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Veterans and Agent Orange: Update 2012 (2014)

Chapter: 8 Cancer

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Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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8


Cancer

Chapter Overview

Based on new evidence and a review of prior studies, the committee for did not find any new significant associations between the relevant exposures and particular types of cancer. Current evidence supports the findings of earlier studies that

•   There is sufficient evidence of an association with the chemicals of interest and soft tissue sarcomas and B-cell lymphomas (Hodgkin lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, hairy cell leukemia).

•   There is limited or suggestive evidence of an association between the chemicals of interest and laryngeal cancer; cancer of the lung, bronchus, or trachea; prostate cancer; multiple myeloma, and AL amyloidosis.

•   There is inadequate or insufficient evidence to determine whether there is an association between the chemicals of interest and any other specific type of cancer.

Cancer is the second-leading cause of death in the United States. Among men 55–69 years old, the group that includes most Vietnam veterans (see Table 8-1), 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 577,000 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 (Siegel et al., 2012).

This chapter summarizes and presents conclusions about the strength of the

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 8-1 Age Distribution of Vietnam-Era and Vietnam-Theater Male Veterans, 2009–2010 (Numbers in Thousands)

Age Group (Years) Vietnam Era Vietnam Theater
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.

evidence from epidemiologic studies regarding associations between exposure to the chemicals of interest (COIs)—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlo-rodibenzo-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. However, studies that report TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration since mono-ortho PCBs typically contribute less than 10% to total TEQs, based on the WHO revised TEFs of 2005 (La Rocca et al., 2008; Van den Berg et al., 2006). 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 6.

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 COIs are discussed in Chapter 10, 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 find-

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

ings. As noted in Chapters 3 and 6, 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, a form of measurement error, 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). 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 COIs.

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); Update 2008 (IOM, 2009); and Update 2010 (IOM, 2011). 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

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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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 COIs 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. A large literature indicates that carcinogenesis is a process that involves not only genetic changes but also epigenetic changes, which modify DNA and its expression without altering its sequence of bases (Johnstone and Baylin, 2010). There is increasing evidence that TCDD and the COIs may disturb cellular processes by epigenetic mechanisms (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 COIs. Many of the veteran, occupational, and environmental studies reviewed by the committee did not control fully for important 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 COIs. 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, Ninth Revision (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 ICD-9. ICD-9 was in effect

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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from 1979 to 1998; because ICD-9 is the version most prominent in the research reviewed in this series, it is used when codes are given for a specific health outcome. Appendix C describes the correspondence between the NIOSH cause-of-death groupings and ICD-9 codes (see Table C-1); the groupings for mortality are largely congruent with those of the SEER program for cancer incidence (see Table C-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 of lymphohematopoietic neoplasms (WHO, 2008), which stresses partitioning of the 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 with exposure to the COIs, 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 an association with such a disease outcome.

BIOLOGIC PLAUSIBILITY

The studies considered with respect to the biologic plausibility of associations between exposure to the COIs 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 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. Recently, Hernández et al. (2009) have reviewed the mechanisms of action of nongenotoxic carcinogens, including TCDD in this category.

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 of cancer bioassays; for instance, there is some question as to whether the highest doses (generally 30–50 mg/kg) in some of the studies reached a maximum tolerated dose. 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

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

findings on genotoxic effects in assays conducted primarily in vitro. The evidence indicates that 2,4-D and 2,4,5-T are genotoxic only at very high concentrations.

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). Treatment with cacodylic acid induced formation of neoplasms of the lung 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 this 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 (Wyde et al., 2004). In exerting its carcinogenic effects, TCDD 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 of 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 has been known for many years that it is a potent tumor-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 its skin-tumor promotion depends on the AHR. Recent evidence has shown that AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the interleukin-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

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

other tissues (Hollingshead et al., 2008). In rat liver, TCDD downregulates reduced folate carrier (Rfc1) mRNA and protein, whose normal levels are 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), insulin-secreting beta cells (Piaggi et al., 2007), peripheral T cells (Singh et al., 2008), and neuronal cells (Bredhult et al., 2007) have been identified, and the results suggest possible carcinogenic mechanisms. TCDD may contribute to tumor progression by inhibiting p53 regulation (phosphorylation and acetylation) triggered by genotoxicants through 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,” in which 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 between the AHR and the mitogen-activated protein kinase signaling pathway in chemically induced hepatocarcinogenesis. TCDD inhibits ultraviolet-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-OHdG (Shertzer et al., 2002) involving AHR-dependent uncoupling of mitochondrial respiration (Senft et al., 2002). Mitochondrial reactive-oxygen production depends on the AHR. Other than the occasional observation of 8-OHdG, there is little evidence that TCDD is genotoxic, and it appears likely that some of these mechanisms of action may be induced by epigenetic modifications (events that affect gene function but do not involve a change in gene coding sequence) of the genome.

Electronics-dismantling workers who experienced complex exposures, including exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs), had increased concentrations of urinary 8-OHdG indicative of oxidative stress and genotoxicity; this cannot, however, be ascribed directly to the DLCs (Wen et al., 2008). 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 Zea-

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

land Vietnam War veterans and 23 control volunteers (Rowland et al., 2007). 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 did 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-promoting activity 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 in The Committee’s View of “General” Human Carcinogens below) it must be determined case by case whether such potential contributes to each individual type of cancer. Experiments with 2,4-D, 2,4,5-T, and picloram in animals and cells have not provided a strong biologic basis for either the presence or the absence of carcinogenic effects.

THE COMMITTEE’S VIEW OF “GENERAL” HUMAN CARCINOGENS

To address its charge, the committee weighed the scientific evidence linking the COIs 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 must occur to accelerate the mutational process and provide growth advantages for the more aggressive clones of cells. Both genetic (mutational) and epigenetic (nonmutational) activities of carcinogenic agents can stimulate the process of cancer development.

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 promot-

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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ers, 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 chemical in humans are based heavily on the results of epidemiologic studies, especially on the question of whether there is evidence of excess cancer risk at multiple organ sites. As the evaluations of specific types of cancer in the remainder of this chapter indicate, the committee finds that TCDD appears to be 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” (Baan et al., 2009); with the US Environmental Protection Agency (EPA), which has concluded that TCDD is “likely to be carcinogenic to humans” (http://www.epa.gov/ttn/atw/hlthef/dioxin.html; updated Januarary 2000; accessed September 21, 2013); and with the National Toxicology Program (NTP), which regards TCDD as “known to be a human carcinogen” (NTP, 2011). 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 are analyses based on specific sites, for which more substantial biologically based hypotheses can be developed. The size of a cohort and the

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

length of the observation period often constrain the number of cancer cases observed and which specific types of cancer have enough observed cases to permit analysis. For instance, an analysis of cumulative results on diabetes and cancer in the prospective Air Force Health Study (Michalek and Pavuk, 2008) produced important information summarizing previous findings on the fairly common condition of diabetes, but the cancer analysis does not go beyond “all cancers.” The committee does not accept the cancer findings as an indication that exposure to Agent Orange increases the risk of every variety of cancer. It acknowledges that the results of the highly stratified analyses conducted suggest that the incidence of some cancers did increase in the Operation Ranch Hand veterans, 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 as meriting individual longitudinal analysis to resolve outstanding questions.

For this report, updated mortality information was available on four occupational cohorts that have been followed in VAO updates, which included risk statistics for overall cancer mortality. In three of the four (Manuwald et al., 2012; Ruder and Yiin, 2011; Waggoner et al., 2011), there was a modest increase in cancer mortality; in the fourth, the observed cancer mortality matched expectation (Boers et al., 2012).

The committee notes that current information on overall mortality in US Vietnam veterans themselves has been elusive. Considerable confusion and alarm has arisen from Internet attribution of all of the approximately 800,000 deaths among all 9.2 million US Vietnam-era veterans to the 2.7 million who served in Vietnam (Brady, 2011; Gelman, 2013). The most recent reliable information was obtained in the 30-year update of mortality through 2000 of the deployed and nondeployed veterans in the Vietnam Experience Study (Boehmer et al., 2004), which found that mortality among the deployed veterans slightly exceeded that of their non-deployed counterparts, but was only about 9%. A followup study (O’Toole et al., 2010) of a random sample of 1,000 Australian Vietnam veterans selected from Australia’s comprehensive roster of 57,643 service members deployed to Vietnam may provide a somewhat newer estimate of mortality through 2004 of 11.7%, which may be fairly comparable with that of their American fellows.

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.

A number of studies of populations that received potentially relevant exposures were identified in the literature search for this review but did not characterize exposure with sufficient specificity for their results to meet the committee’s criteria for inclusion in the evidentiary database. For instance, the British Pesticide Users Health Study has followed almost 60,000 men and 4,000 women who

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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were certified for agricultural pesticide use in Great Britain since 1987. Frost et al. (2011) reported cancer incidence and mortality in this cohort up to 2004 for the full array of anatomic sites, but exposure was defined only as being a member of this cohort. Therefore, the cancer-specific findings of Frost et al. (2011) will not be repeatedly noted in the individual sections below. That is also the case for the mortality followup of Japanese Americans in the Honolulu Heart Program reported by Charles et al. (2010). Technically, this rubric would apply to the mortality and morbidity results reported by Waggoner et al. (2011) and Koutrous et al. (2010a); because of the context provided by the extensive pesticide-specific results that have been published on individual cancers in the Agricultural Health Study (AHS) and the knowledge that 2,4-D was one of the most frequently used pesticides in this large prospective cohort, however, those results are presented below, but not given full evidentiary weight. Numerous cancer studies of the case-control design addressing particular cancers had exposure characterizations that were not more specific than job titles, farm residence, or pesticide exposure; therefore, their results are not regarded as fully relevant for the purpose of this review, and such studies are mentioned only in passing in a discussion of the cancer investigated.

ORAL, NASAL, AND PHARYNGEAL CANCER

Oral, nasal, and pharyngeal cancers are found in many anatomic sites: the structures of the mouth (inside lining of the lips, cheeks, gums, tongue, and hard and soft palate—ICD-9 codes 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, and cancer of the nasopharynx is thought 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, and risk estimates are highest for the base of the tongue and tonsils (oropharynx) (Marur et al., 2010).

The American Cancer Society (ACS) estimated that about 40,250 men and women would receive diagnoses of oral, nasal, or pharyngeal cancer in the United States in 2012 and that 7,850 men and women would die from these diseases (Siegel et al., 2012). 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 but 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 8-2 show that men are at greater risk than are women for those cancers and that the incidences increase

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 8-2 Average Annual Incidence (per 100,000) of Nasal, Nasopharyngeal, Oral-Cavity and Pharyngeal, and Oropharyngeal Cancers in the 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
Nose, Nasal Cavity, and Middle Ear:
    Men 1.5 1.5 2.5 2.2 1.9 3.7 2.9 2.6 3.3
    Women 1.2 1.0 1.0 1.1 1.0 1.8 1.6 1.9 0.9
Nasopharynx:
    Men 2.3 1.2 2.0 2.2 1.5 0.8 2.8 1.7 2.8
    Women 1.1 0.6 0.4 0.8 0.7 0.3 1.0 0.9 0.9
Oral Cavity and Pharynx:
    Men 0.8 0.7 1.8 0.8 0.6 2.3 1.4 1.2 3.9
    Women 0.3 0.3 0.2 0.1 0.1 0.3 0.6 0.5 2.1
Oropharynx:
    Men 2.0 1.9 3.5 1.9 1.6 5.2 2.2 2.0 5.0
    Women 0.3 0.3 0.4 0.7 0.7 0.9 0.4 0.5 0.0

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2005–2009 (NCI, 2013).

with age—but 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, 2006), 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 COI 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, Update 2008, and Update 2010 did not change that conclusion.

