, Vietnam Experience Study.

   aSubjects are male, and outcome is mortality unless otherwise noted.
   bGiven when available; results other than estimated risk explained individually.

SMR for esophageal cancer according to estimated effective cumulative exposure to TCDD was not calculated. The results in McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Environmental Studies Esophageal-cancer cases were reported in the cancer-incidence study of the population (males and females combined) exposed to dioxin after the Seveso accident in 1976 (Pesatori et al., 2009). No esophageal cancers were observed in Zone A (high exposure). Only one esophageal-cancer case was found in residents of Zone B (medium exposure area) (RR = 0.26, 95% CI 0.04–1.91). Some 35 esophageal-cancer cases were reported in Zone R (low exposure) (RR = 1.33, 95% CI 0.92–1.92).

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the chemicals of interest on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004), and no increase in the incidence of esophageal cancer has been reported in laboratory animals after exposure to them. A recent biomarker study analyzed esophageal-cell samples from patients who had been exposed to indoor air pollution of different magnitudes and did or did not have high-grade squamous–cell dysplasia or a family history of upper gas-

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

trointestinal tract (UGI) cancer (Roth et al., 2009). AHR expression was higher in patients with a family history of UGI cancer, whereas indoor air pollution, esophageal squamous-cell dysplasia category, age, sex, and smoking were not associated with AHR expression. The results suggest that enhanced expression of the AHR in patients who had a family history of UGI cancer may contribute to UGI-cancer risk associated with AHR ligands, such as polycyclic aromatic hydrocarbons, which are found in cigarette smoke, and with TCDD.

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

The studies reviewed previously did not provide sufficient evidence to determine whether there is an association between exposure to the chemicals of interest and esophageal cancer, and no new additional information that would alter this judgment was found by the present committee. No toxicologic studies provide evidence of the biologic plausibility of an association between the chemicals of interest and tumors of the esophagus.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and esophageal cancer.

Stomach Cancer

The incidence of stomach cancer (ICD-9 151) increases in people 50–64 years old. ACS estimated that 12,730 men and 8,270 women would receive diagnoses of stomach cancer in the United States in 2010 and that 6,350 men and 4,220 women would die from it (Jemal et al., 2010). In general, the incidence is higher in men than in women and higher in blacks than in whites. Other risk factors include family history of this cancer, some diseases of the stomach, and diet. Infection with the bacterium Helicobacter pylori increases the risk of stomach cancer. Tobacco use and consumption of nitrite- and salt-preserved food may also increase the risk of stomach cancer (Brenner et al., 2009; Key et al., 2004; Miller et al., 1996). The average annual incidence of stomach cancer is shown in Table 7-4.

Conclusions from VAO and Previous Updates

Update 2006 considered stomach cancer independently for the first time. Prior updates developed a table of results for stomach cancer, but conclusions about the adequacy of the evidence of its association with herbicide exposure

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

had been reached in the context of gastrointestinal tract cancers. The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the herbicides used by the US military in Vietnam and gastrointestinal tract tumors, including stomach cancer. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the chemicals of interest to sustain this negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Stomach cancer was thus reclassified into the default category of inadequate or insufficient evidence to determine whether there was an association.

Positive findings of an association with phenoxy herbicide exposure from a well-conducted nested case–control study of stomach cancer in the United Farm Workers of America cohort (Mills and Yang, 2007) led the committee responsible for Update 2008 to reconsider the results of several earlier studies. Reif et al. (1989) reported a significant relationship between stomach cancer and the nonspecific exposure of being a forestry worker. Cocco et al. (1999) had found an association with herbicide exposure but had not analyzed specific chemicals, and Ekström et al. (1999) found significant associations between the occurrence of stomach cancer and exposure to phenoxy herbicides in general and to several specific phenoxy herbicide products. In updated mortality findings from Seveso concerning TCDD exposure, Consonni et al. (2008) found no increases in deaths from stomach cancer. In the absence of supportive findings from studies of Vietnam-veteran cohorts or IARC cohorts or from the US Agricultural Health Study (AHS), that committee retained stomach cancer in the inadequate or insufficient category.

Table 7-6 summarizes the results of the relevant studies concerning stomach cancer.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies No studies of exposure to the chemicals of interest and stomach cancer in Vietnam veterans have been published since Update 2008.

Occupational Studies Three occupational-cohort studies have been published since Update 2008. Collins et al. (2008, 2009a,b) published a series of papers examining the mortality experience of workers employed by the Dow Chemical Company in Midland, Michigan, from 1937 to 1980. Serum dioxin was evaluated to estimate exposures to five dioxins in a group of 98 workers (Collins et al., 2008). Although serum dioxin, furan, and PCB concentrations were measured many years after exposure, distinct patterns of dioxin congeners in workers who had different chlorophenol exposures were found. Collins et al. (2009a) described the mortality experience of 1,615 workers who had been exposed to TCP production. The mean duration of follow-up was 36.4 years. Eight cases of stomach

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-6 Selected Epidemiologic Studies—Stomach Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS
US Air Force Health Study—Ranch Hands veterans vs SEA veterans
(unless otherwise noted
All COIs
Pavuk et al., 2005 Comparison subjects only from AFHS (digestive
system)—incidence
   
  Serum TCDD (pg/g) based on model with exposure variable loge(TCDD)    
  Per unit increase of -Ioge(TCDD) (pg/g) 24 1.8 (0.8-3.9)
  0.4-2.6 4 nr
  2.6-3.8 3 1.0 (0.2-4.8)
  3.8-5.2 7 2.0 (0.5-8.2)
  > 5.2 10 3.3 (0.9-12.5)
  Number of years served in SEA
Per year of service
Quartiles (years in SEA)
24 1.2 (1.0-1.4)
  0.8-13 4 nr
  1.3-2.1 4 1.0 (0.2-3.8)
  2.1-3.7 5 1.1 (0.3-4.2)
  3.7-16.4 11 2.1 (0.6-7.3)
Akhtar et al., 2004 White AFIIS subjects vs national rates    
  (digestive system)
Ranch Hand veterans
   
  Incidence 16 0.6 (0.4-1.0)
  Tours 1966-1970 14 0.6 (0.4-1.1)
  Mortality 6 0.4 (0.2-0.9)
  Comparison veterans    
  Incidence 31 0.9 (0.6-1.2)
  Tours 1966-1970 24 0.9 (0.6-1.3)
  Mortality 14 0.7 (0.4-1.1)
US CDC Vietnam Experience Study All COIs
Boehmer et al., 2004 Follow-up of CDC VES (stomach) 5 nr
US VA Mortality Study of Army and Navy Veterans—Ground Troops All COIs
Serving July 4, 1965-March 1, 1973      
Breslin et al., 1988 Army Vietnam veterans 88 1.1 (0.9-1.5)
  Marine Vietnam veterans 17 0.8 (0.4-1.6)
State Studies of US Vietnam Veterans All COIs
Anderson et al., 1986 Wisconsin Vietnam veterans 1 nr
Australian Vietnam Veterans vs Australian Population All COIs
ADVA, 2005a Australian male Vietnam veterans vs Australian 104 0.9 (0.7-1.1)
  population—incidence    
  Navy 28 1.1 (0.7-1.6)
  Army 66 0.9 (0.7-1.1)
  Air Force 10 0.7 (0.3-1.3)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
ADVA, 2005b Australian male Vietnam veterans vs Australian 76 0.9 (0.7-1.21
  population—mortality    
  Navy 22 1.3 (0.8-1.81
  Army 50 0.9 (0.7-1.2)
  Air Force 4 0.4 (0.1-1.0)
CDVA, 1997a Australian military Vietnam veterans 32 1.1 (0.7-1.4)
Australian Conscripted Army National Service Vietnam-Era Veterans (deployed vs nondeployed) All COIs
ADVA, 2005c Australian male conscripted Army National    
  Service Vietnam-era veterans: deployed vs nondeployed    
  Incidence 11 0.6 (0.2-1.2)
  Mortality 7 0.7 (0.2-2.0)
CDVA, 1997b Australian National Service Vietnam veterans 4 1.7 (0.3- > 10)
OCCUPATIONAL
IARC Phenoxy Herbicide Cohort (mortality vs national mortalityrates) Dioxin, phenoxy herbicides
Kogevinas et al., 1997 IARC cohort, male and female workers exposed 72 0.9 (0.7-1.1)
  to any phenoxy herbicide or chlorophenol    
  Exposed to highly chlorinated PCDDs 42 0.9 (0.7-1.2)
  Not exposed to highly chlorinated PCDDs 30 0.9 (0.6-1.3)
Kogevinas et al., 1993 IARC cohort—women 1 1.4 (nr)
Saracci IARC cohort—exposed subcohort (men and 40 0.9 (0.6-1.2)
NIOSH Mortality Cohort (12 US plants, production 1942-1984)
(included inIARC cohort)
Dioxin, Phenoxy
Herbicides
Steenland et al., 1999 US chemical production workers 13 1.0 (0.6-1.81
Fingerhut et al., 1991 NIOSH—entire cohort 10 1.0 (0.5-1.9)
  ≥ 1-year exposure, ≥ 20-year latency 4 1.4 (0.4-3.5)
Monsanto Plant in Nitro. WV (included in IARC and KIOSH cohorts Dioxin, Phenoxy
Herbicides
Collins Monsanto Company workers 0 0.0 (0.0-1.1)
Dow Chemical Company—Midland, MI (included in IARC and NIOSH cohorts) Dioxin, Phenoxy
Herbicides
Collins et al.,2009a Trichlorophenol workers 8 1.4 (0.6-2.7)
Collins et al.,2009b Pcntachlorophenol workers 4 1.2 (0.3-3.1)
Bodner et al.,2003 Dow production workers nr 1.5 (0.7-2.7)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Burns et al., 2001 Dow 2,4-D production worker    
  Digestive organs, peritoneum 16 0.7 (0.4-1.2)
Ramlow et al., 1996 Dow pentachlorophenol production workers    
  0-yr latency 4 1.7 (0.5-4.3)
  15-yr latency 3 1.8 (0.4-5.2)
Bond et al., 1988 Dow 2.4-D production workers 0 nr (0.0-3.7)
BASF Cohort (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Ott and Zober, 1996 BASF employees—incidence 3 1.0 (0.2-2.9)
  TCDD < 0.1 µg/kg of body weight 0 0.0 (0.0-3.4)
  TCDD 0.1-0.99 µg/kg of body weight 1 1.3 (0.0-7.0)
  TCDD ≥ 1 µg/kg of body weight 2 1.7 (0.2-6.2)
Zober et al., 1990 BASF employees—basic cohort   90% CI
    3 3.0 (0.8-7.7)
Danish Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Lynge, 1985 Danish production workers—incidence    
  Men 12 1.3 (nr)
  Women 1 0.7 (nr)
Dutch Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Boers et al., 2010 Dutch chlorophenoxy workers    
  Factory A 5 2.2 (0.4-13.2)
  Factory B 4 1.2 (0.3-4.7)
Hooiveld et al., 1998 Dutch chemical production workers 3 1.0 (0.2-2.9)
Bueno de Dutch phenoxy herbicide workers 2 0.7 (0.1-2.7)
Mcsquita et al., 1993
German Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Becher et al., 1996 German production workers    
  Plant I 12 1.3 (0.7-2.2)
  Plant II 0 nr
  Plant 111 0 nr
  Plant IV 2 0.6 (0.1-2.3)
Manz et al., 1991 German production workers—men, women    
  Men 12 1.2 (0.6-2.1)
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort) Dioxin, Phenoxy
Herbicides
McBride et al., 2009a 1.599 production workers (male and female) vs
national rates—mortality 1969 through 2004
   
  Ever exposed 4 14 (0.4-3.6)
  Never exposed 2 2.3 (0.3-8.4)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
’t Mannetje et al., 2005 New Zealand phenoxy herbicide producers (men and women) 2 1.1 (0.1-4.0)
  Phenoxy herbicide sprayers ( > 99% men) 3 1.4 (0.3-4.0)
United Kingdom Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Coggon et al., 1986 British MCPA production workers 26 0.9 (0.6-1.3)
Agricultural Health Study Herbicides
Alavanja et al., 2005 AHS—incidence (all digestive cancers)    
  Private applicators (men and women) 462 0.8 (0.8-0.9)
  Spouses of private applicators (> 99% women) 161 0.9 (0.7-1.0)
  Commercial applicators (men and women) 24 1.0 (0.6-1.4)
Blair et al., 2005a AHS (stomach cancers)    
  Private applicators (men and women) 10 0.5 (0.2-1.0)
  Spouses of private applicators ( > 99% women) 4 1.1 (0.3-2.8)
Other Agricultural Workers Herbicides
Mills and Yang. 2007 Nested case-control study of agricultural    
  Ever worked in area where 2.4-D used
Quartile of lifetime exposure to 2,4-D (lb)
42 1.9 (1.1-3.3)
  0 58 1.0
  1-14 17 2.2 (1.0-4.6)
  15-85 14 1.6 (0.7-3.5)
  86-1.950 11 2.1 (0.9-5.1)
Lee et al., 2004a Population-based case—control—agricultural 170  
  pesticide use and adenocarcinoma of stomach    
  Insecticides   0.9 (0.6-1.4)
  Herbicides   0.9 (0.5-1.4)
Ekström et al., 1999 Case—control study of Swedish residents with
gastric adenocarcinoma
   
  All occupational herbicide exposure 75 1.6 (1.1-2.2)
  Phenoxyacetic acid exposure 62 1.8 (1.3-2.6)
  Hormoslyr (2,4-D and 2,4,5-T) 48 1.7 (1.2-2.6)
  2,4-D only 3 nr (vs 0 controls)
  MCPA 11 1.8 (0.8-4.1)
  Duration of exposure    
  Nonexposed to all herbicides 490 1.0
  < 1 month 11 1.6 (0.7-3.5)
  1-6 months 30 1.9 (1.1-3.2)
  7-12 months 7 1.7 (0.6-4.7)
  > 1 year 13 1.4 (0.6-3.0)
  Other herbicide exposure 13 1.0 (0.5-1.9)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Gambini et al., 1997 Italian rice growers 39 1.0 (0.7-1.3)
Blair et al., 1993 US farmers in 23 slates    
  While men 657 1.0 (1.0-1.1)
  While women 12 1.2 (0.6-2.0)
Ronco et al., 1992 Danish farm workers—incidence    
  Men 286 0.9 (nr)
  Women 5 1.0 (nr)
Wigle et al., 1990 Canadian farmers 246 0.9 (0.8-1.0)
Alavanja et al., 1988 USDA agricultural extension agents in 0.7 (0.4-1.4)
Burmeisler et al., 1983 Iowa residents—farming exposures 1,812 1.3 (p < 0.05)
Wiklund, 1983 Swedish male and female agricultural   99% CI
  workers—incidence 2,599 1.1 (1.0-1.2)
Burmeister, 1981 Iowa farmers 338 l.l(p < 0.0l)
Other Studies of Herbicide and Pesticide Applicators Herbicides
Torchio et al., 1994 Italian licensed pesticide users 126 0.7 (0.6-0.9)
Swaen et al., 2004 Dutch licensed herbicide applicators    
  Stomach and small intestine 3 0.4 (0.1-1.3)
Swaen et al., 1992 Dutch licensed herbicide applicators
Stomach and small intestine
   
    1 0.5 (0.0-2.7)
Blair et al., 1983 Florida pesticide applicators   Expected exposed cases
    4 3.3
Forestry Workers Herbicides
Alavanja et al., 1989 USDA forest, soil conservationists 9 0.7 (0.3-1.3)
Reif et al., 1989 New Zealand forestry workers—nested case-control (incidence) 13 2.2 (1.3-3.9)
Paper and Pulp Workers Dioxins
McLean et al., 2006 IARC cohort of pulp and paper workers
Exposure to nonvolatile organochlorine compounds
   
  Never 146 0.9 (0.8-1.1)
  Ever 98 0.9 (0.7-1.1)
Rix et al., 1998 Danish paper-mill workers—incidence    
  Men 48 1.1 (0.8-1.4)
  Women 7 1.0 (0.4-2.1)
Henneberger et al., 1989 New Hampshire pulp and paper workers 5 1.2 (0.4-2.8)
Robinson et al., 1986 Northwestern US paper and pulp workers   90% CI
    17 1.2 (0.8-1.9)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Solet et al., 1989 US paper and pulp workers 1 0.5 (0.1-3.0)
Other Environmental Studies Dioxin, 2,4.5-T/
Thomas, 1987 US flavor and fragrance chemical plant workers   Expected exposed cases
    6 4.2
Axelson et al., 1980 Swedish railroad workers—tolal exposure to herbicides   Phenoxy acids
    3 2.2 (nr)
ENVIRONMENTAL
Seveso, Italy Residential Cohort
    TCDD
Consonni et al., 2008 Seveso residents—25-yr follow-up—men, women    
  Zone A 3 0.7 (0.2-2.0)
  Zone B 24 0.8 (0.5-1.2)
  Zone R 212 1.0 (0.8-1.1)
Pesatori et al., 2009 Seveso—20-yr follow-up to 1996—incidence
(men and women, combined)
   
  Zone A 3 0.9 (0.3-2.7)
  Zone B 19 0.9 (0.6-1.4)
  Zone R 131 0.8 (0.7 1.0)
Bertazzi et al., 2001 Seveso residents—20-yr follow-up
Zones A, B—men
16 0.9 (0.5-1.5)
  women 11 1.0 (0.6-1.9)
Bertazzi et al., 1997 Seveso residents—15-yr follow-up
Zone A—women
1 0.9 (0.0-5.3)
  Zone B—men 10 0.8 (0.4-1.5)
  women 7 1.0 (0.4-2.1)
  Zone R—men 76 0.9 (0.7-1.1)
  women 58 1.0 (0.8-1.3)
Bertazzi et al., 1993 Seveso residents—10-yr follow-up—incidence
Zone B—men
7 1.0 (0.5-2.1)
  women 2 0.6 (0.2-2.5)
  Zone R—men 45 0.9 (0.7-1.2)
  women Sadzn 1.0 (0.6-1.5)
Pesatori et al., 1992 Seveso residents—incidence
Zones A, B—men
7 0.9 (0.4-1.8)
  women 3 0.8 (0.3-2.5)
Bertazzi et al., 1989a Seveso residents—10-yr follow-up
Zones A, B, R—men
40 0.8 (0.6-1.2)
  women 22 1.0 (0.6-1.5)
Bertazzi et al., 1989b Seveso residents—10-yr follow-up
Zone B—men
7 1.2 (0.6-2.6)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Chapaevsk, Russia Cohort
Revich et al., 2001 Residents of Chapaevsk, Russia
Men

59

1.7 (1.3-2.2)
  Women 45 0.7 (0.5-0.9)
Other Environmental Studies Serum dioxin
Turunen et al., 2008 Finnish fishermen and spouses
Fishermen

16

0.8 (0.5-1.3)
  Spouses 2 0.3 (0.0-1.1)
Fukuda et al., 2003 Residents of Japanese municipalities with and
without waste-incineration plants
  Dioxin emissions/
Age-adjusted mortality
(per 100,000)(p = 0.92)
  Men    
  With   38.2±7.8 vs
  Without   39.0 ± 8.8 (p = 0.29)
  Women    
  With   20.7 ± 5.0 vs
  Wiihout   20.7 ± 5.8 (p = 0.92)
Svensson et al., 1995 Swedish fishermen—mortality (men and
women)
  Organochlorine compounds
  East coast 17 1.4 (0.8-2.2)
  West coast 63 0.9 (0.7-1.2)
  Swedish fishermen—incidence (men and women)    
  East coast 24 1.6 (1.0-2.4)
  West coast 71 0.9 (0.7-1.2)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; UFW, United Farm Workers of America; USDA, US Department of Agriculture; VA, US Department of Veterans Affairs; VES, Vietnam Experience Study; WV, West Virginia.

aSubjects are male, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

cancer were observed (SMR = 1.4, 95% CI 0.6–2.7). The later Collins et al. report (2009b) described the mortality experience of 773 workers who were exposed to chlorinated dioxins in the production of PCP. SMRs were calculated to compare the PCP workers with the general US population and with that of Michigan. There were four observed deaths from stomach cancer (SMR = 1.2, 95% CI 0.3–3.1).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×



McBride et al. (2009a,b) published two reports on a mortality follow-up of the workers in the Dow AgroSciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD. The first report (2009a) compared the SMR for stomach cancer in ever-exposed workers with that in never-exposed workers. The SMR for stomach-cancer deaths was 1.4 (95% CI 0.4–3.6) in exposed workers and 2.3 (95% CI 0.3–8.4) in the never-exposed group. The results in the second report (2009b) have not been included here, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Boers et al. (2010) published the third follow-up results of a retrospective cohort study of two Dutch chlorophenoxy herbicide manufacturing factories that produced mainly 2,4,5-T (factory A) and 2-methyl-4-chlorophenoxyacetic acid (MCPA), 2-methyl-4-chlorophenoxy propanoic acid (MCPP), and 2,4-D (factory B). The cohort consisted of all persons who worked in the factories during 1955–1985 (factory A) or 1965–1986 (factory B). No increases in stomach-cancer deaths were observed. The SMR was 2.23 (95% CI 0.38–13.2) in factory A and 1.21 (95% CI 0.31–4.65) in factory B.

Environmental Studies Stomach-cancer cases were reported in the cancer-incidence study of the population (males and females combined) exposed to dioxin after the Seveso accident in 1976 (Pesatori et al., 2009). Three stomach cancers were observed in Zone A (high exposure) (RR = 0.86, 95% CI 0.28–2.69); 19 in residents of Zone B (medium exposure) (RR = 0.87, 95% CI 0.55–1.37), and 131 in Zone R (the low exposure) (RR = 0.84, 95% CI 0.70–1.01).

A second environmental study was published by Turunen et al. (2008), who assessed the mortality experience of fishermen (registered since 1980) and fishermen’s wives in Finland, presuming that their mortality would reflect their high consumption of contaminated fish. SMRs for the 6,410 fishermen and 4,260 wives were calculated on the basis of national mortality figures. The investigators had previously compared fish consumption and serum dioxin in fishermen and wives with those in control populations and found that consumption of fish and serum dioxin concentrations were higher in the fishermen and their wives. The fishermen and their wives were also more likely to be obese. Mortality rates from stomach cancer were found to be elevated in the study cohort (SMR = 0.82, 95% CI 0.47–1.33 in fishermen and SMR = 0.30, 95% CI 0.04–1.08 in their wives).

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the chemicals of interest (2,4-D and TCDD) on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of gastrointestinal cancer has been reported in laboratory animals. However, studies performed in laboratory animals have observed dose-dependent

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

increases in the incidence of squamous-cell hyperplasia of the forestomach or fundus of the stomach after administration of TCDD (Hebert et al., 1990; Walker et al., 2006). Similarly, in a long-term TCDD-treatment study in monkeys, hypertrophy, hyperplasia, and metaplasia were observed in the gastric epithelium (Allen et al., 1977). A transgenic mouse bearing a constitutively active form of the AHR has been shown to develop stomach tumors (Andersson et al., 2002a); the tumors are neither dysplastic nor metaplastic but are indicative of both squamous-cell and intestinal-cell metaplasia (Andersson et al., 2005). The validity of the transgenic-animal model is indicated by the similarities in the pheno-type of the transgenic animal (increased relative weight of the liver and heart, decreased weight of the thymus, and increased expression of the AHR target gene CYP1A1) and animals treated with TCDD (Brunnberg et al., 2006).

In a biomarker study of cancer patients, AHR expression and nuclear translocation were significantly higher in gastric-cancer tissue than in precancerous tissue (Peng et al., 2009a). The results suggest that the AHR plays an important role in gastric carcinogenesis. AHR activation in a gastric-cancer cell line (AGS) has also been shown to enhance gastric-cancer cell invasiveness potentially through a c-Jun-dependent induction of matrix metalloproteinase-9 (Peng et al., 2009b).

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

The committee responsible for Update 2008 noted several studies reporting evidence of association of stomach cancer with herbicides and with phenoxy herbicides in particular: two well-done occupational studies (Ekström et al., 1999; Mills and Yang, 2007) and a case–control study (Cocco et al., 1999) that indicated a relationship with herbicide exposure but was not specific as to type of herbicide. There was no suggestion of an association between TCDD and mortality from stomach cancer in the 25-year update of the Seveso population (Consonni et al., 2008). That committee noted that there had been no suggestion of an association between the chemicals of interest and stomach cancer in the studies of Vietnam-veteran cohorts, the IARC cohort studies, or the AHS. The several additional studies reviewed for the current update provided no new evidence of an association between the chemicals of interest and stomach cancer.

There is some evidence of biologic plausibility in animal models, but overall the epidemiologic studies do not support an association between exposure to the chemicals of interest and stomach cancer.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

determine whether there is an association between exposure to the chemicals of interest and stomach cancer.

Colorectal Cancer

Colorectal cancers include malignancies of the colon (ICD-9 153) and of the rectum and anus (ICD-9 154); less prevalent tumors of the small intestine (ICD-9 152) are often included. Findings on cancers of the retroperitoneum and other unspecified digestive organs (ICD-9 159) are considered in this category. Colorectal cancers account for about 55% of digestive tumors; ACS estimated that 154,790 people would receive diagnoses of colorectal cancer in the United States in 2010 and that 53,190 would die from it (Jemal et al., 2010). Excluding basal-cell and squamous-cell skin cancers, colorectal cancer is the third-most common form of cancer both in men and in women. The average annual incidence of colorectal cancers is shown in Table 7-4.

The incidence of colorectal cancer increases with age; it is higher in men than in women and higher in blacks than in whites. Because it is recommended that all persons over 50 years old receive colon-cancer screening, screening can affect the incidence. Other risk factors include family history of this form of cancer, some diseases of the intestines, and diet. Type 2 diabetes is associated with an increased risk of cancer of the colon (ACS, 2007a).

Conclusions from VAO and Previous Updates

Update 2006 considered colorectal cancer independently for the first time. Prior updates developed tables of results on colon and rectal cancer, but conclusions about the adequacy of the evidence of their association with herbicide exposure had been reached only in the context of gastrointestinal tract cancers. The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the herbicides used by the US military in Vietnam and gastrointestinal tract tumors, including colorectal cancer. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the chemicals of interest to sustain that negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Colorectal cancer was thus reclassified into the default category of inadequate or insufficient evidence to determine whether there is an association. The information considered in Update 2008 did not provide evidence to support moving colorectal cancers out of the category of inadequate or insufficient evidence.

Table 7-7 summarizes the results of the relevant studies concerning colon and rectal cancers.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-7 Selected Epidemiologic Studies—Colon and Rectal Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
(95% CI)b
VIETNAM VETERANS
US Air Force Health Study All COIs
AFHS, 2000 Ranch Hand veterans from AFHS—mortality
Colon, rectum combined 7 1.5(0.4-5.5)
US CDC Vietnam Experience Study All COIs
Boehmer Follow-up of CDC Vietnam Experience
et aL, 2004 Cohort—mortality (1965-2000)
Colon, rectum, and anus 9 1.0(0.4-2.6)
US VA Mortality Study of Army and Marine Veterans—Ground troops serving July 4,1965-March 1,1973 All COIs
Breslin Army and Marine Vietnam veterans—mortality
etal.. 1988 Army Vietnam veterans
Colon, other gastrointestinal (ICD-8 209 1.0(0.7-1.3)
152-154, 158, 159)
Marine Vietnam veterans
Colon, other gastrointestinal (ICD-8 33 1.3(0.7-2.2)
152-154, 158, 159)
US VA Cohort of Female Vietnam Veterans All COIs
Cypel and US female Vietnam Veterans—mortality
Rang, 2008 through 2004
US Vietnam veterans 11 0.5(0.2-1.0)
Vietnam-veteran nurses 9 0.6(0.2-1.4)
Dalager US female Vietnam Veterans—mortality
etal., 1995 through 1991 US Vietnam veterans
Colon 4 0.4(0.1-1.2)
Vietnam-veteran nurses
Colon 4 0.5(0.2-1.7)
State Studies of US Vietnam Veterans All COIs
Anderson etal.. 1986 Wisconsin Vietnam veterans—mortality
Colon 6 1.0(0.4-2.2)
Rectum 1 nr
Australian Vietnam Veterans vs Australian Population All COIs
ADVA,2005a Australian male Vietnam veterans vs Australian population
Colon—incidence 376 1.1(1.0-1.2)
Navy 91 1.3(1.0-1.5)
Army 239 1.1(0.9-1.2)
Air Force 47 1.1(0.8-1.5)
Rectum—incidence
Navy 54 1.1(0.8-1.4)
Army 152 1.0(0.8-1.1)
Air Force 28 1.0(0.6-1.4)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
(95% CI)b
ADVA, 2005b Australian male Vietnam veterans vs Australian
population
   
  Colon—mortality 176 1.0 (0.8-1.1)
  Navy 49 1.3 (0.9-1.6)
  Army 107 0.9 (0.7-1.0)
  Air Force 21 0.9 (0.5-1.3)
  Rectum—mortality    
  Navy 13 0.8 (0.4-1.4)
  Army 44 0.9 (0.6-1.1)
  Air Force 12 1.3 (0.6-2.2)
AIHW, 1999 Australian Vietnam veterans (men)—incidence   Expected number of exposed cases (95% CI)
  Colorectal cancer 188 221 (191-251)
CDVA, 1998a Australian Vietnam veterans (men)—incidence    
  Self-reported colon cancer 405 117 (96-138)
CDVA, 1998b Australian Vietnam veterans (women)—    
  incidence    
  Self-reported colon cancer 1 1 (0-5)
CDVA, 1997a Australian military Vietnam veterans—mortality    
  Colon 78 1.2 (0.9-1.5)
  Rectum 16 0.6 (0.4-1.0)
Australian Conscripted Army National Service (deployed vs nondeployed) All COIs
ADVA, 2005c Australian male conscripted Army National    
  Service Vietnam-era veterans: deployed vs nondeployed Colon    
  Incidence 54 0.9 (0.7-1.4)
  Mortality 29 0.8 (0.5-1.3)
  Rectum    
  Incidence 46 1.4 (0.9-2.2)
  Mortality 10 1.8 (0.6-5.6)
CDVA, 1997b Australian National Service Vietnam    
  veterans—mortality    
  Colon 6 0.6 (0.2-1.5)
  Rectum 3 0.7 (0.2-9.5)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
(95% CI)b
OCCUPATIONAL
IARC Phenoxy Herbicide Cohort (mortality vs national mortality rates)
Dioxin, Phenoxy
Herbicides
Kogevinas et al., 1997 IARC cohort, male and female workers exposed
to any phenoxy herbicide or chlorophenol
   
  Colon 86 1.1 (0.9-1.3)
  Rectum 44 1.1 (0.8-1.4)
  Exposed to highly chlorinated PCDDs    
  Colon 52 1.0 (0.8-1.3)
  Rectum 29 1.3 (0.9-1.9)
Saracci et al., 1991 IARC cohort—exposed subcohort (men and women)—mortality    
  Colon (except rectum) 41 1.1 (0.8-1.5)
  Rectum 24 1.1 (0.7-1.6)
NIOSH Mortality Cohort (12 US plants, production 1942-1984) (included in IARC cohort) Dioxin, Phenoxy Herbicides
Steenlan et al., 1999 US chemical production workers    
  Small intestine and colon 34 1.2 (0.8-1.6)
  Rectum 6 0.9 (0.3-1.9)
Fingerhut et al., 1991 NK iSH cohort—mortality    
  Entire NIOSH cohort    
  Small intestine, colon 25 1.2 (0.8-1.8)
  Rectum 5 0.9 (0.3-2.1)
  ≥ l-yr exposure, ≥ 20-yr latency    
  Small intestine, colon 13 1.8 (1.0-3.0)
  Rectum 2 1.2 (0.1-4.2)
Monsanto Plant in Nitro, WV (included in IARC and KIOSH cohorts) Dioxin, phenoxy herbicides
Collins Monsanto Company workers—mortality    
  Colon 3 0.5 (0.1-1.3)
Dow Chemical Company—Midland, MI (included in IARC and NIOSH cohorts) Dioxin, Phenoxy
Herbicides
Collins et al., 2009a Trichlorophenol workers    
  Large intestine 18 1.2 (0.7-1.8)
  Rectum 2 0.6 (0.1-2.1)
Collins et al., 2009b Pentachlorophenol workers    
  Large intestine 10 1.2 (0.6-2.3)
  Rectum 1 0.5 (0.0-2.9)
Ramlow et al., 1996 Dow pentachlorophenol production workers—mortality    
  0-yr latency    
  Colon 4 0.8 (0.2-2.1)
  Rectum
15-yr latency
0 nr
  Colon 4 1.0 (0.3-2.6)
  Rectum 0 nr
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
(95% CI)b
Bond et al., 1988 Dow 2,4-D production workers—mortality
Colon
4 2.1 (0.6-5.4)
  Rectum 1 1.7 (0.0-9.3)
BASF Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Oil and Zober. 1996 BASF employees—colorectal—incidence 5 1.0 (0.3-2.3)
  TCDD < 0.1 μg/kg of body weight 2 1.1 (0.1-3.9)
  TCDD 0.1-0.99 μg/kg of body weight 2 1.4 (0.2-5.1)
  TCDD ≥ 1 μg/kg of body weight 1 0.5 (0.0-3.0)
Zober et al., 1990 BASF employees—basic cohort—mortality   90% CI
  Colon, rectum 2 2.5 (0.4-7.8)
Thiess et al., 1982 BASF production workers—mortality
Colon
1 0.4 (nr)
Danish Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Lynge, 1985 Danish production workers—incidence
Men
  Colon 10 1.0 (nr)
  Rectum 14 1.4 (nr)
Women
  Colon 1 0.3 (nr)
  Rectum 2 1.0 (nr)
Dutch Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Hooiveld et al., 1998 Dutch chemical production workers    
  Intestine (except rectum) 3 1.4 (0.3-4.0)
  Rectum 1 1.0 (0.0-5.6)
Bueno de Mcsquita et al., 1993 Dutch phenoxy herbicide workers—mortality
Colon
3 1.8 (0.4-5.4)
  Rectum 0 nr
German Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Becher et al., 1996 German production workers—mortality    
  Plant I    
  Colon 2 0.4 (0.1-1.4)
  Rectum 6 1.9 (0.7-4.0)
  Plant II    
  Colon 0 nr
  Rectum 0 nr
  Plant III    
  Colon 1 2.2 (0.1-2.2)
  Rectum 0 nr
  Plant IV    
  Colon 0 nr
  Rectum 1 0.9 (0.0-4.9)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Reference Study Populationa Exposed
Casesb
Exposure of Interest/
(95% CI)b
Manz et al.,1991 German production workers—mortality Colon 8 0.9 (0.4-1.8)
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort) Dioxin, Phenoxy
Herbicides
McBride et al., 2009a 1,599 production workers (male and female) vs
national rates—mortality 1969 through 2004
Large intestine
   
  Ever 3 0.6 (0.1-1.7)
  Never 0 0.0 (0.0-2.0)
  Rectum    
  Ever 6 2.0 (0.7-4.4)
  Never 2 2.1 (0.3-7.7)
’t Mannetje et al., 2005 New Zealand phenoxy herbicide producers,    
  sprayers—mortality
Phenoxy herbicide producers (men and women)
   
  Colon 2 0.6 (0.0-2.3)
  Rectum, rectosigmoid junction, anus 5 2.5 (0.8-5.7)
  Phenoxy herbicide sprayers ( > 99% men)    
  Colon 8 1.9 (0.8-3.8)
  Rectum, rectosigmoid junction, anus 4 1.5 (0.4-3.8)
United Kingdom Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Coggon et al., 1986 British MCPA production workers—mortality    
  Colon 19 1.0 (0.6-1.6)
  Rectum 8 0.6 (0.3-1.2)
Agricultural Health Study Herbicides
Lee WJ et al., 2007 Pesticide applicators (men and women) in AHS—colorectal-cancer incidence (enrollment–2002) and any use before enrollment of:    
  2,4-D 204 0.7 (0.5-0.9)
  2,4,5-T 65 0.9 (0.7-1.2)
  2,4,5-TP 24 0.8 (0.5-1.2)
  Dicamba 110 0.9 (0.7-1.2)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Reference Study Populationa Exposed
Casesb
Exposure of Interest/
(95% CI)b
Samanic et al., 2006 Pesticide applicators in AHS—colon-cancer
incidence (lenrolImenl-2002)
Dicamba—days of use
   
  None 76 1.0
  l- < 20 9 0.4 (0.2-0.9)
  20-< 56 20 0.9 (0.5-1.5)
  56- < 116 13 0.8 (0.4-1.5)
  ≥ 116 17 1.4 (0.8-2.9)
p-trend = 0.10
  Dicamba—intensity-weighted quartiles    
  None 76 1.0
  Lowest 16 0.6 (0.4-1.1)
  Second 17 0.7 (0.4-1.2)
  Third 6 0.5 (0.2-1.2)
  Highest 20 1.8 (1.0-3.1)
p-trend = 0.02
Alavanja el al., 2005 US AHS—incidence    
  Colon    
  Private applicators (men and women) 208 0.9 (0.8-1.0)
  Spouses of private applicators ( > 99% women) 87 0.9 (0.7-1.1)
  Commercial applicators (men and women) 12 1.2 (0.6-2.1)
  Rectum    
  Private applicators (men and women) 94 0.8 (0.7-1.0)
  Spouses of private applicators ( > 99% women) 23 0.6 (0.4-0.9)
  Commercial applicators (men and women) 7 1.3 (0.5-2.6)
Blair et al., 2005a US AHS—mortality    
  Colon    
  Private applicators (men and women) 56 0.7 (0.6-1.0)
  Spouses of private applicators ( > 99% women) 31 1.2 (0.8-1.6)
  Rectum    
  Private applicators (men and women) nr nr
  Spouses of private applicators ( > 99% women) nr nr
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
(95% CI)b
Other Agricultural Workers Herbicides
Gambini et al., 1997 Italian rice growers—mortality    
  Intestines 27 1.1 (0.7-1.6)
Blair et al., 1993 US farmers in 23 slates—mortality    
  White men    
  Colon 2,291 1.0 (0.9-1.0)
  Rectum 367 1.0 (0.9-1.1)
  White women    
  Colon 59 1.0 (0.8-1.3)
  Rectum 4 0.5 (0.1-1.3)
Ronco et al., 1992 Danish workers—incidence    
  Men—self-employed    
  Colon 277 0.7 (p < 0.05)
  Rectum 309 0.8 (p< 0.05)
  Men—employees    
  Colon 45 0.6 p< 0.05)
  Rectum 55 0.8 (nr)
  Women—self-employ ed    
  Colon 14 0.9 (nr)
  Rectum 5 0.6 (nr)
  Women—employees    
  Colon 112 0.9 (nr)
  Rectum 55 0.8 (nr)
  Women—family worker    
  Colon 2 0.2 p< 0.05)
  Rectum 2 0.4 (nr)
Alavanja et al., 1988 USDA agricultural extension agents—mortality    
  Colon 41 1.0 (0.7-1.5)
  Rectum 5 nr
Wiklund, 1983 Swedish male and female agricultural workers—    
  Colon 1.332
99% CI
  Rectum 1,083 0.8 (0.7-0.8)
Burmeister, 1981 Iowa farmers—mortality    
  Colon 1,064 0.9 (0.9-1.0)
Other Studies of Herbicide and Pesticide Applicators Herbicides
Swaen et al., 2004 Dutch licensed herbicide applicators—mortality    
  Colon 7 1.0 (0.4-2.1)
  Rectum 5 2.1 (0.7-4.8)
Torchio et al., 1994 Italian licensed pesticide users—mortality    
  Colon 84 0.6 (0.5-0.7)
  Rectum nr nr
Swaen et al., 1992 Dutch licensed herbicide applicators—mortality    
  Colon 4 2.6 (0.7-6.5)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
(95% CI)b
Blair et al., 1983 Florida pesticide applicators—mortality    
  Colon 5 0.8 (nr)
  Rectum 2 nr
Forestry Workers Herbicides
Alavanja et al., 1989 USDA forest or soil conservationists—mortality    
  Colon 44 1.5 (1.1-2.0)
  Rectum 9 1.0 (0.5-1.9)
Reif et al., 1989 New Zealand forestry workers—nested case-control (incidence)    
  Colon 7 0.5 (0.2-1.1)
  Small intestine 2 5.2 (1.4-18.9)
  Rectum 10 1.2 (0.6-2.3)
Paper and Pulp Workers Dioxins
McLean et al., 2006 IARC cohort of pulp and paper workers—    
  mortality
Ever exposed to nonvolatile organochlorine compounds
   
  Colon 62 0.7 (0.6-1.0)
  Rectum 11 0.9 (0.7-1.1)
Rix et al., 1998 Danish paper-mill workers—incidence    
  Men    
  Colon 58 1.0 (0.7-1.2)
  Rectum 43 0.9 (0.6-1.2)
  Women    
  Colon 23 1.1 (0.7-1.7)
  Rectum 15 1.5 (0.8-2.4)
Henneberger et al., 1989 New Hampshire pulp and paper workers—mortality    
  Colon 9 1.0 (0.5-2.0)
  Rectum 1 0.4 (0.0-2.1)
Solet et al., 1989 US pulp and paper workers—mortality    
  Colon 7 1.5 (0.6-3.0)
Robinson et al., 1986 Northwestern US pulp and paper workers    
  Intestines (ICD-7 152. 153) 7 0.4 (0.2-0.7)
Other Occupational Studies Herbicides
Lo et al., 2010 Egyptian case—control study    
  Colorectal cancer nr 5.5 (2.4-12.3)
Thomas, 1987 US flavor and fragrance chemical plant workers   Dioxin, 2,4,5-T
  exposed to 2,4,5-T, TCDD    
  Colon 4 0.6 (nr)
  Rectum 6 2.5 (nr)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
(95% CI)b
Hardell, 1981 Swedish residents—incidence   Phenoxy acid and chlorophenils
  Colon    
  Exposed to phenoxy acids 11 1.3 (0.6-2.8)
  Exposed to chlorophenols 6 1.8 (0.6-5.3)
ENVIRONMENTAL
Seveso, Italy Residential Cohort

TCDD
Consonni et al., 2008 Seveso residents—25-yr follow-up—men,    
  women    
  Zone A    
  Colon 3 1.0 (0.3-3.0)
  Rectum 1 0.9 (0.1-6.4)
  Zone B    
  Colon 12 0.6 (0.3-1.1)
  Rectum 11 1.5 (0.8-2.8)
  Zone R    
  Colon 137 0.9 (0.7-1.3)
  Rectum 50 0.9 (0.7-1.3)
Pesatori et al., 2009 Seveso—20-yr follow-up to 1996—incidence
(men and women, combined)
   
  Zone A    
  Colon 2 0.7 (0.2-2.7)
  Rectum 0  
  Zone B    
  Colon 19 1.0 (0.7-1.6)
  Rectum 17 1.8 (1.1-2.9)
  Zone R    
  Colon 137 1.0 (0.9-1.3)
  Rectum 71 1.1 (0.8-1.4)
Bertazzi et al., 2001 Seveso residents—20-yr follow-up—mortality    
  Zones A, B—men    
  Colon 10 1.0 (0.5-1.9)
  Rectum 9 2.4 (1.2-4.6)
  Zones A, B—men    
  Colon 5 0.6 (0.2-1.4)
  Rectum 3 1.1 (0.4-3.5)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
(95% CI)b
Bertazzi et al., 1997 Seveso residents—15-yr follow-up—mortality    
  Zone A—women
Colon

2
2.6 (0.3-9.4)
  Zone B—men
Colon

5
0.8 (0.3-2.0)
  Rectum 7 2.9 (1.2-5.9)
  Zone B—women
Colon

3
0.6 (0.1-1.8)
  Rectum 2 1.3 (0.1-4.5)
  Zone R—men
Colon

34
0.8 (0.6-1.1)
  Rectum 19 1.1 (0.7-1.8)
  Zone R—women
Colon

33
0.8 (0.6-1.1)
  Rectum 12 0.9 (0.5-1.6)
Bertazzi et al., 1993 Seveso residents—10-yr follow-up—morbidily    
  Zone B—men    
  Colon 2 0.5 (0.1-2.0)
  Rectum 3 1.4 (.04-4.4)
  Zone B—women    
  Colon 2 0.6 (0.1-2.3)
  Rectum 2 1.3 (0.3-5.4)
  Zone R—men    
  Colon 32 1.1 (0.8-1.6)
  Rectum 17 1.1 (0.7-1.9)
  Zone R—women    
  Colon 23 0.8 (0.5-1.3)
  Rectum 7 0.6 (.03-1.3)
Pesatori et al., 1992 Seveso residents—incidence    
  Zones A, B—men    
  Colon 3 0.6 (0.2-1.9)
  Rectum 3 1.2 (0.4-3.8)
  Zones A, B—women    
  Colon 3 0.7 (0.2-2.2)
  Rectum 2 1.2 (0.3-4.7)
Bertazzi et al., 1989a Seveso residents—10-yr follow-up—mortality    
  Zones A, B, R—men    
  Colon 20 1.0 (0.6-1.5)
  Rectum 10 1.0 (0.5-2.7)
  Zones A, B, R—women    
  Colon 12 0.7 (0.4-1.2)
  Rectum 7 1.2 (0.5-2.7)
Bertazzi et al., 1989b Seveso residents—10-yr follow-up—mortality    
  Zone B—men    
  Rectum 2 1.7 (0.4-7.0)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
(95% CI)b
Chapaevsk, Russia Cohort
Revich et al., 2001 Residents of Chapaevsk, Russia—mortality    
  Men    
  Colon 17 1.3 (0.8-2.2)
  Rectum 21 1.5 (1.0-2.4)
  Women    
  Colon 24 1.0 (0.7-1.5)
  Rectum 24 0.9 (0.6-1.4)
Other Environmental Studies
Turunen et al., 2008 Finnish fishermen and spouses   Serum dioxin
  Fishermen   SMRs
  Colon 8 0.5 (0.2-1.0)
  Rectum and anus 8 0.8 (0.4-1.6)
  Spouses    
  Colon 10 1.3 (0.6-2.4)
  Rectum and anus 8 2.1 (0.9-4.2
Svensson et al., 1995 Swedish fishermen—mortality (men and women)   Organochlorine
  East coast   compounds
  Colon 1 0.1 (0.0-0.7)
  Rectum 4 0.7 (0.2-1.9)
  West coast    
  Colon 58 1.0 (0.8-1.3)
  Rectum 31 1.0 (0.7-1.5)
  Swedish fishermen—incidence (men and women)    
  East coast    
  Colon 5 0.4 (0.1-0.9)
  Rectum 9 0.9 (0.4-1.6)
  West coast    
  Colon 82 1.0 (0.8-1.2)
  Rectum 59 1.1 (0.8-1.4)
Lampi et al., 1992 Finnish community exposed to chlorophenolcontamination—incidence   Chlorophenols
  Colon—men, women 9 1.1 (0.7-1.8)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture; VA, US Department of Veterans Affairs; WV, West Virginia.

aSubjects are male, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Update of the Epidemiologic Literature

Vietnam-Veteran Studies No studies of exposure to the chemicals of interest and colorectal cancer in Vietnam veterans have been published since Update 2008.

Occupational Studies Two occupational-cohort studies have been updated since Update 2008. Collins et al. (2008, 2009a,b) published a series of papers examining the mortality experience of workers employed in a Dow Chemical Company in Midland, Michigan, from 1937 to 1980. Serum dioxin was evaluated to estimate exposures to five dioxins in a group of 98 workers (Collins et al., 2008). Although the serum dioxin, furan, and PCB concentrations were measured many years after exposure, distinct patterns of dioxin congeners were found in workers who had different chlorophenol exposures. Collins et al. (2009a) examined 1,615 workers who had been exposed to TCP production. The mean duration of follow-up was 36.4 years. Some 18 cases of cancer of the large intestine were observed, for an SMR of 1.2 (95% CI 0.7–1.8); two cases of rectal cancer were observed, for an SMR of 0.6 (95% CI 0.1–2.1). Collins et al. (2009b) also described the mortality experience of 773 workers who were exposed to chlorinated dioxins in the production of PCP. SMRs were calculated to compare the PCP workers with the general US population and with that of Michigan. There were 10 observed deaths from cancer of the large intestine (SMR = 1.2, 95% CI 0.6–2.3) and 1 death from cancer of the rectum (SMR = 0.5; 95% CI 0.0–2.9).

The second occupational-cohort follow-up study was that of workers in the Dow AgroSciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD (McBride et al., 2009a,b). Workers employed during the period from January 1969 to November 1988 (when 2,4,5-T was no longer produced at the work sites) were followed to the end of 2004, and SMRs were calculated by using national mortality figures. In McBride et al. (2009a), the SMR for large intestine–cancer deaths was 0.6 (95% CI 0.1–1.7) in workers exposed to TCDD and 0.0 (95% CI 0.0–2.0) in the never-exposed group. The SMR for rectal-cancer deaths was 2.0 (95% CI 0.7–4.4) in exposed workers and 2.1 (95% CI 0.3–7.7) in nonexposed workers. The SMRs for large intestine and rectal cancer according to estimated effective cumulative exposure to TCDD were not calculated; however, no trend was observed for all cancers of the digestive organs and peritoneum. The results in McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Lo et al. (2010) published a case–control study of 421 Egyptian cases of colorectal carcinoma and 439 hospital-matched controls. Histories of lifestyle, occupational, and reproductive factors were obtained with questionnaires. A history of pesticide exposure was significantly associated with a higher risk of

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

colorectal carcinoma (odds ratio [OR] = 2.6, 95% CI 1.1–5.9). Among 73 subjects who reported farming as their longest lifetime occupation, self-reported exposure to herbicides was associated with increased risk of colorectal cancer (adjusted OR = 5.5, 95% CI 2.4–12.3). Information on specific types of herbicides was not obtained.

Environmental Studies Colon-cancer cases were reported in the cancer- incidence study of the population (males and females combined) exposed to dioxin after the Seveso accident in 1976 (Pesatori et al., 2009). Two colon cancers were observed in Zone A (high exposure) (RR = 0.68, 95% CI 0.17–2.72); 19 in Zone B (medium exposure) (RR = 1.04, 95% CI 0.66–1.64), and 137 in Zone R (low exposure) (RR = 1.04, 95% CI 0.87–1.26). Rectal-cancer cases were reported separately. No rectal-cancer cases were observed in Zone A, 17 in Zone B (RR = 1.78, 95% CI 1.09–2.88), and 71 in Zone R (RR = 1.05, 95% CI 0.82–1.35).

A second environmental study was published by Turumen et al. (2008), who assessed the mortality experience of fishermen (registered since 1980) and fishermen’s wives in Finland, presuming that their mortality reflected their high consumption of contaminated fish. SMRs for the 6,410 fishermen and 4,260 wives were calculated on the basis of national mortality figures. The investigators had previously compared fish consumption and serum dioxin level in fishermen and their wives with those in control populations and found that consumption of fish and serum dioxin were higher in the fishermen and their wives. The fishermen and their wives were also more likely to be obese. Mortality from colon cancer was not increased in the study cohort (SMR = 0.52, 95% CI 0.23–1.03 in fishermen; SMR = 1.30, 95% CI 0.62–2.39 in fishermen’s wives). Mortality from rectal and anal cancers also was not increased (SMR = 0.82, 95% CI 0.35–1.60 in fishermen; SMR = 2.13, 95% CI 0.92–4.19 in fishermen’s wives).

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the chemicals of interest on tumor incidences (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of colorectal cancer in laboratory animals exposed to the chemicals of interest has been reported.

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

The epidemiologic studies reviewed yielded no evidence that suggested an association between the chemicals of interest and colorectal cancer. There is no evidence of biologic plausibility of an association between exposure to any of the

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

chemicals of interest and tumors of the colon or rectum. Overall, the available evidence does not support an association between the chemicals of interest and colorectal cancer.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and colorectal cancer.

Hepatobiliary Cancers

Hepatobiliary cancers include cancers of the liver (ICD-9 155.0, 155.2) and the intrahepatic bile duct (ICD-9 155.1). ACS estimated that 17,430 men and 6,690 women would receive diagnoses of liver cancer or intrahepatic bile duct cancer in the United States in 2010 and that 12,720 men and 6,190 women would die from these cancers (Jemal et al., 2010). Gallbladder cancer and extrahepatic bile duct cancer (ICD-9 156) are fairly uncommon and are often grouped with liver cancers when they are addressed.

In the United States, liver cancers account for about 1.5% of new cancer cases and 3.3% of cancer deaths. Misclassification of metastatic cancers as primary liver cancer can lead to overestimation of the number of deaths attributable to liver cancer (Percy et al., 1990). In developing countries, especially those in sub-Saharan Africa and Southeast Asia, liver cancers are common and are among the leading causes of death. Known risk factors for liver cancer include chronic infection with hepatitis B or hepatitis C virus and exposure to the carcinogens aflatoxin and vinyl chloride. Alcohol cirrhosis and obesity-associated metabolic syndrome may also contribute to the risk of liver cancer. In the general population, the incidence of liver and intrahepatic bile duct cancer increases slightly with age; at the ages of 50–64 years, it is greater in men than in women and greater in blacks than in whites. The average annual incidence of hepatobiliary cancers is shown in Table 7-4.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and hepatobiliary cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion.

Table 7-8 summarizes the results of the relevant studies.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-8 Selected Epidemiologic Studies—Hepatobiliary Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS    
US Air Force Health Study—Ranch Hand veterans vs SEA veterans All COIs
AFHS, 2000 Air Force Ranch Hand veterans—incidence 2 1.6 (0.2-11.4)
US CDC Vietnam Experience Study
Boehmer et al., 2004 Follow-up of CDC Vietnam Kxpcrience Cohort
(liver, intrahepatic bile ducts [ICD-9 155])
5 nr
CDC, 1990a US men born 1921-1953—incidence 8 1.2 (0.5-2.7)
US VA Mortality Study of Army and Marine Veterans   All COIs
Breslin et al., 1988 Army Vietnam veterans (liver, bile duct) 34 1.0 (0.8-1.4)
  Marine Vietnam veterans (liver, bile duct) 6 1.2 (0.5-2.8)
State Studies of US Vietnam Veterans   All COIs
Anderson et al., 1986 Wisconsin Vietnam veterans 0 nr
Australian Vietnam Veterans vs Australian Population
ADVA, 2005a Australian male Vietnam veterans vs Australian 27  
  population—incidence    
  Navy 8 1.0 (0.4-1.9)
  Army 18 0.7 (0.4-1.1)
  Air Force 1 0.2 (0.0-1.2)
ADVA, 2005b Australian male Vietnam veterans vs Australian 48 0.9 (0.6-1.1)
  population-mortality (liver, gallbladder)    
  Navy 11 1.0 (0.5-1.7)
  Army 33 0.9 (0.6-1.2)
  Air Force 4 0.6 (0.2-1.5)
CDVA, 1997a Australian military Vietnam veterans    
  Liver (ICD-9 155) 8 0.6 (0.2-1.1)
  Gallbladder (ICD-9 156) 5 1.3 (0.4-2.8)
Australian Conscripted Army National Service (deployed vs nondeployed)   All COIs
ADVA, 2005c Australian male conscripted Army National    
  Service Vietnam-era veterans: deployed vs    
  nondeployed    
  Incidence 2 2.5 (0.1-147.2)
  Mortality (liver, gallbladder) 4 2.5 (0.4-27.1)
CDVA, 1997b Australian National Service Vietnam veterans 1 nr
       
OCCUPATIONAL      
IARC Phenoxy Herbicide Cohort (mortality vs national mortality rates)   Dioxin, phenoxy herbicides
Kogevinas et al., 1997 IARC cohort, male and female workers exposed 15 0.7 (0.4-1.2)
  to any phenoxy herbicide or chlorophenol    
  Exposed to highly chlorinated PCDDs 12 0.9 (0.5-1.5)
  Not exposed to highly chlorinated PCDDs 3 0.4 (0.1-1.2)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Saracci et al., 1991 IARC cohort—exposed subcohort (men and women)    
  Liver, gallbladder, bilcduct (ICD-8 155-156) 4 0.4 (0.1-1.1)
NIOSH Mortality Cohort (12 U'S plants, production 1942-1984) (included inIARC cohort)   Dioxin, phenoxy herbicides
Slecnlond et al., 1999 US chemical production workers    
  Liver, biliary tract (ICD-9 155-156) 7 0.9 (0.4-1.6)
Fingerhut et al., 1991 NIOSH—entire cohort (liver, biliary tract)— 6 1.2 (0.4-2.5)
  ≥1 -jt exposure, ≥ 20-yr latency 1 0.6 (0.0-3.3)
BASF Production Workers (included in I ARC cohort)   Dioxin, phenoxy herbicides
Oil and Zobcr. 19% BASF employees—incidence
Liver, gallbladder, and bile duct
2 2.1 (0.3-7.5)
  TCDD < 0.1 ug/kg of body weight 1 2.8 (0.1-155)
  TCDD 0.1-0.99 ug/kg of body weight 0 0.0 (0.0-15.4)
  TCDD ≥ 1 ug/kg of body weight 1 2.8 (0.1-15.5)
Dow Chemical Company—Midland. Ml (included in I ARC an NOSH cohorts)   Dioxin, phenoxy herbicides
Collins et al., 2009a Trichlocophcnol workers 2 05 (0.1-1.6)
Collins et al., 2009b Pcntachlorophcnol workers 0 0.0 (0.0-1.7)
Ramlow et al., 1996 Dow pcntachlorophcnol production workers
Liver, primary (ICDA-8 155-156)
   
  0-yr latency 0 nr
  15-yr latency 0 nr
Bond et al., 1988 Dow 2,4-D production workers    
  Liver, biliary tract (ICDA-8 155-156) 0 1.2 (nr)
Monsanto Plant in Nitro, WV (included in 1ARC and NIOSH cohorts)   Dioxin, phenoxy herbicides
Collins et al., 1993 Monsanto Company 2,4-D production workers
Liver, biliary tract
2 1.4 (0.2-5.2)
Zackand Suskind,1980 Monsanto Company production workers 0 nr
Danish Production Workers (included in IARC cohorti   Dioxin, phenoxy herbicides
Lyngc. 1985 Danish production workers—incidence    
  Men 3 1.0 (nr)
  Women 0 nr
German Production Workers (included in IARC cohort)   Dioxin, phenoxy herbicides
Bechcrd et al., 1996 German production workers
Liver and biliary tract
1 1.2 (0.0-6.9)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
New Zealand Production Workers—Dow plant in Plymouth,(included in IARC cohort)NZ   Dioxin, phenoxy herbicides
Mc Bride et al., 2009a 1,599 production workers (male and female) vs
national rates—mortality 1969 through 2004
   
  Ever 2 1.4 (0.2-5.1)
  Never 0 0.0 (0.0-8.2)
’t Mannetje et al., 2005 New Zealand phenoxy herbicide workers (ICD-9 155)    
  Producers (men and women) 1 1.6 (0.0-8.8)
  Sprayers ( > 99% men) 0 0.0 (0.0-4.2)
Agricultural Health Study   Herbicides
Alavanja et al., 2005 US AHS—incidence    
  Liver    
  Private applicators (men and women) 35 1.0 (0.7-1.4)
  Spouses of private applicators ( > 99% women) 3 0.9 (0.2-2.5)
  Commercial applicators (men and women) nr 0.0 (0.0-4.2)
  Gallbladder    
  Private applicators (men and women) 8 2.3 (1.0-4.5)
  Spouses of private applicators ( > 99% women) 3 0.9 (0.2-2.5)
  Commercial applicators (men and women) nr 0.0 (0.0-35.8)
Blair et al., 2005a US AHS    
  Liver    
  Private applicators (men and women) 8 0.6 (0.2-1.1)
  Spouses of private applicators ( > 99% women) 4 1.7 (0.4-4.3)
  Gallbladder    
  Private applicators (men and women) 3 2.0 (0.4-5.7)
  Spouses of private applicators ( > 99% women) 2 l.3 (0.M.6)
Other Agricultural Workers   Herbicides
Gambini et al., 1997 Italian rice growers 7 1.3 (0.5-2.6)
Blair et al., 1993 US farmers in 23 states    
  White men 326 1.0 (0.9-1.1)
  White women 6 0.7 (0.3-1.6)
Wiklund, 1983 Swedish male and female agricultural   99% CI
  workers—incidence    
  Liver (primary) 103 0.3 (0.3-0.4)
  Biliary tract 169 0.6 (0.5-0.7)
  Liver (unspecified) 67 0.9 (0.7-1.3)
Other Studies of Herbicide and Pesticide Applicators   Herbicides
Torchio et al., 1994 Italian licensed pesticide users    
  Liver 15 0.6 (0.3-0.9)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Swaen et al.,, 2004 Dutch licensed herbicide applicators 0 nr
Asp et al., 1994 Finnish herbicide applicators—liver, biliary tract    
  Incidence 3 0.9 (0.2-2.6)
  Mortality 2 0.6 (0.1-2.2)
Ronco et al., 1992 Danish farm workers—incidence    
  Liver    
  Men—self-employed 23 0.4 (p< 0.05)
  employees 9 0.8 (nr)
  Women—family workers 5 0.5 (nr)
  Gallbladder    
  Men—self-employed 35 0.8 (nr)
  employees 7 0.8 (nr)
  Women—self-employed 7 2.7 <p < 0.05)
  employees 1 0.7 (nr)
  family workers 17 1.0 (nr)
Forestry Workers     Herbicides
Reif et al., 1989 New Zealand forestry workers—nested    
  case-control—incidence    
  Liver 1 0.8 (0.1-5.8)
  Gallbladder 3 4.1 (1.4-12.0)
Paper and Pulp Workers     Dioxins
McLean et al., 2006 IARC cohort of pulp and paper workers    
  Exposure to nonvolatile organochlorine compounds    
  Never 27 0.9 (0.6-1.3)
  Ever 16 0.7 (0.4-1.1)
Rix et al., 1998 Danish paper-mill workers—incidence    
  Liver—men 10 1.1 (0.5-2.0)
  women 1 0.6 (0.0-3.2)
  Gallbladder—men 9 1.6 (0.7-3.0)
  women 4 1.4 (0.4-3.7)
Solet et al., 1989 US pulp and paper workers (ICD-8 155-156) 2 2.0 (0.2-7.3)
Other Occupational Studies     Phenoxy acids, chlorophenols
Hardell et al., 1984 Swedish residents—incidence, mortality
combined
102 1.8 (0.9-4.0)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
ENVIRONMENTAL    
Seveso, Italy Residential Cohort   TCDD
Consonni et al., 2008 Seveso residents—25-yr follow-up—men.    
  women    
  Liver (ICD-9 155)    
  Zone A 3 1.0 (0.3-3.2)
  Zone B 16 0.9 (0.5-1.4)
  Zone R 107 0.8 (0.7-1.0)
  Biliary tract (ICD-9 156)    
  Zone A 0 0.0 (nr)
  Zone B 2 0.6 (0.1-2.3)
  Zone R 31 1.2 (0.8-1.7)
Pesatori et al., 2009 Seveso—20-yr follow-up to 1996—incidence    
  (men and women, combined)    
  Zone A    
  Liver 0  
  Biliary tract 0  
  Zone B    
  Liver 14 1.3 (0.8-2.2)
  Biliary tract 6 2.3 (1.0-5.2)
  Zone R    
  Liver 56 0.7 (0.6-1.0)
  Biliarv tract 16 0.8 (0.5-1.4)
Bertazzi et al., 2001 Seveso residents—20-yr follow-up    
  Zone A, B—men (liver, gallbladder) 6 0.5 (0.2-1.0)
  (liver) 6 0.5 (0.2-1.1)
  women (liver, gallbladder) 7 1.0 (0.5-2.2)
  (liver) 6 1.3 (0.6-2.9)
Bertazzi et al., 1997 Seveso residents—15-yr follow-up    
  Zone B—men (liver, gallbladder) 4 0.6 (0.2-1.4)
  (liver) 4 0.6 (0.2-1.6)
  women (liver, gallbladder) 4 1.1 (0.3-2.9)
  (liver) 3 1.3 (0.3-3.8)
  Zone R—men (liver, gallbladder) 35 0.7 (0.5-1.0)
  (liver) 31 0.7 (0.5-1.0)
  women (liver, gallbladder) 25 0.8 (0.5-1.3)
  (liver) 12 0.6 (0.3-1.1)
Bertazzi et al., 1993 Seveso residents—10-yr follow-up—incidence    
  Zone B—men (liver) 4 2.1 (0.8-5.8)
  (gallbladder—ICD-9 156) 1 2.3 (0.3-17.6)
  women (gallbladder—ICD-9 156) 4 4.9 (1.8-13.6)
  Zone R—men (liver) 3 0.2 (0.1-0.7)
  (gallbladder—ICD-9 156) 3 1.0 (0.3-3.4)
  women (liver) 2 0.5 (0.1-2.1)
  (gallbladder—ICD-9 156) 7 1.0 (0.5-2.3)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Pesatori et al., 1992 Saeveso residents—incidence    
  Zone A, B—men (liver) 4 1.5 (0.5-4.0)
  (gallbladder—ICD-9 156) 1 2.1 (0.3-15.6)
  women (liver) 1 1.2 (0.2-9.1)
  (gallbladder—ICD-9 156) 5 5.2 (2.1-13.2)
  Zone R—men (liver) 8 0.5 (0.2-0.9)
  (gallbladder—ICD-9 156) 3 1.0 (0.3-3.4)
  women (liver) 5 0.8 (0.3-2.1)
  (gallbladder—ICD-9 156) 7 1.0 (0.5-2.3)
Bertazzi et al., 1989b Seveso residents—10-yr follow-up    
  Zone A—women (gallbladder—ICD-9 156) 1 12.1 (1.6-88.7)
  Zone B—men (liver) 3 1.2 (0.4-3.8)
  women (gallbladder—ICD-9 156) 2 3.9 (0.9-16.2)
  Zone R—men (liver) 7 0.4 (0.2-0.8)
  women (liver) 3 0.4 (0.1-1.4)
  (gallbladder—ICD-9 156) 5 1.2 (0.5-3.1)
Quail Run Cohort   TCDD
Hoffman et al., 1986 Residents of Quail Run Mobile Home Park 0 nr
  (men and women)    
Other Environmental Studies
Svensson et al., 1995 Swedish fishermen (men and   Organochlorine compounds
  women)—mortality    
  East coast 1 0.5 (0.0-2.7)
  West coast (liver, bile ducts) 9 0.9 (0.4-1.7)
  Swedish fishermen (men and women)—incidence    
  East coast 6 1.3 (0.5-2.9)
  West coast (liver, bile ducts) 24 1.0 (0.6-1.5)
Cordier et al., 1993 Risk factors for hepatocellular carcinoma in
Hanoi. Vietnam
  Herbicides
  Military service in South Vietnam for ≥ 10 years after 1960 11 8.8 (1.4-41.0)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; ICDA, International Classification of Diseases, Adapted for Use in the United States; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VA, US Department of Veterans Affairs; WV, West Virginia.

aSubjects are male, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×



Update of the Epidemiologic Literature

Vietnam-Veteran Studies No studies of exposure to the chemicals of interest and hepatobiliary cancer in Vietnam veterans have been published since Update 2008.

Occupational Studies Two occupational-cohort follow-up studies have been published since Update 2008. Collins et al. (2008, 2009a,b) published a series of papers examining the mortality experience of workers employed in a Dow Chemical Company in Midland, Michigan, from 1937 to 1980. Collins et al. (2009b) described the mortality experience of 773 workers who were exposed to chlorinated dioxins in the production of PCP; 75% of the cohort have been followed for more than 27 years. SMRs were calculated to compare the PCP workers with the general US population and the population of the state of Michigan. There were no observed deaths from cancer of the hepatobiliary tract. In a companion paper, the authors examined 1,615 workers who had been exposed to TCP production (Collins et al., 2009a). The mean duration of follow-up was 36.4 years. Two cases of cancer of the hepatobiliary tract were observed, for an SMR of 0.5 (95% CI 0.1–1.6).

The second occupational mortality study was of workers in the Dow Agro-Sciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD (McBride et al., 2009a,b). Workers employed during the period from January 1969 to November 1988 (when 2,4,5-T was no longer produced at the work sites) were followed to the end of 2004, and SMRs were calculated by using national mortality figures. McBride et al. (2009a) found that the SMR for hepatobiliary cancer deaths was 1.4 (95% CI 0.2–5.1) in exposed workers and 0.0 (95% CI 0.0–8.2) in the never-exposed group. The results of McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Environmental Studies Hepatobiliary cancer was reported in the cancer-incidence study of the population (males and females combined) exposed to dioxin after the Seveso accident in 1976 (Pesatori et al., 2009). No liver-cancer cases were observed in Zone A (high exposure), 14 cases in Zone B (medium exposure) (RR = 1.29, 95% CI 0.76–2.20), and 56 in Zone R (low exposure) (RR = 0.74, 95% CI 0.56–0.97). Bilary-cancer cases were reported separately. No biliary cases were observed in Zone A, 6 in Zone B (RR = 2.28, 95% CI 1.00–5.17), and 16 in Zone R (RR = 0.82, 95% CI 0.49–1.39).