In Update 2006, at the request of 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 the studies did not provide sufficient evidence to determine whether an association existed between exposure to the COIs and tonsil cancer. No new studies have offered any important

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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additional insight into the question. The committee 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. Increasing evidence indicating that some cancers of the oropharynx and oral cavity can have a viral (HPV) etiology is consistent with the mechanistic hypothesis explaining an excess of these cancers in Vietnam veterans: immune alterations associated with Agent Orange exposure may have increased susceptibility to HPV infection in the oral cavity and tonsils of Vietnam veterans, thereby making them more prone to the development of squamous-cell carinomas in these tissues. The present committee strongly reiterates the 2006, 2008, and 2010 recommendation that VA develop a strategy that uses existing databases to evaluate tonsil cancer in Vietnam-era veterans.

The small numbers of oral, nasal, or pharyngeal cancer cases in prior studies limit interpretation of the data. Cypel and Kang (2010) updated the study of Vietnam-era Army Chemical Corps (ACC) veterans, comparing mortality through 2005 in ACC veterans by Vietnam service. They reported a nonsignificant increase in oral-cavity and pharyngeal cancers in the deployed cohort compared with cases in the nondeployed cohort—a result that is consistent with a prior report on mortality through 1991 (Dalager and Kang, 1997).

McBride et al. (2009a) reported on mortality through 2004 in 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. They reported a nonsignificant excess in mortality from buccal cavity and pharyngeal cancer and no deaths from nasopharyngeal cancer in either group.

Studies evaluated previously and in the present report are summarized in Table 8-3.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

There have been no Vietnam-veteran studies of exposure to the COIs and oral, nasal, or pharyngeal cancers since Update 2010.

Occupational Studies

Burns et al. (2011) published an update examining the cancer incidence through 2007 in workers who were alive on January 1, 1985, and had been employed at any time from 1945 to 1994 in 2,4-D production by the Dow Chemical Company in Midland, Michigan. They found no evidence of significantly increased cancer rates overall. The incidence of lip, oral, and pharyngeal cancer

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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TABLE 8-3 Selected Epidemiologic Studies—Oral, Nasal, and Pharyngeal Cancer (Shaded Entries Are New Information for This Update)

Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans

US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)

All COIs Akhtar et al., 2004

Incidence

Ranch Hand veterans (n = 1,189)

    6 0.9 (0.4–1.9)

With tours between 1966–1970

    6 1.1 (0.5–2.3)

SEA comparison veterans (n = 1,776)

    5 0.6 (0.2–1.2)

With tours between 1966–1970

    4 0.6 (0.2–1.4)

Mortality

Through 1999—White subjects vs national rates

Ranch Hand veterans (n = 1,189)

    0 0.0 (nr)

SEA comparison veterans (n = 1,776)

    1 0.5 (nr)

US VA Cohort of Army Chemical Corps

All COIs

Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 nondeployed) serving during Vietnam era (July 1, 1965–March 28, 1973)

Mortality—Oral cavity and pharyngeal cancer

Through 2005

Cypel and Kang, 2010

Deployed veterans (2,872) vs nondeployed (2,737)

6 vs 2 1.7 (0.3–8.7)

Army Chemical Corps 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—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

All COIs

Mortality

1965–2000 (ICD-140–149)

    6 nr Boehmer et al., 2004

US CDC Selected Cancers Study—Case-control study of incidence (Dec 1, 1984–Nov 30, 1989) among US males born 1929–1953

All COIs CDC, 1990a

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

Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs nondeployed (lip, oral cavity, pharynx)

  12 1.0 (0.5–1.8) Visintainer et al., 1995
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
International Vietnam-Veterans Studies

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

Incidence

All branches, 1982–2000 (head and neck)

247 1.5 (1.3–1.6) ADVA,

Navy

  56 1.6 (1.1–2.0) 2005a

Army

174 1.6 (1.3–1.8)

Air Force

  17 0.9 (0.5–1.5)

Mortality

All branches, return–2001

ADVA,

Head and neck

101 1.4 (1.2–1.7) 2005b

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)

1980–1994

CDVA,

Lip (ICD-9 140)

    0 nr 1997a

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 (18,940 deployed vs 24,642 nondeployed)

All COIs

Incidence

1982–2000

ADVA,

Head and Neck

  44 2.0 (1.2–3.4) 2005c

Mortality

1966–2001

ADVA,

Head and neck

  16 1.8 (0.8–4.3) 2005c

Nasal

    0 0.0 (0.0–48.2)

1982–1994

CDVA,

Nasopharyngeal cancer (ICD-9 147)

    1 1.3 (0.0– > 10) 1997b

Nasal cavities (ICD-9 160)

    0 0.0 (0.0– > 10)
OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates

Mortality 1939–1992

Kogevinas et al., 1997

Oral cavity, pharynx cancer (ICD-9 140–149)

  26 1.1 (0.7–1.6)

13,831 exposed to highly chlorinated

  22 1.3 (0.8–2.0)

PCDDs

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

7,553 not exposed to highly chlorinated PCDDs

    3 0.5 (0.1–1.3)

Nasal, nasal sinus cancer (ICD-9) 160)

    3 1.6 (0.3–4.7)

13,831 exposed to highly chlorinated PCDDs

    0 0.0 (0.0–3.5)

7,553 not exposed to highly chlorinated PCDDs

    3 3.8 (0.8–11.1)

Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort

Saracci et al., 1991

Bucal cavity, pharynx (ICD-8 140–149)

  11 1.2 (0.6–2.1)

Nose, nasal cavities (ICD-8 160)

    3 2.9 (0.6–8.5)

British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)

MCPA

Mortality through 1983

Coggon

Lip (ICD-9 140)

    0 nr et al., 1986

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)

Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)

Dioxins, 2,4,5-T, 2,4,5-TCP

Mortality 1955–1991 (lip, oral cavity, pharynx)

Hooiveld

All working anytime in 1955–1985

    1 2.3 (0.1–12.4) et al., 1998

Cleaned up 1963 explosion

    1 7.1 (0.2–39.6)

German Production Workers—2,479 workers at 4 plants (in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

All for plants—Buccal cavity, pharynx (ICD-9 140–149)

    9 3.0 (1.4–5.6) Becher et al., 1996

Tongue

    3 nr

Floor of mouth

    2 nr

Tonsil

    2 nr

Pharynx

    2 nr

German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 month in 1951–1976) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4, 5-TCP

Mortality 1951–1992

    0 Becher et al., 1996

German Production Workers at Bayer Plant in Dormagen (520 men working > 1 month in 1965–1989) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1965–1989

    0 Becher et al., 1996
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 month in 1957–1987) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1956–1989

    6 8.2 (3.0–17.9) Becher et al., 1996

BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)

Focus on TCDD

Mortality

Through 1987

90% CI Zober et al.,

Buccal cavity, pharynx

    1 4.8 (0.3–22.9) 1990

Squamous-cell carcinoma of tonsil

    1 nr

German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)

Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP

Mortality 1952–2007 (ICD-9 140–149)

  11 2.2 (1.1–3.9) Manuwald

Men

    9 2.0 (0.9–3.8) et al., 2012

Women

    2 3.4 (0.4–12.5)

Mortality 1952–1989

    3 1.8 (0.4–5.2) Becher et al., 1996

New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram

Mortality 1969–2004 (buccal cavity and pharynx)

McBride et al., 2009a

Ever-exposed workers

    3 2.6 (0.5–7.6)

Never-exposed workers

    0 0.0 (0.0–11.5)

Production Workers—Mortality 1969–2000

713 men and 100 women worked > 1 month in 1969–1984

    2 2.8 (0.3–9.9) ’t Mannetje et al., 2005

Lip (ICD-9 140)

    0 nr

Mouth (ICD-9 141–145)

    2 5.4 (0.7–20.0)

Oropharynx (ICD-9 146)

    0 nr

Nasopharynx (ICD-9 147)

    0 0.0 (0.0–41.8)

Hypopharynx, other (ICD-9 148–149)

    0 nr

Phenoxy herbicide sprayers (> 99% men)

    1 1.0 (0.0–5.7) ’t Mannetje et al., 2005

Lip (ICD-9 140)

    0 nr

Mouth (ICD-9 141–145)

    0 0.0 (0.0–7.5)

Oropharynx (ICD-9 146)

    0 nr
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Nasopharynx (ICD-9 147)

    1 8.3 (0.2–46.3)

Hypopharynx, other (ICD-9 148–149)

    0 nr

NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

All Dow PCP-Exposed Workers (All workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

1940–2005 (n = 2,122) (buccal, pharynx; ICD-9 140–149)

    5 0.8 (0.3–1.8)

PCP and TCP (n = 720)

    1 0.5 (0.0–2.7)

PCP (no TCP) (n = 1,402)

    4 0.9 (0.2–2.3)

Dow 2,4-D Production Workers (1945–1982 in Midland, Michigan) (subset of all TCP-exposed workers)

2,4-D, lower chlorinated dioxins

Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3)

    7 1.1 (0.4–2.2) Burns et al., 2011
OCCUPATIONAL—PAPER AND PULP WORKERS TCDD

IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM (oral cavity, pharynx)

McLean et al., 2006

Exposure to nonvolatile organochlorine compounds

Never

  33 0.9 (0.6–1.3)

Ever

  15 0.5 (0.3–0.9)

Danish male, female paper workers

Rix et al.,

Buccal cavity (ICD-7 140–144)

1998

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

Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and California, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977

90% CI Robinson et al., 1986

Buccal cavity, pharynx (ICD-7 140–148)

    1 0.1 (0.0–0.7)

Nasal (ICD-7 160)

    0 nr
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)

DENMARK

Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)

Herbicides Ronco et al., 1992

Danish self-employed farmers

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

  11 0.6 (nr)

Danish farming employees

Lip

  43 2.1 (p < 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, sinuses

    5 1.3 (nr)

Danish gardeners—incidence from 3,156 male and 859 female gardeners (buccal cavity, pharynx, ICD-7 140–148)

Herbicides Hansen et al., 2007

10-yr followup (1975–1984) reported in Hansen et al. (1992)

    6 1.1 (0.4–2.5)

25-yr followup (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)

FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC

Phenoxy herbicides Asp et al., 1994

Buccal, pharynx (ICD-8 140–149)

Incidence

    5 1.0 (0.3–2.3)

Mortality 1972–1989

    0 0.0 (0.0–3.0)

“Other Respiratory” (ICD-8 160, 161, 163)—nose, larynx, pleura

Incidence

    4 1.1 (0.3–2.7)

Mortality 1972–1989

    1 0.5 (0.0–2.9)

ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974

Mortality 1970–1986 (n = 23,401) (buccal cavity, pharynx)

  18 0.3 (0.2–0.5) Torchio et al., 1994
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Italian Farmers—mortality odds ratios from linking farmers on 1970 census with national cancer registry (1970–1980)

Herbicides Ronco et al., 1992

Self-employed

  13 0.9 (nr)

Employee

    4 0.5 (nr)

NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 649 incident buccal cavity cancer cases and 49 incident nasopharynx cancer cases vs 19,904 men with any incident cancer

Reif et al., 1989

Forestry workers (n = 134)

Herbicides

Buccal cavity

    3 0.7 (0.2–2.2)

Nasopharynx

    2 5.6 (1.6–19.5)

Aged 20–59

    1 3.5 (0.6–22.6)

Aged ≥ 60

    1 13.4 (2.7–65.1)

Sawmill workers (n = 139)

Herbicides, chlorophenols

Nasopharynx

    0

NORWEGIAN farmers born 1925–1971—incidence, lip cancer

Pesticides Nordby et al., 2004

Reported pesticide use

nr 0.7 (0.4–1.0)

SWEDEN

Swedish pesticide applicators—incidence

Wiklund et al., 1989a

Lip cancer

  14 1.8 (1.0–2.9)

Incident cancer cases 1961–1973 with agriculture as economic activity in 1960 census (male, female)

Wiklund, 1983
99% CI

Lip

508 1.8 (1.6–2.2)

Tongue

  32 0.4 (0.2–0.6)

Salivary Gland

  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)