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the chemicals of interest on tumor incidences (Charles et al., 1996; Stott et al., 1990; Walker

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

et al., 2006; Wanibuchi et al., 2004). Studies performed in laboratory animals have consistently demonstrated that long-term exposure to TCDD results in the formation of liver adenomas and carcinomas (Knerr and Schrenk, 2006; Walker et al., 2006). Furthermore, TCDD increases the growth of hepatic tumors that are initiated by treatment with a complete carcinogen, and pathologic liver changes have been observed after exposure to TCDD, including nodular hyperplasia and massive inflammatory cell infiltration (Kociba et al., 1978; NTP, 2006; Walker et al., 2006; Yoshizawa et al., 2007). Inflammation and cancer are strongly intertwined in the development and progression of many cancers, including liver cancers (Mantovani et al., 2008). Similarly, in monkeys treated with TCDD, hyperplasia and an increase in cells that stain positive for alpha-smooth muscle actin have been observed (Korenaga et al., 2007). Postive staining for alpha-smooth muscle actin is thought to be indicative of a process (epithelial–mesenchymal transition) that is associated with the progression of malignant tumors (Weinberg, 2008).

With respect to cancers of the bile duct, bile duct hyperplasia (but not tumors) has been reported (Knerr and Schrenk, 2006; Walker et al., 2006; Yoshizawa et al., 2007). Similarly, monkeys treated with TCDD developed metaplasia, hyperplasia, and hypertrophy of the bile duct (Allen et al., 1977). Hollingshead et al. (2008) showed that TCDD-activated AHR in human breast and endocervical cell lines induces sustained high concentrations of the IL-6 cytokine, which has tumor-promoting effects in numerous tissues, including cholangiocytes. Thus TCDD might promote carcinogenesis in biliary tissue.

TCDD may contribute to tumor progression by inhibiting p53 regulation (phosphorylation and acetylation) triggered by genotoxicants via the increased expression of the metastasis marker AGR2 (Ambolet-Camoit et al., 2010) and through a functional interaction between the AHR and FHL2 (Kollara and Brown, 2009). The AHR was also shown to be a regulator of c-raf and propose cross-talk between the AHR and the mitogen-activated protein kinase signaling pathway in chemically induced hepatocarcinogenesis (Borlak and Jenke, 2008). TCDD inhibits UV-C radiation-induced apoptosis in primary rat hepatocytes and Huh-7 human hepatoma cells, and this supports the hypothesis that TCDD acts as a tumor-promoter by preventing initiated cells from undergoing apoptosis (Chopra et al., 2009).

In rodents, TCDD may promote hepatocarcinogenesis by cytotoxicity, chronic inflammation, and liver regeneration and by hyperplastic and hypertrophic growth due to sustained activation of the AHR (Köhle et al., 2008). Species differences associated with AHR activation are supported by the divergence in the transcriptomic responses to TCDD in mouse, rat, and human liver (Boutros et al., 2008, 2009; Carlson et al., 2009; Kim et al., 2009), but it should be noted that these in vitro human hepatocyte studies may not reflect the in vivo response of human liver to TCDD. In vitro studies with transformed cell-line and primary hepatocytes cannot replicate the complexity of a tissue response that is important in eliciting the toxic responses observed in vivo (Dere et al., 2006).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

The isolated finding of a barely significant increase in mortality from biliary cancer in the intermediate-exposure zone at Seveso does not establish a consistent pattern of increased risk for biliary cancer. Despite the evidence of TCDD’s activity as a hepatocarcinogen in animals, the evidence from epidemiologic studies remains inadequate to link the chemicals of interest with hepatobiliary cancer, which has a relatively low incidence in Western populations.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and hepatobiliary cancer.

Pancreatic Cancer

The incidence of pancreatic cancer (ICD-9 157) increases with age. ACS estimated that 21,370 men and 21,770 women would receive a diagnosis of pancreatic cancer in the United States in 2010 and that 18,770 men and 18,030 women would die from it (Jemal et al., 2010). The incidence is higher in men than in women and higher in blacks than in whites. Other risk factors include family history, diet, and tobacco use; the incidence is about twice as high in smokers as in nonsmokers (Miller et al., 1996). Chronic pancreatitis, obesity, and type 2 diabetes are also associated with an increased risk of pancreatic cancer (ACS, 2006). The average annual incidence of pancreatic cancers is shown in Table 7-4.

Conclusions from VAO and Previous Updates

Update 2006 considered pancreatic cancer independently for the first time. Prior updates developed tables of results for pancreatic cancer but reached conclusions about the adequacy of the evidence of its association with herbicide exposure in the context of gastrointestinal tract cancers. The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the herbicides used by the US military in Vietnam and gastrointestinal tract tumors, including pancreatic cancer. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the chemicals of interest to sustain that negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

should be evaluated separately. Pancreatic cancer was thus reclassified into the default category of inadequate or insufficient evidence of an association. The Update 2006 committee reviewed the increased rates of pancreatic cancer in Australian National Service Vietnam veterans but concluded that the increased rates could be attributed to the rates of smoking in the cohort (ADVA, 2005c). The committee also noted the report of increased rates of pancreatic cancer in US female Vietnam nurse veterans (Dalager et al., 1995). That increase persisted in the follow-up study of the American female veterans (Cypel and Kang, 2008) considered in Update 2008, but the update on mortality in the Seveso population (Consonni et al., 2008) did not support an association with pancreatic cancer.

Table 7-9 summarizes the results of the relevant studies concerning pancreatic cancer.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies No studies of exposure to the chemicals of interest and pancreatic cancer in Vietnam veterans have been published since Update 2008.

Occupational Studies Collins et al. (2008, 2009a,b) published a series of papers on the mortality experience of workers employed in a Dow Chemical Company in Midland, Michigan, from 1937 to 1980. Serum dioxin was evaluated to estimate exposures to five dioxins in a group of 98 workers (Collins et al., 2008). Although the serum dioxin, furan, and PCB concentrations were measured many years after exposure, distinct patterns of dioxin congeners were found in workers who had different chlorophenol exposures. Collins et al. (2009b) described the mortality experience of 773 workers who were exposed to chlorinated dioxins in the production of PCP. Some 75% of the cohort have been followed for more than 27 years. SMRs were calculated to compare the PCP workers with the general US population and the population of the state of Michigan. There were five observed deaths from pancreatic cancer (SMR 1.1, 95% CI 0.3–2.5). In a companion paper, the authors examined 1,615 workers who had been exposed to TCP production (Collins et al., 2009a). The mean duration of follow-up was 36.4 years. Six deaths from pancreatic cancer were observed, for an SMR of 0.7 (95% CI 0.2–1.4).

McBride et al. (2009a,b) conducted an occupational mortality study of workers in the Dow AgroSciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD. Workers employed during the period from January 1969 to November 1988 (when 2,4,5-T was no longer produced at the work sites) were followed to the end of 2004, and SMRs were calculated by using national mortality figures. McBride et al. (2009a) found the SMR for pancreatic-cancer deaths was 0.3 (95% CI 0.13–3.39) in exposed workers and 0.0 (95% CI 0.0–4.9) in the never-exposed group. The results in McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-9 Selected Epidemiologic Studies—Pancreatic Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS
US CDC Vietnam Experience Study
Boehmer et al., 2004 Mortality (1965-2000)    
  Follow-up of CDC Vietnam Experience Cohort 5 1.0 (0.3-3.5)
US VA Mortality Study of Army and Marine Veterans—Ground troops serving July 4, 1965—March 1, 1973 All COIs
Breslin et al., 1988 Army Vietnam veterans 82 0.9 (0.6-1.2)
  Marine Vietnam veterans 18 1.6 (0.5-5.8)
US VA Cohort of Eemale Vietnam Veterans All COIs
Cypel and Kang, 2008 Mortality through 2004    
  US Vietnam veterans—women 17 2.1 (1.0-4.5)
  Vietnam-veteran nurses 14 2.5 (1.0-6.0)
Dalager et al., 1995 Mortality through 1991    
  US Vietnam veterans—women 7 2.8 (0.8-10.2)
  Vietnam-veteran nurses 7 5.7 (1.2-27.0)
Thomas et al., 1991 Mortality through 1987    
  US Vietnam veterans—women 5 2.7 (0.9-6.2)
State Studies of US Vietnam Veterans All COIs
Visintainer et al., 1995 PM study of deaths (1974-1989) of Michigan 14 1.0 (0.6-1.7)
  Vietnam-era veterans—deployed vs nondeployed    
  Non-black 9 0.7 (0.3-1.3)
  Black 5 9.1 (2.9-21.2)
Anderson et al., 1986 Wisconsin Vietnam veterans 4 nr
Australian Vietnam Veterans vs Australian Population All COIs
ADVA, 2005a Australian male Vietnam veterans vs Australian 86 1.2 (0.9-1.4)
  population—incidence    
  Navy 14 0.9 (0.5-1.5)
  Army 60 1.2 (0.9-1.5)
  Air Force 12 1.3 (0.7-2.3)
ADVA, 2005b Australian male Vietnam veterans vs Australian 101 1.2 (1.0-1.5)
  population—mortality    
  Navy 18 1.0 (0.6-1.6)
  Army 71 1.3 (1.0-1.6)
  Air Force 11 1.1 (0.5-1.8)
CDVA, 1997a Australian military Vietnam veterans 38 1.4 (0.9-1.8)
Australian Conscripted Army National Service (deployed vsnondeployed) All COIs
ADVA, 2005c Australian male conscripted Army National    
  Service Vietnam-era veterans: deployed vs nondeployed    
  Incidence 17 2.5 (1.0-6.3)
  Mortality 19 3.1 (1.3-8.3)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
CDVA, 1997b Australian National Service Vietnam veterans 6 1.5 (nr)
OCCUPATIONAL
IARC Phcnoxy Herbicide Cohort (mortality vs national mortality rates) Dioxin, phenoxy herbicides
Kogevinas et al., 1997 IARC cohort, male and female workers exposed
to any phenoxy herbicide or chlorophenol
47 0.9 (0.7-1.3)
  Exposed to highly chlorinated PCDDs 30 1.0 (0.7-1.4)
  Not exposed to highly chlorinated PCDDs 16 0.9 (0.5-1.4)
Saracci et al., 1991 IARC cohort—exposed subcohort (males.females) 26 1.1 (0.7-1.6)
NIOSH Mortality Cohort (12 US plants, production 1942-1984) (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Steenland et al., 1999 US chemical production workers 16 1.0 (0.6-1.6)
Fingerhul et al., 1991 NIOSH—entire cohort 10 0.8 (0.4-1.6)
  ≥ l-yr exposure, ≥ 20-yr latency 4 1.0 (0.3-2.5)
Dow Chemical Company—Midland. MI (included in IARC and NIOSH cohorts) Dioxin, Phenoxy
Herbicides
Collins et al., 2009a Trichlorophenol workers 6 0.7 (0.2-1.4)
Collins et al., 2009b Pentachlorophenol workers 5 1.1 (0.3-2.5)
Ramlow et al., 1996 Dow pentachlorophenol production workers    
  0-yr latency 2 0.7 (0.1-2.7)
  15-yr latency 2 0.9 (0.1-3.3)
Danish Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Lynge, 1985 Danish production workers—incidence    
  Men 3 0.6 (nr)
  Women 0 nr
Dutch Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Boers et al., 2010 Dutch chlorophenoxy workers    
  Factory A 4 0.9 (0.2-4.2)
  Factory B 1 nr
Hooiveld et al., 1998 Dutch chemical production workers 4 2.5 (0.7-6.3)
Bueno de Mesquita et al., 1993 Dutch phenoxy herbicide workers 3 2.2 (0.5-6.3)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
German Production Workers (included in I ARC cohort) Dioxin, Phenoxy
Herbicides
Becher et al., 1996 German production workers    
  Plant 1 2 0.6 (0.1-2.3)
  Plant II 0 nr
  Plant III 0 nr
  Plant IV 2 1.7 (0.2-6.1)
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort) Dioxin, Phenoxy
Herbicides
McBride et al., 2009a 1,599 production workers (male and female) vs
national rates—mortality 1969 through 2004
   
  Ever 3 1.3 (0.3-3.9)
  Never 0 0 (0.0-4.9)
't Mannetje et al., 2005 Phenoxy herbicide producers (men and women) 3 2.1 (0.4-6.1)
  Phenoxv herbicide spravers ( > 99% men) 0 0.0 (0.0-2.1)
United Kingdom Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Coggon et al., 1986 British MCPA production workers 9 0.7 (0.3-1.4)
Agricultural Health Study Herbicides
Andreotti et al., 2009 A1IS nested case—control (applicators and spouses combined)    
  2,4-D 48 0.9 (0.5-1.5)
  Dicamba 23 0.9 (0.6-1.6)
Alavanja et al., 2005 US AHS—incidence    
  Private applicators (men and women) 46 0.7 (0.5-1.0)
  Spouses of private applicators ( > 99%women) 20 0.9 (0.6-1.4)
  Commercial applicators (men and women) 3 1.1 (0.2-3.2)
Blair et al., 2005a US AHS    
  Private applicators (men and women) 29 0.6 (0.4-0.9)
  Spouses of private applicators ( > 99%women)   0.7 (0.3-1.2)
Other Agricultural Workers Herbicides
Gambini et al., 1997 Italian rice growers 7 0.9 (0.4-1.9)
Blair et al.,1993 US farmers in 23 states    
  White men 1,133 1.1 (1.1-1.2)
  White women 23 1.0 (0.6-1.5)
Ronco et al., 1992 Danish farm workers—incidence    
  Men—self-employed 137 0.6 (p < 0.05)
  employees 23 0.6 (p < 0.05)
  Women—self-employ ed 7 1.2 (nr)
  employees 4 1.3 (nr)
  family workers 27 0.7 (p <0.05)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Alavanja et al., 1988 USUA agricultural extension agenis 21 1.3 (0.8-1.9)
Wiklund, 1983 Swedish male and female agricultural   99% CI
  workers—incidence 777 0.8 (0.8-0.9)
Burmeisler,1981 Iowa farmers 416 1.1 (nr)
Other Studies of Herbicide and Pesticide Applicators Herbicides
Swaen et al., 2004 Dutch licensed herbicide applicators 5 1.2 (0.4-2.7)
Torchio et al., 1994 Italian licensed pesticide users 32 0.7 (0.5-1.0)
Swaen et al., 1992 Dutch licensed herbicide applicators 3 2.2 (0.4-6.4)
Blair et al., 1983 Honda pesticide applicators   Expected exposed cases
    4 4.0
Forestry Workers Herbicides
Alavanja et al., 1989 USDA forest, soil conservationists 22 1.5 (0.9-2.3)
Reif et al., 1989 New Zealand forestry workers—nested
case-control—incidence
6 1.8 (0.8-4.1)
Paper and Pulp Workers Dioxins
McLean et al., 2006 IARC cohort of pulp and paper workers    
  Exposure to nonvolatile organochlorine compounds    
  Never 67 0.8 (0.7-1.1)
  Ever 69 1.1 (0.9-1.4)
Rix et al., 1998 Danish paper-mill workers—incidence    
  Men 30 1.2 (0.8-1.7)
  Women 2 0.3 (0.0-1.1)
Henneberger et al., 1989 New Hampshire paper and pulp workers 9 1.9 (0.9-3.6)
Solei et al.,1989 US pulp and paper workers 1 0.4 (0.0-2.1)
Robinson et al., 1986 Northwestern US paper and pulp workers   90% CI
Other Occupational Studies
Magnani et al., 1987 UK case-control   Herbicides and chlorophenols
  Herbicides nr 0.7 (0.3-1.5)
  Chlorophenols nr 0.8 (0.5-1.4)
Thomas, 1987 US flavor and fragrance chemical plant workers 6 Dioxin, 2,4.5-T
      1.4 (nr)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
ENVIRONMENTAL
Seveso, Italy Residenlial Cohort
TCDD
Consonni et al., 2008 Seveso residents (men and women)—25-yr follow-up    
  Zone A 2 1.2 (0.3-4.7)
  Zone B 5 0.5 (0.2-1.1)
  Zone R 76 1.0 (0.7-1.7)
Pesatori et al., 2009 Seveso—20-yr follow-up to 1995—incidence    
  Zone A 1 1.2 (0.2-8.2)
  Zone B 3 0.6 (0.2-1.7)
  Zone R 38 1.0 (0.7-1.4)
Bertazzi 2001 Seveso residents—20-yr follow-up    
  Zones A, B—men 4 0.7 (0.3-1.9)
  women 1 0.3 (0.0-2.0)
Bertazzi et al., 1997 Seveso residents—15-yr follow-up    
  Zone A—men 1 1.9 (0.0-10.5)
  Zone B—men 2 0.6 (0.1-2.0)
  women 1 0.5 (0.0-3.1)
  Zone R—men 20 0.8 (0.5-1.2)
  women 11 0.7 (0.4-1.3)
Pesatori et al., 1992 Seveso residents—incidence    
  Zones A, B—men 2 1.0 (0.3-4.2)
  women 1 1.6 (0.2-12.0)
Bertazzi et al., 1989a Seveso residents—10-yr follow-up    
  Zones A, B, R—men 9 0.6 (0.3-1.2)
  women 4 1.0 (0.3-2.7)
Bertazzi et al., 1989b Seveso residents—10-yr follow-up    
  Zone B—men 2 1.1 (0.3-4.5)
Other Environmental Studies
Svensson et al., 1995 Swedish fishermen (men and women)—   Organochlorine
  mortality   compounds
  East coast 5 0.7 (0.2-1.6)
  West coast 33 0.8 (0.6-1.2)
Svensson et al., 1995 Swedish fishermen (men and women)—incidence    
  East coast 4 0.6 (0.2-1.6)
  West coast 37 1.0 (0.7-1.4)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PM, proportionate mortality; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; UK United Kingdom; USDA, US Department of Agriculture; VA, Department of Veterans Affairs.

aSubjects are male, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Andreotti et al. (2009) published a nested case–control study of pancreatic cancer in the AHS cohort. The analysis included 93 incident pancreatic-cancer cases—64 applicators (two female) and 29 spouses (all female)—and more than 82,000 controls. Applicators and their spouses had similar risks of pancreatic cancer, so risk estimates were shown for both combined. Exposure to 13 pesticides was examined, including two chemicals of interest: 2,4-D and dicamba. There were 48 cases of pancreatic cancer in the group exposed to 2,4-D (OR = 0.9, 95% CI 0.5–1.5) and 23 cases in the group exposed to dicamba (OR = 0.9, 95% CI 0.6–1.6); age, diabetes, and smoking were adjusted for. Results were also shown for intensity-weighted lifetime days of pesticide use and pancreatic-cancer risk. No statistically significant associations were seen for the two chemicals of interest.

Boers et al. (2010) published the third set of follow-up results of a retrospective cohort study of two Dutch chlorophenoxy herbicide manufacturing factories, producing mainly 2,4,5-T (factory A) and MCPA, MCPP, and 2,4-D (factory B). The cohort consisted of all persons who worked in either of the two factories during 1955–1985 (factory A) or 1965–1986 (factory B). No increases in pancreatic-cancer deaths were observed. The hazard ratio (HR) in factory A was 0.86 (95% CI 0.18–4.19). One case of pancreatic cancer was observed in factory B in exposed workers and none in controls.

Environmental Studies Pancreatic-cancer cases were reported in the cancer-incidence study of the population (males and females combined) exposed to dioxin after the Seveso accident in 1976 (Pesatori et al., 2009). One pancreatic-cancer case was observed in Zone A (high exposure) (RR = 1.15, 95% CI 0.16– 8.19), 3 in Zone B (medium exposure) (RR = 0.56, 95% CI 0.18–1.74), and 38 in Zone R (low exposure) (RR = 0.99, 95% CI 0.70–1.40).

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the chemicals of interest on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of pancreatic cancer in laboratory animals after the administration of cacodylic acid, 2,4-D, or picloram has been reported. A 2-year study of female rats has reported increased incidences of pancreatic adenomas and carcinomas after treatment at the highest dose of TCDD (100 ng/kg per day) (Nyska et al., 2004). Other studies have observed chronic active inflammation, acinar-cell vacuolation, and an increase in proliferation of the acinar cells surrounding the vacuolated cells (Yoshizawa et al., 2005b). As previously discussed, both chronic inflammation and hyperproliferation are closely linked to the formation and progression of cancers, including that of the pancreas (Hahn and Weinberg, 2002; Mantovani et al., 2008). Metaplastic changes in the pancreatic ducts were also observed in female monkeys treated with TCDD (Allen et al., 1977).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

The large excess of pancreatic cancers in female Vietnam veterans vs their nondeployed counterparts observed by Thomas et al. (1991) and Dalager et al. (1995) prevailed in a study by Cypel and Kang (2008), who found a significant increase in all female Vietnam veterans and in the nurse subset. The committee responsible for Update 2006 reported a higher incidence of and mortality from pancreatic cancer in deployed Australian National Service veterans than in nondeployed veterans (ADVA, 2005c). A limitation of all the veteran studies considered has been the lack of control for the effect of smoking. For the 31 female and 62 male cases in the AHS case–control study considered in the present update (Andreotti et al., 2009), however, the risk of pancreatic cancer was not associated with 2,4-D exposure. No increase in risk has been reported in US male Vietnam veterans or in IARC follow-up studies.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and pancreatic cancer.

LARYNGEAL CANCER

ACS estimated that 10,110 men and 2,610 women would receive diagnoses of cancer of the larynx (ICD-9 161) in the United States in 2010 and that 2,870 men and 730 women would die from it (Jemal et al., 2010). Those numbers constitute a little more than 0.9% of new cancer diagnoses and 0.7% of cancer deaths. The incidence of cancer of the larynx increases with age, and it is more common in men than in women, with a sex ratio in the United States of about 4:1 in people 50–64 years old. The average annual incidence of laryngeal cancer is shown in Table 7-10.

Established risk factors for laryngeal cancer are tobacco use and alcohol use, which are independent and act synergistically. Occupational exposures—long and intense exposures to wood dust, paint fumes, and some chemicals used in the metalworking, petroleum, plastics, and textile industries—also could increase risk (ACS, 2007b). An Institute of Medicine committee concluded that asbestos is a causal factor in laryngeal cancer (IOM, 2006); infection with human papilloma virus is also thought to raise the risk of laryngeal cancer (Baumann et al., 2009; Hobbs and Birchall, 2004).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-10 Average Annual Incidence (per 100,000) of Laryngeal Cancer in United Statesa

55-59 Years Old 60-64 Years Old 65-69 Years Old
All Races While Black All Races While Black All Races While Black
Men 13.0 12.0 2.9 27.1 18.9 17.8 4.1 40. 26.8
Women 3.0 26.4 6.2 6.1 51.2 12.4 4.0 16.3 6.2

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2004–2008 (NCI, 2010).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest and laryngeal cancer on the basis of the evidence discussed below in the section “Synthesis.” Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion.

Table 7-11 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

No Vietnam-veteran studies addressing exposure to the chemicals of interest and laryngeal cancer have been published since Update 2008.

Occupational Studies

Collins et al. (2009a) reported on the mortality experience through 2003 of a group of workers in the Midland, Michigan, Dow Chemical plant previously included in analyses of the NIOSH mortality cohort, as reported by Fingerhut et al. (1991) and added to the expanded IARC phenoxy herbicide cohort (Kogevinas et al., 1997). In the updated analysis completed by Dow-employed epidemiologists, three laryngeal-cancer deaths were reported, and this led to estimated nonsignificant SMRs of 1.3 (95% CI 0.3–3.9) in all TCP workers and 1.5 (95% CI 0.3–4.4) when 196 workers who had some PCP exposure were excluded. As pointed out in follow-up correspondence (Collins et al., 2010; Villeneuve and Steenland, 2010), different latency models, different dose–response models, and in-depth analysis of serum exposure concentrations could alter some of the results reported in the analysis, but there were only three deaths from laryngeal cancer, so these issues are unlikely to affect the laryngeal-cancer risk estimates appreciably.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-11 Selected Epidemiologic Studies—Laryngeal Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS    
US Air Force Health Study—Ranch Hand veterans vs SEA veterans   All COIs
AFHS, 2000 AFHS veterans—incidence    
  Oral cavity, pharynx, larynx 4 0.6 (0.2-2.4)
US CDC Vietnam Experience Study   All COIs
Boehmer et al., 2004 CDC Vietnam Experience Cohort 0 0.0 (nr)
US VA Mortality Study of Army and Marine Veterans (ground troops serving July 4.1965-March 1,1973)   All COIs
Watanabe and Kang. 1996 Army Vietnam veterans compared with US men (follow-up through 1988) 50 1.3 (nr)
  Marine Vietnam veterans 4 0.7 (nr)
  Army Vietnam veterans 50 1.4 (p < 0.05)
Australian Vietnam Veterans vs Australian Population   All COIs
ADVA, 2005a Australian Vietnam veterans vs Australian 97 1.5 (1.2-1.8)
  population—incidence    
  Navy 21 1.5 (0.9-2.1)
  Army 69 1.6 (1.2-1.9)
  Air Force 7 0.8 (0.3-1.7)
ADVA, 2005b Australian Vietnam veterans vs Australian 28 1.1 (0.7-1.5)
  population—mortality    
  Navy 6 1.1 (0.4-2.4)
  Army 19 1.1 (0.7-1.7)
  Air Force 3 0.9 (0.2-2.5)
CDVA, 1997a Australian military Vietnam veterans 12 1.3 (0.7-2.2)
Australian Conscripted Army National Service (deployed vs All COIsnon deployed)   All COLs
ADVA, 2005c Australian men conscripted Army National    
  Service Vietnam-era veterans: deployed vs nondeployed    
  Incidence 8 0.7 (0.2-1.6)
  Mortality 2 0.4 (0.0-2.4)
CDVA, 1997b Australian National Service Vietnam veterans 0 0 (0- >10)
OCCUPATIONAL    
IARC Phenoxy Herbicide Cohort (mortality vs national mortality rates)   Dioxin, phenoxy herbicides
Kogevinas et al., 1997 IARC cohort, male and female workers exposed
to any phenoxy herbicide or chlorophenol
21 1.6 (1.0-2.5)
  Exposed to highly chlorinated PCDDs 15 1.7 (1.0-2.8)
  Not exposed to highly chlorinated PCDDs 5 1.2 (0.4-2.9)
Saracci et al., 1991 IARC cohort (men and women)—exposed subcohort 8 1.5 (0.6-2.9)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
NIOSH Mortality Cohort (12 US plants, production 1942–1984) (included in IARC cohort)   Dioxin, phenoxy herbicides
Fingerhut et al., 1991 NIOSH—entire cohort 7 2.1 (0.8-4.3)
  ≥1-yr exposure, ≥ 20-yr latency 3 2.7 (0.6-7.8)
Dow Chemical Company—Midland. MI (included in IARC and NOISH cohorts)   Dioxin, phenoxy herbicides
Collins et al., 2009a Trichlorophenol workers 3 1.3 (0.3-3.9)
Collins et al., 2009b Pentachlorophenol workers 2 1.7 (0.2-6.2)
Ramlow et al., 2009b Dow pentachlorophenol production workers 2 2.9 (0.3-10.3)
  0-yr latency 2 2.9 (0.4-10.3)
  15-yr latency 1 nr
Bond et al.,1988 Dow 2,4-D production workers 1 3.0 (0.0-16.8)
German Production Workers (included in I ARC cohort)   Dioxin. phenoxy herbicides
Manz et al., 1991 German production workers—men, women 2 2.0 (0.2-7.1)
New Zealand Production Workers—Dow plant in Plymouth.NZ (included in IARC cohort)   Dioxin, phenoxy herbicides
McBride et al., 2009a 1,599 production workers (male and female) vs 1 2.5 (0.1-14.0)
’t Mannetje et al., 2005 New Zealand phenoxy herbicide producers, sprayers—mortality    
  Phenoxy herbicide producers (men and women) 0 nr
  Phenoxy herbicide sprayers ( > 99% men) 0 nr
United Kingdom Production Workers (included in IARC cohort)    
Coggon et al., 1986 British MCPA production workers 4 1.7 (0.5-4.5)
Herbicide and Pesticide Applicators   Herbicides
Swaen et al., 2004 Dutch licensed herbicide applicators 1 1.0 (0.0-5.1)
Torchio et al., 1994 Italian farmers licensed to use pesticides 25 0.5 (0.3-0.7)
Agricultural Workers   Herbicides
Gambini et al.,1997 Italian rice growers 7 0.9 (0.4-1.9)
Blair et al., 1993 US farmers in 23 states    
  White men 162 0.7 (0.6-0.8)
  White women 0 nr (0.0-3.3)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Forestry Workers   Herbicides
Thörn et al., 2000 Swedish lumberjacks exposed to phenoxyacetic herbicides    
  Foremen incidence 0 nr
Reif et al., 1989 New Zealand forestry workers—nested 2 1.1 (0.3-4.7)
Paper and Pulp Workers   Dioxins
McLean et al., 2006 IARC cohort of pulp and paper workers    
  Exposure to nonvolatile organochlorine chemicals    
  Never 18 0.9 (0.5-1.5)
  Ever 20 1.2 (0.8-1.9)
ENVIRONMENTAL    
Seveso, Italy Residential Cohort   TCDD
Consonni et al., 2008 Seveso residents (men and women)—25-yrfollow-up—all respiratory cancers (ICD-9 160—165) excluding reported lung cancers (ICD-9 162)    
  Zone A 0 nr
  Zone B ≤ 8 nr
  Zone R ≤ 49 nr
Bertazzi et al., 2001 Seveso residents (men and women)—20-yrfollow-up—all respiratory cancers (ICD-9 160—165) excluding reported lung cancers (ICD-9 162)    
  Zone A 0 nr
  Zone B 8 nr
Bertazzi et al., 1998 Seveso residents—15-yr follow-up—allrespiratory cancers (ICD-9 160—165) excluding reported lung cancers (ICD-9 162)    
  Zone B—men 6 nr
  women 0 nr
  Zone R—males 32 nr
  women 6 nr
Chapaevsk, Russia   Dixin
Revich et al., 2001 Residents of Chapaevsk, Russia    
  Men 13 2.3 (1.2-3.8)
  Wowen 1 0.1 (0.0-0.6)

ABBREVIATIONS: AFHS, Air Force Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VA, US Department of Veterans Affairs.

aSubjects are male, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×



Collins et al. (2009b) also reported on mortality in 773 Dow employees in Midland who were exposed to dioxins in the manufacture of PCP. They reported an estimated nonsignificant excess of laryngeal cancer with an SMR of 1.7 (95% CI 0.2–6.2) or, when they excluded 196 workers who had TCP exposure, 2.2 (95% CI 0.3–8.1). Again, those estimates were based on only two deaths from laryngeal cancer, so the study did not have sufficient power to support a strong inference on causality.

McBride et al. (2009a,b) studied mortality through 2004 in 1,599 Dow employees of an agricultural manufacturing plant in New Zealand that produced phenoxy herbicides and picloram. The cohort also was included in the original IARC Cohort of Phenoxy Herbicide Workers (Saracci et al., 1991). There were crude exposure estimates in this study and only one death from laryngeal cancer. When mortality from laryngeal cancer in ever-exposed workers was compared with New Zealand national death rates, the SMR was a nonsignificant 2.5 (0.1– 14.0). The study was too small to be useful for establishing an etiologic role of the chemicals of interest. The results in McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Environmental Studies

Turunen et al. (2008) studied fishermen’s health in Finland, including in their assessment of mortality exposure to dioxins and PCBs by using assessment of serum and adipose tissue from a set of the study participants. They reported a deficit of laryngeal, tracheal, and lung cancers. It is difficult to interpret those results given the small numbers and the unknown effects of the diet high in fish that was probably consumed by the subjects.

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the chemicals of interest on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of laryngeal cancer in laboratory animals after the administration of any of the chemicals of interest has been reported.

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

The original VAO committee reviewed five studies that presented data separately for laryngeal cancer (Bond et al., 1988; Coggon et al., 1986; Fingerhut et al., 1991; Manz et al., 1991; Sarracci et al., 1991). That committee concluded

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

that “although the numbers are too small to draw strong conclusions, the consistency of a mild elevation in relative risk is suggestive of an association for laryn-geal cancer.” The original VAO committee also noted that the studies reviewed for laryngeal cancer did not control for potential confounders, such as smoking and alcohol consumption (IOM, 1994).

Since then, a combined analysis of many of the separate cohorts has been conducted (the IARC Cohort of Phenoxy Herbicide Workers analyzed by Kogevinas et al., 1997) and has shown significant effects in workers exposed to any phenoxyacetic acid herbicide or chlorophenol (RR = 1.6, 95% CI 1.0–2.5; 21 deaths), especially workers exposed to TCDD (or higher-chlorinated dioxins) (RR = 1.7, 95% CI 1.0–2.8; 15 deaths). Those RRs are remarkably close to the pooled estimate computed by the committee responsible for VAO. The study by Kogevinas et al. was a high-quality study that used an excellent method for assessing exposure, and its results were unlikely to have been affected by confounding, because the distribution of smoking in working cohorts is not likely to differ with degree of exposure (Siemiatycki et al., 1988). Another IARC cohort that was used in studying pulp and paper workers also showed an increase in risk (RR = 1.2, 95% CI 0.8–1.9; 20 deaths; McLean et al., 2006).

With regard to veteran studies, a positive association was found in the study of veterans in Australia that compared mortality from laryngeal cancer with that in the general population (ADVA, 2005a) but not in the study that compared Australian veterans of the Vietnam conflict with nondeployed soldiers (ADVA, 2005c). In contrast, Watanabe and Kang (1996) found a significant 40% excess of mortality from laryngeal cancer in Army personnel deployed to the Vietnam theater. The Ranch Hand study is not large enough to have sufficient power to detect an association if one exists.

An environmental study (Revich et al., 2001) of residents of Chapaevsk, Russia, which was heavily contaminated by many industrial pollutants, including dioxin, showed an association with laryngeal cancer in men (RR = 2.3, 95% CI 1.2–3.8).

The committee for Update 2008 extensively reviewed and discussed the literature as part of its reassessment of all health outcomes. The additional data reviewed for the present update (the updated mortality study of Dow chemical workers) are largely consistent with the prior work, reporting a nonsignificant excess of laryngeal cancer. Although some 10% of laryngeal cancers now being diagnosed are associated with HPV, the small fraction is unlikely to have a substantial effect on studies over time.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one chemical of interest and laryngeal cancer.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

LUNG CANCER

Lung cancer (carcinoma of the lung or bronchus, ICD-9 162.2–162.9) is the leading cause of cancer death in the United States. ACS estimated that 116,750 men and 105,770 women would receive diagnoses of lung cancer in the United States in 2010 and that about 86,220 men and 71,080 women would die from it (Jemal et al., 2010). Those numbers represent roughly 15% of new cancer diagnoses and 28% of cancer deaths in 2010. The principal types of lung neoplasms are identified collectively as bronchogenic carcinoma and carcinoma of the lung. Cancer of the trachea (ICD-9 162) is often grouped with cancer of the lung and bronchus under ICD-9 162. The lung is also a common site of metastatic tumors.

In men and women, the incidence of lung cancer increases greatly beginning at about the age of 40 years. The incidence in people 50–54 years old is double that in people 45–49 years old, and it doubles again in those 55–59 years old. The incidence is consistently higher in black men than in women or white men. The average annual incidence of lung cancer in the United States is shown in Table 7-12.

ACS estimates that 87% of lung-cancer deaths are attributable to cigarette-smoking (ACS, 2011a). Smoking increases the risk of all histologic types of lung cancer, but the associations with squamouscell and small-cell carcinomas are strongest. Other risk factors include exposure to asbestos, uranium, vinyl chloride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, diesel exhaust, and inorganic arsenic. The latter statement does not imply that cacodylic acid, which is a metabolite of inorganic arsenic, can be assumed to be a risk factor. Important environmental risk factors include exposure to tobacco smoke and radon (ACS, 2007c).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to at least one chemical of interest and lung cancer on the basis of the evidence discussed below in the section “Synthesis.” Additional information available to the committees responsible

TABLE 7-12 Average Annual Incidence (per 100,000) of Lung and Bronchial Cancer in United Statesa

55-59 Years Old 60-64 Years Old 65-69 Years Old
All Races While Black All Races While Black All Races While Black
Men 101.8 95.1 179.8 182.0 175.1 299.8 308.5 301.4 475.4
Women 75.2 75.5 98.1 144.8 150.6 163.3 230.3 242.1 248.3

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2004–2008 (NCI, 2010).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×



for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion.

Table 7-13 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

The mortality experience of the ACC veterans, who were responsible for handling and spraying herbicides around the perimeters of military base camps in Vietnam, was updated through 2005 by Cypel and Kang (2010). Vital status (through 1991) had last been reported in 1997 (Dalager and Kang, 1997). The new analysis abstracted records from some 18,000 Army personnel with chemical operations experience to create cohorts that had Vietnam experience (2,872) and did not have Vietnam experience (2,737). There were 593 deaths in the Vietnam cohort and 355 in the non-Vietnam cohort. It classified lung cancer with all cancers of the “respiratory system.” There were 60 observed respiratory-cancer deaths in the Vietnam group and 26 in the non-Vietnam group, for a crude rate ratio of 2.22 and an adjusted relative risk of 1.29 (95% CI 0.79–2.10) for respiratory cancer. Compared with those in the US male population, the SMRs for respiratory cancers were significantly higher at 1.35 (95% CI 1.03–1.73) in the Vietnam cohort and 1.01 (95% CI 0.66–1.48) in the non-Vietnam veterans. The study did not have data on tobacco use, but questionnaire responses collected in 1999–2000 from a subset of ACC veterans who had documented exposure to herbicides used in theater showed that adjustment for the patterns of cigarette use did not affect their higher risk estimates for respiratory disease. The follow-up is long enough to allow for extended latency and to account for selection of healthy soldiers to apply these agents.

Occupational Studies

In an updated analysis of the mortality experience of a group of workers in the Midland, Michigan, Dow chemical plant previously studied by NIOSH as part of data reported in 1991 (Fingerhut et al., 1991), Collins et al. (2009a) found no excess lung cancer in 1,615 workers exposed to dioxin in TCP production. There were 46 deaths attributable to bronchial, lung, and tracheal cancers (SMR = 0.7, 95% CI 0.5–0.9) in all TCP workers and 41 deaths (SMR = 0.7, 95% CI 0.5–1.0) when 196 workers who had some PCP exposure were excluded. As pointed out in follow-up correspondence (Collins et al., 2010; Villeneuve and Steenland, 2010), different latency models, different dose–response models, and in-depth analysis of the serum exposure concentrations might alter some of the results reported.

Collins et al. (2009b) also reported on mortality in 773 Dow employees in Midland, Michigan, who were exposed to dioxins in the manufacture of PCP.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-13 Selected Epidemiologic Studies—Lung and Bronchus Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans All COIs
Pavuk et al., 2005 Comparison subjects only from AFHS
(respiratory system)—incidence
Serum TCDD (pg/g) based on model with exposure variable loge (TCDD)
   
  Per unit increase of -loge(TCDD) (pg/g) 36 1.7 (0.9-3.2)
  Quartiles (pg/g)    
  0.4-2.6 6 1.0 (nr)
  2.6-3.8 8 1.1 (0.3-3.4)
  3.8-5.2 9 1.2 (0.4-3.5)
  > 5.2 13 1.9 (0.7-5.5)
  Number of years served in SEA    
  Per year of service 36 1.1 (0.9-1.2)
  Quartiles (years in SEA)    
  0.8-1.3 8 1.0 (nr)
  1.3-2.1 4 0.5 (0.2-1.8)
  2.1-3.7 11 0.7 (0.3-2.0)
  3.7-16.4 13 0.7 (0.3-2.0)
Akhtar et al., 2004 White AFHS subjects vs national rates    
  (respiratory system)    
  Ranch Hand veterans    
  Incidence 33 1.1 (0.8-1.6)
  With tours between 1966-1970 26 1.1 (0.7-1.6)
  Mortality 21 0.9 (0.6-1.3)
  Comparison veterans    
  Incidence 48 1.2 (0.9-1.6)
  With tours 1966-1970 37 1.2 (0.9-1.6)
  Mortality 38 1.1 (0.8-1.5)
AFHS, 2000 Ranch Hand veterans from AFHS (lung and bronchus)—incidence 10 3.7 (0.8-17.1)
US VA Cohort of Armv Chemical Corns All COIs
Cypel and Kang, 2010 ACC—deployed vs nondeployed and vs US    
  men (Vietnam-service status through 2005)
Respiratory system
   
  Deployed vs nondeployed 60 vs 26 1.3 (0.8-2.1)
  ACC vs US men    
  ACC Vietnam Cohort 60 1.4 (1.0-1.7)
  Non-Vietnam Cohort (no service in SEA) 26 1.0 (0.7-1.5)
Dalager and Kang, 1997 ACC veterans (respiratory system)—mortality 11 1.4 (0.4-5.4)
US CDC Vietnam Experience Study All COIs
Boehmer et al., 2004 Follow-up of CDC Vietnam Experience Cohort(trachea, bronchus, and lung) 41 1.0 (0.6-1.5)
  Low pay grade at time of discharge nr 1.6 (0.9-3.0)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
US VA Marine Post Service Mortality Study (all Marines active 1967–1969) All COIs
Watanabe and Kang, 1995 Marine Vietnam service vs non-Vietnam (lung) 42 1.3 (0.8-2.1)
US VA Mortality Study of Army and Marine Veterans (Ground troopsserving July 4.1965-March 1,1973) All COIs
Watanabe and Kang, 1996 US Army and Marine Corps Vietnam veterans
(lung)—mortality
   
  Army Vietnam service 1,139 1.1 (nr)(p < 0.05)
  Non-Vietnam 1,141 1.1 (nr)(p < 0.05)
  Non-Vietnam 77 0.9 (nr)
US VA Cohort of Female Vietnam Veterans All COIs
Cypel and Kang, 2008 US Vietnam veterans—women (lung) 50 1.0 (0.7-1.4)
  Vietnam veteran nurses 35 0.8 (0.5-1.2)
Australian Vietnam Veterans vs Australian General Population All COIs
ADVA, 2005a Australian male Vietnam veterans vs 576 1.2 (1.1-1.3)
  Australian population—incidence    
Branch of service Navy 141 1.4 (1.2-1.7)
  Army 372 1.2 (1.1-1.3)
  Air Force 63 1.0 (0.7-1.2)
  Histologic type—all service branches combined    
  Adenocarcinoma 188 1.5 (1.2-1.7)
  Squamous 152 1.2 (1.0-1.4)
  Small-cell 87 1.2 (0.97-1.5)
  Iarge-cell 79 1.1 (0.8-1.3)
  Other 70 1.1 (0.8-1.3)
ADVA, 2005b Australian male Vietnam veterans vs 544 1.2 (1.1-1.3)
  Australian population—mortality
Branch of service
   
  Navy 135 1.4 (1.2-1.6)
  Army 339 1.1 (1.0-1.3)
  Air Force 71 1.1 (0.9-1.4)
AIHW, 1999 Australian Vietnam veterans—(lung cancer)—incidence (validation study)   Expected number of exposed cases (95% CI)
    46 65 (49-81)
CDVA,1998a Australian Vietnam veterans (lung)—incidence 120 65 (49-89)
CDVA, 1997a Australian Vietnam veterans    
  Lung(ICD-9 162) 212 1.3 (1.1-1.4)
  Respiratory systems (ICD-9 163-165) 13 1.8 (1.0-3.0)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Australian Conscripted Army National Service (deployed vs ememployed) All COls
ADVA, 2005c Australian male conscripted Army National
Service Vietnam-era veterans: deployed vs nondeployed
   
  Incidence (1982-2000) 78 1.2 (1.0-1.5)
  Histologic type    
  Adenocarcinoma 27 1.4 (0.8-1.9)
  Squamous 19 1.5 (0.9-2.3)
  Small-cell 14 1.4 (0.8-2.4)
  Large-cell 8 0.7 (0.3-1.3)
  Other 10 1.2 (0.6-2.2)
  Mortality (1966-2001) 67 1.8 (1.2-2.7)
CDVA, 1997b Australian National Service Vietnam veterans (lung)—mortality 27 2.2 (1.1-4.3)
State Studies of US Vietnam Veterans All COIs
Mahan et al., 1997 Case—control of Vietnam-era Vietnam veterans 134 1.4 (1.0-1.9)
  (lung)—incidence    
Visintainer et al., 1995 PM study of deaths (1974-1989) of Michigan 80 0.9 (0.7-1.1)
  Vietnam-era veterans—deployed vs nondeployed (lung)    
OCCUPATIONAL
IARC Phenoxy Herbicide Cohort (mortality vs national mortalityrates)
Dioxin, Phenoxy
Herbicides
Kogevinas et al., 1997 IARC cohort, male and female workers
exposed to any phenoxy herbicide or chlorophenol
   
  Lung(ICD-9 162) 380 1.1 (1.0-1.2)
  Other respiratory organs (ICD-9 163-165) 12 2.3 (1.2-3.9)
  Kxposed to highly chlorinated PCDDs    
  Lung (ICD-9 162) 225 1.1 (1.0-1.3)
  Other respiratory organs (ICD-9 163-165)
Not exposed to highly chlorinated PCDDs
9 3.2 (1.5-6.1)
  Lung (ICD-9 162) 148 1.0 (0.9-1.2)
  Other respiratory organs (ICD-9 163-165) 3 1.2 (0.3-3.6)
Saracci et al., 1991 IARC cohort, men, women—mortality    
  Trachea, bronchus, lung 173 1.0 (0.9-1.2)
NIOSH Mortality Cohort (12 US plants, production 1942-1984) Dioxin, Phenoxy
Herbicides
Steenland et al., 1999 US chemical production workers—-mortality    
  Lung 125 1.1 (0.9-1.3)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Fingerhut et al., 1991 NIOSH workers exposed to TCDD—mortality
Entire cohort
   
  Trachea, bronchus, lung (1CD-9 162) 89 1.1 (0.9-1.4)
  Respiratory system (ICD-9 160-165) 96 1.1 (0.9-1.4)
  ≥ 1-yr exposure, ≥ 20-yr latency    
  Trachea, bronchus, lung (ICD-9 162) 40 1.4 (1.0-1.9)
  Respiratory system (ICD-9 160-165) 43 1.4 (1.0-1.9)
Dow Production Workers—Midland. MI (included in IARC and NIOSH cohorts) Dioxin, phenoxy herbicides
Collins et al., 2009a Trichlorophenol workers    
  Cancers of the bronchus, trachea, and lung 46 0.7 (0.5-0.9)
Collins et al., 2009b Pentachlorophenol workers    
  Cancers of the bronchus, trachea, and lung 30 1.0 (0.6-1.4)
Bodner et al., 2003 Dow chemical production workers—mortality    
  Lung 54 0.8 (0.6-1.1)
Burns et al., 2001 Dow 2,4-D production workers—mortality    
  Respiratory system (ICD-8 160-163) 1 0.9 (0.6-1.3)
Ramlow et al., 1996 Dow pentachlorophenol production    
  workers—mortality
0-yr latency
   
  Respiratory system (ICD-8 160-163) 18 1.0 (0.6-1.5)
  Lung (ICD-8 162) 16 0.9 (0.5-1.5)
  Respiratory system (ICD-8 160-163) 17 1.1 (0.6-1.8)
  Lung (ICD-8 162) 16 1.1 (0.6-1.8)
Bloemen et al., 1993 Dow 2,4-D production workers    
  Respiratory system (ICD-8 162-163) 9 0.8 (0.4-1.5)
Bond et al., 1988 Dow 2,4-D production workers—mortality    
  Lung (ICD-8 162-163) 8 1.0 (0.5-2.0)
  Low cumulative exposure   0.7 nr
  Medium cumulative exposure 2 1.0 (nr)
  High cumulative exposure 5 1.7 (m)
BASF Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Ott and Zober, 1996 BASF employees—incidence
Respiratory system
13 1.2 (0.6-2.0)
  TCDD 0.1-0.99 µg/kg of body weight 2 0.7 (0.1-2.5)
  TCDD ≥ 1 µg/kg of body weight 8 2.0 (0.9-3.9)
  Lung, bronchus 11 1.1 (0.6-2.0)
  TCDD 0.1-0.99 µg/kg of body weight 2 0.8 (0.1-2.8)
  TCDD ≥ 1 µg/kg of body weight 8 2.2 (1.0-4.3)
Zober et al., 1990 BASF employees—incidence   90% CI
  Trachea, bronchus, lung 4 2.0 (0.7-4.6)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Danish Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Lynge, 1993 Danish production workers—incidence (2 of original 4 plant)    
  Lung 13 1.6 (0.9-2.8)
Lynge, 1985 Danish production workers—incidence (all 4 plants)
Lung
   
  Men 38 1.2 (nr)
  Women 6 2.2 (nr)
Dutch Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Boers et al., 2010 Dutch chlorophenoxy workers    
  Factory A    
  Respiratory cancer 21 1.1 (0.5-2.5)
  Trachea, lung, bronchus cancers 20 1.2 (0.5-2.8)
  Factory B    
  Respiratory cancer 12 1.2 (0.6-2.7)
  Trachea, lung, bronchus cancers 12 1.2 (0.6-2.7)
Bueno de Mcsquita et al., 1993 Dutch phenoxy herbicide workers—mortality    
  Trachea, bronchus, lung (ICD-8 162) 9 0.8 (0.4-1.5)
  Respiratory system (ICD-8 160-163) 9 1.7 (0.5-6.3)
German Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Becher et al.,1996 German production workers—lung 47 1.4 (1.1-1.9)
Manz et al., 1991 German production workers—mortality    
  Lung 26 1.7 (1.1-2.4)
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Mc Bride et al., 2009a 1,599 production workers (male and female) vs
national rates—mortality 1969 through 2004
   
  Respiratory cancer 13 0.9 (0.5-1.6)
  Trachea, bronchus, and lung 11 0.8 (0.4-1.5)
’t Mannetje et al., 2005 New Zealand phenoxy herbicide
workers—mortality Producers (men and women)
   
  Trachea, bronchus, lung (1CD-9 162) 12 1.4 (0.7-2.4)
  Other respiratory system sites (ICD-9163-165) 1 3.9 (0.1-21.5)
  Sprayers ( > 99% men)    
  Trachea, bronchus. lung (ICD-9 162) 5 0.5 (0.2-1.1)
  Other respiratory system sites (ICD-9163-165) 1 2.5 (0.1-13.7)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
United Kingdom Production Workers (included in IARC cohort) Dioxin, Phenoxy
Herbicides
Coggon et al., 1991 British phenoxy herbicide workers—mortality    
Coggon et al., 1986 Lung 19 1.3 (0.8-2.1)
  Workers with exposure above background 14 1.2 (0.7-2.1)
Coggon et al., 1986 British MCPA production workers—mortality    
  Lung, pleura, mediastinum (ICD-8 162—164) 117 1.2 (1.0-1.4)
  Background exposure 39 1.0 (0.7-1.4)
  Low-grade exposure 35 1.1 (0.8-1.6)
  High-grade exposure 43 1.3 (1.0-1.8)
Agricultural Health Study Herbicides
Samanic et al., 2006 Pesticide applicators in AHS—lung-cancer
incidence from enrollment through 2002
Dicamba—lifetime days exposure
   
  None 95 1.0
  1–<20 14 0.8 (0.5-1.5)
  20–<56 11 0.6 (0.3-1.3)
  56–< 116 12 1.0 (0.5-1.9)
  ≥ 116 15 1.5 (0.8-2.7)
p-trend = 0.13
Alavanja et al., 2005 US AHS—incidence    
  Private applicators (men and women)
Lung
266 0.5 (0.4-0.5)
  Respiratory system 294 0.5 (0.4-0.5)
  Spouses of private applicators ( > 99% women)    
  Lung 68 0.4 (0.3-0.5)
  Respiratory system 71 0.4 (0.3-0.5)
  Commercial applicators (men and women)    
  Lung 12 0.6 (0.3-1.0)
  Respiratory system 14 0.6 (0.3-1.0)
Blair et al., 2005a US AHS (lung)—mortality    
  Private applicators (men and women) 129 0.4 (0.3-0.4)
  ≤ 10 years 25 0.4 (nr)(p < 0.05)
  > 10 years 80 0.3 (nr)(p < 0.05)
  Spouses of private applicators ( > 99% women) 29 0.3 (0.2-0.5)
Other Agricultural Workers
Herbicides
Hansen et al.,2007 Danish gardeners (nasal, laryngeal, lung, and
bronchus. ICD-7 160-165)—incidence
   
  10-yr follow-up (1975-1954) reported in Hansen et al. (1992) 41 1.0 (0.7-1.3)
  25-yr follow-up (1975-2001)    
  Born before 1915 (high exposure) 34 0.9 (0.6-1.3)
  Born 1915-1934 (medium exposure) 72 1.0 (0.8-1.2)
  Born after 1934 (low exposure) 8 0.8 (0.4-1.7)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Gambini et al., 1997 Italian rice growers—mortality    
  Ling 45 0.8 (0.6-1.1)
  Pleura 2 2.2 (0.2-7.9)
Torchio et al.,1994 Italian licensed pesticide users—mortality    
  Lung 155 0.5 (0.4-0.5)
Blair et al., 1993 US farmers in 23 states (lung)—mortality    
  While men 6,473 0.9 (0.9-0.9)
  White women 57 0.8 (0.6-1.1)
Dutch Licensed Herbicide Applicators Herbicides
Swaen et al.,2004 Dutch licensed herbicide applicators (trachea, and lung)—mortality 27 0.7 (0.5-1.0)
Swaen et al.,1992 Dutch herbicide applicators—mortality    
  Trachea and lung 12 1.1 (0.6-1.9)
Other Studies of Herbicide and Pesticide Applicators Herbicides
Asp et al.,1994 Finnish herbicide applicators, 1972-1989
Incidence
   
  Trachea, bronchus, lung (ICD-8 162) 39 0.9 (0.7-1.3)
  Other respiratory (ICD-8 160, 161, 163) 4 1.1 (0.7-1.3)
  Trachea, bronchus, lung (ICD-8 162) 37 1.0 (0.7-1.4)
  Other respiratory (ICD-8 160, 161, 163) 1 0.5 (0.0-2.9)
Green, 1991 Herbicide sprayers in Ontario (lung)— mortality 5 nr
McDuffie et al., 1990 Saskatchewan farmers applying herbicides—incidence    
  Lung 103 0.6 (nr)
Bender et al.,1989 Herbicide sprayers in Minnesota—mortality    
  Trachea, bronchus, lung IICD-9 162.0-162.8) 54 0.7 (0.5-0.9)
  All respiratory (ICD-9 160.0-165.9) iT 0.7 (0.5-0.9)
Wiklund et al., 1989a Swedish pesticide applicators—incidence    
  Trachea, bronchus, lung 38 0.5 (0.4-0.7)
Blair et al., 1983 Licensed pesticide applicators in Florida, lawn.    
  Lung (ICD-8 162-163) 7 0.9 (nr)
Axelson et al., 1980 Swedish herbicide sprayers (lung)—mortality 3 1.4 (nr)
Forestry Workers Herbicides
Thörn et al., 2000 Swedish lumberjacks exposed to phenoxy herbicides  
  Foremen (bronchus and lung)—incidence 1 4.2 (0.0-23.2)
Reif et al., 1989 New Zealand forestry workers—incidence
(nested case-control)
   
  Lung 30 1.3 (0.8-1.9)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Paper and Pulp Workers Dioxins
McLean et al., 2006 IARC cohort of pulp and paper workers—
exposure to nonvolatile organochlorine compounds
Lung (ICD-9 162)
   
  Never 356 1.0 (0.9-1.1)
  Ever 314 1.0 (0.9-1.2)
  Pleura (ICD-9 163)    
  Never 17 2.8 (1.6-4.5)
  Ever 4 0.8 (0.2-2.0)
  Other respiratory (ICD-9 164-165)    
  Never 8 2.1 (0.9-4.2)
  Ever 2 0.7 (0.1-2.4)
ENVIRONMENTAL
Seveso, Italy Residential Cohort
TCDD
Consonni et al., 2008 Seveso residents—25-yr follow-up—men, women flung ICD-9 162)    
  Zone A 11 1.1 (0.6-2.0)
  Zone B 62 1.1 (0.9-1.4)
  Zone R 383 1.0 (0.8-1.1)
Pesatori et al., 2009 Seveso residents—20-yr follow-up to 1996—    
  incidence flung ICD-9 162)    
  Zone A 7 1.1 (0.5-2.4
  Zone B 37 0.96 (0.7-1.3)
  Zone R 280 1.0 (0.9-1.2)
Bertazzi et al., 2001 Seveso residents—20-yr follow-up (lung)—incidence    
  Zones A, B—men iT 1.3 (1.0-1.7)
  women 4 0.6 (0.2-1.7)
Bertazzi et al., 1998 Seveso residents—15-yr follow-up (lung)—incidence    
  Zone A—men 4 1.0 (0.4-2.6)
  women 0 nr
  Zone B—men 34 1.2 (0.9-1.7)
  women 2 0.6 (0.1-2.3)
  Zone R—men 176 0.9 (0.8-1.1)
  women 29 1.0 (0.7-1.6)
Bertazzi et al. 1997 Seveso residents—15-yr follow-up (lung)—incidence    
  Zone A—men 4 1.0 (0.3-2.5)
  Zone B—men 34 1.2 (0.9-1.7)
  women 2 0.6 (0.1-2.1)
  Zone R—men 176 0.9 (0.8-1.0)
  women 29 1.0 (0.7-1.5)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Bertazzi et al., 1993 Seveso residents—10-yr follow-up(trachea, bronchus, lung)—incidence    
  Zone A—men 2 0.8 (0.2-3.4)
  Zone B—men 18 1.1 (0.7-1.8)
  Zone R—men 96 0.8 (0.7-1.0)
  women 16 1.5 (0.8-2.5)
Chapaevsk, Russia Dioxin
Revich et al., 2001 Residents of Chapaevsk, Russia (lung)    
  Men 168 3.1 (2.6-3.5)
  Women 40 0.4 (0.3-0.6)
Other Environmental Studies
Turunen et al., 2008 Finnish fishermen and spouses    
  Larynx, trachea, and lung combined    
  Fishermen 72 0.8 (0.6-1.0)
  Spouses 8 0.7 (0.3-1.4)
Fukuda et al., 2003 Residents of Japanese municipalities with and without waste-incineration plants   Age-adjusted
mortality (per 100.000)
  Men    
  With   39.0 ± 6.7 vs
  Without   41.6 ± 9.1 (p=0.001)
  Women    
  With   13.7 ± 3.8 vs
  Without   14.3 ± 4.6 (p=0.11)
Svensson et al., 1995 Swedish fishermen    
  East coast (lung, larynx) 16 0.8 (0.5-1.3)
  West coast (Uine. larvnxl) 77 0.9 (0.7-1.1)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ACC, Army Chemical Corps; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PM, proportionate mortality; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VA, US Department of Veterans Affairs.

aSubjects are male, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

In that report, there were 30 lung-, tracheal-, or bronchial-cancer deaths, for an estimated SMR of 1.0 (95% CI 0.6–1.4) or 1.1 (95% CI 0.7–1.6) when 196 workers who had TCP exposure were excluded. An accompanying estimated dose–response relationship did not support an increase in risk associated with an estimated increase in exposure.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×



McBride et al. (2009a,b) studied 1,599 Dow employees who manufactured 2,4,5-TCP in New Zealand. McBride et al. (2009a) reported crude exposure estimates and 13 deaths from respiratory cancer (11 of the bronchus, trachea, or lung). The SMR for lung cancer was not increased (0.9 for respiratory cancer and 0.8 for cancer of the trachea, bronchus, or lung). The highest SMR for lung cancer was observed in the highest exposure category created in an effort to perform exposure–response analysis, but the other risk estimates were not increased for other exposure categories. A crude effort was made to control for smoking, but its overall effect is difficult to assess. The proportional-hazards model also showed that the highest RR estimate occurred in the most heavily exposed workers, but again this was not reported to be significantly increased or to represent a trend. The results in McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Finally, Boers et al. (2010) reported on the mortality experience of workers in two chlorophenoxy herbicide plants in the Netherlands. The previously significant increases in respiratory cancer were attenuated in this follow-up. Increased risk remained significant for all cancers. Factory A had 1,167 workers from 1955 to 1985. Factory B included 1,143 who had worked from 1965 to 1986. Crude exposure estimates were based on job. Respiratory-cancer risks were not significantly increased, with HRs of 1.11 (95% CI 0.49–2.52) for factory A (21 deaths in the exposed) and 1.22 (95% CI 0.56–2.66) for factory B (12 deaths in the exposed). Similar estimates of risk were evident for tracheal, lung, and bronchial cancers (factory A, HR = 1.15, 95% CI 0.48–2.77; factory B, HR = 1.22, 95% CI 0.56–2.66). HRs, calculated by factory did not show significant increases although the data were unstable when broken down into finer exposure categories (exposed in 1963 accident for factory A, main production worker exposed, and occasionally exposed for both factories). Although the previously reported significant increases in risks of respiratory cancer were not replicated in this analysis with 15 years of additional follow-up, the magnitude of the risks estimated in the Dutch workers was quite similar to that of the significant risks estimated by the ACC follow-up.

Environmental Studies

Pesatori et al. (2009) reported on cancer incidence in a 20-year follow-up of people exposed in the industrial accident in Seveso. Cancer of the lung occurred with an RR estimated by zone, drawn from residents in three exposure zones— very high (Zone A), high (Zone B), and low (Zone R). The RRs for lung-cancer incidence in the exposure groups were 1.12 (95% CI 0.53–2.36) in Zone A, 0.96 (95% CI 0.69–1.33) in Zone B, and 1.04 (95% CI 0.92–1.19) in Zone R. There were 7, 37, and 280 lung-cancer cases during the follow-up period in Zones A,

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

B, and R, respectively. The highest lung-cancer risk estimates were found in the longest-latency group in each exposure zone, although there was no clear evidence of an exposure–response relationship based on the small numbers of cases.

Turunen et al. (2008) conducted a study of dioxin-exposed and PCB-exposed fisherman in Finland that included assessment of mortality and estimates of exposure to dioxins and PCBs derived by using serum and adipose tissue from a set of the study participants. They reported a deficit (SMR = 0.80, 95% CI 0.63–1.01) of laryngeal, tracheal, and lung cancers—72 cases—and the SMR in their wives was even lower (0.70, 95% CI 0.30–1.38) with eight cases. The exposed fishermen were at slightly higher RR than their wives, but this excess was not significant and there was a deficit of these cancers compared with those in the general population.

Biologic Plausibility

Long-term animal studies have examined the effects of exposure to the chemicals of interest on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). As noted in previous VAO reports, there is evidence of increased incidence of squamous-cell carcinoma of the lung in male and female rats exposed to TCDD at high concentrations (Kociba et al., 1978; Van Miller et al., 1977). A significant increase in neoplastic and non-neoplastic lung lesions was found in female rats exposed to TCDD for 2 years (Kociba et al., 1978; NTP, 1982a,b, 2006; Walker et al., 2006, 2007). The most common nonneoplastic lesions were bronchiolar metaplasia and squamous metaplasia of the alveolar epithelium. Cystic keratinizing epithelioma was the most commonly observed neoplasm. The lung was also identified as a target organ in a tumor-promotion study after 60 weeks of exposure to TCDD in ovariectomized female Sprague Dawley rats initiated with a single dose of diethyl-N-nitrosamine (Beebe et al., 1995; Tritscher et al., 2000). Those studies ended with increased incidences of alveolar epithelial hyperplasia and alveolar–bronchiolar metaplasia; this result was similar to what was observed in the National Toxicology Program (NTP) studies (Tritscher et al., 2000).

A 2-year study of F344 rats exposed to cacodylic acid at 0–100 ppm and B6C3F1 mice exposed at 0–500 ppm failed to detect lung neoplasms at any dose (Arnold et al., 2006); this finding is consistent with those of previous studies. However, exposure to cacodylic acid had previously been shown to increase tumor multiplicity in mouse strains that were susceptible to developing lung tumors (for example, A/J strain; Hayashi et al., 1998) or in mice pretreated with an intitiating agent (4-nitroquinoline 1-oxide; Yamanaka et al., 1996). The data indicate that cacodylic acid may act as a tumor-promoter in the lung.

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Synthesis

The evidence remains limited but suggestive of an association between exposure to at least one chemical of interest and the risk of developing or dying from lung cancer. In the present update, there are compelling new data from the follow-up of the heavily exposed ACC (Cypel and Kang, 2010) that show significantly increased lung-cancer risks in ACC veterans who used herbicides in Vietnam; the magnitude of the estimated risk is consistent with those in many similar investigations. Additional updates of occupational data are unchanged, showing no increase in respiratory-cancer risk (Collins et al., 2009a,b). The latest update of the Netherlands occupationally exposed cohort is somewhat changed, showing still increased but now nonsignificant lung-cancer risk (Boers et al., 2010). Those estimates are not significant, but they remain increased and, in magnitude, again very similar to the ACC estimates and other published data.

In the past, the most compelling evidence has come from studies of heavily exposed occupational cohorts, including British MCPA production workers (Coggon et al., 1986), German production workers (Becher et al., 1996; Manz et al., 1991), a BASF cohort (Ott and Zober, 1996), a NIOSH cohort (Fingerhut et al., 1991; Steenland et al., 1999), and Danish production workers (Lynge, 1993). The latest findings from the Ranch Hand study (Pavuk et al., 2005) suggest an increase in risk with serum TCDD concentration even in subjects who made up the comparison group, whose TCDD exposure was considerably lower (but not zero) than that of the Ranch Hand cohort. The American and Australian cohort studies of Vietnam veterans (ADVA, 2005a,b,c; Dalager and Kang, 1997), which presumably cover a large proportion of exposed soldiers, showed higher than expected incidence of and mortality from lung cancer. The main limitations of those studies are that there was no assessment of exposure—as there was in, for example, the Ranch Hand study—and that some potential confounding variables, notably smoking, could not be accounted for. The committee believes that it is unlikely that the distribution of smoking differed greatly between the two cohorts of veterans, so confounding by smoking is probably minimal. The studies therefore lend support to the findings of the Ranch Hand study. The methodologically sound AHS did not show any increased risk of lung cancer, but, although there was substantial 2,4-D exposure in this cohort (Blair et al., 2005b), dioxin exposure of the contemporary farmers was probably negligible.

Results of the environmental studies were mostly consistent with no association, although in the cancer-incidence update from Seveso the highest risks occurred in the most exposed.

Also supportive of an association, however, are the numerous lines of mechanistic evidence, discussed in the section on biologic plausibility, which provide further support for the conclusion that the evidence of an association is limited or suggestive.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one chemical of interest and carcinomas of the lung, bronchus, and trachea.

BONE AND JOINT CANCER

ACS estimated that about 1,530 men and 1,120 women would receive diagnoses of bone or joint cancer (ICD-9 170) in the United States in 2010 and that 830 men and 630 women would die from these cancers (Jemal et al., 2010). Primary bone cancers are among the least common malignancies, but the bones are frequent sites of tumors secondary to cancers that have metastasized. Only primary bone cancer is considered here. The average annual incidence of bone and joint cancer is shown in Table 7-14.

Bone cancer is more common in teenagers than in adults. It is rare among people in the age groups of most Vietnam veterans (50–64 years). Among the risk factors for bone or joint cancer in adults are exposure to ionizing radiation in treatment for other cancers and a history of some noncancer bone diseases, including Paget disease.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and bone and joint cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion. Table 7-15 summarizes the results of the relevant studies.