THE NETHERLANDS

Dutch Licensed Herbicide Sprayers—1,341 certified before 1980

Through 2000

Swaen

Nose

    0 et al., 2004

Pharynx

    0

UNITED STATES

US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states

Herbicides PCMRs Blair et al., 1993

Men

Whites (n = 119,648)

  21 2.3 (1.4–3.5)

Nonwhites (n = 11,446)

    0
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Women

Whites (n = 2,400)

    1 12.2 (0.2–68.0)

Nonwhites (n = 2,066)

    0 0.0 (0.0–103.6)

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides

Incidence

Enrollment through 2006—SIRs for participants

Koutros et al., 2010a

Private applicators

  93 0.6 (0.5–0.7)

Commercial applicators

    5 0.5 (0.2–1.3)

Spouses

  22 0.6 (0.4–1.0)

Enrollment through 2002—buccal cavity
    Private applicators (men and women)

Alavanja et al., 2005
  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

    5 0.9 (0.3–2.2)

Lip

    3 2.7 (0.6–8.0)

Mortality

Enrollment through 2007, vs state rates (buccal cavity, pharynx)

  16 0.3 (0.2–0.6) Waggoner et al., 2011

Enrollment through 2000, vs state rates (buccal cavity, pharynx)

Blair et al., 2005a

Private applicators (men and women) Spouses of private applicators (> 99% women)

    5 0.3 (0.1–0.7)
    0 0.0 (0.0–25.4)

White Male Residents of Iowa—Lip cancer on death certificate, usual occupation: farmers vs not

Herbicides

> 20 yrs old when died 1971–1978—PMR

  20 2.1 (p < 0.01) Burmeister, 1981
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171) TCDD
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Incidence

10-yr followup to 1991—men

Bertazzi et al., 1993

Buccal cavity (ICD-9 140–149)

Zone B

    6 1.7 (0.8–3.9)

Zone R

  28 1.2 (0.8–1.7)

Nose, nasal cavities (ICD-9 160)

Zone R

    0 nr

10-yr followup to 1991—women

Bertazzi et al., 1993

Buccal cavity (ICD-9 140–149)

Zone B

    0 nr

Zone R

    0 nr

Nose, nasal cavities (ICD-9 160)

Zone R

    2 2.6 (0.5–13.3)
CASE-CONTROL STUDIES

US Case-Control Studies

US males born 1929–1953, all 70 nasal cancers (52 carcinomas, 11 lymphomas, 5 sarcomas) in CDC (1990a) study population

Herbicides, pesticides Caplan et al., 2000

Selected landscaping, forestry occupation

  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)

International Case-Control Studies

Residents of northern Sweden (44 nasal, 27 nasopharyngeal cancers)

Phenoxy acids, chlorophenols Hardell et al., 1982

Phenoxy herbicide exposed

    8 2.1 (0.9–4.7)

Chlorophenol exposure

    9 6.7 (2.8–16.2)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, 2,4-dichlorophenoxypropanoic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; AFHS, Air Force Health Study; CATI, computer-assisted telephone interviewing; 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; JEM, job-exposure matrix; MCPA, 2 methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy) butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, military occupational specialty; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxins (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PM, proportionate mortality; PMR, proportionate mortality ratio; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol.

aSubjects are male and outcome is mortality unless otherwise noted.

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

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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in the most restrictively defined cohort was not increased (standardized incidence ratio [SIR] = 1.09, 95% confidence interval [CI] 0.44–2.24), as was the case for the two more inclusive but potentially more biased cohorts.

Manuwald et al. (2012) reported on mortality in 1,191 men and 398 women who had been employed for at least 3 months in 1952–1984 at a chemical plant in Hamburg (a subcohort of the IARC phenoxy herbicide cohort). During that period, the plant produced insecticides and herbicides, including 2,4,5-T, so cohort members had the possibility of exposure to TCDD. Subjects entered the cohort at the date of their first employment at the plant, and vital status was sought through 2007. Standardized mortality ratios (SMRs) calculated relative to the population of Hamburg showed that death from lip, oral-cavity, or pharyngeal cancers was not significantly increased in men (SMR = 2.00, 95% CI 0.91–3.79) or women (SMR = 3.42, 95% CI 0.39–12.45) but was significantly increased in the entire cohort (SMR = 2.17, 95% CI 1.08–3.87).

Ruder and Yiin (2011) reported mortality from 1940 to 2005 in the NIOSH pentachlorophenol (PCP) cohort of 2,122 workers in the US four plants that had been involved in PCP production. PCP production entailed exposure to PCDDs and PCDFs but not to the most toxic 2,3,7,8 dioxin congener. A subcohort of 720 workers (all men, the PCP-plus-TCDD group) had also been employed in TCP production and so had also been exposed to TCDD. In the total cohort, five deaths were attributed to buccal or pharyngeal cancer; this was consistent with the mortality experience of the US population (SMR = 0.76, 95% CI 0.25–1.77). There was only one death from this type of cancer in the PCP-plus-TCDD group, which also was not more than expected (SMR = 0.48, 95% CI 0.01–2.68). The results were effectively the same in the 1,402 workers who had not had any opportunity for occupational exposure to TCDD (SMR = 0.89, 95% CI 0.24–2.28).

The participants in the AHS are known to have had extensive exposure to the phenoxy herbicides, but the analyses of updated mortality through 2007 (Waggoner et al., 2011) and cancer incidence through 2006 (Koutros et al., 2010a) addressed only exposure to pesticides in general. The SMR was lower than expected for oral (buccal) and pharyngeal cancers in the applicators (16 deaths, SMR = 0.34, 95% CI 0.19–0.55), and only three deaths from these types of cancer were observed in their spouses. Koutros et al. (2010a) found 93 cases of oral-cavity and pharyngeal cancers in the private applicators (SIR = 0.56, 95% CI 0.45–0.69) and 22 cases in their spouses (SIR = 0.64, 95% CI 0.40–0.97). A nonsignificant increase in lip cancer was reported for the private applicators (SIR = 1.30, 95% CI 0.90–1.83), but these 33 cases may have more in common with skin cancers than with head and neck squamous-cell carcinomas. The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Environmental Studies

No new studies of environmental exposures to the COIs and these types of cancer have been published since Update 2010.

Case-Control Studies

A single case-control study of nasopharyngeal carcinoma (NPC) was identified in this publication period; it explored dietary, social, and environmental risk factors in 1,289 subjects (Aussem et al., 2012). Using a novel analytic procedure involving Baysian networks, the authors investigated whether exposure to pesticides and intake of domestic fumes from incomplete combustion of coal and wood were significantly associated with NPC risk. The characterization of exposure was insufficiently specific for the present committee to factor in the findings of the study. In any event, NPC is rare outside southern China and is known to be associated with Epstein-Barr virus infection, so it is unlikely to be a concern in American Vietnam veterans.

Biologic Plausibility

As noted above, there is increasing evidence that HPV contributes causally to cancers of the head and neck (Marur et al., 2010; Szentirmay et al., 2005) and to pharyngeal cancers in particular (Gillison and Shah, 2001; Gillison et al., 2012). 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 current literature.

Long-term animal studies have examined the effect of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). A National Toxicology Program study (Yoshizawa et al., 2005a) 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 incidence 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. This NTP study did not, however, find any pathologic effect of TCDD on nasal tissues (Nyska et al., 2005). Increased neoplasms of the oral mucosa were previously 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.

Recently, DiNatale et al. (2011) utilized head and neck squamous-cell carcinoma cell lines to investigate mechanisms for tumor progression associated

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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with this AHR activation. This tumor type typically produces large amounts of cytokines, and its IL6 expression levels correlate with disease aggressiveness. In this model, AHR activation by TCDD enhances IL6 production induced by another cytokine (IL 1β), so TCDD may promote head and neck squamous-cell carcinoma.

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

Synthesis

Most of the new studies that reported results on oral, nasal, and pharyngeal cancers noted estimated reductions or nonsignificant excesses in mortality from oral and pharyngeal cancers. With a total of 11 oral, pharyngeal, or lip cancers, however, a significantly increased risk was reported for the Hamburg cohort overall; but with nine and two cases, respectively, the increased estimates of risk for men and women did not achieve the traditional level (p = 0.05) of statistical significance. In the AHS, the incidence of oral and pharyngeal cancers was significantly decreased for both private applicators and their spouses. Those 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 COIs 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; esophageal cancer has been formally included only since Update 2004. 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 226,160 people would receive diagnoses of those cancers in the United States in 2012 and that 114,690 people would die from them (Siegel et al., 2012). Other digestive cancers (for example, small intestine, anal, and hepatobiliary cancers) added about 58,520

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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new diagnoses and 27,820 deaths to the 2012 estimates for the United States (Siegel et al., 2012). Collectively, tumors of the digestive organs were expected to account for 17% of new cancer diagnoses and 25% of cancer deaths in 2012. The average annual incidences of gastrointestinal cancers are presented in Table 8-4.

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

TABLE 8-4 Average Annual Incidence (per 100,000) of Selected Gastrointestinal Cancers in the 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 15. 0 13.7 23.2 23.3 21.0 38.6 35.9 31.2 66.2
    Women 7.0 5.3 12.4 8.8 7.1 13.9 14.6 11.3 23.0
Esophagus:
    Men 15.8 15.9 21.0 24.7 25.3 30.3 33.0 35.2 32.3
    Women 3.0 2.6 6.1 4.2 3.8 9.5 7.8 7.2 13.2
Colon (excluding rectum):
    Men 52.4 48.2 83.6 80.4 76.1 127.3 123.8 120.1 170.1
    Women 41.0 37.0 61.9 58.7 54.5 93.4 99.6 95.9 134.7
Rectum and rectosigmoid junction:
    Men 32.5 30.5 37.9 42.0 40.2 41.2 59.8 57.4 58.4
    Women 19.9 18.1 24.6 23.2 22.4 30.7 30.7 29.3 36.7
Liver and intrahepatic bile duct:
    Men 35.9 28.5 84.6 35.5 28.2 74.5 38.0 30.2 51.7
    Women 8.9 6.8 17.3 8.5 6.4 14.5 13.1 10.9 14.1
Pancreas:
    Men 22.1 21.1 33.7 36.2 35.0 55.0 54.7 53.3 80.6
    Women 15.9 15.2 23.1 25.5 24.7 35.8 37.4 35.0 61.4
Small Intestine:
    Men 5.0 5.1 6.5 6.7 6.8 8.6 9.3 8.9 13.3
    Women 3.6 3.5 6.5 4.5 4.0 8.6 6.7 6.6 11.9
Anus, anal canal, and anorectum:
    Men 3.4 3.6 4.2 3.4 3.8 3.0 4.2 4.7 2.8
    Women 4.6 5.0 4.5 4.9 5.1 4.1 5.5 6.1 5.1
Other digestive organs:
    Men 0.8 0.7 2.0 1.7 1.2 1.9 2.3 2.5 1.1
    Women 0.7 0.6 0.8 1.2 1.2 1.2 1.6 1.5 2.6
Gallbladder:
    Men 1.0 0.8 1.5 1.5 1.1 3.4 2.9 2.5 3.3
    Women 1.9 1.4 4.3 2.8 2.5 4.1 4.9 4.5 6.8
Other Biliary:
    Men 2.6 2.2 5.2 5.2 4.9 5.2 7.1 6.8 5.6
    Women 1.9 2.0 1.2 2.7 2.6 3.3 5.2 4.7 6.4

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2005–2009 (NCI, 2013).

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

in blacks than in whites. 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 pylori increases the risk of stomach and pancreatic cancer. Type 2 diabetes is associated with an increased risk of colorectal and pancreatic cancers (ACS, 2013a).

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 disease-related mortality in 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 of 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 relative risk [RR] = 1.01, 95% CI 0.56–1.83).