TABLE 7-14 Average Annual Incidence (per 100,000) of Bone and Joint Cancer in United Statesa

55-59 Years Old 60-64 Years Old 65-69 Years Old
All Races While Black All Races While Black All Races While Black
Men 1.1 1.3 0.3 1.1 1.0 17.8 1.2 1.6 2.9
Women 0.8 0.9 0.6 1.6 1.7 2.2 0.9 16.3 0.4

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2004–2008 (NCI, 2010).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-15 Selected Epidemiologic Studies—Bone and Joint Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS    
US Air Force Health Study—Ranch Hand veterans vs SEA veterans All COIs
AFHS 1996 Air Force Ranch Hand veterans 0 nr
US VA Mortality Study of Army and Marine Veterans (ground troops serving July 4.1965-March 1,1973) All COIs
Breslin et al., 1988 Army Vietnam veterans 27 0.8 (0.4-1.7)
  Marine Vietnam veterans 11 1.4 (0.1-21.5)
State Studies of Vietnam Veterans All COIs
Clapp, 1997 Massachusetts Vietnam veterans 4 0.9 (0.1-11.3)
Anderson et al., 1986 Wisconsin Vietnam veterans 1 nr
Lawrence et al., 1985 New York Vietnam veterans 8 1.0 (0.3-3.0)
OCCUPATIONAL
IARC Phenoxy Herbicide Cohort (mortality vs national mortality rates) Dioxin. phenoxy herbicides
Kogevinas et al., 1997 IARC cohort, male and female workers exposed
to any phenoxy herbicide or chlorophenol
5 1.2 (0.4-2.8)
  Exposed to highly chlorinated PCDDs 3 1.1 (0.2-3.1)
  Not exposed to highly chlorinated PCDDs 2 1.4 (0.2-5.2)
NIOSH Mortality Cohort (12 US plants, production 1942-1984)(included in IARC cohort) Dioxin, phenoxy herbicides
Fingerhut et al., 1991 NIOSH—entire cohort 2 2.3 (0.3-8.2)
  ≥1-yr exposure, ≥ 20-yr latency 1 5.5 (0.1-29.0)
Dow Production Workers—Midland. MI (included in IARC and NTOSH cohorts)   Dioxin, phenoxy herbicides
Ramlow et al., 1996 Dow pentachlorophenol production workers 0 nr
  0-yr latency 0 nr
  15-yr latency 0 nr
Bond et al., 1988 Dow 2,4-D production workers 0 nr (0.0-31.1)
BASF Production Workers (included in IARC cohort) Dioxin, phenoxy herbicides
Zober et al., BASF employees—basic cohort 90% CI
1990 0 0 (0.0-65.5)
Monsanto Production Workers (included in IARC cohort) Dioxin, phenoxy herbicides
Collins et al., 1993 Monsanto Company workers 2 5.0 (0.6-18.1)
New Zealand Production Workers—Dow plant in Plymouth.NZ (included in IARC cohort) Dioxin, phenoxy herbicides
McBride et al., 2009a 1,599 production workers (male and female) vs national rates—mortality 1969 through 2004 0 0 (0.0-21.8)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
’t Mannetje et al., 2005 Phenoxy herbicide producers and sprayers (men and women) 0 nr
United Kingdom Production Workers (included in IARC cohort) Dioxin, phenoxy herbicides
Coggon et al., 1986 British MCPA production workers 1 0.9 (0.0-5.0)
Studies of Agricultural Workers Herbicides
Gambini et al., 1997 Italian rice growers 1 0.5 (0.0-2.6)
Blair et al., 1993 US farmers in 23 states    
  White men 49 1.3 (1.0-1.8)
  White women 1 1.2 (0.0-6.6)
Ronco et al., 1992 Danish, Italian farm workers    
  Male Danish farmers 9 0.9 (nr)
  Female Danish farmers 0 nr
Wiklund, 1983 Swedish male and female agricultural 44 99% CI
  workers—incidence   1.0 (0.6-1.4)
Burmeister, 1981 Iowa farmers 56 1.1 (nr)
Other Studies of Herbicide and Pesticide Applicators Herbicides
Swaen et al., 2004 Dutch licensed herbicide applicators 0 nr
Torchio et al., 1994 Italian licensed pesticide users 10 0.8 (0.4-1.4)
Forestry Workers   Herbicides
Hcrtzman et al., 1997 British Columbia sawmill workers    
  Mortality 5 1.3 (0.5-2.7)
  Incidence 4 1.1 (0.4-2.4)
  Not exposed to highly chlorinated PCDDs 2 1.4 (0.2-5.2)
Rix et al., 1989 New Zealand forestry workers—nested 1 1.7 (0.2-13.3)
  case-control—incidence    
Paper and Pulp Workers Dioxins
Rix et al., 1998 Danish paper-mill workers—incidence    
  Men 1 0.5 (0.0-2.7)
  Women 0 nr
Other Occupational Studies
Herbicides
Mcrlctti et al., 2006 Association between occupational exposure and risk of bone sarcoma 18 2.6 (1.5-4.6)
ENVIRONMENTAL
Seveso, Italy Residential Cohort    
Bertaz et al., 1998 Seveso residents—15-yr follow-up    
  Zone B women 1 2.6 (0.3-19.4)
  Zone R men 2 0.5 (0.1-2.0)
  Zone R women 7 2.4 (1.0-5.7)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Bertazzi et al., 1997 Seveso residents—15-yr follow-up    
  Zone B women 1 2.6 (0.0-14.4)
  Zone R men 2 0.5 (0.1-1.7)
  Zone R women 7 2.4 (1.0-4.9)
Chapaevsk, Russia
Revich et al., 2001 Residents of Chapaevsk, Russia    
  Mortality standardized to Samara region(bone.soft-tissue cancer)    
  Men 7 2.1 (0.9-4.4)
  Women 7 1.4 (0.6-3.0)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; MCPA, methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); SEA, Southeast Asia; VA, US Department of Veterans Affairs.

aSubjects are male, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Update of the Epidemiologic Literature

Vietnam-Veteran and Occupational Studies

No Vietnam-veteran studies or occupational studies concerning exposure to the chemicals of interest and bone and joint cancer have been published since Update 2008.

Environmental Studies

McBride et al. (2009a,b) examined mortality in an occupational cohort of TCP workers employed in a Dow Agrosciences site in New Zealand during the period 1969–1988. This set of the IARC occupational cohort (see Chapter 5) includes 1,599 workers. No bone-cancer deaths were identified in the study. The results in McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Biologic Plausibility

No animal studies have reported an increased incidence of bone and joint cancers after exposure to the chemicals of interest. The biologic plausibility of

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

The new study of Dow production workers in New Zealand found no cases of bone and joint cancer, and the previous body of results summarized in Table 7-15 does not indicate an association between exposure to the chemicals of interest and bone cancer.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and bone and joint cancers.

SOFT-TISSUE SARCOMA

Soft-tissue sarcoma (STS) (ICD-9 164.1, 171) arises in soft somatic tissues in and between organs. Three of the most common types of STS—liposarcoma, fibrosarcoma, and rhabdomyosarcoma—occur in similar numbers in men and women. Because of the diverse characteristics of STS, accurate diagnosis and classification can be difficult. ACS estimated that about 5,680 men and 4,840 women would receive diagnoses of STS in the United States in 2010 and that about 2,020 men and 1,900 women would die from it (Jemal et al., 2010). The average annual incidence of STS is shown in Table 7-16.

Among the risk factors for STS are exposure to ionizing radiation during treatment for other cancers and some inherited conditions, including Gardner syndrome, Li-Fraumeni syndrome, and neurofibromatosis. Several chemical exposures have been identified as possible risk factors (Zahm and Fraumeni, 1997).

TABLE 7-16 Average Annual Incidence (per 100,000) of Soft-Tissue Sarcoma (Including Malignant Neoplasms of the Heart) in United Statesa

55-59 Years Old 60-64 Years Old 65-69 Years Old
All Races While Black All Races While Black All Races While Black
Men 5.3 5.4 5.2 6.7 7.1 5.2 8.6 8.9 6.4
Women 4.5 4.4 6.2 5.3 5.2 7.3 6.7 6.9 4.0

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2004–2008 (NCI, 2010).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×



Conclusions from VAO and Previous Updates

The committee responsible for VAO judged that the strong findings in the IARC and NIOSH cohorts and the extensive Scandinavian case–control studies, complemented by consistency in preliminary reports on the Seveso population and one statistically significant finding in a state study of Vietnam veterans, constituted sufficient information to determine that there is an association between exposure to at least one of the chemicals of interest and STS. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, and Update 2006 did not change that conclusion. A case–control study conducted in Italy (Zambon et al., 2007) and an update on Danish gardeners (Hansen et al., 1992) considered in Update 2008 reinforced the evidence of an association, but the TCDD-exposed Seveso population has shown no evidence of an association (Consonni et al., 2008). Table 7-17 summarizes the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

No Vietnam-veteran studies concerning exposure to the chemicals of interest and STS have been published since Update 2008.

Occupational Studies

Collins et al. (2009a,b) reported on the mortality experience of the occupational cohort in the Midland, Michigan, Dow Chemical plant previously included in analyses of the NIOSH Mortality Cohort, as reported by Fingerhut et al. (1991) and added to the expanded IARC Cohort of Phenoxy Herbicide Workers (Kogevinas et al., 1997). TCP was produced at the plant from 1942 to 1979, and PCP was produced from 1937 to 1980. Job histories of the workers were used to determine duration of time spent in the TCP or PCP units. Mortality in the workers and SMRs were calculated by using the US population as the referent. In the PCP analysis (Collins et al., 2009b), one death from STS of a worker who was exposed to both PCP and TCP was identified, for a PCP SMR for STS of 2.2 (95% CI 0.0–12.1). In a separate analysis of the 1,615 TCP workers (Collins et al., 2009a), four deaths from STS were identified, for a TCP SMR of 4.1 (95% CI 1.1–10.5). One of the deaths occurred in a worker who was exposed to both TCP and PCP; when this death was removed from the analysis, the SMR was reduced to 3.5 (95% CI 0.7–10.2). As pointed out in follow-up correspondence (Collins et al., 2010; Villeneuve and Steenland, 2010) and discussed in detail in Chapter 5, different latency models, different dose–response models, and in-depth analysis of the serum concentrations could alter some of the results reported in

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-17 Selected Epidemiologic Studies—Soft-Tissue Sarcoma

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS    
US Air Force Health Study   All COIs
AFHS, 2000 AFHS veterans 1 0.8 (0.1-12.8)
AFHS, 1996 Ranch Hand veterans 0 nr
Michalek et al., 1990 Ranch Hand veterans 1 nr
  Comparisons 1 nr
US VA Marine Post-service Mortality Study (all Marines active 1967-1969)   All COIs
Watanabe and Rang, 1995 US Marines in Vietnam 0 nr
US VA Mortality Study of Army and Marine Veterans (ground troops serving July 4, 1965-March 1, 1973)   All COIs
Watanabe et al., 1991 Army Vietnam veterans 43 1.1
  Marine Vietnam veterans 11 0.7
Bullman et al.,1990 Army 1 Corps Vietnam veterans 10 0.9 (0.4-1.6)
Breslin et al.,1988 Army Vietnam veterans 30 1.0 (0.8-1.2)
  Marine Vietnam veterans 8 0.7 (0.4-1.3)
Breslin et al.,1986 US Vietnam veterans    
  Army 30 1.0 (nr)
  Marines 8 0.7 (nr)
Australian Vietnam Veterans vs Australian General Population   All COIs
ADVA, 2005a Australian Vietnam veterans vs Australian population—incidence 35 (0.7-1.3)
  Navy 6 0.8 (0.3-1.7)
  Army 29 1.2 (0.8-1.6)
  Air Force 0 0.0 (0.0-1.1)
ADVA, 2005b Australian Vietnam veterans vs Australian population—mortality 12 0.8 (0.4-1.3)
  Navy 3 0.9 (0.2-2.4)
  Army 9 0.8 (0.4-1.5)
  Air Force 0 0.0 (0.0-2.3)
AIHW, 1999 Male Australian Vietnam veterans—incidence (validation study)   Expected number of exposed cases (95% CI)
    14 27 (17-37)
CDVA, 1998a Male Australian Vietnam veterans—self-reported incidence 398 27 (17-37)
CDVA, 1998b Female Australian Vietnam veterans—self-reported incidence 2 0 (0-4)
CDVA, 1997a Australian military Vietnam veterans 9 1.0 (0.4-1.8)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Australian Conscripted Army National Service (deployed vs nondeployed)   All COIs
ADVA, 2005c Australian men conscripted Army National Service Vietnam era veterans—deployed vs nondeployed    
  Incidence 10 1.0 (0.4-2.4)
  Mortality 3 0.5 (0.1-2.0)
CDVA, 1997b Australian National Service Vietnam veterans 2 0.7 (0.6-4.5)
Feit et al., 1987 Australian Vietnam veterans 1 1.3 (0.1-20.0)
VA Case-control Studies   All COIs
Kang et al.,1986 Vietnam veterans vs Vietnam-era veterans 86 0.8 (0.6-1.1)
Vietnam Veterans of Massachusetts   All COIs
Clapp, 1997 Massachusetts Vietnam veterans 18 1.6 (0.5-5.4)
Kogan and Clapp, 1988 Massachusetts Vietnam veterans 9 5.2 (2.4-11.1)
State Studies of US Vietnam Veterans   All COIs
Visintainer et al., 1995 PM study of deaths (1974-1989) of
Michigan Vietnam-era veterans—deployed vs nondeployed
8 1.1 (0.5-2.2)
Anderson et al., 1986 Wisconsin Vietnam veterans 4 nr
Lawrence et al., 1985 New York State Vietnam veterans 2 1.1 (0.2-6.7)
Greenwald et al., 1984 New York State Vietnam veterans 10 0.5 (0.2-1.3)
OCCUPATIONAL    
IARC Phenoxy :Herbicide Cohort (mortality vs national mortality   Dioxin, phenoxy herbicides
Kogevinas et al., 1997 IARC cohort, male and female workers
exposed to any phenoxy herbicide or chlorophenol
9 2.0 (0.9-3.8)
  Exposed to highly chlorinated PCDDs 6 2.0 (0.8-4.4)
  Not exposed to highly chlorinated PCDDs 2 1.4 (0.2-4.9)
Kogevinas et al., 1995 IARC cohort (men and women)—incidence 11 nr
Kogevinas et al., 1992 10-19 years since first exposure IARC cohort (men and women) 4 6.1 (1.7-15.5)
Saracci et al.,1991 IARC cohort—exposed subcohort (men and women) 4 2.0 (0.6-5.2)
NIOSH Mortality Cohort (12 US plants, production 1942-19841 (included in IARC cohort)   Dioxin, phenoxy herbicides
Steenland et al., 1999 US chemical production workers 0 nr
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Fringerhut et al., 1991 NIOSH cohort—enure cohort 4 3.4 (0.9-8.7)
  ≥ l-yr exposure, ≥ 20-yr latency 3 9.2 (1.9-27.0)
BASF Production Workers (included in IARC cohort)   Dioxin, phenoxy herbicides
Ott and Zober, 1996 BASF; employees—incidence 0 Expected number of exposed cases 0.2
Zober et al.,1990 BASF employees—basic cohort 0 nr
Dow Production Workers—Midland. MI (included in IARC and MOSH cohorts)   Dioxin, phenoxy herbicides
Collins et al.2009a Trichlorophenol workers 4 4.1 (1.1-10.5)
Collins et al., 2009b Pentachlorophenol workers 1 2.2 (0.0-12.1)
Bodner et al., 2003 Dow chemical production workers 2 2.4 (0.3-8.6)
Ramlow et al., 1996 Dow pentachlorophenol production workers 0 Expected number of exposed cases 0.2
Bond et al.1988 Dow 2,4-D production workers 0 nr
Danish Production Workers (included in IARC cohort)   Dioxin, phenoxy herbicides
Lynge, 1993 Danish production workers—updated incidence for men, women 5 2.0 (0.7-4.8)
Lynge, 1985 Danish production workers—incidence    
  Men 5 2.7 (0.9-6.3)
  Women 0 nr
Dutch Production Workers (included in IARC cohort)   Dioxin, phenoxy herbicides
Hooiveld et al., 1998 Dutch chemical production workers 0 nr
Bueno de Mesquita et al., 1993 Dutch phenosy herbicide workers 0 0.0 (0.0-23.1)
German Production Workers (included in IARC cohort)   Dioxin, phenoxy herbicides
Manz et al., 1991 German production workers—men, women 0 nr
United Kingdom Production Workers (included in IARC cohort)   Dioxin, phenoxy herbicides
Coygon et al., 1986 British MCPA chemical workers 1 1.1 (0.03-5.9)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort)   Dioxin, phenoxy herbicides
McBride et al., 2009a 1,599 production workers (male and female)
vs national rates—mortality 1969 through 2004
   
  Ever exposed workers 1 3.4 (0.1-19.5)
’t Mannetje et al., 2005 Phenoxy herbicide producers (men and women) 0 0.0 (0.0-19.3)
  Phenoxy herbicide sprayers ( > 99% men) 1 4.3 (0.1-23.8)
Agricultural Health Study   Herbicides
Alavanja et al., 2005 US AHS—incidence    
  Private applicators (men and women) 10 0.7 (0.3-1.2)
  Spouses of private applicators ( > 99%'women) 3 0.5 (0.1-1.4)
  Commercial applicators (men and women) nr 0.0 (0.0-3.8)
Blair et al., 2005a US AHS    
  Private applicators (men and women) 4 0.7 (0.2-1.8)
  Spouses of private applicators ( > 99%women) 3 1.4 (0.3-4.1)
Other Agricultural Workers   Herbicides
Hansen et al., 2007 Danish gardeners (ICD-7 197)—incidence    
  10-yr follow-up (1975-1984) reported in
Hansen et al. (1992)
3 5.3 (1.1-15.4)
  25-yr follow-up (1975-2001)    
  Born before 1915 (high exposure) 3 5.9 (1.9-18.2)
  Born 1915-1934 (medium exposure) 0 0.0 (0.0-3.8)
  Born after 1934 (low exposure) 1 1.8 (0.3-12.9)
Blair et al., 1993 US farmers in 23 states 1993 9S 0.9 (0.8-1.1)
Hansen et al.,1992 Danish gardeners—incidence 3 5.3 (1.1-15.4)
Wiklund et al., 1988, 1989b Swedish agricultural workers (men and   99% CI
  women) 7 0.9 (0.4-1.9)
Hoar et al., 1986 Kansas residents—incidence    
  All farmers 95 1.0 (0.7-1.6)
  Farm use of herbicides 22 0.9 (0.5-1.6)
Vineis et al., 1986 Italian rice growers    
  Among all living females 5 2.4 (0.4-16.1)
Balarajan and Acheson, 1984 Agricultural workers in England    
  Overall 42 1.7 (1.0-2.9)
  Under 75 yrs of age 33 1.4 (0.8-2.6)
New Zealand Pesticide Workers   Herbicides
Smith and Pearce, 1986 Reanalysis of New Zealand workers   90% CI
    133 1.1 (0.7-1.8)
Smith et al., 1984 Update of New Zealand workers   90% CI
    17 1.6 (0.7-3.8)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Smith et al., 1983 New Zealand workers exposed to herbicides   90% CI
    17 1.6 (0.8-3.2)
Other Studies of Herbicide and Pesticide Applicators   Herbicides
Torchio et al., 1994 Italian licensed pesticide users 2 1.0 (0.1-3.5)
Blair et al., 1983 Florida pesticide applicators 0 nr
Forestry Workers   Herbicides
Hertzman et al., 1997 Canadian sawmill workers 11 1.0 (0.6-1.7)
Alavanja et al., 1989 USDA forest and soil conservationists 2 1.0 (0.1-3.6)
Reif et al., 1989 New Zealand forestry workers—nested case-control—incidence 4 3.2 (1.2-9.0)
Paper and Pulp Workers   Dioxins
McLean et al., 2006 IARC cohort of pulp and paper workers
Exposure to nonvolatile organochlorine compounds
   
  Never 8 1.2 (0.5-2.4)
  Ever 4 0.8 (0.2-2.0)
Rix et al., 1998 Danish paper-mill workers—incidence    
  Women employed in sorting and packing 8 4.0 (1.7-7.8)
  Men employed in sorting and packing 12 1.2 (0.6-2.0)
Other Occupational Studies   Herbicides
Mack. 1995 US cancer registry data (SEER program) review    
  Men 3.526 nr
  Women 2,886 nr
Smith and Christophers,1992 Australia residents 30 1.0 (0.3-3.1)
Woods et al., 1987 Washington state residents—incidence    
  High phenoxy exposure nr 0.9 (0.4-1.9)
  Self-reported chloracne nr 3.3 (0.8-14.0)
Hardell, 1981 Swedish residents    
  Exposed to phenoxy acids 13 5.5 (2.2-13.8)
  Exposed to chlorophenols 6 5.4 (1.3-22.5)
Eriksson et al., 1979, 1981 Swedish workers   (2.5-10.4)
    25 5:1 matched
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
ENVIRONMENTAL    
Seveso, Italy Residential Population   Dioxin
Consonni et al., 2008 Seveso residents—25-yr follow-up—men.    
  women    
  Zone A 0 nr
  Zone B 0 nr
  Zone R 4 0.8 (0.3-2.1)
Pesatori et al., 2009 Seveso—20-yr follow-up to 1996—incidence    
  Zone A 0 nr
  Zone B 0 nr
  Zone R 9 1.3 (0.6-2.7)
Bcrtazzi et al.,2001 Seveso—20-yr follow-up (men and women) 0 nr
Bcrtazzi et al., Seveso—15-yr follow-up (men and women)    
1998 Zone R men 4 2.1 (0.7-6.5)
Bertazzi et al., 1997 Seveso residents—15-yr follow-up (men and women)    
  Zone R men 4 2.1 (0.6-5.4)
Bcrtazzi et al.,1993 Seveso residents—10-yr follow-up—morbidity    
  Zone R men 6 2.8 (1.0-7.3)
  Zone R women 2 1.6 (0.3-7.4)
Bcrtazzi et al., 1989a Seveso residents—10-yr follow-up    
  Zone A, B, R men 2 5.4 (0.8-38.6)
  Zone A, B, R women 1 2.0 (0.2-1.9)
Bcrtazzi et al., 1989b Seveso residents—10-yr follow-up    
  Zone R men 2 6.3 (0.9-45.0)
  Zone B women 1 17.0 (1.8-163.6)
Other Environmental Studies   2,4,5-T
Read et al.2007 Residents of New Plymouth Territorial
Authority, New Zealand near plant manufacturing
2,4,5-T in 1962-1987
   
  Incidence 56 1.0 (0.8-1.4)c
  1970-1974 7 1.0 (0.4-2.1)
  1975-1979 3 0.4 (0.1-2.1)
  1980-1984 10 1.3 (0.6-2.4)
  1985-1989 11 1.2 (0.6-2.2)
  1990-1994 9 0.9 (0.4-1.7)
  1995-1999 14 1.3 (0.7-2.2)
  2000-2001 2 0.8 (0.1-3.0)
  Mortality 27 l.2 (0.8-I.8)c
  1970-1974 5 1.8 (0.6-4.3)
  1975-1979 1 0.4 (0.0-2.0)
  1980-1984 4 1.1 (0.3-2.9)
  1985-1989 5 1.5 (0.5-3.6)
  1990-1994 5 1.3 (0.4-3.0)
  1995-1999 5 1.3 (0.4-3.0)
  2000-2001 2 0.9 (0.1-3.1)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Zambon et al.2007 Population-based Veneto Tumour Registry,
Italy, average exposure based on duration
and distance of residence from 33 industrial sources—incidence
  Dioxin
  Sarcoma (ICD-9 158, 171, 173, visceral sites)    
  Men    
  < 4 TCDD (fg/m3) 31 1.0
  4-6 39 1.1 (0.6-2.0)
  ≥ 6 17 1.9 (0.9-4.0)
p-trend = 0.15
  Women    
  < 4 TCDD (fg/m3) 24 1.0
  4-6 44 1.5 (0.8-2.7)
  ≥ 6 17 2.4 (1.0-5.6)
p-trend = 0.04
  Men, women combined    
  Connective, other soft tissue (ICD-9 171)    
  < 4 TCDD (fg/m3) 25 1.0
  4-6 39 1.4 (0.7-2.5)
  ≥ 6 17 3.3 (1.4-7.9)
p-trend = 0.01
  Skin (ICD-9 173)    
  < 4 TCDD (fg/m3) 5 1.0
  4-6 10 0.0 (0.3-4.7)d
  ≥ 6 2 0.3 (0.0-3.4)
p-trend = 0.48
  Retroperitoneum, peritoneum (ICD-9 158)    
  < 4 TCDD (fg/m3) 6 1.0
  4-6 12 1.1 (0.3-3.4)
  ≥ 6 3 0.8 (0.1-4.5)
p-trend = 0.86
  Visceral sites    
  < 4 TCDD (fg/m3) 19 1.0
  4-6   1.2 (0.6-2.6)
  ≥ 6 12 2.5 (1.0-6.3)
p-trend = 0.08
Pahwa et al., 2006 Canadian residents   Phenoxyherbicides
  Any phenoxyherbictde 46 1.1 (0.7-1.5)
  2,4-D 4 1.0 (0.6-1.5)
  Mecoprop 12 1.0 (0.5-1.9)
  MCPA 12 1.1 (0.5-2.2)
Comba et al., 2003 Residents near industrial-waste incinerator in   Dioxin
  Mantua, Italy—incidence    
  Residence within 2 km of incinerator 5 31.4 (5.6-176.1)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Tuomisto et al., 2004 Finnish STS patients vs controls within
quintiles based on TEQ in subcutaneous fat—incidence
110 Dioxin
  Quintile 1 (median,∼12 ng/kg TEQ) nr 1.0
  Quintile 2 (median, ∼20 ng/kg TEQ) nr 0.4 (0.2-1.1)
  Quintile 3 (median, ∼28 ng/kg TEQ) nr 0.6 (0.2-1.7)
  Quintile 4 (median, ∼40 ng/kg TEQ) nr 0.5 (0.2-1.3)
  Quintile 5 (median, ∼62 ng/kg TEQ) nr 0.7 (0.2-2.0)
Costani et al., 2000 Residents near chemical plant in Mantua, 20 TCDD emissions
  Italy—incidence   2.3 (1.3-3.5)
Viel et al., 2000 Residents near French solid-waste
incinerator—incidence
  Dioxin
  Spatial cluster 45 1.4 (p = 0.004)
  1994-1995 12 3.4 (p = 0.008)
Gambini et al.,1997 Italian rice growers
and chloniphenols
  Chlophenoxy acids and chlorophenols
Svensson et al., 1995 Swedish fishermen—incidence (men and women)   Organochlorine compounds and chlorophenol
  West coast 3 0.5 (0.1-1.4)
Lampi et al., 1992 Finnish community exposed to chlorophenol
contamination (men and women)
6 1.6 (0.7-3.5)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PM, proportionate mortality; SEER, Surveillance, Epidemiology, and End Results; STS, soft-tissue sarcoma; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, toxicity equivalent; USDA, US Department of Agriculture; VA, US Department of Veterans Affairs.

aSubjects are male, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

cCommittee computed total SMR and standard incidence ratio by dividing sum of observed values by sum of expected values over all years; 95% CIs on these total ratios were computed with exact methods.

dThere appears to be an error in this entry because lower 95% CL (0.3) is not smaller than odds ratio (0.0).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×



the analysis; given the small number of deaths from STS, however, those methodologic considerations are unlikely to alter the conclusions regarding STS.

McBride et al. (2009a,b) evaluated mortality from cancers in an occupational cohort of TCP workers in New Zealand, a set of the IARC cohort (see Chapter 5). Workers were employed at the plant from 1969 to 1988, and SMRs were calculated by using the New Zealand population as the comparison group. Exposure was classified as ever exposed or never exposed to TCDD. One case of STS was identified in the ever-exposed group and none in the never-exposed group. When compared with the expected number of deaths in the New Zealand population, an increased association was observed, with an SMR of 3.4 (95% CI 0.1–19.5) for the ever-exposed workers. Results in McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Environmental Studies

Cancer incidence was re-evaluated in the Seveso cohort for the period 1977– 1996 (Pesatori et al., 2009). The Seveso cohort, described in Chapter 5, includes all residents of Seveso at the time of the accident and those who migrated into or were born in the area in the 10-year period after the accident. A total of 218,761 residents are included in the analysis: 723 residents in the high-exposure zone (Zone A); 4,821 in the medium-exposure zone (Zone B); 31,643 in the low- exposure zone (Zone R); and the remainder who lived outside the zone of exposure. A total of nine STS cases were identified; all nine were in Zone R. Compared with the incidence in the reference zone, STS incidence in Zone R was higher, with an RR of 1.32 (95% CI 0.64–2.73).

Biologic Plausibility

In a 2-year study, dermal application of TCDD to Swiss-Webster mice led to an increase in fibrosarcomas in females but not in males (NTP, 1982b). There is some concern that the increase in fibrosarcomas may be associated with the treatment protocol rather than with TCDD. The NTP gavage study (NTP, 1982a) also found increased incidences of fibrosarcomas in male and female rats and in female mice.

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

Previous committees have concluded that the occupational, environmental, and Vietnam-veteran studies showed sufficient evidence to link herbicide exposure to STS. Although confidence intervals in the new studies were broad because

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

of the small samples, that conclusion is consistent with the findings of McBride et al. (2009a), Collins et al. (2009a,b), and Pesatori et al. (2009).

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the chemicals of interest and STS.

SKIN CANCER—MELANOMA

Skin cancers are generally divided into two broad categories: neoplasms that develop from melanocytes (malignant melanoma, or simply melanoma) and neoplasms that do not. Nonmelanoma skin cancers (primarily basal-cell and squamous-cell carcinomas) have a far higher incidence than melanoma but are considerably less aggressive and therefore more treatable. The average annual incidence of melanoma is shown in Table 7-18. The committee responsible for Update 1998 first chose to address melanoma studies separately from those of nonmelanoma skin cancer. Some researchers report results by combining all types of skin cancer without specifying type. The present committee believes that combined information is not interpretable (although there is a supposition that mortality figures refer predominantly to melanoma and that sizable incidence figures refer to nonmelanoma skin cancer); therefore, it is interpreting data only when results specify melanoma or nonmelanoma skin cancer.

ACS estimated that about 38,870 men and 29,260 women would receive diagnoses of cutaneous melanoma (ICD-9 172) in the United States in 2008 and that about 5,670 men and 3,030 women would die from it (Jemal et al., 2010). More than a million cases of nonmelanoma skin cancer (ICD-9 173), primarily basal-cell and squamous-cell carcinomas, are diagnosed in the United States each year (ACS, 2006); it is not required to report them to registries, so the numbers of cases are not as precise as those of other cancers. ACS reports that although

TABLE 7-18 Average Annual Incidence (per 100,000) of Skin Cancers (Excluding Basal-Cell and Squamous-Cell Cancers) in United Statesa

55-59 Years Old 60-64 Years Old 65-69 Years Old
All Races While Black All Races While Black All Races While Black
Melanomas of the Skin:
Men 49.0 58.8 1.8 68.7 81.4 2.0 86.7 103.0 5.2
Women 30.2 37.2 1.5 35.5 43.0 1.6 39.2 47.2 2.2

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2004–2008. SEER incidence data not available for nonmelanocytic skin cancer (NCI, 2010).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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melanoma accounts for less than 5% of skin-cancer cases, it is responsible for about 73% of skin-cancer deaths (ACS, 2011a). It estimates that 2,000 people die each year from nonmelanoma skin cancer (ACS, 2011b).

Melanoma occurs more frequently in fair-skinned people than in dark-skinned people; the risk in whites is roughly 20 times that in dark-skinned blacks. The incidence increases with age, more strikingly in males than in females. Other risk factors include the presence of particular kinds of moles on the skin, suppression of the immune system, and excessive exposure to UV radiation, typically from the sun. A family history of the disease has been identified as a risk factor, but it is unclear whether that is attributable to genetic factors or to similarities in skin type and sun-exposure patterns.

Excessive exposure to UV radiation is the most important risk factor for nonmelanoma skin cancer; some skin diseases and chemical exposures have also been identified as potential risk factors. Exposure to inorganic arsenic is a risk factor for skin cancer; this does not imply that exposure to cacodylic acid, which is a metabolite of inorganic arsenic, can be assumed to be a risk factor.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and skin cancer. Additional information available to the committee responsible for Update 1996 did not change that conclusion. The committee responsible for Update 1998 considered the literature on melanoma separately from that of nonmelanoma skin cancer and found that there was inadequate or insufficient information to determine whether there is an association between the chemicals of interest and melanoma. The committees responsible for Update 2000, Update 2002, and Update 2004 concurred with the findings of Update 1998. The committee responsible for Update 2006 was unable to reach a consensus as to whether there was limited or suggestive evidence of an association between exposure to the chemicals of interest and melanoma or inadequate or insufficient evidence to determine whether there is an association, so melanoma was left in the lower category. The committee for Update 2008 determined that evidence of an association between exposure to the chemicals of interest and melanoma remained inadequate or insufficient to determine whether an association exists. Table 7-19 summarizes the relevant melanoma studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Cypel and Kang (2010) analyzed the mortality of ACC veterans who used herbicides in Vietnam (see Chapter 5). All-causes mortality and cause-specific

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-19 Selected Epidemiologic Studies—Melanoma

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans
All COIs
Pavuk et al., 2005 White Air Force comparison subjects
only—incidence
Serum TCDD (pg/g), based on model with expousure variable loge(TCDD)
   
  Per unit increase of -loge(TCDD)
Quartiles (pg/g)
25 2.7 (1.1-6.3)
  0.4-2.6 3 1.0
  2.6-3.8 5 2.1 (0.4-11.0)
  3.8-5.2 8 3.2 (0.7-15.5)
  > 5.2 9 3.6 (0.7-17.2)
  Number years served SEA    
  Per year of service 25 1.1 (0.9-1.3)
  Quartiles (years in SEA)    
  0.8-1.3 3 1.0
  1.3-2.1 4 1.9 (0.3-10.3)
  2.1-3.7 8 3.2 (0.7-15.3)
  3.7-16.4 10 4.1 (0.9-19.7)
Akhtar et al., 2004 AFHS subjects vs national rates    
  White AFHS Ranch Hand veterans    
  Incidence 17 2.3 (1.4-3.7)
  With tours between 1966-1970 16 2.6 (1.5-4.1)
  Mortality nr  
  White AFHS comparison veterans    
  Incidence 15 1.5 (0.9-2.4)
  With tours between 1966-1970 12 1.5 (0.8-2.6)
  Mortality nr  
  White AFHS subjects—incidence    
  Who spent at most 2 yrs in SEA    
  Per unit increase of -loge(TCDD) (pg/g) 14 2.2 (1.3-3.9)
  Comparison group 3 E0
  Ranch Hand—< 10 TCDD pg/g in 4 3.0 (0.5-16.8)
  Ranch Hand—< 118.5 TCDD pg/g at 4 7.4 (1.3-41.0)
  end of service    
  Ranch Hand— > 118.5 TCDD pg/g at 3 7.5 (1.1-50.2)
  end of service    
  Only Ranch Hands with 100% service in    
  Vietnam, comparisons with 0% service in    
  Vietnam    
  Per unit increase of -loge(TCDD) in pg/g 14 1.7 (1.0-2.8)
  Comparison group 2 E0
  Ranch Hand— < 10 TCDD pg/g in 1987 5 3.9 (0.4-35.3)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
  Ranch Hand—< 118.5 TCDD pg/g atend of service 4 7.2 (0.9-58.8)
  Ranch Hand—> 118.5 TCDD pg/g atend of service 3 5.5 (0.6-46.1)
AFHS, 2000 Air Force Ranch Hand veterans—incidence 16 1.8 (0.8-3.8)
Kelchum et al., 1999 Ranch Hand veterans, comparisons throughJune 1997—incidence    
  Comparisons 9 1.0
  Ranch Hand background exposure 4 1.1 (0.3-4.5)
  Ranch Hand low exposure 6 2.6 (0.7-9.1)
  Ranch Hand high exposure 2 0.9 (0.2-5.6)
Wolfe et al 1990 Air Force Ranch Hand veterans—incidence 4 1.3 (0.3-5.2)
US VA Cohort of Army Chemical Corps     All COIs
Cypel and Kang et al., 2010 ACC—deployed vs nondeployed and vs USmen (Vietnam-service status throught 2005)Deployed vs nondeployed 5 vs 4 1.5 (0.4–6.2)
  ACC veterans vs US men    
  Vietnam cohort 5 1.3 (0.4–3.1)
  Non-Vietnam cohort 4 1.3 (0.4–3.4)
US CDC Vietnam Experience Study     All COIs
Boehmer et al., 2004 Follow-up of CDC Vietnam Experience Cohort 6 1.4 (0.4–4.9)
US VA Mortality Study of Army and Marine Veterans (ground troops serving July 4, 1965–March 1, 1973) All COIs
Breslin et al., 1988 Army Vietnam veterans 145 1.0 (0.9–1.1)
  Marine Vietnam veterans 36 0.9 (0.6–1.5)
State Studies of US Vietnam Veterans     All COIs
Clapp, 1997 Massachusetts Vietnam veterans—incidence 21 1.4 (0.7–2.9)
Australian Vietnam Veterans vs Australian population     All COIs
O’Toole et al., 2009 Survey of Australian Vietnam Veteranscompared to Australian general populations nr 4.7 (1.3–8.2)
ADVA, 2005a Australian male Vietnam veterans vsAustralian population—incidence 756 1.3 (1.2–1.4)
  Navy 173 1.4 (1.2–1.6)
  Army 510 1.2(1.2–1.4)
  Air Force 73 1.4(1.1–1.7)
ADVA, 2005b Australian male Vietnam veterans vsAustralian population—mortality 111 1.1(0.9–1.3)
  Navy 35 1.6 (1.0–2.1)
  Army 66 1.0 (0.7–1.2)
  Air Force 10 1.0 (0.5–1.8)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
AIHW, 1999 Australian Vietnam veterans—incidence
(validation study)
  Expected number
of exposed cases (95% CI)
    483 380 (342-418)
CDVA, 1998a Australian Vietnam veterans (men)—self- 2,689 380 (342-418)
  reported incidence    
CDVA, 1998b Australian Vietnam veterans (women)—self- 7 3 (1-8)
  reported incidence    
CDVA, 1997a Australian Vietnam veterans (men) 51 1.3 (0.9-1.7)
Australian Conscripted Army National Service (deployed vs nondeployed) All COIs
ADVA, 2005c Australian male conscripted Army National
Service Vietnam-era veterans—deployed vs nondeployed
   
  Incidence 204 1.1 (0.9-1.4)
  Mortality 14 0.6 (0.3-1.1)
CDVA, 1997b Australian National Service Vietnam veterans 16 0.5 (0.2-1.3)
OCCUPATIONAL
IARC Phenoxy Herbicide Cohort (mortality vs national mortality rates)
All COIs
Kogevinas et al., 1997 IARC cohort, male and femable workers exposed to any phenoxy herbicide or chlorophenol 9 0.6 (0.3-1.2)
  Exposed to highly chlorinated PCDDs 5 0.5 (0.2-3.2)
  Not exposed to highly chlorinated PCDDs 4 0.0 (0.3-2.4)
Dow Chemical Company—Midland, MI (included in [ARC and NIOSH cohorts) All COIs
Collins et al., 2009a Trichlorophenol workers 2 0.6 (0.1-2.3)
Collins et al., 2009b Pentachlorophenol workers 1 0.7 (0.0-4.0)
Danish Production Workers (included in I ARC cohort) Dioxin, phenoxy herbicides
Lynge, 1993 Danish production workers—updated incidence 4 4.3 (1.2-10.9)
Dutch Production Workers (included in IARC cohort) Dioxin, phenoxy herbicides
Hooiveld et al., 1998 Dutch chemical production workers (included in IARC cohort) 1 2.9 (0.1-15.9)
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort) Dioxin, Phenoxy
Herbicides
McBride et al., 2009a 1,599 production workers (male and female) vs national rates—mortality 1969 through 2004    
  Ever-exposed workers 2 1.0 (0.1-3.7)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
Hansen et al., 2007 Dainish gardeners—incidence
(skin, ICD-7 190-191)
   
  10-yr follow-up (1975-1984) reported in Hansen et al. (1992) 31 1.3 (0.9-1.8)
  25-yr follow-up (1975-2001)    
  Born before 1915 (high exposure) 28 0.9 (0.6-1.4)
  Born 1915-1934 (medium exposure) 36 0.6 (0.4-0.9)
  Born after 1934 (low exposure) 5 0.3 (0.1-0.7)
’t Mannetje at al., 2005 New Zealand phenoxy herbicide producers,    
  sprayers—mortality    
  Phenoxy herbicide producers (men and women) 0 0.0 (0.0-3.0)
  Phenoxy herbicide sprayers ( > 99% men) 1 0.6 (0.0-3.4)
Agricultural Health Study Herbicides
Dennis et al., 2010 AHS (licensed, male pesticide    
  applicators)—150 cutaneous melanomas among 24.704 pesticide applicators    
  Ever-exposed to arsenic-based pesticides vs never-exposed   1.3 (0.7-2.4)
  Ever used lead arsenate insecticide   1.2 (0.6-2.3)
Samanic et al., 2006 Pesticide applicators in AMS—melanoma    
  incidence from enrollment through 2002 Dicamba—lifetime days exposure    
  None 32 1.0
  1– <20 10 1.0 (0.5-2.1)
  20– <56 18 1.6 (0.8-3.0)
  56– < 116 6 0.7 (0.3-1.8)
  ≥ 116 6 0.8 (0.3-2.1)
p-trend = 0.5l
Alavanja et al., 2005 US AHS—incidence    
  Private applicators (men and women) 100 1.0 (0.8-1.2)
  Spouses of private applicators ( > 99%women) 67 1.6 (1.3-2.1)
  Commercial applicators (men and women) 7 1.1 (0.4-2.2)
Blair et al.,2005a US AHS    
  Private applicators (men and women) 13 0.7 (0.4-1.3)
  Spouses of private applicators 2 0.4 (0.1-1.6)
  ( > 99%women)    
Other Agricultural Workers     Herbicides
Blair et al., 1993 US farmers in 23 states    
  White men 244 1.0 (0.8-1.1)
  White women 5 1.1 (0.4-2.7)
Ronco et al., 1992 Danish workers—incidence    
  Men 72 0.7 (p < 0.05)
  Women 5 1.2 (nr)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
Wigle et al., 1990 Canadian farmers 24 1.1 (0.7-1.6)
Wiklund, 1983 Swedish male and female agricultural   99% CI
  workers—incidence 268 0.8 (0.7-1.0)
Other Studies of Herbicide and Pesticide Applicators Herbicides
Swaen et al., 2004 Dutch licensed herbicide applicators    
  Melanoma, squamous-cell carcinoma, unknown skin cancer
(mortality presumably attributable to melanoma)
5 3.6 (1.2-8.3)
Torchio et al., 1994 Italian licensed pesticide users 9 1.2 (0.6-2.3)
Magnani el al., 1987 UK case—control    
  Herbicides nr 1.2 (0.4-4.0)
  Chlorophenols nr 0.9 (0.4-2.3)
Forestry Workers Herbicides
Thörn et al., 2000 Swedish lumberjack workers exposed to    
  Women 1 3.5 (0.1-19.2)
  Men 0 nr
Hertzman et al., 1997 British Columbia sawmill workers    
  Incidence 38 1.0 (0.7-1.3)
  Mortality 17 1.4 (0.9-2.0)
Paper and Pulp Workers Dioxins
McLean et al., 2006 IARC cohort of pulp and paper workers
Exposure to nonvolatile organochlorine
   
  Never 20 0.8 (0.5-1.3)
  Ever 21 1.2 (0.7-1.8)
ENVIRONMENTAL
Seveso, Italy Residential Cohort

TCDD
Consonni et al., 2008 Seveso residents—25-yr follow-up—men, women    
  Zone A 1 3.1 (0.4-22.0)
  Zone B 2 1.0 (0.2-3.9)
  Zone R 12 0.8 (0.4-1.5)
Pesatori et al., 2009 Seveso—20-yr follow-up to 1996—incidence    
  Zone A 1 1.6 (0.2-11.6)
  Zone B 2 0.5 (0.1-2.0)
  Zone R 19 0.7 (0.4-1.1)
Bertazzi et al., 2001 Seveso residents—20-yr follow-up    
  Zones A, B—men 1 1.5 (0.2-12.5)
  women 2 1.8 (0.4-7.3)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
Bertazzi et al., 1997 Seveso residents—I5-yr follow-up
Zone A—women 1 9.4(0.1-52.3)
Zone R—men 3 1.1(0.2-3.2)
                women 3 0.6(0.1-1.8)
Bertazzi et al.. Seveso residents—10-yr follow-up
1989a Zones A, B, R—men 3 3.3(0.8-13.9)
                            women 1 0.3(0.1-2.5)
Other Environmental Studies
Svensson et al., 1995 Swedish fishermen (men and women) Organochlorine
compounds
East coast compounds
Incidence 0 0.0 (0.0-0.7)
Mortality 0 0.0(0.0-1.7)
West coast
Incidence 20 0.8(0.5-1.2)
Mortality 6 0.7(0.3-1.5)

ABBREVIATIONS: ACC, Army Chemical Corps; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VA, US Department of Veterans Affairs.

aCohorts are male, and outcome mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

mortality were compared in people who served in Vietnam (2,872) and those who did not (2,737). In comparing the Vietnam cohort with the nondeployed cohort, a moderate but not statistically significant increase in risk of malignant skin cancer was observed (adjusted RR = 1.52, 95% CI 0.37–6.20). In comparing mortality with that in males in the US population, the risk of skin cancer was slightly increased in both veteran cohorts (SMR = 1.33, 95% CI 0.43–3.10 for Vietnam veterans; SMR = 1.31, 95% CI 0.36–3.36 for the nondeployed veterans). Analyses of examining those who reported spraying herbicides in Vietnam (compared with veterans who reported no spraying) did not measure risk of mortality from malignant skin cancer associated with herbicide exposure.

A cohort study of Australian Vietnam veterans (O’Toole et al., 2009) was conducted in 1990–1993 and re-examined in 2005–2006. In the original assessment, 641 Australian Vietnam veterans were randomly selected for participation from the list of Army veterans deemed eligible for previous studies of Agent Orange, and 450 are included in the more recent assessment. Interviewers ad-

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

ministered the Australian Bureau of Statistics National Health Survey that assessed physical health and associated risk factors, a 32-item combat index, an assessment for combat-related posttraumatic stress disorder and an assessment of general psychiatric status. The prevalence of a variety of self-reported health conditions was compared with that in the general population, and SMRs were calculated (standardized to the Australian male population in 5-year age groups). Compared with the general population, Vietnam veterans had a higher prevalence of melanoma (SMR = 4.73, 95% CI 1.25–8.21). Given the self-reported outcome, the possibility that nonmelanoma skin cancers were misclassified into the melanoma category cannot be ruled out.

Occupational Studies

McBride et al. (2009a,b) evaluated mortality from cancers in an occupational cohort of TCP workers in New Zealand, a set of the IARC cohort (see Chapter 5). Workers were employed during the period 1969–1988, and SMRs were calculated by using the New Zealand population as the comparison group. Exposure was classified as ever exposed or never exposed to TCDD. In McBride et al. (2009a), two cases of malignant melanoma were identified in the ever-exposed group and none in the never-exposed group. When those cases were compared with the expected number of deaths in the New Zealand population, no association was observed (SMR = 1.0, 95% CI 0.1–3.7) in the ever-exposed workers. Results in McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Collins et al. (2009a,b) reported the mortality experience in the occupational cohort in the Midland, Michigan, Dow Chemical plant previously included in analyses of the NIOSH mortality cohort, as reported by Fingerhut et al. (1991) and added to the expanded IARC phenoxy herbicide cohort (Kogevinas et al., 1997). TCP was produced at the plant in 1942–1979 and PCP in 1937–1980. Job histories of the workers were used to determine the amount of time that they spent in the TCP or PCP units. Mortality in the workers and SMRs were calculated by using the US population as the referent. One death from malignant melanoma was identified in the PCP-only workers (SMR = 0.7, 95% CI 0.0–4.0) (Collins et al., 2009b). In a separate analysis of the TCP workers (Collins et al., 2009a), two deaths from malignant melanoma were identified (SMR = 0.6, 95% CI 0.1–2.3); one of the deaths occurred in a worker who was exposed to both TCDD and PCP, and when this death was removed from the analysis, the SMR was reduced to 0.4 (95% CI 0.0–2.0). As pointed out in follow-up correspondence (Collins et al., 2010; Villeneuve and Steenland, 2010) and discussed in detail in Chapter 5, different latency models, different dose–response models, and in-depth analysis of the serum concentrations could alter some of the results reported in this analysis; given the small number of deaths from malignant melanoma, such methodologic considerations are unlikely to alter the conclusions regarding melanoma.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

A possible association between pesticide use and melanoma was also evaluated in the AHS (Dennis et al., 2010). The AHS is described in Chapter 5. Among the pesticides of interest, any history of exposure to arsenic-based pesticides was weakly associated with melanoma in comparison with applicators who reported never using these types of pesticides (adjusted OR = 1.3, 95% CI 0.7–2.4). A similar result was observed for applicators who reported ever using lead arsenate insecticides (OR = 1.2, 95% CI 0.6–2.3).

Environmental Studies

Cancer incidence was re-evaluated in the Seveso cohort for the period 1977– 1996 (Pesatori et al., 2009). The Seveso cohort, described in Chapter 5, includes all residents of Seveso at the time of the accident and those who migrated into or were born in the area in the 10-year period after the accident. A total of 218,761 residents are included in the analysis: 723 in the high-exposure zone (Zone A), 4,821 in the medium-exposure zone (Zone B), 31,643 in the low-exposure zone (Zone R), and the remainder who lived in the noncontaminated zone. A total of 22 melanoma cases were identified: 1 in Zone A, 2 in Zone B, and 19 in Zone R. Compared with the incidence in the reference zone, melanoma incidence was higher, but imprecise, in Zone A (RR = 1.62, 95% CI 0.23–11.61) and lower in Zones B and R (RR = 0.50, 95% CI 0.12–2.03; RR = 0.71, 95% CI 0.44–1.14, respectively).

Biologic Plausibility

There have been no new studies of animal models of skin cancer. TCDD and related herbicides have not been found to cause melanoma in animal models. In general, rodents, which are used in most toxicology studies, are not a good model for studying melanoma. TCDD does produce nonmelanoma skin cancers in animal models (Wyde et al., 2004). As discussed elsewhere in this chapter, TCDD is a known tumor-promoter and could act as a promoter for skin-cancer initiators, such as UV radiation. Ikuta et al. (2009) examined the physiologic role of the AHR in human skin and theorized that overactivation can lead to skin cancers, but they provided no evidence that melanoma incidence is increased after TCDD exposure.

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

No association between the chemicals of interest and melanoma was observed in any of the three new occupational studies. Although the risk of melanoma was increased in those living in the highest-exposure zone in the Seveso

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

cohort, this finding was based on only one melanoma case. The new studies do not provide evidence to support moving melanoma to the category of limited or suggestive evidence. Of the two new Vietnam veteran studies, no association was observed in the ACC study, which was based on five cases of malignant skin cancer in the Vietnam cohort and four cases in the non-Vietnam cohort, as reflected in the similar RRs in the two cohorts when mortality was compared with that in the general population. An increased risk of melanoma was reported in the O’Toole study of Australian Vietnam veterans, but the prevalence of self-reported melanoma in the veteran population (1.6%) suggests that nonmelanoma skin cancer may have been misclassified as melanoma.

The committee responsible for Update 2006 was unable to reach a consensus as to whether there was limited or suggestive evidence of an association between exposure to the chemicals of interest and melanoma or inadequate or insufficient evidence to determine whether there is an association. That committee recognized that the findings from the AFHS, including the evaluation of TCDD measurements and melanoma (Akhtar et al., 2004; Pavuk et al., 2005), were of prime interest. However, the data from the final AFHS examination cycle indicate that many more melanoma cases were diagnosed in the comparison veterans than in the Ranch Hand subjects, so the committee responsible for Update 2006 recommended that the Akhtar et al. analyses be rerun on the final AFHS dataset. The final data on the Ranch Hand and comparison subjects still have not been analyzed in a satisfactory and uniform manner, so the present committee also strongly encourages such an analysis to provide documentation of the full melanoma experience revealed by the AFHS and to permit definitive evaluation of the possible association between the chemicals of interest and melanoma.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and melanoma.

SKIN CANCER—BASAL-CELL CANCER AND SQUAMOUS-CELL CANCER (NONMELANOMA SKIN CANCERS)

The preceding section on melanoma presented background information on nonmelanoma skin cancers (ICD-9 173).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

exposure to the chemicals of interest and skin cancer, and additional information available to the committee responsible for Update 1996 did not change that conclusion. The committee responsible for Update 1998 considered the literature on nonmelanocytic skin cancer separately from that on melanoma and concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and basal-cell or squamous-cell cancer. The committees responsible for Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion. Table 7-20 summarizes the relevant studies.

Update of the Epidemiologic Literature

No Vietnam-veteran studies or occupational studies concerning exposure to the chemicals of interest and basal-cell or squamous-cell cancer have been published since Update 2006.

Environmental Studies

Cancer incidence was re-evaluated in the Seveso cohort for the period 1977– 1996 (Pesatori et al., 2009). The Seveso cohort, described in Chapter 5, includes all residents of Seveso at the time of the accident and those who migrated into or were born in the area in the 10-year period after the accident. A total of 218,761 residents are included in the analysis: 723 in the high-exposure zone (Zone A), 4,821 in the medium-exposure zone (Zone B), 31,643 in the low-exposure zone (Zone R), and the remainder who lived outside the zone of exposure. A total of 96 skin-cancer cases were identified; 3 in Zone A, 5 in Zone B, and 88 in Zone R. Compared with the incidence in the reference zone, the incidence of skin cancer was increased, but imprecise, in Zone A (RR = 1.39, 95% CI 0.45–4.32) and decreased in Zones B and R (RR = 0.37, 95% CI 0.15–0.90; RR = 0.93, 95% CI 0.75–1.17, respectively).

Biologic Plausibility

There are no new studies on animal models of skin cancer to report. TCDD has been shown to produce nonmelanoma skin cancers in animal models (Wyde et al., 2004). As discussed elsewhere in this chapter, TCDD is a known tumor-promoter and could act as a promoter for skin-cancer initiators, such as UV radiation, but no experiments have been conducted specifically to support this potential mechanism.

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-20 Selected Epidemiologic Studies—Other Nonmelanoma (Basal-Cell and Squamous-Cell) Skin Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS
US Air Force Health Study—Ranch Hand veterans vs SEA veterans All COIs
Pavuk et al., 2005 While Air Force comparison subjects only (basal cell and squamous cell) —incidence    
  Serum TCDD (pg/g). based on model with exposure variable loge(TCDD)    
  Per unit increase of -loge(TCDD) Quaniles (pg/g) 253 1.2 (0.9-1.4)
  0.4-2.6 50 nr
  2.6-3.8 59 1.2 (0.8-1.8)
  3.8-5.2 71 1.5 (1.1-2.3)
  >5.2 73 1.4 (0.9-2.0)
  Number of years served in SEA    
  Per year of service Quaniles (years in SEA) 253 1 (0.9-1.1)
  0.8-1.3 55 nr
  1.3-2.1 50 0.9 (0.6-1.4)
  2.1-3.7 73 1.1 (0.8-1.6)
  3.7-16.4 75 1.2 (0.8-1.7)
AFHS, 2000 Air Force Ranch Hand veterans—incidence    
  Basal-cell carcinoma 121 1.2 (0.9-1.6)
  Squamous-cell carcinoma 20 1.5 (0.8-2.8)
Wolfe et al., 1990 Air Force Ranch Hand veterans—incidence    
  Basal cell carcinoma 78 1.5 (1.0-2.1)
  Squamous cell carcinoma 6 1.6 (0.5-5.1)
Australian Vietnam Veterans vs Australian Population All COIs
CDVA,1998a Australian Vietnam veterans (men)—self-reported incidence 6,936 nr
CDVA,1998b Australian Vietnam veterans (women)—self-reported incidence 37 nr
OCCUPATIONAL    
IARC Phenoxy Herbicide Cohort (mortality vs national mortality) Dioxin, phenoxy herbicides
Kogevinas et al., 1997 IARC cohort, male and female workers exposed to any phenoxy herbicide or chlorophenol 4 0.9 (0.3-2.4)
  Exposed to highly chlorinated PCDDs 4 1.3 (0.3-3.2)
  Not exposed to highly chlorinated PCDDs 0 0.0 (0.0-3.4)
Dow Production Workers—Midland. MI (included in IARC NTOSH cohorts) Dioxin, phenoxy herbicides
Burns et al., 2001 Dow 2,4-D production workers    
  Nonmelanoma skin cancer 0 nr
United Kingdom Production Workers (included in IARC cohort ) Dioxin, phenoxy herbicides
Coggon et al., 1986 British MCPA production workers 3 3.1 (0.6-9.0)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Agricultural Workers   Herbicides
Hansen et al., 2007 Danish gardener;—incidence
(skin, ICD-7 190-191)
   
  10-yr follow-up (1975-1984) reported inHansen etal. (1992) 31 1.3 (0.9-1.8)
  25-yr follow-up (1975-2001)    
  Born before 1915 (high exposure) 28 0.9 (0.6-1.4)
  Born 1915-1934 (medium exposure) 36 0.6 (0.4-0.9)
  Born after 1934 (low exposure) 5 0.3 (0.1-0.7)
Blair et al., 1993 US farmers in 23 states    
  Skin (including melanoma)    
  White men 425 1.1 (1.0-1.2)
  White women 6 1.0 (0.4-2.1)
Ronco et al., 1992 Danish workers—incidence    
  Men—self-employed 493 0.7 <p < 0.05)
  employee 98 0.7 (p< 0.05)
  Women—self-employed 5 0.3 (p< 0.05)
  employee 10 0.9 <nr)
  family worker 90 0.6 (p< 0.05)
Wiklund, 1983 Swedish male and female agricultural   99%CI
  workers—incidence 708 1.1 (1.0-1.2)
Studies of Herbicide and Pesticide Applicators Herbicides
Swaen et al., 2004 Dutch licensed herbicide applicators    
  Melanoma, squamous-cell carcinoma,
unknown skin cancer (mortality presumably attributable to melanoma)
5 3.6 (1.2-8.3)
Torchio et al., 1994 Italian licensed pesticide users 3 0.6 (0.1-1.8)
Zhong and Rafnsson. 1996 Icelandic pesticide users (men, women —incidence)    
  Men 5 2.8 (0.9-6.6)
Forestry Workers   Herbicides
Thörn et al., 2000 Swedish lumberjacks exposed to phenoxyacetic
herbicides—incidence
   
  Foremen 1 16.7 (0.2-92.7)
ENVIRONMENTAL
Seveso, Italy Residential Cohort   TCDD
Pesatori et al., 2009 Seveso—20-yr follow-up to 1996—incidence    
  Zone A 3 1.4 (0.5-4.3)
  Zone B 5 0.4 (0.2-0.9)
  Zone R 88 0.9 (0.8-1.2)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
Bertazzi et al., 1993 Seveso residents—10-yr follow
-up—incidence
   
  Zone A—men 1 2.4 (0.3-17.2)
                   women 1 3.9 (0.5-28.1)
  Zone B—men 2 0.7 (0.2-2.9)
                   women 2 1.3 (0.3-5.1)
  Zone R—men 20 1.0 (0.6-1.6)
                   women 13 1.0 (0.6-1.9)
Pesatori et al., 1992 Seveso residents—incidence    
  Zones A, B—men 3 1.0 (0.3-3.0)
                   women 3 1.5 (0.5-4.9)
  Zone R—men 20 1.0 (0.6-1.6)
                   women 13 1.0 (0.5-1.7)
Other Environmental Studies Herbicides
Gallagher et al., 1996 Alberta, Canada, residents—squamous-cell    
  carcinoma-incidence    
  All herbicide exposure 79 1.5 (1.0-2.3)
  Low herbicide exposure 33 1.9 (1.0-3.6)
  High herbicide exposure 46 3.9 (2.2-6.9)
  Alberta, Canada, residents—basal-cell carcinoma  
  All herbicide exposure 70 1.1 (0.8-1.7)
Svensson et al., 1995 Swedish fishermen East coast   Organochlorine compounds
  Incidence   2.3 (1.5-3.5)
  Mortality 0 0.0 (0.0-15.4)
  West coast    
  Incidence 69 1.1 (0.9-1.4)
  Mortality 5 3.1 (1.0-7.1)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

aSubjects are male, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Synthesis

In accord with the results of reports previously assessed, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and basal-cell or squamous-cell cancer.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and basal-cell or squamous-cell cancer.

BREAST CANCER

Breast cancer (ICD-9 174 for females, ICD-9 175 for males) is the second-most common type of cancer (after nonmelanoma skin cancer) in women in the United States. ACS estimated that 207,090 women would receive diagnoses of breast cancer in the United States in 2010 and that 39,840 would die from it (Jemal et al., 2010). Overall, those numbers represent about 28% of the new cancers and 15% of cancer deaths in women. Incidence data on breast cancer are presented in Table 7-21.

Breast-cancer incidence generally increases with age. In the age groups of most Vietnam veterans, the incidence is higher in whites than in blacks. Established risk factors other than age include personal or family history of breast cancer and some characteristics of reproductive history—specifically, early menarche, late onset of menopause, and either no pregnancies or first full-term pregnancy after the age of 30 years. A pooled analysis of six large-scale prospective studies of invasive breast cancer showed that alcohol consumption over the range of consumption reported by most women was associated with a small linear increase in incidence in women (Smith-Warner et al., 1998). It is now generally accepted that breast-cancer risk is increased by prolonged use of hormone-replacement therapy, particularly preparations that combine estrogen and progestins (Chlebowski et al., 2003). The potential of other personal behavioral and environmental factors (including use of exogenous hormones) to affect breast-cancer incidence is being studied extensively.

Most of the roughly 10,000 female Vietnam veterans who were potentially exposed to herbicides in Vietnam are approaching or have recently reached meno-

TABLE 7-21 Average Annual Incidence (per 100,000) of Breast Cancer in United Statesa

55-59 Years Old 60-64 Years Old 65-69 Years Old
All Races While Black All Races While Black All Races While Black
Men 1.9 2.9 3.3 3.3 7.2 4.9 5.3 4.1 1.9
Women 283.2 289.4 273.6 357.1 369.8 339.6 412.1 430.9 376.9

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2004–2008 (NCI, 2010).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×



pause. Given the high incidence of breast cancer in older and postmenopausal women in general, it is expected on the basis of demographics alone that the breast-cancer burden in female Vietnam veterans will increase in the near future.

The vast majority of breast-cancer epidemiologic studies involve women, but the disease also occurs rarely in men, with 1,970 new cases expected in 2010 (Jemal et al., 2010). Reported instances of male breast cancer are noted, but the committee’s conclusions are based on the studies in women.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and breast cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. After consideration of a new study with positive findings for association of breast cancer with 2,4-D exposure in female farm workers in California (Mills and Yang, 2005)—in conjunction with the earlier findings of Kang et al. (2000), Kogevinas et al. (1997), Revich et al. (2001), and Warner et al. (2002)—the committee responsible for Update 2006 was unable to reach consensus as to whether there might be limited or suggestive evidence of an association between the chemicals of interest and breast cancer. After reviewing studies that had null findings on mortality from breast cancer in the important cohorts of female Vietnam-era veterans (Cypel and Kang, 2008) and Seveso residents (Consonni et al., 2008), all members of the committee for Update 2008 concurred that breast cancer should remain in the category of inadequate or insufficient evidence of an association.

Table 7-22 summarizes the relevant research.

Update of the Epidemiologic Literature

No Vietnam-veteran studies concerning exposure to the chemicals of interest and breast cancer have been published since Update 2008.

Occupational Studies

McBride et al. (2009a,b) extended their earlier research by including additional exposed and unexposed workers, constructing exposure estimates based on serum dioxin (TCDD) concentrations in exposed and unexposed workers, and extending follow-up by 4 years. The authors reported on the mortality experience of 1,599 workers employed during 1969–1988 in a New Zealand site that manufactured TCP and a nearby field station where 2,4,5-T was occasionally used and tested (McBride et al., 2009a). Measurements of 346 blood samples confirmed higher exposure than New Zealand background. The study was limited

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-22 Selected Epidemiologic Studies—Breast Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
VIETNAM VETERANS    
US CDC Vietnam Experience Study    
Boehmer et al., 2004 Follow-up of CDCVES 0 nr
US VA Cohort of Eemale Vietnam Veterans   All COIs
Cypel and Kang, 2008 US Vietnam veterans—women 57 1.0 (0.7-1.4)
  Vietnam-veteran nurses 44 0.9 (0.6-1.4)
Kang et al., 2000 Female US Vietnam veterans 170 1.2 (0.9-1.5)
Dalager et al., 1995 Female US Vietnam veterans 26 1.0 (0.6-1.8)
Thomas et al.1991 Female US Vietnam veterans 17 1.2 (0.6-2.5)
Australian Vietnam Veterans vs Australian General Population   All COIs
ADVA,2005a Australian male Vietnam veterans vs Australian
popul ation—incidence
7 0.9 (0.4-1.9)
  Navy 1 0.6 (0.0-3.3)
  Army 5 1.0 (0.3-2.2)
  Air Force 1 1.1 (0.0-6.3)
ADVA,2005b Australian male Vietnam veterans vs Australian
population—mortality
4 2.2 (0.6-5.4)
  Navy 1 2.5 (0.0-13.5)
  Army 3 2.5 (0.5-7.2)
  Air Force 0 0.0 (0.0-14.6)
Expected number of exposed cases
CDVA, 1998b Australian Vietnam veterans (women)—self-   (95% CI)
  reported incidence 17 5 (2-11)
CDVA, 1997a Australian military Vietnam veterans (men) 3 5.5 (1.0- > 10.0)
Australian Conscripted Army National Service (deployed vs nondeployed)   All COIs
ADVA, 2005c Australian male conscripted Army National
Service Vietnam era veterans—deployed vs nondeployed
0 nr
  Incidence 0 0.0 (0.0-2.4)
  Mortality nr  
OCCUPATIONAL    
IARC Phenoxy Herbicide Cohort (mortality vs national mortality rates)   Dioxin, phenoxy herbicides
Kogevinas et al., 1993 IARC cohort—women 7 0.9 (0.4-1.9)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
Saracci et al., 1991 IARC cohort—exposed subcohort (men and women)    
  Men 2 3.5 (0.4-12.5)
  Women 1 0.3 (0.0-1.7)
Danish Production Workers (included in IARC cohort)   Dioxin, phenoxy herbicides
Lynge,1985 Danish male and female production    
  workers—incidence    
  Women 13 0.9 (nr)
German Production Workers (included in IARC cohort)   Dioxin, phenoxy herbicides
Manaz et al., 1991 German production workers—men, women    
  Women 9 2.2 (1.0-4.1)
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort)   Dioxin, phenoxy herbicides
McBride et al., 2009a 1,599 production workers (male and female) vs national rates—mortality 1969 through 2004    
  Ever-exposed female workers 2 1.4 (0.2-5.0)
’t Mannetje et al., 2005 Phenoxy herbicide producers    
  Women 1 1.3 (0.0-7.2)
  Men 1 32 (0.8-175)
  Phenoxy herbicide sprayers ( > 99% men) 0 0.0 (nr)
Agricultural Health Study   Herbicides
Alavanja et al., 2005 US AHS—incidence    
  Private applicators (men and women) 27 1.1 (0.7-1.6)
  Spouses of private applicators ( > 99IA- women) 474 1.0 (0.9-1.1)
  Commercial applicators (men and women) 1 0.6 (0.1-3.5)
Engel et al., 2005 US AHS, wives of private applicators—incidence    
  Wives’ own use of phenoxy herbicides 41 0.8 (0.6-1.1)
  2.4-D 4] 0.8 (0.6-1.1)
  Husbands’ use of phenoxy herbicides 110 1.1 (0.7-1.8)
  2,4-D 107 0.9 (0.6-1.4)
  2,4,5-T u 1.3 (0.9-1.9)
  2.4,5-TP 19 2.0 (1.2-3.2)
Blair et al., 2005a US AHS—mortality    
  Private applicators (men and women) 3 0.9 (0.2-2.7)
  Spouses of private applicators ( > 99% women) 54 0.9 (0.7-1.1)
Paper and Pulp Workers   Dioxin
McLean et al., 2006 IARC cohort of pulp and paper workers    
  Exposure to nonvolatile organochlorine compounds    
  Never 21 0.9 (0.6-1.4)
  Ever 32 0.9 (0.6-1.3)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
Other Agricultural Workers   Herbicides
Mills and Yang. 2005 Hispanic agricultural farm workers (women) Cancer diagnosis 1987-1994    
  Low 2.4-D use 12 0.6 (0.2-1.9)
  High 2.4-D use 8 0.6 (0.2-1.7)
  Cancer diagnosis 1995-2001    
  Low 2.4-D use 19 2.2 (1.0-4.9)
  High 2,4-D use 21 2.1 (1.1-4.3)
Duell et al., 2000 Female farm workers, residents in North Carolina    
  Used pesticides in garden 228 2.3 (1.7-3.1)
  Laundered clothes for pesticide user 119 4.1 (2.8-5.9)
Blair et al., 1993 US farmers in 23 states    
  Men—while 18 0.7 (0.4-1.2)
  nonwhite 4 1.7 (0.5-4.4)
  Women—white 71 1.0 (0.8-1.3)
  nonwhite 30 0.7 (0.5-1.0)
Ronco et al., 1992 Danish, Italian farm workers    
  Male farmers 5 0.5 (nr)
  Female farmers 41 0.9 (nr)
  Female family workers 429 0.8 (p< 0.05)
Wiklund, 1983 Swedish agricultural workers—incidence   99% CI
  Men and women 444 0.8 (0.7-0.9)
  Men only or 1.0 (nr)
ENVIRONMENTAL    
Seveso, Italy Residential Cohort
TCDD
   