Several studies identified for the present update did analyses that combined several digestive cancers, so the results are not particularly informative for any cancer in the group. Boers et al. (2012) reported on stomach and pancreatic cancers, leaving an additional 28 cases of other digestive cancers, which closely matched expectation. Burns et al. (2011) reported on cancers of the stomach, colon, rectum, and pancreas individually, leaving eight deaths from “other GI and digestive cancers” (SIR = 0.73, 95% CI 0.32–1.44). After reporting on cancers of the esophagus, stomach, colon, rectum, and pancreas separately, 5 of 58 digestive cancers remained unidentified in the update on mortality in the Hamburg cohort (Manuwald et al., 2012).

Esophageal Cancer

Epithelial tumors of the esophagus (squamous-cell carcinomas and adenocarcinomas) are responsible for more than 95% of all esophageal cancers (ICD-9 150); 17,460 newly diagnosed cases and 15,070 deaths were estimated for 2012 (Siegel et al., 2012). 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

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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the link between GERD and esophageal adenocarcinoma. The average annual incidence of esophageal cancers is shown in Table 8-4.

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 cancer was not separately evaluated and was not categorized with this group until Update 2004, so by default it fell into the category of inadequate or insufficient evidence of an association. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the COIs 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. Esophageal cancer was thus formally placed into the inadequate or insufficient category. No additional studies of esophageal cancer were reviewed in Update 2008.

Update 2010 considered a series of papers on mortality in TCP and PCP workers employed by Dow Chemical Company in Midland, Michigan, from 1937 to 1980. Collins et al. (2009a) followed 1,615 workers who worked at least 1 day in a department that had potential TCDD exposure, among whom five esophageal-cancer deaths were observed, for an SMR of 1.0 (95% CI = 0.3–2.2); none of the five had had concurrent PCP exposure. Collins et al. (2009b) described mortality in 773 PCP workers who were exposed to chlorinated dioxins that did not include TCDD; there were two observed deaths from esophageal cancer (SMR = 0.8, 95% CI 0.1–2.9). McBride et al. (2009a) reported on a mortality followup of the workers in the Dow AgroSciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD. 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. In following up cancer incidence in the men and women exposed to dioxin in the Seveso accident, Pesatori et al. (2009) observed no esophageal cancers in the high-exposure zone and no exposure-related pattern in the occurrence of esophageal cancer in the moderate- and low-exposure areas.

Table 8-5 summarizes the results of the relevant studies concerning esophageal cancer.

Update of the Epidemiologic Literature

Vietnam-Veteran and Environmental Studies No Vietnam-veterans studies or environmental studies of exposure to the COIs and esophageal cancer have been published since Update 2010.

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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TABLE 8-5 Selected Epidemiologic Studies—Esophageal Cancer (Shaded Entries Are New Information for This Update)

Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans

US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

All COIs

Mortality

1965–2000

    6 1.2 (0.4–4.0) Boehmer et al., 2004
State Studies of US Vietnam Veterans

Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs nondeployed

    9 0.9 (0.4–1.6) Visintainer et al., 1995
International Studies of Vietnam Veterans

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

Incidence

All branches, 1982–2000

  70 1.2 (0.9–1.5) ADVA,

Navy

  19 1.6 (0.9–2.4) 2005a

Army

  40 1.1 (0.7–1.4)

Air Force

  11 1.5 (0.8–2.8)

Mortality

All branches, return–2001

  67 1.1 (0.8–1.3) ADVA,

Navy

  13 1.0 (0.5–1.7) 2005b

Army

  42 1.0 (0.7–1.3)

Air Force

  12 1.5 (0.8–2.6)

1980–1994

  23 1.2 (0.7–1.7) CDVA, 1997a

Australian Conscripted Army National Service (18,940 deployed vs 24,642 nondeployed)

All COIs

Incidence

1982–2000

    9 1.9 (0.6–6.6) ADVA, 2005c

Mortality

1966–2001

  10 1.3 (0.5–3.6) ADVA, 2005c

1982–1994

    1 1.3 (0.0– > 10) CDVA, 1997b
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Mortality 1939–1992

  28 1.0 (0.7–1.4) Kogevinas et al., 1997

13,831 exposed to highly chlorinated PCDDs

  20 1.3 (0.8–1.9)

7,553 not exposed to highly chlorinated PCDDs

    6 0.5 (0.2–1.1)

Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort

Saracci et al., 1991
    8 0.6 (0.3–1.2)

British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)

MCPA

Mortality through 1983

    8 0.9 (0.4–1.9) Coggon et al., 1986

German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)

Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP

Mortality 1952–2007 (ICD-9 150)

Manuwald et al., 2012

Men

  11 2.6 (1.3–4.6)

Women

    0 nr

New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram

Mortality 1969–2004

McBride et al., 2009a

Ever-exposed workers

    4 2.5 (0.7–6.4)

Never-exposed workers

    1 2.1 (0.1–12.2)

Production Workers (713 men and 100 women worked > 1 month in 1969–1984)

Mortality 1969–2000

    2 2.0 (0.2–7.0) ’t Mannetje et al., 2005

Phenoxy herbicide sprayers (> 99% men)

    1 0.7 (0.0–4.0)

All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts)

2,4,5-T; 2,4,5-TCP

1942–2003 (n = 1,615)

Collins et al., 2009a

Trichlorophenol workers

    5 1.0 (0.3–2.2)

Pentachlorophenol workers

    2 0.8 (0.1–2.9)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

All Dow PCP-Exposed Workers—all workers from two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

1940–2005 (n = 2,122)

    8 1.0 (0.4–2.0)

PCP and TCP (n = 720)

    2 0.8 (0.1–3.0)

PCP (no TCP) (n = 1,402)

    6 1.1 (0.4–2.3)
OCCUPATIONAL—PAPER AND PULP WORKERS TCDD

IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM

McLean et al., 2006

Exposure to nonvolatile organochlorine compounds

Never

  27 0.7 (0.4–1.0)

Ever

  26 0.8 (0.5–1.2)
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)

DENMARK

Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)

Herbicides Ronco et al., 1992

Men

Self-employed

  32 0.4 (p < 0.05)

Employee

  13 0.9 (nr)

Women

Self-employed

    1 1.4 (nr)

Employee

    2 0.4 (nr)

FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC

Phenoxy herbicides

Incidence

    3 1.6 (0.3–4.6) Asp et al.,

Mortality 1972–1989

    2 1.3 (0.2–4.7) 1994

NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 385 incident esophageal cancer cases vs remainder of 19,904 men with any incident cancer

Reif et al., 1989

Forestry workers (n = 134)

Herbicides
    4 1.8 (0.7–4.8)

Aged 20–59

    1 1.6 (0.2–11.3)

Aged ≥ 60

    3 1.9 (0.6–5.8)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Sawmill workers (n = 139)

Herbicides, chlorophenols
    2 0.7 (0.2–2.9)

SWEDEN

Incidence cancer cases 1961–1973 with agriculture as economic activity in 1960 census (male, female)

169 99% CI 0.6 (0.5–0.7) Wiklund et al., 1983

UNITED STATES

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides

Incidence

Enrollment through 2006—SIRs for participants

Koutros et al., 2010a

Private applicators

    52 0.6 (0.5–0.9)

Commercial applicators

    2 nr

Spouses

    2 nr

Mortality

Enrollment through 2007, vs state rates

Waggoner et al., 2011

Applicators (n = 1,641)

  48 0.5 (0.4–0.7)

Spouses (n = 676)

    3 nr

Enrollment through 2000, vs state rates Private applicators (men and women) Spouses of private applicators (> 99% women)

Blair et al., 2005a
  16 0.5 (0.3–0.9)
    1 0.3 (0.1–1.9)
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) TCDD

Incidence

20-yr followup to 1996—men and women

Zone A

    0 Pesatori

Zone B

    1 0.3 (0.0–1.9) et al., 2009

Zone R

  35 1.3 (0.9–1.9)
CASE-CONTROL STUDIES

US Case-Control Studies

Nebraska—agricultural pesticide use and adenocarcinoma of the esophagus

Phenoxy herbicides, 2,4-D Lee et al., 2004a
137
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed
Casesb
Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Insecticides

0.7 (0.4–1.1)

Herbicides

0.7 (0.4–1.2)

International Case-Control Studies

UK men, 18–35 yrs of age from counties with particular chemical manufacturing—mortality

Herbicides, chlorophenols Magnani et al., 1987

Herbicides

  nr 1.6 (0.7–3.6)

Chlorophenols

  nr 1.2 (0.7–2.2)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DCP, 2,4-dichlorophenol; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CATI, computer-assisted telephone interviewing; 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; JEM, job-exposure matrix; MCPA, 2 methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PM, proportionate mortality; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCP, pentachlorophenol; TCDD, 2,3,7,8-tetra-chlorodibenzo-p-dioxin; TCP, trichlorophenol.

aSubjects are male and outcome is mortality unless otherwise noted.

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

Occupational Studies Starting with a set of 1,316 in 2,4-D-exposed workers, Burns et al. (2011) identified cancer cases through 2007 in the Michigan’s cancer registry from its start in 1985. The analysis of the third (and most stringently defined in terms of continued residence in Michigan) of the nested cohorts of workers included 1,108 men who were employed in a Dow facility in Midland during 1945–1994 and were alive on January 1, 1985. Esophageal cancers were not reported separately and so would have fallen in the category of “other GI and digestive cancers,” in which there were eight cases (SIR = 1.02, 95% CI 0.44–2.02).

Manuwald et al. (2012) reported mortality in 1,191 men and 398 women who had been employed for at least 3 months during 1952–1984 in a chemical plant in Hamburg (a subcohort of the IARC phenoxy-herbicide cohort). During that period, the plant produced insecticides and herbicides, including 2,4,5-T, so cohort members had the possibility of exposure to TCDD. Subjects entered the cohort on the date of their first employment at the plant, and vital status was sought through 2007. No deaths from esophageal cancer in female workers were reported, but esophageal-cancer mortality relative to that in the population of Hamburg was increased in men (SMR = 2.56, 95% CI 1.27–4.57).

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Ruder and Yiin (2011) reported mortality in 1940–2005 in the NIOSH PCP cohort of 2,122 workers in the four US plants that had been involved in PCP production. PCP production entailed exposure to PCDDs and PCDFs but not to the most toxic 2,3,7,8 dioxin congener. A subcohort of 720 workers (all men, the PCP-plus-TCDD group) had also been employed in TCP production and so had also been exposed to TCDD. In the total cohort, eight deaths were attributed to esophageal cancer; that is consistent with the mortality experience of the US population (SMR = 0.99, 95% CI 0.43–1.96). There were two deaths in the PCP-plus-TCDD group, not more than expected (SMR = 0.82, 95% CI 0.10–2.95). The results were effectively the same in the 1,402 workers who had not had any opportunity for occupational exposure to TCDD (SMR = 1.07, 95% CI 0.39–2.33).

The participants in the AHS are known to have had extensive exposure to the phenoxy herbicides, but the analyses of updated mortality (Waggoner et al., 2011) and cancer incidence (Koutros et al., 2010a) address only exposure to pesticides in general. Waggoner et al. (2011) reported lower numbers of deaths from cancer of the esophagus than expected on the basis of state rates in the applicators (SMR = 0.51, 95% CI 0.38–0.68). Only three cases of espophageal cancer were observed in the spouses. In the update of cancer incidence through 2006, Koutros et al. (2010a) found a significant decrease in the incidence of esophageal cancer in the private applicators (52 cases, SIR = 0.64, 95% CI 0.48–0.85). Only two cases of esophageal cancer were observed in the spouses. The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Case-Control Studies Meyer et al. (2011) conducted a case-control study of esophageal cancer in Brazilians in which occupation was obtained from death certificates. Being an agricultural worker was used as a surrogate for pesticide exposure, so exposure specificity was inadequate for the purpose of this review.

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs 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 previous 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 gastrointestinal-tract (UGI) cancer (Roth et al., 2009). AHR expression was higher in patients who had a family history of UGI cancer but was not associated with indoor air pollution, esophageal squamous-cell dysplasia category, age, sex, or smoking. The results suggest that enhanced expression of the AHR in patients who had a family his-

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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tory 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.

In a small series, AHR expression was found to be higher in esophageal tumors than in corresponding normal mucosa (Zhang et al., 2012).

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

Synthesis

Manuwald et al. (2012) reported a significant increase in mortality from esophageal cancer in the men in the Hamburg cohort of phenoxy-herbicide workers. In combination with the studies reviewed previously, however, that single new finding did not provide adequate evidence to establish an association between exposure to the COIs and esophageal cancer. No toxicologic studies provide evidence of the biologic plausibility of an association between the COIs 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 COIs and esophageal cancer.

Stomach Cancer

The incidence of stomach cancer (ICD-9 151) increases with age. ACS estimated that 13,020 men and 8,300 women would receive diagnoses of stomach cancer in the United States in 2012 and that 6,190 men and 4,350 women would die from it (Siegel et al., 2012). 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 Helicobacter pylori increases the risk of stomach cancer. Tobacco use and consumption of nitrite- and salt-preserved food may also increase the risk (Brenner et al., 2009; Key et al., 2004; Miller et al., 1996). The average annual incidence of stomach cancer is shown in Table 8-4.

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 drew conclusions about the adequacy of the evidence of its association with herbicide expo-

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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sure 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 COIs 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. Stomach cancer was thus reclassified into the default category of inadequate or insufficient evidence to determine whether there is 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 AHS, that committee retained stomach cancer in the inadequate or insufficient category.

Between Update 2008 and Update 2010, studies of three occupational cohorts and two environmental-study populations were published. In examining mortality in workers employed by Dow Chemical Company in Midland, Michigan, during 1937–1980, Collins et al. (2009a) observed eight cases of stomach cancer in 1,615 TCP workers (SMR = 1.4, 95% CI 0.6–2.7) and four deaths from stomach cancer in 773 PCP workers (SMR = 1.2, 95% CI 0.3–3.1). McBride et al. (2009a) reported on mortality in workers in the Dow AgroSciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD; mortality from stomach cancer was somewhat higher in the never-exposed group (SMR = 2.3, 95% CI 0.3–8.4) than in exposed workers (SMR = 1.4, 95% CI 0.4–3.6). In the third followup of a retrospective cohort study of two Dutch chlorophenoxyherbicide manufacturing factories, Boers et al. (2010) found that neither had increased mortality from stomach cancer. An update of cancer incidence in the Seveso cohort (Pesatori et al., 2009) found no evidence of an increase in stomach cancer. In a second environmental study, Turunen et al. (2008) assessed mortality in Finnish fishermen and their wives, presuming that their mortality would reflect their high consumption of contaminated fish; death from stomach cancer was not increased.

Table 8-6 summarizes the results of the relevant studies concerning stomach cancer.

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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TABLE 8-6 Selected Epidemiologic Studies—Stomach Cancer (Shaded Entries Are New Information for This Update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans

US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)

All COIs

Incidence

1982–2003—White SEA comparison veterans only (n = 1,482). Serum TCDD (pg/g) based on model with exposure variable loge(TCDD)

Pavuk et al., 2005

Per unit increase of –loge(TCDD) (pg/g) Quartiles (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)

0.8–1.3

    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)

Through 1999—White subjects vs national rates

Akhtar et al., 2004

Ranch Hand veterans (n = 1,189)

  16 0.6 (0.4–1.0)

With tours between 1966–1970

  14 0.6 (0.4–1.1)

SEA comparison veterans (n = 1,776)

  31 0.9 (0.6–1.2)

With tours between 1966–1970

  24 0.9 (0.6–1.3)

Mortality

Through 1999—White subjects vs national rates

Akhtar et al., 2004

Ranch Hand veterans (n = 1,189)

    6 0.4 (0.2–0.9)

SEA comparison veterans (n = 1,776)

  14 0.7 (0.4–1.1)

US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

All COIs

Mortality

1965–2000

    5 nr Boehmer et al., 2004

US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973

All COIs
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

1965–1982

Breslin

Army, deployed (n = 19,708) vs nondeployed (n = 22,904)

  88 1.1 (0.9–1.5) et al., 1988

Marine Corps, deployed (n = 4,527) vs nondeployed (n = 3,781)

  17 0.8 (0.4–1.6)
State Studies of US Vietnam Veterans

923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans

    1 nr Anderson et al., 1986
International Vietnam-Veteran Studies

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

Incidence

All branches, 1982–2000

104 0.9 (0.7–1.1) ADVA,

Navy

  28 1.1 (0.7–1.6) 2005a

Army

  66 0.9 (0.7–1.1)

Air Force

  10 0.7 (0.3–1.3)

Mortality

All branches, return–2001

  76 0.9 (0.7–1.2) ADVA,

Navy

  22 1.3 (0.8–1.8) 2005b

Army

  50 0.9 (0.7–1.2)

Air Force

    4 0.4 (0.1–1.0)

1980–1994

  32 1.1 (0.7–1.4) CDVA, 1997a

Australian Conscripted Army National Service (18,940 deployed vs 24,642 nondeployed)

All COIs

Incidence

1982–2000

  11 0.6 (0.2–1.2) ADVA, 2005c

Mortality

1966–2001

    7 0.7 (0.2–2.0) ADVA, 2005c

1982–1994

    4 1.7 (0.3– > 10) CDVA, 1997b
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates Phenoxy herbicides, chlorophenols

Mortality 1939–1992

  72 0.9 (0.7–1.1) Kogevinas

13,831 exposed to highly chlorinated PCDDs

  42 0.9 (0.7–1.2) et al., 1997

7,553 not exposed to highly chlorinated PCDDs

  30 0.9 (0.6–1.3)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort

Saracci et al., 1991

Nested case-control study

  40 0.9 (0.6–1.2)

Mortality, incidence of women in production (n = 699) and spraying (n = 2) compared to national death rates and cancer incidence rates

TCDD Kogevinas et al, 1993
    1 1.4 (nr)

British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)

MCPA

Mortality through 1983

  26 0.9 (0.6–1.3) Coggon et al., 1986

Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)

Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP

Incidence 1943–1982

Lynge, 1985

Men

  12 1.3 (nr)

Women

    1 0.7 (nr)

Mortality 1955–2006

  14 1.1 (0.8–1.5) Boers et al., 2012

TCDD plasma level (hazard ratios, by tertile)

Background (≤ 0.4)

    8

Low (0.4–1.9)

    1 0.1 (0.0–1.0)

Medium (1.9–9.9)

    2 0.5 (0.1–2.6)

High (≥ 9.9)

    3 2.5 (0.7–9.2)

Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)

Dioxins, 2,4,5-T, 2,4,5-TCP

Mortality 1955–2006 (HRs for lagged TCDD plasma levels)

    6 1.5 (1.1–2.2) Boers et al., 2012

Mortality 1955–2006

    5 2.2 (0.4–13.2) Boers et al. 2010

Mortality 1955–1991

    3 1.0 (0.2–2.9) Hooiveld et al., 1998

Mortality 1955–1985

    2 0.9 (0.1–3.4) Bueno de Mesquita et al., 1993

Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)

2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely

Mortality 1965–2006

    4 1.2 (0.3–4.7) Boers et al., 2010
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Mortality 1965–1986

    0 0.0 (0.0–6.5) Bueno de Mesquita et al., 1993

German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 month in 1951–1976) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4,5-TCP

Mortality 1951–1992

    0 nr Becher et al., 1996

German Production Workers at Bayer Plant in Dormagen (520 men working > 1 month in 1965–1989) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1965–1989

    0 nr Becher et al., 1996

German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 month in 1957–1987) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1956–1989

    2 0.6 (0.1–2.3) Becher et al., 1996

BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)

Focus on TCDD

Incidence

1960–1992

    3 1.0 (0.2–2.9) Ott and Zober, 1996

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)

Mortality

Through 1987

90% CI Zober et al., 1990
    3 3.0 (0.8–7.7)

German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)

Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP

Mortality 1952–2007 (ICD-9 140–149)

  17 1.0 (0.6–1.6) Manuwald et al., 2012

Men

  17 1.3 (0.7–2.0)

Women

    0 nr

Mortality 1952–1989

  12 1.3 (0.7–2.2) Becher et al., 1996
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Mortality 1952–1989—stats on men only, 1,184 (tables all for 1,148 men, not necessarily German nationals) vs national rates (also vs gas workers); same observation period as Becher et al., 1996

  12 1.2 (0.6–2.1) Manz et al., 1991

New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram

Mortality 1969–2004

McBride et al., 2009a

Ever-exposed workers

    4 1.4 (0.4–3.6)

Never-exposed workers

    2 2.3 (0.3–8.4)

Production Workers (713 men and 100 women worked > 1 month in 1969–1984)

Mortality 1969–2000

    2 1.1 (0.1–4.0) ’t Mannetje et al., 2005

Phenoxy herbicide sprayers (> 99% men)

    3 1.4 (0.3–4.0)

NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

Through 1993

  13 1.0 (0.6–1.8) Steenland et al., 1999

Through 1987

    10 1.0 (0.5–1.9) Fingerhut et al., 1991

≥ 1-year exposure, ≥ 20-year latency

    4 1.4 (0.4–3.5)

Mortality—754 Monsanto workers, among most highly exposed workers from Fingerhut et al. (1991)

    0 0.0 (0.0–1.1) Collins et al., 1993

All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts)

2,4,5-T; 2,4,5-TCP

1942–2003 (n = 1,615)

    8 1.4 (0.6–2.7) Collins et al., 2009a

1940–1994 (n = 2,187 men)

  nr 1.5 (0.7–2.7) Bodner et al., 2003

All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

1940–2005 (n = 2,122)

    9 0.9 (0.4–1.7)

PCP and TCP (n = 720)

    3 1.0 (0.2–2.9)

PCP (no TCP) (n = 1,402)

    6 0.8 (0.3–1.8)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Dow 2,4-D Production Workers (1945–1982 in Midland, Michigan) (subset of all TCP-exposed workers)

2,4-D, lower chlorinated dioxins

Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3)

    3 0.8 (0.2–2.3) Burns et al., 2011

Through 1994 (n = 1,517) (digestive organs, peritoneum)

  16 0.7 (0.4–1.2) Burns et al., 2001

Through 1982 (n = 878)

    0 nr (0.0–3.7) Bond et al., 1988

Dow PCP Production Workers (1937–1989 in Midland, Michigan) (not in IARC and NIOSH cohorts)

Low chlorinated dioxins, 2,4-D

Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) Mortality 1940–1989 (n = 770)

    4 1.2 (0.3–3.1) Collins et al., 2009b Ramlow et al., 1996

0-yr latency

    4 1.7 (0.5–4.3)

15-yr latency

    3 1.8 (0.4–5.2)
Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohorts) Dioxins, phenoxy herbicides

1,412 white male US flavor and fragrance chemical plant workers (1945–1965)

Dioxin, 2,4,5-T Expected exposed Thomas, 1987
    6 cases
4.2
OCCUPATIONAL—PAPER AND PULP WORKERS TCDD

IARC cohort of pulp and paper workers—60,468 workers from 11 countries,

McLean et al., 2006

TCDD among 27 agents assessed by JEM

Exposure to nonvolatile organochlorine compounds

Never

146 0.9 (0.8–1.1)

Ever

  98 0.9 (0.7–1.1)

14,362 Danish paper workers employed 1943–1990, followed through 1993

Rix et al., 1998

Men

  48 1.1 (0.8–1.4)

Women

    7 1.0 (0.4–2.1)

New Hampshire pulp and paper workers, 883 white men working ≥ 1 yr, mortality through July 1985

    5 1.2 (0.4–2.8) Henneberger et al., 1989

Pulp and Paper cohorts independent of IARC cohort

United Paperworkers International, 201 white men employed ≥ 10 yrs and dying 1970–1984

    1 0.5 (0.1–3.0) Solet et al., 1989
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and California, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977