Consonni et al., 2008 Seveso residents (men and women)—25-yr follow-up    
  Zone A 2 0.6 (0.2-2.4)
  Zone B 13 0.6 (0.3-1.2)
  Zone R 133 0.9 (0.7-1.1)
Pesatori et al., 2009 Seveso—20-yr follow-up to 1996—incidence    
  Zone A 8 1.4 (0.7-2.9)
  Zone B 30 0.9 (0.6-1.2)
  Zone R 249 1.0 (0.9-1.2)
  Zone A only (15+yrs after accident) 5 2.6 (1.1-6.2)
  Zone A only (10-14 yrs after accident) 2 1.4 (0.4-5.7)
  Zone A onlv (5-9 yrs after accident) 1 0.8 (0.1-5.7)
Bertazzi et al., 2001 Seveso residents—20-yr follow-up    
  Zone A, B—females 14 0.7 (0.4-1.3)
Bertazzi et al., 1997 Seveso residents—15-yr follow-up    
  Zone A—women 1 0.6 (0.0-3.1)
  Zone B—women 9 0.8 (0.4-1.5)
  Zone R—women 67 0.8 (0.6-1.0)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
Bertazzi el al., 1993 Seveso residents—10-yr follow-up—incidence    
  Zone A—women 1 0.5 (0.1-3.3)
  Zone B—women 10 0.7 (0.4-1.4)
  Zone R—women 106 1.1 (0.9-1.3)
  men 1 1.2 (0.1-10.2)
Bertazzi el al., 1989b Seveso residents—10-yr follow-up    
  Zone A—women 1 1.1 (0.1-7.5)
  Zone B—women 5 0.9 (0.4-2.1)
  Zone R—women 28 0.6 (0.4-0.9)
Seveso Women's Health Study   Dioxin
Warner et al., 2002 SWIIS—981 women who were infants to 40 yrs
of age when exposed—incidence
   
  With 10-fold increase in TCDD 15 2.1 (1.0-4.6)
Chapaevsk, Russia Residential Cohort      
Revich et al.,2001 Residents of Chapaevsk, Russia—women 58 2.1 (1.6-2.7)
Other Knvironmental Studies    
Turunen et al., 2008 Finnish fishermen and spouses   Dioxin
  Fishermen's wives 18 0.810.5-1.3)
Viel et al., 2008 Case—control study in Besancon,    
  France—incidence    
  Residence in zones of dioxin exposure around solid-waste incinerator    
  Women, 20-59 yrs of age    
  Very low 41 1.0
  Low 81 1.1 (0.7-1.6)
  Intermediate 64 1.3 (0.8-1.9)
  High 11 0.9 (0.4-1.8)
  Women, at least 60 yrs of age    
  Very low u 1.0
  Low 111 0.9 (0.6-1.3)
  Intermediate 72 1.0 (0.7-1.4)
  High 4 0.3 (0.1-0.9)
Teilelbaum et al., 2007 Case—control study in Long Island, New   Pesticides
  York—incidence    
  Used lawn and garden pesticides    
  Never 240 1.0
  Ever 1,254 1.3 (1.1-1.6)
  Product for weeds 1,109 1.4 (1.2-1.8)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
Reynolds et al., 2005 Women undergoing breast biopsies in San   PCDDs, PCDFs
  Francisco area hospitals—79 breast-cancer cases vs 52 controls with benign breast conditions—incidence    
  Total TEQs Ipg/g) in adipose breast tissue    
  ≤ 14.0 24 1.0
  14.1-20.9 22 0.7 (0.3-1.9)
  ≤ 21.0 33 0.3 (0.3-2.0)
p-trend = 0.99
Reynolds et al., 2004 California Teachers Study cohort   2.4-D, cacodylic acid
  Residential proximity to use of "endocrine
disruptors" (including 2.4-D, cacodylic acid) Quartiles of use (lb/mi1)
   
  < 1 1,027 1.0
  1-21 274 1.0 (0.8-1.1)
  22-323 114 0.9 (0.7-1.1)
  ≥ 324 137 1.0 (0.9-1.3)
Bagga et al., 2000 Women receiving medical care in Woodland 73 Organochlorines
  Hills, California   nr
Demers et al., 2000 Women in Quebec City—newly diagnosed   Organochlorines
    314 nr
Holford et al., 2000 Patients at Yale-New Haven hospital with breast nr dl-PCBs
  Related surgery; dioxin-like congener 156   0.9 (0.8-1.0)
Høyer et al., 2000 Female participants in Copenhagen City Heart   Organochlorines
  Study 195 Overall survival relative risk
2.8 (1.4—5.6)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TP, 2 (2,4,5-trichlorophenoxy) propionic acid; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCDF, polychlorinated dibenzofurans; SWHS, Seveso Women’s Health Study; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TEQ, toxicity equivalent quotient; VA, US Department of Veterans Affairs; VES, Vietnam Experience Study.

aSubjects are female, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

by a high loss of follow-up (21%). The SMR for ever-exposed female workers was 1.4 ((95% CI 0.2–5.0) on the basis of two observed death. It should be noted that the authors reported increased SMRs for other cancers previously found to be associated with dioxins. Results in McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×



Environmental Studies

Pesatori et al. (2009) updated mortality and cancer-incidence results for the study conducted among residents of Seveso, Italy. Poisson regression models were used to calculate sex-, age-, and period-adjusted rate ratios. The use of exposure zones (A, B, and R) to define individual exposure introduces misclassification that is likely to be random and to attenuate associations. However, later serum measurements on a subset confirmed the utility of assigning zone of residence as a proxy for exposure to TCDD.

The rate ratio for Zone A was increased (1.43, 95% CI 0.71–2.87), whereas the RRs for Zones B and R were 0.85 (95% CI 0.59–1.22) and 1.00 (95% CI 0.88–1.15), respectively. Analyses accounting for time since acute high exposure to TCDD found a significantly increased incidence of breast cancer 15 or more years after the accident in Zone A (RR 2.57, 95% CI 1.07–6.20) on the basis of five cases. The RR 10–14 years after the accident was 1.42 (95% CI 0.35–5.68), and for 5–9 years after the accident it was 0.81 (95% CI 0.11–5.74) on the basis of two and one deaths, respectively.

Turunen et al. (2008) conducted a mortality study of Finnish fishermen and fishermen’s wives. The cohort consisted of 6,410 Finnish professional fisherman and their wives (4,260). The cohort was linked with Statistics Finland’s national cause-of-death data for 1980–2005. SMRs were calculated by using national mortality figures. The SMR for breast cancer in fishermen’s wives was not increased (SMR = 0.80, 95% CI 0.47–1.25) on the basis of 18 observed deaths.

Dai and Oyana (2008) conducted an epidemiologic study with an ecologic study design to explore the spatial variation in breast-cancer incidence in Midland, Saginaw, and Bay Counties in Michigan. They used spatial modeling and soil concentrations to assign exposure on the basis of ZIP codes. The authors reported that there was a temporal increase in the number of breast-cancer cases from 1985 to 2002; that ZIP codes with the highest rates were clustered in or near contaminated areas, adjusted for age; and that living near or close to contaminated areas was spatially associated with increased breast-cancer incidence. The study has several limitations, the most important of which is that it did not collect information on individual exposure to dioxins. Therefore, the relevance of the study to the VAO report is low.

Biologic Plausibility

The experimental evidence indicates that 2,4-D, 2,4,5-T, and TCDD are weakly genotoxic at most. However, TCDD is a demonstrated carcinogen in animals and is recognized as having carcinogenic potential in humans because of the mechanisms discussed in Chapter 4.

With respect to breast cancer, studies performed in laboratory animals (Sprague-Dawley rats) indicate that the effect of TCDD may depend on the age

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

of the animal. For example, TCDD exposure was found to inhibit mammary-tumor growth in the adult rat (Holcombe and Safe, 1994) but to increase tumor growth in the neonatal rat (21 days old) (Desaulniers et al., 2001). Other studies have failed to demonstrate an effect of TCDD on mammary-tumor incidence or growth (Desaulniers et al., 2004).

Fenton (2009) recently reviewed the literature on TCDD and breast cancer and suggested that a mechanism may be related to endocrine disruption, which might indicate a close association between the development of mammary cancers and mammary gland differentiation. Agents capable of disrupting the ability of the normal mammary epithelial cell to enter or maintain its appropriate status (a proliferative, differentiated, apoptotic state), to maintain its appropriate architecture, or to conduct normal hormone (estrogen) signaling are likely to act as carcinogenic agents (Fenton, 2006; McGee et al., 2006). In that light, it is interesting that postnatal exposure of pregnant rats to TCDD has been found to alter proliferation and differentiation of the mammary gland (Birnbaum and Fenton, 2003; Vorderstrasse et al., 2004). Jenkins et al. (2007) used a carcinogen-induced rat mammary-cancer model to show that prenatal exposure to TCDD alters mammary gland differentiation and increases susceptibility to mammary cancer by altering the expression of estrogen-receptor genes and of genes involved in oxidative-stress defense. Thus, the effect of TCDD may depend on the timing of the exposure and on the magnitude of gene expression at the time of exposure; TCDD may influence mammary-tumor development only if exposure to it occurs during a specific window during breast development. The breast is the only human organ that does not fully differentiate until it becomes ready for use; nulliparous women have less-differentiated breast lobules, which are presumably more susceptible to carcinogenesis.

Activation of the AHR by dioxin or by the nondioxin ligand indole-3-carbinol is believed to protect against breast cancer by mechanisms that disrupt migration and metastasis (Bradlow, 2008; Hsu et al., 2007).

TCDD has been shown to modulate the induction of DNA chain breaks in human breast-cancer cells by regulating the activity of the enzymes responsible for estradiol catabolism and generating more reactive intermediates, which might contribute to TCDD-induced carcinogenesis by altering the ratio of 4-OH-estradiol to 2-OH-estradiol (Lin et al., 2007, 2008). A similar imbalance in metabolite ratios has been observed in pregnant Taiwanese women, in whom the ratio of 4-OH-estradiol to 2-OH-estradiol, a breast-cancer–risk marker, decreased with increasing exposure to TCDD (Wang et al., 2006). Expression of CYP1B1, the cytochrome P450 enzyme responsible for 2-OH-estradiol formation, but not CYP1A1, the one responsible for 4-OH estradiol formation, was found to be highly increased in premalignant and malignant rat mammary tissues in which the AHR was constitutively active in the absence of ligand (Yang et al., 2008). On the basis of recent mechanistic data, it has been proposed that the AHR contributes to mammary-tumor cell growth by inhibiting apoptosis while promoting

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

transition to an invasive, metastatic phenotype (Marlowe et al., 2008; Schlezinger et al., 2006).

Recent evidence has shown that AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the IL-6 cytokine, which has tumor-promoting effects in numerous tissues, including breast tissue, so TCDD might promote carcinogenesis in these tissues (DiNatali et al., 2010; Hollingshead et al., 2008). Degner et al. (2009) have shown that AHR ligands can upregulate the expression of COX-2, and this may lead to a proinflammatory environment that can support tumor development.

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

In the early 1990s, it was suggested that exposure to some environmental chemicals, such as organochlorine compounds, might play a role in the etiology of breast cancer through estrogen-related pathways. The relationship between organochlorines and breast-cancer risk has been studied extensively especially in the last decade; TCDD and dioxin-like compounds have been among the organochlorines so investigated. Today, there is no clear evidence of a causal role of most organochlorines in human breast cancer (Salehi et al., 2008).

Because of concerns raised by a combination of a new study that had good exposure assessment and positive findings (Mills and Yang, 2005) and several earlier studies (Kang et al., 2000; Kogevinas et al., 1997; Revich et al., 2001; Warner et al., 2002), some members of the committee responsible for Update 2006 believed that there was suggestive evidence of an association, but that committee was unable to reach a consensus. After reviewing new studies that had null findings on mortality from breast cancer in the important cohorts of female Vietnam-era veterans (Cypel and Kang, 2008) and Seveso residents (Consonni et al., 2008), the committee for Update 2008 readily reached consensus that breast cancer should remain in the category of inadequate or insufficient evidence of an association.

New evidence since the last VAO report includes the updated cancer- incidence results for residents of Seveso (Pesatori et al., 2009). The most compelling evidence from the recent study was the increased RR in Zone A for breast-cancer incidence after time since the accident was accounted for: 15 or more years and 10–14 years after the accident, the RR for breast cancer was RR 2.57 (95% CI 1.07–6.20), 1.42 (95% CI 0.35–5.68), respectively, whereas it was 0.81 (95% CI 0.11–5.74) 5–9 years after the accident. Accounting for latency between exposure and outcome led to stronger associations. However, despite evidence from the Seveso cohort, results from the occupational study by McBride et al. (2009a) did not support an increased risk of mortality from breast cancer.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Conclusion

Having considered the new evidence and the results of studies reviewed in previous updates, the present committee concludes that there is inadequate or insufficient evidence to determine whether there is an association (either positive or negative) between exposure to the chemicals of interest and breast cancer.

CANCERS OF THE FEMALE REPRODUCTIVE SYSTEM

This section addresses cancers of the cervix (ICD-9 180), endometrium (also referred to as the corpus uteri; ICD-9 182.0–182.1, 182.8), and ovary (ICD-9 183). Other cancers of the female reproductive system that are infrequently reported separately are unspecified cancers of the uterus (ICD-9 179), placenta (ICD-9 181), fallopian tube and other uterine adnexa (ICD-9 183.2–183.9), and other female genital organs (ICD-9 184); findings on these cancers are included in this section. It also presents statistics on other cancers of the female reproductive system. ACS estimates of the numbers of new female reproductive-system cancers in the United States in 2010 are presented in Table 7-23, with genital-system cancers representing roughly 10% of new cancer cases and 12% of cancer deaths in women (Jemal et al., 2010).

Cervical cancer occurs more often in blacks than in whites, whereas whites are more likely to develop endometrial and ovarian cancer. The incidence of endometrial and ovarian cancer is increased in older women and in those with positive family histories. Use of unopposed estrogen-hormone therapy and obesity, which increases endogenous concentrations of estrogen, both increase the risk of endometrial cancer. Human papilloma virus (HPV) infection, particularly infection with HPV types 16 and 18, is the most important risk factor for cervical cancer. Use of oral contraceptives is associated with a substantial reduction in the risk of ovarian cancer.

TABLE 7-23 Estimates of New Cases and Deaths from Selected Cancers of the Female Reproductive System in the United States in 2010


Site New Cases Deaths

Cervix 12,200 4,210
Endometrium 43,470 7,950
Ovary 21,880 13,850
Other female genital 2,300 7,810

SOURCE: Jemal et al., 2010.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and female reproductive cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion.

Tables 7-24, 7-25, and 7-26 summarize the results of the relevant studies.

Update of the Epidemiologic Literature

No Vietnam-veteran studies concerning exposure to the chemicals of interest and cancers of the female reproductive system have been published since Update 2008.

Occupational Studies

McBride et al. (2009a,b) published two reports of a mortality follow-up of the workers in the Dow AgroSciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD. No deaths were attributed to cancer of the corpus uteri (ICD-10 C54–C55) or ovary (ICD-10 C56). One death due to cancer of the cervix uteri (ICD-10 C53) was recorded in the group of never-exposed workers; no deaths from this cancer were recorded in the exposed workers. The results in McBride et al. (2009b) have not been included, because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

TABLE 7-24 Selected Epidemiologic Studies—Cervical Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
VIETNAM VETERANS
US VA Cohort of Female Vietnam Veterans
All COIs
Kang et aL,2000 Female Vietnam veterans 57 1.1(0.7-1.7)
Australian Vietnam Veterans vs Australian General Population
All COIs
CDVA,1998b Australian Vietnam veterans—self-reported 8 Expected number of exposed cases
(95% CI)
1 (0–5)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
OCCUPATIONAL
IARC Phcnoxy Herbicide Cohort (mortality vs national mortality rates) Dioxin, Phenoxy
Herbicides
Kogevinas et al., 1997 IARC cohort, female workers exposed to any phenoxy herbicide or chlorophenol 3 1.1 (0.2-3.3)
  Exposed to highly chlorinated PCDDs 0 0.0 (0.0-3.8)
  Not exposed to highly chlorinated PCDDs 3 1.8 (0.4-5.2)
Danish Production Workers (included in IARC cohort) Dioxin, phenoxy herbicides
Lynge, 1993 Danish phenoxy herbicide workers 7 3.2 (1.3-6.6)
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort) Dioxin, Phenoxy
Herbicides
McBride et al., 2009a Dow trichlorophenol workers Cervix uteri (ICD-10 C53) 0 0.0 (0.0-14.6)
Agricultural Workers Herbicides
Blair et al., 1993 US farmers in 23 slates    
  Whites 6 0.9 (0.3-2.0)
  Nonwhites 21 2.0 (1.3-3.1)
Ronco et al., 1992 Danish farmers—incidence    
  Self-employed farmers 7 0.5 (p < 0.05)
  Family workers 100 0.5 (p < 0.05)
  Employees 12 (0.8 <nr)
Wiklund, 1983 Swedish female agricultural workers—incidence   99% CI
    82 0.6 (0.4-0.8)
ENVIRONMENTAL
Seveso, Italv Residential Cohort TCDD
Pesatori et al., 2009 Seveso—20-yr follow-up to 1996—incidence    
  Zone A 2 2.7 (0.7-10.8)
  Zone B 7 1.5 (0.7-3.1)
  Zone R 28 0.8 (0.6-1.3)
Chapaevsk, Russia Residential Cohort Dioxin
Revich et al., 2001 Residents of Chapaevsk, Russia 13 1.8 (1.0-3.1)

ABBREVIATIONS: CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VA, US Department of Veterans Affairs.

aSubjects are female, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×



TABLE 7-25 Selected Epidemiologic Studies—Uterine Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
VIETNAM VETERANS
US VA Cohort of Female Vietnam Veterans All COIs
Cypel and Kang, 2008 US non-Vietnam veterans 5 0.8 (0.2-2.8)
  vs non-Vietnem nurses 5 1.3 (0.3-5.0)
Kang et al., 2000 US Vietnam veterans—incidence 41 1.0 (0.6-1.6)
Dalager et al., 1995 US Vietnam veterans 4 2.1 (0.6-5.4)
Australian Vietnam Veterans vs Australian Population All COIs
CDVA, 1998b Australian Vietnam veterans—self-reported incidence   Expected number of exposed cases (95% CI)
    4 1 (0-5)
OCCUPATIONAL All COIs
IARC Phenoxy Herbicide Cohort (mortality vs national mortality Dioxin, Phenoxy
Herbicides
Kogevinas et al., 1997 IARC cohort, female workers exposed to any cancers of endometrium (includes cancers of endometrium) 3 3.4 (0.7-10.0)
  Exposed to highly chlorinated PCDDs 1 1.2 (0.0-6.5)
  Not exposed to highly chlorinated PCDDs 4 2.3 (0.6-5.9)
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort) Dioxin, Phenoxy
Herbicides
McBride et al., 2009a 1,599 production workers (male and female) 2004    
  Corpus uteri (ICD-10 C54-C55) 0 0.0 (0.0-30.6)
Agricultural Workers Herbicides
Blair et al., 1993 US farmers in 23 states    
  Whites 15 1.2 (0.7-2.1)
  Nonwhites 17 1.4 (0.8-2.2)
Ronco et al., 1992 Danish farmers—incidence    
  Self-employed farmers 8 0.6 (nr)
  Family workers 103 0.8 (p< 0.05)
  Employees 9 0.9 (nr)
Wiklund, 1983 Swedish female agricultural   99% CI
  workers—incidence 135 0.9 (0.7-1.1)
ENVIRONMENTAL
Seveso, Italy Residential Cohor TCDD
Consonni et al., 2008 Seveso residents—25-yr follow-up    
  Zone A 0 0
  Zone B 2 0.5 (0.1-1.9)
  Zone R 41 1.3 (0.9-1.8)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk (95%
CI)b
Pesatori et al., 2009 Seveso—20-yr follow-up lo 1996—incidenceUterus (ICD-9 179-182)    
  Zone A 4 2.3 (0.9-6.3)
  Zone B 10 0.9 (0.5-1.7)
  Zone R 61 0.8 (0.6-1.0)
  Endometrium (ICD-9 182)    
  Zone A 1 1.2 (0.2-8.8)
  Zone B 3 0.6 (0.2-1.9)
  Zone R 27 0.7 (0.5-1.1)
Bertazzi et al., 2001 Seveso residents—20-yr follow-up    
  Zones A, B 2 0.5 (0.1-1.9)
Bertazzi et al., 1998 Seveso residents—15-yr follow-up    
  Zone B 1 0.3 (0.0-2.4)
Bertazzi et al., 1997 Seveso residents—15-yr follow-up    
  Zone B 1 0.3 (0.0-1.9)
  Zone R 27 1.1 (0.8-1.7)
Other Environmental Studies
Weiderpass et al., 2000 Swedish women 154 1.0 (0.6-2.0)

ABBREVIATIONS: CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VA, US Department of Veterans Affairs.

aSubjects are female, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

Environmental Studies

Pesatori et al. (2009) updated cancer-incidence results for the study conducted among residents of Seveso, Italy. Poisson regression models were used to calculate sex-, age- and period-adjusted rate ratios. The use of exposure zones (A, B, and R) to define individual exposure introduces misclassification that is likely to be random and attenuate associations. However, later serum measurements of a subset confirmed the utility of assigning zone of residence as a proxy for exposure to TCDD.

The rate ratios for cancer of the uterus in Zones A, B, and R were 2.34 (95% CI 0.87–6.27), 0.93 (95% CI 0.49–1.73), and 0.79 (95% CI 0.60–1.03), respectively. The rate ratios for cancer of the cervix in Zones A, B, and R were 2.67 (95% CI 0.66–10.77), 1.47 (95% CI 0.69–3.12), and 0.84 (95% CI 0.57–1.25), respectively. Although cancer of the uterus and cancer of the cervix were higher in Zone A, the estimates were not statistically significant. For cancer of the en-

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-26 Selected Epidemiologic Studies—Ovarian Cancer

Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS
US VA Cohort of Female Vietnam Veterans All COIs
Kang et al., 2000 Vietnam veterans—prevalence 16 1.8 (0.7-4.7)
Australian Vietnam Veterans vs Australian General Population All COIs
CDVA, 1998b Australian Vietnam veterans—self-reported incidence   Expected number of exposed cases (95% CI)
    1 0 (0-4)
OCCUPATIONAL  
IARC Phenoxy Herbicide Cohort (mortality vs national mortality rates) Dioxin, phenoxy herbicides
Kogevinas et al., 1997 IARC cohort, female workers exposed to any
phenoxy herbicide or chlorophenol
1 0.3 (0.0-1.5)
  Exposed to highly chlorinated PCDDs 0 0.0 (0.0-2.6)
  Not exposed to highly chlorinated PCDDs 1 0.5 (0.0-2.5)
Kogevinas et al., 1993 IARC cohort 1 0.7 (nr)
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort) Dioxin, Phenoxy
Herbicides
McBride et al., 2009a 1,599 production workers (male and female) vs national rates—mortality 1969 through 2004    
  Ovarian cancer (ICD-I0C56) 0 0.0 (0.0-9.5)
Agricultural Health Study Herbicides
Blair et al., 2005a US AHS    
  Private applicators (men and women) 4 3.9 (1.1-10.1)
  Spouses of private applicators (> 99% women) 13 0.7 (0.4-1.2)
Alavanja et al., 2005 US AHS—incidence    
  Private applicators (men and women) 8 3.0 (1.3–5.9)
  Spouses of private applicators (> 99% women) 32 0.6 (0.4-0.8)
  Commercial applicators (men and women) 0 0.0 (0.0-16.0)
Other Agricultural Workers Herbicides
Ronco et al., 1992 Danish farmers—incidence    
  Self-employed farmers 12 0.9 (nr)
  Family workers 104 0.8 (p< 0.05)
  Employees 5 0.5 (nr)
Other Occupational Studies Herbicides
Donna et al., 1984 Female residents near Alessandria, Italy 18 4.4 (1.9-16.1)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed
Casesb
Exposure of Interest/
Estimated Risk
(95% CI)b
ENVIRONMENTAL  
Seveso, Italy Residenlial Cohort TCDD
Consonni et al., 2008 Seveso residents—25-yr follow-up    
  Zone A 1 1.2 (0.2-8.5)
  Zone B 2 0.4 (0.1-1.6)
  Zone R 37 1.0 (0.7-1.4)
Pesalori et al., 2009 Seveso—20-yr follow-up to 1996—incidence    
  Zone A 1 1.1 (0.2-7.9)
  Zone B 1 0.2 (0.0-1.3)
  Zone R 45 1.1 (0.8-1.5)
Bertazzi et al., 2001 Seveso residents—20-yr follow-up    
  Zones A, B 3 0.7 (0.2-2.0)
Bertazzi et al., 1998 Seveso residents—15-yr follow-up    
  Zone A 1 2.3 (0.3-16.5)
Bertazzi et al., 1997 Seveso residents—15-yr follow-up    
  Zone A—women 1 2.3 (0.0-12.8)
  Zone R—women 21 1.0 (0.6-1.6)

ABBREVIATIONS: AHS, Agricultural Health Study; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; nr, not reported; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); TCDD, 2,3,7,8-tetrachlorodibenxo-p-dioxin; VA, US Department of Veterans Affairs.

aSubjects are female, and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

dometrium, the RRs in Zones A, B, and R were 1.24 (95% CI 0.17–8.82), 0.6 (95% CI 0.19–1.87), and 0.73 (95% CI 0.49–1.1), respectively. The RRs for ovarian cancer in Zones A, B, and R were 1.11 (95% CI 0.16–7.90), 0.18 (95% CI 0.02–1.25), and 1.12 (95% CI 0.82–1.54), respectively.

Biologic Plausibility

Yoshizawa et al. (2009) have shown that chronic administration of TCDD and other AHR ligands to female adult Harlan Sprague-Dawley rats results in chronic inflammation and increases in reproductive-tissue tumors, including cystic endometrial hyperplasia and uterine squamous-cell carcinoma. The mechanism of action might be related to endocrine disruption and chronic inflammation. Hollingshead et al. (2008) also showed that TCDD activation of the AHR in human breast and endocervical cell lines induces sustained high concentrations

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

of the IL-6 cytokine, which has tumor-promoting effects in numerous tissues, including ovarian; thus, TCDD might promote carcinogenesis in these tissues.

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

New information concerning female reproductive cancers since Update 2008 was sparse and inconsistent. The results from the updated follow-up of residents of Seveso and the occupational study add little weight to the existing body of evidence.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the chemicals of interest and uterine, ovarian, or cervical cancer.

PROSTATE CANCER

ACS estimated that 217,730 new cases of prostate cancer (ICD-9 185) would be diagnosed in the United States in 2010 and that 32,050 men would die from it (Jemal et al., 2010). That makes prostate cancer the second-most common cancer in men (after nonmelanoma skin cancers); it is expected to account for about 28% of new cancer diagnoses and 11% of cancer deaths in men in 2010. The average annual incidence of prostate cancer is shown in Table 7-27.

The incidence of prostate cancer varies dramatically with age and race. The risk more than doubles from the ages of 50–54 years and 55–59 years, and it nearly doubles again from the ages of 55–59 years and 60–64 years. As a group, American black men have the highest recorded incidence of prostate cancer in the world (Miller et al., 1996); their risk is roughly twice that in whites in the

TABLE 7-27 Average Annual Incidence (per 100,000) of Prostate Cancer in United Statesa

55-59 Years Old 60-64 Years Old 65-69 Years Old
All Races White Black All Races White Black All Races White Black
347.7 330.6 616.7 609.6 586.6 1,020.7 887.2 864.2 1,387.4

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2004–2008 (NCI, 2010).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

United States, 5 times that in Alaska natives, and nearly 8.5 times that in Korean Americans. Little is known about the causes of prostate cancer. Other than race and age, risk factors include a family history of the disease and possibly some elements of the Western diet, such as high consumption of animal fats. The drug finasteride, which has been widely used to treat benign enlargement of the prostate, was found to decrease the prevalence of prostate cancer substantially in a major randomized trial (Thompson et al., 2003). Finasteride acts by decreasing the formation of potent androgen hormones in the prostate.

The study of the incidence of and mortality from prostate cancer is complicated by trends in screening for the disease. The widespread adoption of serum prostate-specific antigen (PSA) screening in the 1990s led to very large increases in prostate-cancer incidence in the United States, which have recently subsided as exposure to screening has become saturated. The long-term influence of better screening on incidence and mortality in any country or population is difficult to predict and will depend on the rapidity with which the screening tool is adopted, its differential use in men of various ages, and the aggressiveness of tumors detected early with this test (Gann, 1997). Because exposure to PSA testing is such a strong determinant of prostate-cancer incidence, epidemiologic studies must be careful to exclude differential PSA testing as an explanation of a difference in risk observed between two populations.

Prostate cancer tends not to be fatal, so mortality studies might miss an increased incidence of the disease. Findings that show an association between an exposure and prostate-cancer mortality should be examined closely to determine whether the exposed group might have had poorer access to treatment that would have increased the likelihood of survival.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to the chemicals of interest and prostate cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion.

Table 7-28 summarizes results of the relevant studies, including both morbidity and mortality studies. The type, quality, and specificity of each study must be considered in the interpretation and weighing of evidence. Because of study heterogeneity, simply examining all the estimated risks in the table together will not yield a good assessment of the risks.