  17 90% CI 1.2 (0.8–1.9) Robinson et al., 1986
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)

CANADA

Canadian Farm Operator Study—156,242 men farming in Manitoba, Saskatchewan, and Alberta in 1971; mortality from stomach cancer June 1971–December 1987

Linkage of records for ~70,000 male Saskatchewan farmers (1971–1985)

246 0.9 (0.8–1.0) Wigle et al., 1990

DENMARK

Danish farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)

Herbicides Ronco et al., 1992

Men

Self-employed

286 0.9 (nr)

Employee

  71 1.2 (nr)

Women

Self-employed

    5 1.0 (nr)

Employee

    5 1.7 (nr)

ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974

Mortality 1970–1986 (n = 23,401)

126 0.7 (0.6–0.9) Torchio et al., 1994

Italian rice growers with documented phenoxy use (n = 1,487)

Phenoxy herbicides Gambini et al., 1997
  39 1.0 (0.7–1.3)

NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident stomach cancer cases vs remainder of 19,904 men with any incident cancer

Reif et al., 1989

Forestry workers (n = 134)

Herbicides
  13 2.2 (1.3–3.9)

Aged 20–59

    3 0.7 (0.2–2.2)

Aged ≥ 60

  10 2.4 (1.2–4.5)

Sawmill workers (n = 139)

Herbicides, chlorophenols
    7 1.0 (0.4–2.1)

SWEDEN

348 Swedish railroad workers (1957–October, 1978)—total exposure to herbicides

Phenoxy acids Axelson et al., 1980
    3 2.2 (nr)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Incident stomach cancer cases 1961–1973 with agriculture as economic activity in 1960 census

99% CI Wiklund, 1983
2,599 1.1 (1.0–1.2)

THE NETHERLANDS

Dutch Licensed Herbicide Sprayers—1,341 certified before 1980

Through 2000 (stomach, small intestine)

    3 0.4 (0.1–1.3) Swaen et al., 2004

Through 1987 (stomach, small intestine)

    1 0.5 (0.0–2.7) Swaen et al., 1992

UNITED STATES

US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states

Herbicides PCMRs Blair et al., 1993

Men

Whites (n = 119,648)

657 1.0 (1.0–1.1)

Nonwhites (n = 11,446)

115 1.1 (0.9–1.3)

Women

Whites (n = 2,400)

  12 1.2 (0.6–2.0)

Nonwhites (n = 2,066)

  23 1.9 (1.2–2.8)

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides

Incidence

Enrollment through 2006—SIRs for participants

Koutros et al., 2010a

Private applicators

  61 0.9 (0.7–1.1)

Commercial applicators

    2 nr

Spouses

  15 0.9 (0.5–1.5)

Enrollment through 2002

Alavanja et al., 2005

Private applicators

462 0.8 (0.8–0.9)

Spouses of private applicators (> 99% women)

161 0.9 (0.7–1.0)

Commercial applicators

  24 1.0 (0.6–1.4)

Mortality

Enrollment through 2007, vs state rates

Waggoner et al., 2011

Applicators (n = 1,641)

  26 0.5 (0.3–0.8)

Spouses (n = 676)

    5 0.4 (0.1–1.0)

Enrollment through 2000, vs state rates

Blair et al., 2005a

Private applicators (men and women) Spouses of private applicators (> 99% women)

  10 0.5 (0.2–1.0)
    4 1.1 (0.3–2.8)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

California United Farm Workers of America

2,4-D

Nested case-control study of agricultural exposure and gastric cancer in UFW cohort

Mills and Yang, 2007

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)

85–1,950

  11 2.1 (0.9–5.1)

US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of stomach cancer

Herbicides

Agricultural extension agents

  10 0.7 (0.4–1.4) Alavanja et al., 1988

Forest conservationists

p-trend < over years worked Alavanja et al., 1989
    9 0.7 (0.3–1.3)

Soil conservationists

Florida pesticide applicators licensed 1965–1966 (n = 3,827)—mortality through 1976

Herbicides Blair et al., 1983

Any pesticide (dose-response by length of licensure)

Expected exposed cases
    4 3.3

White Male Residents of Iowa—stomach cancer on death certificate, usual occupation: farmers vs not

Herbicides

> 30 yrs old when died 1964–1978—case-control

1,812 1.3 (p < 0.05) Burmeister et al., 1983

H0: only for “modern methods” → born after 1900

Born before 1880

458 1.3 (p < 0.05)

Born 1980–1900

639 1.3 (p < 0.05)

Born after 1900

715 1.3 (p < 0.05)

> 20 yrs old when died 1971–1978—PMR

338 1.1 (p < 0.01) Burmeister, 1981

ENVIRONMENTAL

Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171)

TCDD

Incidence

20-yr followup to 1996—men and women

Zone A

    3 0.9 (0.3–2.7) Pesatori

Zone B

  19 0.9 (0.6–1.4) et al., 2009
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Zone R

131 0.8 (0.7–1.0)

10-yr followup to 1991—men

Bertazzi et al., 1993

Zone B

    7 1.0 (0.5–2.1)

Zone R

  45 0.9 (0.7–1.2)

10-yr followup to 1991—women

Bertazzi et al., 1993

Zone B

    2 0.6 (0.2–2.5)

Zone R

  25 1.0 (0.6–1.5)

Mortality

25-yr followup to 2001—men and women

Consonni et al., 2008

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)

20-yr followup to 1996

Bertazzi et al., 2001

Zones A and B—men

  16 0.9 (0.5–1.5)

Zones A and B—women

  11 1.0 (0.6–1.9)

15-yr followup to 1991—men

Bertazzi et al., 1997, 1998

Zone B

  10 0.8 (0.4–1.5)

Zone R

  76 0.9 (0.7–1.1)

15-yr followup to 1991—women

Bertazzi et al., 1997, 1998

Zone A

    1 0.9 (0.0–5.3)

Zone B

    7 1.0 (0.4–2.1)

Zone R

  58 1.0 (0.8–1.3)

10-yr followup to 1986—men

Bertazzi et al., 1989a

Zone A, B, R

  40 0.8 (0.6–1.2)

10-yr followup to 1986—women

Bertazzi et al., 1989a

Zone A, B, R

  22 1.0 (0.6–1.5)

10-yr followup to 1986—men

Bertazzi et al., 1989b

Zone B

  7 1.2 (0.6–2.6)

Ecological Study of Residents of Chapaevsk, Russia

Dioxin Revich et al., 2001

Incidence—Crude incidence rate in 1998 vs

Men

Regional (Samara)

nr 44.0 (nr)

National (Russia)

nr 48.1 (nr)

Women

Regional (Samara)

nr 17.6 (nr)

National (Russia)

nr 20.7 (nr)

Mortality—1995–1998 (SMR vs regional rates)

Men

  59 1.7 (1.3–2.2)

Women

  45 0.7 (0.5–0.9)

FINLAND

Finnish fishermen (n = 6,410) and spouses (n = 4,260) registered between 1980 and 2002 compared to national statistics

Serum dioxin Turunen et al., 2008

Fisherman

  16 0.8 (0.5–1.3)
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Spouses

    2 0.3 (0.0–1.1)

JAPAN

Residents of municipalities with and without waste incineration plants (cross-sectional)

Dioxin emissions age-adjusted mortality (per 100,000) Fukuda et al., 2003

Men

With

38.2 ± 7.8 vs 39.0 ± 8.8 (p = 0.29)

Without

Women

With

20.7 ± 5.0 vs 20.7 ± 5.8 (p = 0.92)

Without

SWEDEN

Swedish fishermen (high consumption of fish with persistent organochlorines)

Organochlorine compounds Svensson et al., 1995

Incidence

East coast

  24 1.6 (1.0–2.4)

West coast

  71 0.9 (0.7–1.2)

Mortality

East coast

  17 1.4 (0.8–2.2)

West coast

  63 0.9 (0.7–1.2)
CASE-CONTROL STUDIES

US Case-Control Studies

Eastern Nebraska—population-based case-control, agricultural pesticide use and adenocarcinoma of stomach

Herbicides, pesticides Lee et al., 2004a
170

Insecticides

0.9 (0.6–1.4)

Herbicides

0.9 (0.5–1.4)

International Case-Control Studies

Swedish—population-based case-control study of residents (40–79 yrs of age) with gastric adenocarcinoma (February 1989–January 1995)

Phenoxy herbicides Ekström et al., 1999

All occupational herbicide exposures

  75 1.6 (1.1–2.2)

Phenoxyacetic acid exposure

  62 1.8 (1.3–2.6)

   Hormoslyr (2,4-D, 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)
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

      > 1 yr

  13 1.4 (0.6–3.0)

   Other herbicide exposure

  13 1.0 (0.5–1.9)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; 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; JEM, job-exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PMR, proportionate mortality ratio; SEA, Southeast Asia; SIR, standardized incidence ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorod-ibenzo-p-dioxin; TCP, trichlorophenol; UFW, United Farm Workers of America; 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 Environmental Studies No Vietnam-veteran studies or environmental studies of exposure to the COIs and stomach cancer have been published since Update 2010.

Occupational Studies Burns et al. (2011) published an update examining cancer incidence in 1985–2007 in workers employed in 2,4-D production by Dow Chemical Company in Midland, Michigan, during 1945–1994. There was no evidence of significantly increased rates of cancer overall or of stomach cancer in particular. In the cohort defined most restrictively, the SIR of stomach cancer was 0.8 (95% CI 0.16–2.34), equivalent to the findings in the two more inclusive cohorts.

Boers et al. (2012) provided a quantified, TCDD-based analysis, updated through 2006, of mortality in male workers in two Dutch phenoxy-herbicide factories, which were considered in Update 2010 (Boers et al., 2010). The 1,020 workers in factory A had been involved in production of 2,4,5-T with its associated TCDD contamination; the 1,036 in factory B had produced only phenoxy herbicides that would not have had TCDD contamination. Contemporary TCDD concentrations measured in a subsample of 187 workers were used to derive a model incorporating job history to estimate serum TCDD concentrations of all the men at the end of their employment. Using the estimated TCDD concentra-

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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tions of the workers in both factories did not indicate an increased risk of stomach cancer posed by TCDD (hazard ratio [HR] = 1.06, 95% CI 0.77–1.47). The dose–response modeling applied only to the workers in factory A, however, found a significantly increased risk of stomach cancer (HR = 1.52, 95% CI 1.05–2.20), whereas the qualitative exposure analysis in Boers et al. (2010) had not (HR = 2.23, 95% CI 0.38–13.20).

Manuwald et al. (2012) reported on mortality in 1,191 men and 398 women who had been employed for at least 3 months during 1952–1984 in a chemical plant in Hamburg (a subcohort of the IARC phenoxy-herbicide cohort). During that period, the plant produced insecticides and herbicides, including 2,4,5-T, so cohort members had the possibility of exposure to TCDD. Subjects entered the cohort on the date of their first employment in the plant, and vital status was sought through 2007. All 17 observed deaths from stomach cancer occurred in the male workers, but relative to the population of Hamburg this did not constitute an increase in stomach-cancer mortality in men (SMR = 1.27, 95% CI 0.74–2.03).

Ruder and Yiin (2011) reported mortality in 1940–2005 in the NIOSH PCP cohort of 2,122 workers in the four US plants that had been involved in PCP production. PCP production entailed exposure to PCDDs and PCDFs but not to the most toxic 2,3,7,8 dioxin congener. A subcohort of 720 workers (all men, the PCP-plus-TCDD group) had also been employed in TCP production and so had also been exposed to TCDD. In the total cohort, nine deaths were attributed to stomach cancer; this was consistent with the mortality experience of the US population (SMR = 0.89, 95% CI 0.40–1.68). There were three stomach-cancer deaths in the PCP-plus-TCDD group—also not more than expected (SMR = 0.98, 95% CI 0.20–2.88). The results were effectively the same in the 1,402 workers in the PCP-only group (SMR = 0.84, 95% CI 0.31–1.84).

The participants in the AHS are known to have had extensive exposure to the phenoxy herbicides, but the analyses of updated mortality (Waggoner et al., 2011) and cancer incidence (Koutros et al., 2010a) address only exposure to pesticides in general. Waggoner et al. (2011) updated mortality in the AHS cohort through 2007. The observed number of deaths from stomach cancer was significantly lower than expected in the applicators (26 deaths, SMR = 0.52, 95% CI 0.34–0.76), as was the case for the five deaths from this type of cancer in their spouses (SMR = 0.42, 95% CI 0.14–0.99). Reporting on cancer incidence through 2006, Koutros et al. (2010a) found 61 cases of oral-cavity and pharyngeal cancers in the private applicators (SIR = 0.86, 95% CI 0.66–1.10) and 15 cases in their spouses (SIR = 0.91, 95% CI 0.51–1.50). The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Case-Control Studies In a Spanish study, Santibanez et al. (2012) explored the relationship between 399 stomach cancers of varied histology and occupational

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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exposures estimated by application of a job—exposure matrix to work histories. Of chemicals that might have been of interest, only the category of “pesticides” was used, which is not specific enough for the results to be regarded as informative for the present review.

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs (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 of laboratory animals have observed dose-dependent 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 phenotype of the transgenic animal (increased relative weight of the liver and heart, decreased weight of the thymus, and increased expression of AHR target gene CYP1A1) and animals treated with TCDD (Brunnberg et al., 2006).

In a biomarker study of cancer patients, AHR expression and nuclear trans-location were significantly higher in stomach-cancer tissue than in precancerous tissue (Peng et al., 2009a). The results suggest that the AHR plays an important role in stomach carcinogenesis. AHR activation in a stomach-cancer cell line (AGS) has also been shown to enhance stomach-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 COIs is discussed in general at the beginning of this chapter.

Synthesis

Boers et al. (2012) derived a predictive model based on job histories and current TCDD concentrations in a subset of the workers in two Dutch phenoxy-herbicide factories. Using estimates of each man’s serum TCDD at the end of his employment, they found a significant increase in the risk of death from stomach cancer in the workers in the factory that had TCDD contamination, whereas an earlier categorical analysis of the same data found an increase risk with a very wide confidence interval (Boers et al., 2010); when the workers in the factory that did not have TCDD contamination were added to the continuous analysis,

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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the risk did not remain significant (Boers et al., 2012). Several case-control studies addressing agricultural exposures reported evidence of an association of stomach cancer: both Ekström et al. (1999) and Mills and Yang (2007) found an association with herbicides, and with phenoxy herbicides in particular; Cocco et al. (1999) found a relationship with herbicide exposure, but the results were not specific as to type of herbicide. There has been no suggestion of an association between TCDD and stomach cancer in the Seveso population (Consonni et al., 2008; Pesatori et al., 2009) nor has there been any suggestion of an association between the COIs and stomach cancer in the studies of Vietnam-veteran cohorts or in the AHS.

There is some evidence of biologic plausibility in animal models, but overall the epidemiologic studies do not support an association between exposure to the COIs 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 determine whether there is an association between exposure to the COIs 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 tract tumors; ACS estimated that 157,760 people would receive diagnoses of colorectal cancer in the United States in 2012 and that 53,620 would die from it (Siegel et al., 2012). 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 8-4.

The incidence of colorectal cancer increases with age; it is higher in men than in women and higher in blacks than in whites. (Screening can affect the incidence, and it is recommended for all persons over 50 years old.) 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 colorectal cancer (ACS, 2013a).

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 conclus-

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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ions 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 COIs 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.

The new information considered in Update 2010 also did not provide evidence to suggest that colorectal cancers be moved out of the category of inadequate or insufficient evidence. Collins et al. (2009a) found no increase of deaths from colorectal cancer in PCP workers in a Dow Chemical Company plant in Midland, Michigan, compared with the general US population and the state of Michigan. In a followup study of workers in the Dow AgroSciences plant in New Plymouth, New Zealand, McBride et al. (2009a) did not find an increased SMR for colorectal-cancer deaths in the workers who were exposed to TCDD compared with the never-exposed group. In updating cancer incidence in the Seveso population (males and females combined), Pesatori et al. (2009) found no cases of rectal cancer and a lower risk of colon cancer in the high-exposure zone than in the moderate- and low-exposure zones. Turunen et al. (2008) assessed mortality in Finnish fishermen and their wives and presumed that their high consumption of fish would result in harmful exposure to dioxin-like chemicals, but found no increase in mortality from colon, rectal, or anal cancer in this cohort relative to control populations.

Table 8-7 summarizes the results of the relevant studies concerning colon and rectal cancers.

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies No Vietnam-veteran studies, environmental studies, or case-control studies of exposure to the COIs and colorectal cancer have been published since Update 2010.

Occupational Studies Burns et al. (2011) updated, through 2007, cancer incidence in workers who were alive on January 1, 1985, and had been employed at any time from 1945 to 1994 in 2,4-D production by the Dow Chemical Company in Midland, Michigan. They found no evidence of significantly increased rates of

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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TABLE 8-7 Selected Epidemiologic Studies—Colon and Rectal Cancer (Shaded Entries Are New Information for This Update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS US Vietnam Veterans

US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

All COIs

Mortality

1965–2000

    9 1.0 (0.4–2.6) Boehmer et al., 2004

US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973

All COIs

1965–1982 (Colon, other gastrointestinal, ICD-8 152–154, 158, 159)

Breslin et al., 1988

Army, deployed (n = 19,708) vs nondeployed (n = 22,904)

209 1.0 (0.7–1.3)

Marine Corps, deployed (n = 4,527) vs nondeployed (n = 3,781)

  33 1.3 (0.7–2.2)

US VA Cohort of Female Vietnam Veterans

All COIs

Mortality

Through 2004

Cypel and Kang, 2008

US Vietnam veterans

  11 0.5 (0.2–1.0)

Vietnam-veteran nurses—colon

    9 0.6 (0.2–1.4)

Through 1991

Dalager et al., 1995

US Vietnam veterans

    4 0.4 (0.1–1.2)

Vietnam-veteran nurses—colon

    4 0.5 (0.2–1.7)

State Studies of US Vietnam Veterans

923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans

Anderson et al., 1986

Colon

    6 1.0 (0.4–2.2)

Rectum

    1 nr

International Studies of Vietnam-Veterans

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

Incidence

Colon—All branches, 1982–2000

376 1.1 (1.0–1.2) ADVA,

Navy

  91 1.3 (1.0–1.5) 2005a

Army

239 1.1 (0.9–1.2)

Air Force

  47 1.1 (0.8–1.5)
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Rectum—All branches, 1982–2000

ADVA, 2005a

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)

Validation Study

Expected number of exposed cases

Men—colorectal cancer

188 221 (191–251) AIHW, 1999

Men—self-reported colon cancer

405 117 (96–138) CDVA, 1998a

Women—self-reported colon cancer

    1 1 (0–5) CDVA, 1998b

Mortality

Colon—All branches, return–2001

176 1.0 (0.8–1.1) ADVA, 2005b

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—All branches, return–2001

ADVA, 2005b

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)

1980–1994

CDVA, 1997a

Colon

  78 1.2 (0.9–1.5)

Rectum

  16 0.6 (0.4–1.0)

Australian Conscripted Army National Service

All COIs

(18,940 deployed vs 24,642 nondeployed)

Incidence

1982–2000

ADVA, 2005c

Colon

  54 0.9 (0.7–1.4)

Rectum

  46 1.4 (0.9–2.2)

Mortality

1966–2001

ADVA, 2005c

Colon

  29 0.8 (0.5–1.3)

Rectum

  10 1.8 (0.6–5.6)

1982–1994

CDVA, 1997b

Colon

    6 0.6 (0.2–1.5)

Rectum

    3 0.7 (0.2–9.5)
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Mortality 1939–1992

Kogevinas et al., 1997

13,831 exposed to highly chlorinated PCDDs

Colon

  86 1.1 (0.9–1.3)

Rectum

  44 1.1 (0.8–1.4)

7,553 not exposed to highly chlorinated

PCDDs

Colon

  52 1.0 (0.8–1.3)

Rectum

  29 1.3 (0.9–1.9)

Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort

Saracci et al., 1991

Nested case-control study

Colon (except rectum)

  41 1.1 (0.8–1.5)

Rectum

  24 1.1 (0.7–1.6)

British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)

MCPA Coggon et al., 1986

Mortality through 1983

Colon

  19 1.0 (0.6–1.6)

Rectum

    8 0.6 (0.3–1.2)

Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)

Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP

Incidence 1943–1982

Lynge, 1985

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 in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)

Dioxins, 2,4,5-T, 2,4,5-TCP

Mortality 1955–1991

Hooiveld et al., 1998

Colon

    3 1.4 (0.3–4.0)

Rectum

    1 1.0 (0.0–5.6)

Mortality 1955–1985

Bueno de

Large intestine, except colon

    3 2.4 (0.5–7.0) Mesquita et al., 1993

Rectum

    0 0.0 (0.0–5.6)
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)

2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely

Mortality 1965–1986

    3 1.8 (0.4–5.4) Bueno de Mesquita et al., 1993

Large intestine, except rectum

    0 0.0 (0.0–9.5)

Rectum

    0 0.0 (0.0–19.4)

German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 month in 1951–1976) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4,5-TCP

Mortality 1951–1992

Becher et al., 1996

Colon

    0 nr

Rectum

    0 nr

German Production Workers at Bayer Plant in Dormagen (520 men working > 1 month in 1965–1989) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1965–1989

Becher et al., 1996

Colon

    1 2.2 (0.1–2.2)

Rectum

    0 nr

German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 month in 1957–1987) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1956–1989

Becher et al., 1996

Colon

    0 nr

Rectum

    1 0.9 (0.0–4.9)

BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)

Focus on TCDD

Incidence

1960–1992—colorectal

    5 1.0 (0.3–2.3) Ott and Zober, 1996

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)

Mortality

Through 1987—colon, rectum

90% CI Zober et al., 1990
    2 2.5 (0.4–7.8)

Through 1970—(n = 74; 70 initially exposed, 4 involved with cleaning and testing procedures)

    1 0.4 (nr) Theiss et al., 1982
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)

Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP

Mortality 1952–2007 (ICD-9 140–149)

Manuwald et al., 2012

Colon (ICD-9 153)

  12 0.7 (0.4–1.3)

Men

    7 0.6 (0.3–1.3)

Women

    5 0.9 (0.3–2.1)

Rectum, rectosigmoid junction, anus (ICD-9 154)

  13 1.7 (0.9–2.9)

Men

  11 2.0 (0.98–3.5)

Women

    2 1.0 (0.1–3.7)

Mortality 1952–1989

Becher et al., 1996

Colon

    2 0.4 (0.1–1.4)

Rectum

    6 1.9 (0.7–4.0)

Mortality 1952–1989—stats on men only, 1,184 (tables for 1,148 men, not necessarily German nationals) vs national rates (also vs gas workers); same observation period as Becher et al., 1966)

Manz et al., 1991

Colon

    8 0.9 (0.4–1.8)

New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram

Mortality 1969–2004

McBride et al., 2009a

Large intestine

Ever-exposed workers

    3 0.6 (0.1–1.7)

Never-exposed workers

    0 0.0 (0.0–2.0)

Rectum

Ever-exposed workers

    6 2.0 (0.7–4.4)

Never-exposed workers

    2 2.1 (0.3–7.7)

Production Workers (713 men and 100 women worked > 1 month in 1969–1984)

Mortality 1969–2000

’t Mannetje

Phenoxy herbicide producers (men and women)

et al., 2005

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)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

Through 1993

Steenland et al., 1999

Small intestine, colon

  34 1.2 (0.8–1.6)

Rectum

    6 0.9 (0.3–1.9)

Through 1987

Fingerhut et al., 1991

Entire NIOSH cohort

Small intestine, colon

  25 1.2 (0.8–1.8)