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-28 Selected Epidemiologic Studies—Prostate Cancer

Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS
Air Force Ranch Hands—Ranch Hand veterans vs SEA veterans All COIs
Pavuk el al.,2006 AMIS subjects—incidence
20-year cumulative TCDD (ppt-year)
Comparison group 81 1.0
Ranch Hand low (≤ 434 ppt-year) 31 1.0(0.7-1.6)
Ranch Hand high (> 434 ppt-year) 28 1.2(0.8-1.9)
p-trend = 0.42
Last tour in SKA before 1969 (heavyspraying)
Yes
Comparison group 17 1.0
Ranch Hand low (≤ 434 ppt-year) 9 1.0(0.4-2.3)
Ranch Hand high (> 434 ppt-year) 15 2.3(1.1-4.7)
p-trend = 0.04
No
Comparison group 64 1.0
Ranch Hand low (≤ 434 ppt-year) 22 1.1(0.7-1.8)
Ranch Hand high (> 434 ppt-year) 13 0.9(0.5-1.6)
p-trend = 0.75
Less than 2 years served in SEA
Yes
Comparison group 16 1.0
Ranch Hand low (≤ 434 ppt-year) 20 1.9(1.0-3.7)
Ranch Hand high (> 434 ppt-year) 14 2.2(1.0-4.5)
p-trend = 0.03
No
Comparison group 65 1.0
Ranch Hand low (≤ 434 ppt-year) 11 0.8(0.4-1.5)
Ranch Hand high (> 434 ppt-year) 14 1.1(0.6-1.9)
p-trend = 0.89
Pavuk el al., 2005 While Air Force comparison subjects only—incidence
Serum TCDD (pg/g) based on model with exposure variable loge(TCDD)
Per unit increase of –loge(TCDD) Quaniles (pg/g) 83 1.1(0.7-1.5)
0.4-2.6 13 1.0
2.6-3.8 24 1.7(0.8-3.3)
3.8-5.2 24 1.5(0.7-2.9)
>5.2 22 1.2(0.6-2.4)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
  Number of years served in SEA
Per year of service
83 1.1 (1.0-1.2)
  Quartiles (years in SIEA)    
  0.8-1.3 8 1.0
  1.3-2.1 11 1.3 (0.5-3.2)
  2.1-3.7 28 2.2 (1.0-4.9)
  3.7-16.4 36 2.4 (1.1-5.2)
Akhlar et al., 2004 AFHS subjects vs national rales While AFHS Ranch Hand veterans    
  Incidence 36 1.5 (1.0-2.0)
  With tours in 1966-1970 34 1.7 (1.2-2.3)
  Mortality 2 0.7 (0.1-2.3)
  White AFHS comparison veterans    
  Incidence 54 1.6 (1.2-2.1)
  With tours between 1966-1970 42 1.6 (1.2-2.2)
  Mortality 3 0.8 (0.2-2.1)
  White AFHS subjects—incidence    
  Who spent at most 2 years in SIEA    
  Per unit increase of -loge(TCDD) 28 1.5 (0.9-2.4)
  Comparison group 7 1.0
  Ranch Hand—< 10 TCDD pg/g in 1987 10 1.5 (0.5-4.4)
  Ranch Hand—< 118.5 TCDD pg/g at end of service 6 2.2 (0.7-6.9)
  Ranch Hand—> 118.5 TCDD pg/g at end of service 5 6.0 (1.4-24.6)
  Only Ranch Hands with 100% service in Vietnam and comparisons with no service in Vietnam    
  Per unit increase of –loge(TCDD) 20 1.1 (0.6-1.8)
  Comparison group 3 1.0
  Ranch Hand—< 10 TCDD pg/g in 9 2.5 (0.4-16.1)
  Ranch Hand—< 118.5 TCDD pg/g at end of service 4 2.4 (0.4-16.0)
  Ranch Hand—> 118.5 TCDD pg/g at end of service 4 4.7 (0.8-29.1)
AFHS, 2000 Air Force Ranch Hand veterans 26 0.7 (0.4-1.3)
AFHS, 1996 Air Force Ranch Hand veterans 2 0.6 expected
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
US VA Cohort of Armv Chemical Corps All COIs
Cypcl and Kang. 2010 ACC—deployed vs nondeployed and vs US men (Vietnam-service status throught 2005)    
  Deployed vs nondeployed 5 vs 2 1.0 (0.2-5.6)
  ACC veterans vs US men    
  Vietnam cohort 5 1.1 (0.3-2.5)
  Non-Vietnam cohort 2 0.95 (0.1-3.4)
US CDC Vietnam Kxperience Study All COIs
Boehmer et al., 2004 Follow-up of CDC VES cohort 1 0.4 (nr)
Department of Veterans Affairs All COIs
Watanabe and Kang, 1996 US Army and Marine Corps Vietnam veterans    
  Army Vietnam Service 58 1.1 (nr)
  Non-Vietnam 1 1.2 (nr)c
  Marine Vietnam Service 9 1.2 (nr)
  Non-Vietnam 6 1.3 (nr)
Breslin et al., 1988 Army Vietnam veterans 30 0.9 (0.6-1.2)
  Marine Vietnam veterans 5 1.3 (0.2-10.3)
State Studies of US Vietnam Veterans All COIs
Chamie et al., 2008 Vietnam-era veterans in northern California 239 2.9 (2.3-3.6)
  Veterans Affairs Health System—self-reported exposure to Agent Orange    
Giri et al.,2004 Veterans using the VA Medical Center in Ann Arbor, Michigan    
  All cases 11 OR 2.1 (0.8-5.2)
  Cases in white veterans only nr OR 2.7 (0.9-8.2)
Clapp, 1997 Massachusetts Vietnam veterans—incidence 15 0.8 (0.4-1.6)
Visintainer et al., 1995 PM study of deaths (1974-1989) of Michigan    
  Vietnam-era veterans—deployed vs nondeployed    
  Male genital system 19 1.1 (0.6-1.7)
Anderson et al., 1986 Wisconsin Vietnam veterans 0 nr
Other Studies of US Vietnam Veterans All COIs
Shah et al.,2009 Veterans with radical prostatectomies examined in VA Healthcare facilities    
  AO-exposed veterans with biochemical progression nr 1.5 (1.1-2.0)
Australian Vietnam Veterans vs Australian Population All COIs
O’Toole et al., 2009 Survey of Australian Vietnam Veterans compared to the Australian general population nr 1.3 (0.3-6.7)
ADVA, 2005a Australian male Vietnam veterans vs Australian population—incidence 692 1.3 (1.2-1.3)
  Navy 137 1.2 (1.0-1.4)
  Army 451 1.8 (1.2-1.4)
  Air Force 104 1.3 (1.0-1.5)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
ADVA, 2005b Australian male Vietnam veterans vs Australian population—mortality 107 1.2(1.0-1.5)
Navy 22 1.3(0.8-1.8)
Army 65 1.2(0.9-1.5)
Air Force 19 1.4(0.8-2.1)
AIIIW, 1999 Auslralian Vietnam veterans—incidence (validation study) 212 Expected number of exposed cases (95%CI)
147(123-171)
CDVA, 1998a Australian Vietnam veterans—self-reported incidence 428 147(123-171)
CDVA, 1997a Australian military Vietnam veterans 36 1.5(1.0-2.0)
Australian Conscripted Army National Service (deployed vs nondeployed) All COIs
ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans
Incidence 65 1.2(0.9-1.5)
Mortality 0 0.0 (0.0-0.7)
Other Australian Vietnam Veterans All COIs
Leavy ct al.,2006 606 prostate cancer cases in Western Australia Vietnam service 25 2.1(0.9-5.1)
OCCUPATIONAL
IARC Phenoxy Herbicide Cohort (mortality vs national mortality rates) Dioxin, phenoxy herbicides
Kogevinas etal., 1997 IARC cohort, workers exposed to any phenoxy herbicide or chlorophenol 68 1.1(0.9-1.4)
Exposed to highly chlorinated PCDDs 43 1.1(0.8-1.5)
Not exposed to highly chlorinated PCDDs 25 1.1(0.7-1.6)
Saracci et al., 1991 IARC cohort—exposed subcohort 30 1.1(0.8-1.6)
NIOSH Mortality Cohort (12 US plants, production 1942-1984) (included in IARC cohort) Dioxin, phenoxy herbicides
Stccnland et al., 1999 US chemical production workers 28 1.2(0.8-1.7)
Fingerhut etal., 1991 NIOSH—entire cohort 17 1.2(0.7-2.0)
≥1-yr exposure, ≥ 20-yr latency 9 1.5(0.7-2.9)
Monsanto Plant—Nitro, WV (included in IARC and NIOSH cohort) Dioxin, phenoxy herbicides
Collins etal., 1993 Monsanto Company workers 9 1.6(0.7-3.0)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
Dow Chemical Company—Midland. MI (included in IARC and NIOSH cohorts) Dioxin, phenoxy herbicides
Collins et al., 2009a Trichlorophenol workers 21 1.4(0.9-2.2)
Collins et al., 2009b Pentachlorophenol workers 8 1.0(0.4-1.9)
Bodner et al., 2003 Dow chemical production workers (included in IARC cohort, NIOSH Dioxin Registry) nr 1.7(1.0-2.6)
Burns et al., 2001 Dow 2.4-D production workers (included in IARC cohort. NIOSH Dioxin Registry) 7 1.3(0.5-2.8)
Bond et al., 1988 Dow 2.4-D production workers (included in IARC cohort, NIOSH Dioxin Registry) 1 1.0(0.0-5.8)
BASF Production Workers {included in IARC cohort) Dioxin, phenoxy herbicides
Ott and Zober, 1996 BASF employees—incidence
TCDD < 0.1 μg/kg of body weight 4 1.1 (0.3-2.8)
TCDD 0.1-0.99 μg/kg of body weight 1 1.1 (0.0-5.9)
Zober et al., 1990 BASF employees—basic cohort 0 90% CI
nr (0.0-6.1)
Danish Production Workers (included in IARC cohort) Dioxin, phenoxy herbicides
Lynge, 1985 Danish production workers—incidence 9 0.8 (nr)
Dutch Production Workers (included in IARC cohort) Dioxin, phenoxy herbicides
Boers et al.,2010 Dutch chlorophenoxy workers
Factory A (HR for exposed vs unexposed) 6 vs 2 2.9 (0.6-14.2)
Factory B (HR for exposed vs unexposed) 4 vs 2 2.7 (0.5-14.9)
Bueno de Mesquita et al., 1993 Dutch phenoxy herbicide workers (included in IARC cohort) 3 2.6 (0.5-7.7)
German Production Workers (included in IARC cohort) Dioxin, phenoxy herbicides
Becher et al., 1996 German production workers 9 1.3 (nr)
Manz et al., 1991 German production workers—men, women 7 1.4(0.6-2.9)
New Zealand Production Workers—Dow plant in Plymouth ,NZ (included in IARC cohort) Dioxin, phenoxy herbicides
McBride et al., 2009a 1.599 production workers (male and female) vs national rates—mortality 1969 through 2004
Ever-exposed workers 1 0.2(0.0-1.2)
Never-exposed workers 2 1.9(0.2-6.7)
't Mannetje et al., 2005 Phenoxy herbicide producers 1 0.4(0.0-2.1)
Phenoxy herbicide sprayers (> 99% men) 2 0.6(0.1-2.2)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
United Kingdom Production Workers (included in IARC cohort) Dioxin, plienoxy herbicides
Coggon et al., 1986 British MCPA production workers 18 1.3(0.8-2.1)
Agrlcultuml Health Study Herbicides
Samanic et al., 2006 Pesticide applicators in AHS—prostate cancer incidence from enrollment through 2002 Dicamba—lifetime days exposure
None 343 1.0
1- < 20 106 1.0(0.8-1.3)
20-<56 102 0.9(0.7-1.2)
56- <116 76 1.0(0.7-1.3)
≥ 116 67 1.1 (0.8-1.5)
p-trend = 0.45
Alavanja et al., 2005 US AHS—incidence
Private applicators 1.046 1.3(1.2-1.3)
Spouses of private applicators (> 99% women) 5 1.2(0.4-2.8)
Commercial applicators 41 1.4(1.0-1.9)
Blair et al., 2005a US AHS
Private applicators 48 0.7 (0.5-0.8)
Spouses of private applicators (> 99% women) 0 0.0(0-1.6)
Alavanja et al., 2003 US AHS—pesticide appliers in Iowa and North Carolina—incidence 566 1.1 (1.1-1.2)
Other Agricultural Workers Herbicides
Hansen et al., 2007 Danish gardeners (male genital organs, ICD-7 177-178)—incidence
10-yr follow-up (1975-1984) reported in 20 1.2(0.7-1.8)
Hansen etal. (1992)
25-yr follow-up (1975-2001)
Bom before 1915 (high exposure) 39 1.3(1.0-1.8)
Bom 1915—1934 (medium exposure) 35 0.9(0.6-1.2)
Bom after 1934 (low exposure) 3 0.4(0.1-1.3)
Sharma-Wagner et al., 2000 Swedish citizens
Agriculture, stock raising
6,080 1.1 (1.0-1.1)
(p<0.01)
Farmers, foresters, gardeners 5,219 1.1 (1.0-1.1)
(p<0.01)
Paper-mill workers 304 0.9(0.8-1.0)
Pulp grinding 39 1.4(1.0-1.9)
(p< 0.05)
Gambini et al., 1997 Italian rice growers 19 1.0(0.6-1.5)
Blair et al., 1993 US farmers in 23 states
Whites 3,765 1.2(1.1-1.2)
Nonwhites 564 1.1 (1.1-1.2)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
Morrison et al., 1993 Canadian farmers. 45–69 yrs of age, no employees, or custom workers, sprayed ≥ 250 acres 20 2.2(1.3-3.8)
Ronco et al., 1992 Danish farm workers—incidence
Self-employed 399 0.9 (p< 0.05)
Employee 63 0.8 (p< 0.05)
Alavanja et al., 1988 USDA agricultural extension agents nr 1.0(0.7-1.5)
Burmeister et al., 1983 Iowa residents—farm exposures 4,
827
1.2 (p< 0.05)
Wiklund, 1983 Swedish male agricultural workers 3,890 99% CI
1.0(0.9-1.0)
Burmeister, 1981 Iowa farmers 1,138 1.1 (p<0.01)
Dutch Pesticide Applicators Herbicides
Swaen et al., 2004 Dutch licensed herbicide applicators 6 1.0(0.4-2.2)
Swaen et al., 1992 Dutch licensed herbicide applicators 1 1.3(0.0-7.3)
Other Studies of Herbicide and Pesticide Applicators Herbicides
Fleming et al., 1999a Florida pesticide appliers 353 1.9(1.7-2.1)
Fleming et al., 1999b Florida pesticide appliers 64 2.4(1.8-3.0)
Dich and Wiklund, 1998 Swedish pesticide appliers 401 1.1 (1.0-1.2)
Bom 1935 or later 7 2.0 (0.8-4.2)
Bom before 1935 394 1.1 (1.0-1.2)
Zhong and Rafnsson, 1996 Icelandic pesticide users 10 0.7(0.3-1.3)
Asp et al., 1994 Finnish herbicide applicators
Incidence 6 0.4(0.1-0.8)
Mortality 5 0.8(0.3-1.8)
Torch io et al., 1994 Italian licensed pesticide users 1.0(0.7-1.2)
Blair et al., 1983 Florida pesticide applicators Expected number of exposed cases (95% CI)
2 3.8 (nr)
Forestry Workers Herbicides
Thorn et al.,2000 Swedish lumberjacks exposed to phenoxyacetic herbicides
Foremen—incidence 2 4.7 (nr)
Male lumberjacks—incidence 3 0.9 (nr)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
Hcrlzman et al., 1997 Canadian sawmill workers Morbidity 282 1.0(0.9-1.1)
Mortality from male genital tract cancers 116 1.2(1.0-1.4)
Alavanja et al., 1989 USDA forest conservationists nr 1.6(0.9-3.0)
Soil conservationists nr 1.0(0.6-1.8)
Reifetal., 1989 New Zealand forestry workers—nested case-control —incidence 12 0.7(0.4-1.3)
Paper and Pulp Workers Dioxin
McLean et al., 2006 IARC cohort of pulp and paper workersExposure to nonvolatile organochlorine compounds
Never 117 0.9(0.7-1.0)
Ever 84 0.9(0.7-1.2)
Henneberger et al., 1989 New Hampshire pulp and paper workers 9 1.0(0.5-1.9)
Solet et al.,1989 US paper and pulp workers 4 1.1(0.3-2.9)
Robinson et al., 1986 Northwestern US paper and pulp workers 17 90% CI
1.2(0.7-1.7)
ENVIRONMENTAL
Seveso, Italy Residential Cohort TCDD
Consonni et al, 2008 Seveso residents—25-yr follow-up to 2001—men, women
Zone A 1 0.9(0.1-6.2)
Zone B 8 0.9(0.4-1.8)
Zone R 65 1.1(0.8-1.4)
Pesatori et al., 2009 Seveso—20-yr follow-up to 1996—incidence
Zone A 0
Zone B 7 0.9 (0.5-2.0)
Zone R 39 0.8(0.5-1.1)
Bertazzi et al., 2001 Seveso residents—20-yr follow-up
Zones A, B—men 8 1.1(0.5-2.2)
Bertazzi el al., 1997 Seveso residents—15-yr follow-up
Zone B—men 6 1.2(0.5-2.7)
Zone R—men 39 1.2(0.8-1.6)
Bertazzi el al., 1993 Seveso residents—10-yr follow-up—incidence
Zone R—men 16 0.9(0.5-1.5)
Pesatori et al., 1992 Seveso residents—incidence
Zones A, B—men 4 1.4(0.5-3.9)
Zone R—men 17 0.9(0.6-1.5)
Bertazzi et al., 1989a Seveso residents—10-yr follow-up
Zones A, B, R—men 19 1.6(1.0-2.7)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
Bertazzi et al., 1989b Seveso residents—10-yr follow-up
Zone B—men 3 2.2 (0.7-6.9)
Zone R—men 16 1.6(0.9-2.7)
Other Knvironmenlal Studies Serum dioxin
Turunen et al., 2008 Finnish fishermen and spouses 36 0.99(0.7-1.4)
Svensson et al., 1995 Swedish fishermen—mortality
Organochlorine compounds
East coast 12 1.0(0.5-1.8)
West coast 123 1.1 (0.9-1.3)
Swedish fishermen—incidence
East coast 38 1.1 (0.8-1.5)
West coast 224 1.0(0.9-1.1)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ACC, Army Chemical Corps; AFHS, Air Force Health Study; AHS, Agricultural Health Study; AO, Agent Orange; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; HR, hazard ratio; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; NZ, New Zealand; OR, odds ratio; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PM, proportionate mortality; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; USDA, US Department of Agriculture; VA, US Department of Veterans Affairs; VES, Vietnam Experience Study; WV, West Virginia.

aSubjects are male and outcome is mortality unless otherwise noted.

bGiven when available; results other than estimated risk explained individually.

cStatistically significant with the 95% CI not including 1.0.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Among Australian Vietnam veterans, O’Toole et al. (2009) extended follow-up to 36 years after the war. The relative prevalence of prostate cancer (compared with that in the general population) was 1.29 (95% CI 0.34–6.73) on the basis of a sample size of 450 veterans.

Cypel and Kang (2010) studied 2,872 ACC veterans and compared them with 2,737 non-Vietnam veterans or US men. When Cox adjusted analyses were used, the prostate-cancer mortality in ACC veterans compared with non-Vietnam veterans was 1.02 (95% CI 0.19–5.64); there were five observed deaths in the Vietnam cohort and two in the non-Vietnam cohort. The Cox proportional hazards survival analysis adjusted for race, rank, duration of military service, and age at

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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entry into follow-up. In the analysis in which the ACC veterans were compared with US men, the result was 1.05 (95% CI 0.34–2.45) for five observed cases.

Shah et al. (2009) investigated the association of Agent Orange exposure with prostate-cancer clinicopathologic characteristics, rates of biochemical progression after treatment, and PSA doubling time after recurrence of prostate cancer in patients that had radical prostatectomy (RP). The study population consisted of 1,495 veterans who had undergone RP during 1988–2007 at Veterans Affairs Health Care Facilities in West Los Angeles and Palo Alto, California, Augusta, Georgia, and Durham, North Carolina; veteran’s data was abstracted from the Shared Equal Access Regional Cancer Hospital (SEARCH) database. The authors noted that the men were grouped by the presence or absence of Agent Orange exposure, but a detailed explanation of the criteria used to determine the presence of exposure was not given. After adjustment for clinical variables, there was no significant association of Agent Orange exposure with odds of a pathologic Gleason sum, positive surgical margins, extracapsular extension, or seminal vesicle invasion. During a mean follow-up of 60 months (with a standard deviation of 46 months), men who were exposed to Agent Orange were more likely to progress than men who were not exposed; after adjustment for clinicopathologic findings, they had an increased RR of biochemical progression of 1.47 (95% CI 1.08–2.00). In the 501 men who had PSA recurrence, the PSA doubling time (PSADT) was available for 298 men. Agent Orange exposure was associated with a significantly shorter mean adjusted PSADT (8.2 vs 18.6 months). Study limitations include the potential for more aggressive screening for prostate cancer in men who had been exposed to Agent Orange, which led to earlier diagnosis. A second limitation is that only men with RP were included; that is, men who had more advanced disease were excluded, so an association of Agent Orange with more advanced disease could not be studied. A final limitation is that Agent Orange exposure was not quantified and was assessed subjectively. The authors note that there is potential concern with exposure assignment because there are financial incentives to associate their diagnosis with a history of Agent Orange exposure; this limits the relevance of the results.

Occupational Studies

Boers et al. (2010) published results of the third follow-up of the retrospective Dutch cohort study in two chlorophenoxy herbicide manufacturing factories (Plant A and Plant B). The authors extended follow-up an additional 15 years through the end of 2006 and included data from Plant B that had previously not been included, because of the small number of deaths reported at the last follow-up. The data from the two plants were analyzed separately because exposure to phenoxy herbicides and dioxins was considered to differ between factories. In Plant A, there were 539 exposed male workers and 482 unexposed workers. In Plant B, there were 411 male workers classified as exposed and 626 classified as unexposed. Although the follow-up period is long, the cohort is moderate in size and would have limited

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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power to detect increases in rare cancers. The authors reported increased HRs for prostate cancer that were consistent with earlier published analyses. Specifically, the risk in Plant A (HR = 2.93, 95% CI 0.61–14.15) was based on six and two deaths in the exposed and unexposed workers, respectively. The risk in Plant B (HR = 2.68, 95% CI 0.48–14.85) was based on four and two deaths in exposed and unexposed workers, respectively. For all genital cancers, the HR was increased, but not significantly (HR = 3.28, 95% CI 0.63–17.15).

Collins et al. (2009a) published updated results from a Dow Chemical Company site in Michigan. They followed 1,615 workers who were exposed to dioxins in a TCP production plant. Serum dioxin measurements in a set of 280 (17%) workers were used to estimate historical TCDD exposure of all workers. Serum TCDD concentrations were higher than in the unexposed and the general population. Workers were followed from 1942 to 2003. There was an increase (but not a statistically significant increase) in SMR for prostate cancer (SMR = 1.4, 95% CI 0.9–2.2 in all TCP workers; SMR = 1.5, 95% CI 0.9–2.4 when 196 workers who also had PCP exposure were excluded).

Collins et al. (2009b) examined mortality rates among 773 workers in a PCP manufacturing facility who were exposed to dioxins during PCP manufacturing during 1937–1980. Serum dioxin measurements were used to estimate exposure to five dioxins, including TCDD. In all PCP workers, the SMR was 1.0 (95% CI 0.4–1.9), and the number of observed deaths was eight. When they excluded 196 workers who also had TCP exposure, the SMR was 1.0 (95% CI 0.4–2.1) on the basis of seven observed deaths.

McBride et al. (2009a,b) extended their earlier analyses by including additional exposed and unexposed workers, constructing exposure estimates based on serum dioxin (TCDD) in exposed and unexposed workers, and extending follow-up for 4 additional years. The authors reported on the mortality experience of 1,599 workers employed during 1969–1988 at a New Zealand site that manufactured TCP and a nearby field station where 2,4,5-T was occasionally used and tested (McBride et al., 2009a). Serum measurements from 346 blood samples confirmed higher exposure than New Zealand background. The study was limited by a high loss of follow-up (21%). The SMR for ever-exposed workers was 0.2 (95% CI 0.0–1.2) on the basis of one observed death. The SMR for never-exposed workers was 1.9 (95% CI 0.2–6.7) on the basis of two observed deaths. It should be noted that the authors reported increased SMRs for other cancers previously found to be associated with dioxins. The results in McBride et al. (2009b) have not been included because they were diluted by inclusion of a set of workers who had no opportunity for TCDD exposure and no observed deaths.

Environmental Studies

Pesatori et al. (2009) updated cancer-incidence results for the study of residents of Seveso. Poisson regression models were used to calculate sex-, age-, and

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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period-adjusted rate ratios. The use of exposure zones (A, B, and R) to define individual exposure introduces misclassification, which is likely to be random and to attenuate associations. However, later serum measurements on a subset confirmed the utility of using zone of residence as a proxy for exposure to TCDD. For prostate cancer, none of the RRs (95% CI) were increased: for Zones A, B, and R the RRs were not calculable, 0.94 (95% CI 0.45–1.99), and 0.75 (95% CI 0.54–1.05), respectively.

Turunen et al. (2008) conducted a mortality study of Finnish fishermen and their wives. The cohort consisted of 6,410 Finnish professional fishermen and 4,260 wives. The cohort was linked with Statistics Finland’s national cause-of-death data for 1980–2005. SMRs were calculated by using national mortality figures. The SMR for prostate cancer was 0.99 (95% CI 0.69–1.36) on the basis of 36 observed deaths.

Biologic Plausibility

Prostate cells and prostatic-cancer cell lines are responsive to TCDD in induction of various genes, including those involved in drug metabolism. Simanainen et al. (2004a) used different rat lines (TCDD-resistant Hans/Wistar and TCDD-sensitive Long Evans) and showed that TCDD treatment resulted in a significant decrease in the weight of prostate lobes, but the effect did not appear to be line-specific. In contrast, the TCDD-related reduction in sperm appears to be line-specific and not fully related to the effects of TCDD on serum testosterone (Simanainen et al., 2004b). TCDD effects appear to occur through actions on the urogenital sinus (Lin et al., 2004). In utero and lactational exposure to TCDD appears to retard the aging process in the prostate (Fritz et al., 2005). In a follow-up, progeny mice of a genetic cross between AHR-null mice and the transgenic adenocarcinoma of the mouse prostate (TRAMP) strain that models prostate cancer showed that the presence of the AHR inhibited the formation of prostate tumors that have a neuroendocrine phenotype (Fritz et al., 2008). In agreement with a possible protective role, negative associations were found in the AFHS between the risk of benign prostate hyperplasia and both TCDD exposure and serum testosterone concentration (Gupta et al., 2006).

The biologic plausibility of the carcinogenicity of the chemicals of interest is discussed in general at the beginning of this chapter.

Synthesis

The results on Australian and US ACC Vietnam veterans are weak but consistent with the previous finding of suggestive evidence of an association between the chemicals of interest and prostate cancer. The few occupational and environmental studies published since Update 2008 do not provide substantial evidence for or against the earlier conclusion. The previously existing body of epidemio-

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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logic evidence supporting an association between exposure to the chemicals of interest and prostate cancer is robust enough that the committee’s judgment that there is limited or suggestive evidence of an association is not reversed by the largely negative results in experimental systems.

Analysis of data from VA medical facilities by Shah et al. (2009) found indicators of poor prognosis were associated with self-reported Agent Orange exposure of veterans who had already had radical prostatectomies for diagnosed prostate cancer. The committee had some reservations about possible bias associated with self-reporting of Agent Orange exposure. Furthermore, this interesting finding does not directly address a role of Agent Orange in the occurrence of prostate cancer.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there remains limited or suggestive evidence of an association between exposure to at least one of the chemicals of interest and prostate cancer.

TESTICULAR CANCER

ACS estimated that 8,480 men would receive diagnoses of testicular cancer (ICD-9 186.0–186.9) in the United States in 2010 and that 350 men would die from it (Jemal et al., 2010). Other cancers of the male reproductive system that are infrequently reported separately are cancers of the penis and other male genital organs (ICD-9 187). The average annual incidence of testicular cancer is shown in Table 7-29.

Testicular cancer occurs more often in men younger than 40 years old than in older men. On a lifetime basis, the risk in white men is about 4 times that in black men. Cryptorchidism (undescended testes) is a major risk factor for testicular cancer. Family history of the disease also appears to be a risk factor. Several other hereditary, medical, and environmental risk factors have been suggested, but the results of research are inconsistent (Bosl and Motzer, 1997).

TABLE 7-29 Average Annual Incidence (per 100,000) of Testicular Cancer in United Statesa

55-59 Years Old 60-64 Years Old 65-69 Years Old
All Races White Black All Races White Black All Races White Black
2.8 3.3 0.3 1.5 1.6 0.8 1.3 1.4 0.6

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2004–2008 (NCI, 2010).

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the chemicals of interest and testicular cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, and Update 2008 did not change that conclusion. Table 7-30 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Cypel and Kang (2010) studied 2,872 ACC veterans and compared them with 2,737 non-Vietnam veterans or US men. Using Cox adjusted analyses, the testicular-cancer mortality for ACC veterans compared with non-Vietnam veterans was not calculable; there were two observed deaths in the Vietnam cohort and none in the non-Vietnam cohort. When the ACC veterans were compared with US men, the SMR was 3.63 (95% CI 0.44–13.1) on the basis of two observed cases.

Occupational Studies

Collins et al. (2009a) published updated results from a Dow Chemical Company site in Michigan. They followed 1,615 workers who had been exposed to dioxins in a TCP production plant. Serum dioxin measures in a set of 280 (17%) workers were used to estimate historical TCDD exposure of all workers. Serum TCDD concentrations were higher than in the unexposed and the general population. Workers were followed from 1942 to 2003. There was an increase in SMR (but not a statistically significant one) for testicular cancer in all TCP workers (SMR = 1.6, 95% CI 0.0–8.9). When workers who also had PCP exposure were excluded, the SMR was 1.8 (95% CI 0.0–10.1).

Collins et al. (2009b) examined mortality in 773 workers who had been exposed to dioxins during PCP manufacturing during 1937–1980. Serum dioxin concentrations were used to estimate exposure to five dioxins, including TCDD. No deaths from testicular cancer were observed.

McBride et al. (2009a,b) extended their earlier analyses by including additional exposed and unexposed workers, constructing exposure estimates based on serum dioxin (TCDD) concentrations in exposed and unexposed workers, and extending follow-up for 4 additional years. The authors reported on the mortality experience of 1,599 workers employed during 1969–1988 at a New Zealand site that manufactured TCP and at a nearby field station where 2,4,5-T was occasionally used and tested (McBride et al., 2009a). Serum measurements from 346 blood samples confirmed higher exposure than New Zealand background. The

Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×

TABLE 7-30 Selected Epidemiologic Studies—Testicular Cancer

Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
VIETNAM VETERANS    
US Air Force Health Study—Ranch Hand veterans vs SEA veterans   All COIs
AFHS, 2000 Air Force Ranch Hand veterans 3 nr
US VA Cohort of Armv Chemical Coins   All COIs
Cypel and Kang, 2010 ACC veterans (deployed vs nondeployed) vs US men    
  Vietnam cohort 2 3.6 (0.4-13.1)
Dalager and Kang, 1997 Army Chemical Corps veterans 2 4.0 (0.5-14.5)
US VA Mortality Study of Army and Marine Veterans (ground troops serving July 4,1965-March 1,1973) All COIs
Watanabe Army Vietnam service 114 1.1 (nr)
and Kang, 1996 Marine Vietnam service 28 1.0 (nr)
Watanabe et al., 1991 Army Vietnam veterans 109 1.2 (ns)
  Marine Vietnam veterans 28 0.8 (ns)
Breslin et al., 1988 Army Vietnam veterans 90 1.1 (0.8-1.5)
  Marine Vietnam veterans 26 1.3 (0.5-3.6)
VA Case-Control Studies   All COIs
Bull man et al., 1994 Navy veterans 12 2.6 (1.1-6.2)
Australian Vietnam Veterans vs Australian Population   All COIs
ADVA, 2005a Australian male Vietnam veterans vs Australian population—incidence 54 0.9 (0.6-1.1)
  Navy 17 1.2 (0.7-1.8)
  Army 34 0.8 (0.5-1.0)
  Air Force 3 0.8 (0.2-2.3)
ADVA, 2005b Australian male Vietnam veterans vs Australian population—mortality 14 0.9 (0.4-1.4)
  Navy 3 0.8 (0.2-2.4)
  Army 10 0.9 (0.4-1.7)
  Air Force 0 0.0 (0.0-3.3)
AIIIW, 1999 Australian Vietnam veterans—incidence (validation study) 59 Expected number of exposed cases (95% CI)
110 (89-139)
CDVA, 1998a Australian Vietnam veterans—self-reported incidence 151 110 (89-131)
CDVA, 1997a Australian military Vietnam veterans 4 ns
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
×
Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
Australian Conscripted Army National Service (deployed vs nondcploy) All COIs
ADVA, 2005c Australian male conscripted Army National Service Vietnam-era veterans—deployed vs non-deployed
Incidence 17 0.7(0.4-1.2)
Mortality 4 0.8 (0.2-2.0)
CDVA, 1997b Australian National Service Vietnam veterans 1 1.3
State Studies of US Vietnam Veterans All COIs
Clapp, 1977 Massachusetts Vietnam veterans—incidence 30 1.2(0.4-3.3)
Anderson et al., 1986 Wisconsin Vietnam veterans 9 1.0(0.5-1.9)
Other Studies of US Vietnam Veterans All COIs
Tarone et al., 1991 Patients in three Washington, DC. area hospitals 31 2.3(1.0-5.5)
OCCUPATIONAL
IARC Phenoxy Herbicide Cohort (mortality vs national mortality rates)
Kogevinas et al., 1997 IARC cohort, workers exposed to any phenoxy herbicide or chlorophenol 68 1.1 (0.9-1.4)
Exposed to highly chlorinated PCDDs 43 1.1 (0.8-1.5)
Not exposed to highly chlorinated PCDDs 25 1.1 (0.3-1.6)
Saracci et al., 1991 IARC cohort exposed subcohort 7 2.3 (0.9-4.6)
Dow Chemical Company—Midland, MI (included in IARC and NIOSH cohorts) Dioxin, phenoxy herbicides
Collins et al., 2009a Trichlorophenol workers
Testes and other male genital
1 1.6(0.0-8.9)
Collins et al., 2009b Pentachlorophenol workers
Testes and other male genital
0 0.0(0.0-12.5)
Burns et al., 2001 Dow chemical production workers 1 2.2 (0.0-12.5)
Ramlow et al., 1996 Dow pentachlorophenol production workers 0 nr
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
Bond et al., 1988 Dow 2,4-D production workers 1 4.6 (0.0-25.7)
New Zealand Production Workers—Dow plant in Plymouth, NZ (included in IARC cohort) Dioxin, phenoxy herbicides
Mc Bride et al., 2009a 1,599 production workers (male and female) vs national rates—mortality 1969 through 2004 Ever-exoosed workers 0 0.0(0.0-15.6)
United Kingdom Production Workers (included in IARC cohort)
Coggon et al., 1986 British MCPA production workers 4 2.2 (0.6-5.7)
Agricultural Health Study Herbicides
Alavanja et al., 2005 US AHS—incidence
Private applicators 23 1.1 (0.7-1.6)
Spouses of private applicators (> 99% women) nr 0.0 (0.0-50.2)
Commercial applicators 4 1.2(0.3-3.2)
Blair et al., 2005a US AHS
Private applicators 0 nr
Spouses of private applicators (> 99% women) 0 nr
Other Agricultural Workers Herbicides
Blair et al., 1993 US farmers in 23 states
White men 32 0.8(0.6-1.2)
Nonwhite men 6 1.3(0.5-2.9)
Ronco et al., 1992 Danish farm workers—incidence
Men—self-employed 74 0.9 (nr)
employee 23 0.6 (p< 0.05)
Wiklund, 1983 Swedish male agricultural workers—incidence 101 99% CI
1.0(0.7-1.2)
Other Studies of Herbicide and Pesticide Applicators Herbicides
Flemming et al., 1999b Florida pesticide appliers 23 2.5(1.6-3.7)
Zhong and Rafnsson, 1996 Icelandic pesticide users 2 1.2(0.1-4.3)
Forestry Workers Herbicides
Reifetal., 1989 New Zealand forestry workers—nested case-control—incidence 6 1.0(0.4-2.6)
Hertzman et al., 1997 British Columbia sawmill workers
Mortality (male genital cancers) 116 1.0(0.8-1.1)
Incidence 18 1.0(0.6-1.4)
Suggested Citation:"7 Cancer." Institute of Medicine. 2012. Veterans and Agent Orange: Update 2010. Washington, DC: The National Academies Press. doi: 10.17226/13166.
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Reference Study Populationa Exposed Casesb Exposure of Interest/
Estimated Risk
(95% CI)b
Paper and Pulp Workers Dioxin
McLean et al., 2006 IARC cohort of pulp and paper workers
Exposure to nonvolatile organochlorine compounds
Never 2 1.1 (0.1-4.1)
Ever 5 3.6(1.2-8.4)
Other Occupational Workers Herbicides
Hardell et al., 1998 Swedish workers exposed to herbicides 4 0.3(0.1-1.0)
ENVIRONMENTAL
Seveso, Italy Residential Cohort TCDD
Pesatori et al., 2009 Seveso—20-yr follow-up to 1996—incidence
Zone A 0
Zone B 2 0.8 (0.2-3.3)
Zone R 22 1.4(0.9-2.3)
Bertazzi et al., 2001 Seveso residents—20-yr follow-up
Zone A, B—men 17 1.0(0.6-1.7)
Bertazzi et al., 1998 Seveso residents—15-yr follow-up (genitourinarytract)—incidence
Zone B—men 10 1.0(0.5-1.8)
Zone R—men 73 1.0(0.8-1.3)
Bertazzi et al., 1993 Seveso residents—10-yr follow-up—incidence
Zone B—men 1 1.0(0.1-7.5)
Zone R—men 9 1.4(0.7-3.0)
Pesatori et al., 1992 Seveso residents—incidence
Zones A, B—men 1 0.9(0.1-6.7)
Zone R—men 9 1.5(0.7-3.0)

ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; ACC, Army Chemical Corps; AHS, Agricultural Health Study; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MI, Michigan; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; ns, not significant; NZ, New Zealand; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; VA, US Department of Veterans Affairs.

aSubjects are male, and outcome is mortality unless otherwise noted.