Rectum

    5 0.9 (0.3–2.1)

≥ 1-year exposure, ≥ 20-year latency

Small intestine, colon

  13 1.8 (1.0–3.0)

Rectum

    2 1.2 (0.1–4.2)

Mortality, colon cancer—754 Monsanto workers, among most highly exposed workers from Fingerhut et al. (1991)

    3 0.5 (0.1–1.3) Collins et al., 1993

All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts)

2,4,5-T; 2,4,5-TCP

1942–2003 (n = 1,615)

Collins et al., 2009a

Large intestine

  18 1.2 (0.7–1.8)

Rectum

    2 0.6 (0.1–2.1)

All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

Intestine (ICD-9 152–153)

1940–2005 (n = 2,122)

  26 1.1 (0.7–1.6)

PCP and TCP (n = 720)

  11 1.4 (0.7–2.6)

PCP (no TCP) (n = 1,402)

  15 0.9 (0.5–1.5)

Rectum (ICD-9 154)

1940–2005 (n = 2,122)

    2 0.4 (0.0–1.3)

PCP and TCP (n = 720)

    1 0.5 (0.0–3.0)

PCP (no TCP) (n = 1,402)

    1 0.3 (0.0–1.5)

Dow 2,4-D Production Workers (1945–1982 in Midland, Michigan) (subset of all TCP-exposed workers)

2,4-D, lower chlorinated dioxins

Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3)

Burns et al., 2011

Colon

  16 1.0 (0.6–1.6)

Rectum

    6 0.8 (0.3–1.7)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Through 1982 (n = 878)

Bond et al., 1988

Colon

    4 2.1 (0.6–5.4)

Rectum

    1 1.7 (0.0–9.3)

Dow PCP Production Workers (1937–1989 in Midland, Michigan) (not in IARC and NIOSH cohorts)

Low chlorinated dioxins, 2,4-D

Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP)

Collins et al., 2009b

Large intestine

  10 1.2 (0.6–2.3)

Rectum

    1 0.5 (0.0–2.9)

Mortality 1940–1989 (n = 770)

Ramlow et al., 1996

0-yr latency

Colon

    4 0.8 (0.2–2.1)

Rectum

    0 nr

15-yr latency

Colon

    4 1.0 (0.3–2.6)

Rectum

    0 nr

Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohorts)

1,412 white male US flavor and fragrance chemical plant workers (1945–1965)

Dioxin, 2,4,5-T Thomas, 1987

Colon

    4 0.6 (nr)

Rectum

    6 2.5 (nr)

OCCUPATIONAL—PAPER AND PULP WORKERS

TCDD

IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM

McLean et al., 2006

Exposure to nonvolatile organochlorine

compounds

Colon

  62 0.7 (0.6–1.0)

Rectum

  60 0.9 (0.7–1.1)

Danish paper workers

Rix et al., 1998

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)

New Hampshire pulp and paper workers, 883 white men working ≥ 1 yr, mortality through July 1985

Henneberger et al., 1989

Colon

    9 1.0 (0.5–2.0)

Rectum

    1 0.4 (0.0–2.1)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Pulp and Paper cohorts independent of IARC cohort

United Paperworkers International, 201 white men employed ≥ 10 yrs and dying 1970–1984

Solet et al., 1989

Colon

    7 1.5 (0.6–3.0)

Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and California, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977

Robinson et al., 1986

Intestines (ICD-7 152, 153)

    7 0.4 (0.2–0.7)
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)

DENMARK

Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)

Herbicides Ronco et al., 1992

Men

Self-employed

   

Colon

277 0.7 (p < 0.05)
   

Rectum

309 0.8 (p < 0.05)

Employee

   

Colon

  45 0.6 (p < 0.05)
   

Rectum

  55 0.8 (nr)

Women

Self-employed

   

Colon

  14 0.9 (nr)
   

Rectum

    5 0.6 (nr)

Employee

   

Colon

112 0.9 (nr)
  

Rectum

  55 0.8 (nr)

ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974

Mortality 1970–1986 (n = 23,401)

Torchio et al., 1994

Colon

  84 0.6 (0.5–0.7)

Rectum

nr nr

Italian rice growers with documented phenoxy use (n = 1,487)

Phenoxy herbicides Gambini et al., 1997

Intestines

  27 1.1 (0.7–1.6)

NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident cancer cases (colon, rectum, or small intestine) vs remainder of 19,904 men with any incident cancer

Reif et al., 1989

Forestry workers (n = 134)

Herbicides

Colon

    7 0.5 (0.2–1.1)

Rectum

  10 1.2 (0.6–2.3)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Small intestine

    2 5.2 (1.4–18.9)

Aged 20–59

    2 11.2 (3.4–36.4)

Aged ≥ 60

    0
S

awmill workers (n = 139)

Herbicides, chlorophenols

Small intestine

    0

SWEDEN

Incident cancer cases 1961–1973 with agriculture as economic activity in 1960 census

Wiklund, 1983

Colon

1,332

Rectum

99% CI
1,083 0.8 (0.7–0.8)

THE NETHERLANDS

Dutch Licensed Herbicide Sprayers—1,341 certified before 1980

Through 2000

Swaen et al., 2004

Colon

    7 1.0 (0.4–2.1)

Rectum

    5 2.1 (0.7–4.8)

Through 1987

Swaen et al., 1992

Colon

    4 2.6 (0.7–6.5)
UNITED STATES

US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states

Herbicides PCMRs Blair et al., 1993

Colon

Men

Whites (n = 119,648)

2,291 1.0 (0.9–1.0)

Nonwhites (n = 11,446)

148 0.8 (0.7–0.9)

Women

Whites (n = 2,400)

  59 1.0 (0.8–1.3)

Nonwhites (n = 2,066)

  40 1.0 (0.7–1.3)

Rectum

Men

Whites (n = 119,648)

367 1.0 (0.9–1.1)

Nonwhites (n = 11,446)

  22 0.7 (0.5–1.1)

Women

Whites (n = 2,400)

    4 0.5 (0.1–1.3)

Nonwhites (n = 2,066)

    5 1.1 (0.3–2.5)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides

Incidence

Enrollment through 2006—SIRs for participants

Koutros et al., 2010a

Colon

Private applicators

339 0.9 (0.8–1.0)

Commercial applicators

  17 1.0 (0.6–1.6)

Spouses

144 0.8 (0.7–1.0)

Rectum

Private applicators

117 0.9 (0.7–1.1)

Commercial applicators

    8 1.2 (0.5–2.3)

Spouses

  30 0.7 (0.5–1.0)

Enrollment through 2005—Interactions between dicamba and body mass index

Andreotti et al., 2010

Trend (with dicamba use reported)

  96 1.1 (1.0–1.1)

Trend (with no dicamba use reported)

102 1.0 (1.0–1.1)

Enrollment through 2005—colorectal cancer

Lee WJ et al., 2007

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)

Enrollment through 2002—colon cancer

Samanic et al., 2006

Dicamba—lifetime days exposure

None

  76 1.0

1– < 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

Enrollment through 2002

Alavanja et al., 2005

Colon

Private applicators (men, women)

208 0.9 (0.8–1.0)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Spouses of private applicators (> 99% women)

  87 0.9 (0.7–1.1)

Commercial applicators (men, women)

  12 0.2 (0.6–2.1)

Rectum

Private applicators (men, women)

  94 0.8 (0.7–1.0)

Spouses of private applicators (> 99% women)

  23 0.6 (0.4–0.9)

Commercial applicators (men, women)

    7 1.3 (0.5–2.6)

Mortality

Enrollment through 2007, vs state rates

Waggoner et al., 2011

Intestine

Applicators (n = 1,641)

158 0.8 (0.6–0.9)

Spouses (n = 676)

  68 0.9 (0.7–1.1)

Rectum

Applicators (n = 1,641)

  32 0.7 (0.5–1.0)

Spouses (n = 676)

    4 nr

Enrollment through 2000, vs state rates

Blair et al., 2005a

Colon

Private applicators (men, women) Spouses of private applicators (> 99% women)

  56 0.7 (0.6–1.0)
  31
1.2 (0.8–1.6)

Rectum

Private applicators (men, women) Spouses of private applicators (> 99% women)

nr nr
nr nr

US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of cancer

Herbicides

Agricultural extension agents

Alavanja et al., 1988

Colon

  41 1.0 (0.7–1.5)

Rectum

    5 nr

Forest conservationists

p-trend < over years worked
Alavanja et al., 1989

Colon

  44 1.5 (1.1–2.0)

Rectum

    9 1.0 (0.5–1.9)

Soil conservationists

Florida Licensed Pesticide Applicators [common phenoxy use assumed but not documented; had been listed by Blair et al., 1983]

Herbicides

Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976

Herbicides Blair et al., 1983

Any pesticide (dose-response by length of licensure)

Colon

    5 0.8 (nr)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Rectum

    2 nr

White Male Residents of Iowa—colon cancer on death certificate, usual occupation: farmers vs not

Herbicides

> 20 yrs old when died 1971–1978—PMR

Burmeister, 1981

Colon

1,064 0.9 (0.9–1.0)
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171) TCDD

Incidence

20-yr followup to 1996—men and women

Zone A

Pesatori et al., 2009

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)

10-yr followup to 1991—men

Bertazzi et al., 1993

Zone B

Colon

    2 0.5 (0.1–2.0)

Rectum

    3 1.4 (0.4–4.4)

Zone R

Colon

  32 1.1 (0.8–1.6)

Rectum

  17 1.1 (0.7–1.9)

10-yr followup to 1991—women

Bertazzi et al., 1993

Zone B

Colon

    2 0.6 (0.1–2.3)

Rectum

    2 1.3 (0.3–5.4)

Zone R

Colon

  23 0.8 (0.5–1.3)

Rectum

    7 0.6 (0.3–1.3)

Mortality

25-yr followup to 2001—men and women

Consonni et al., 2008

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)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Zone R

Colon

137 0.9 (0.7–1.3)

Rectum

  50 0.9 (0.7–1.3)

20-yr followup to 1996

Bertazzi et al., 2001

Zones A and B—men

Colon

  10 1.0 (0.5–1.9)

Rectum

    9 2.4 (1.2–4.6)

Zones A and B—women

Colon

    5 0.6 (0.2–1.4)

Rectum

    3 1.1 (0.4–3.5)

15-yr followup to 1991—men

Bertazzi et al., 1997

Zone B

Colon

    5 0.8 (0.3–2.0)

Rectum

    7 2.9 (1.2–5.9)

Zone R

Colon

  34 0.8 (0.6–1.1)

Rectum

  19 1.1 (0.7–1.8)

15-yr followup to 1991—women

Bertazzi et al., 1997

Zone A

Colon

    2 2.6 (0.3–9.4)

Zone B

Colon

    3 0.6 (0.1–1.8)

Rectum

    2 1.3 (0.1–4.5)

Zone R

Colon

  33 0.8 (0.6–1.1)

Rectum

  12 0.9 (0.5–1.6)

10-yr followup to 1986—men

Bertazzi et al., 1989a,b

Zone A, B, R—colon

  20 1.0 (0.6–1.5)

Zone A, B, R—rectum

  10 1.0 (0.5–2.7)

Zone B—rectum

    2 1.7 (0.4–7.0)

10-yr followup to 1986—women

Bertazzi et al., 1989a

Zone A, B, R—colon

  12 0.7 (0.4–1.2)

Zone A, B, R—rectum

    7 1.2 (0.5–2.7)
Ecological Study of Residents of Chapaevsk, Russia Dioxin Revich et al., 2001

Incidence—Crude incidence rate in 1998 vs

Men

Regional (Samara)

Colon

nr 21.7 (nr)

Rectum

nr 17.1 (nr)

National (Russia)

Colon

nr 17.9 (nr)

Rectum

nr 16.6 (nr)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Women

Regional (Samara)

Colon

nr 15.4 (nr)

Rectum

nr 11.2 (nr)

National (Russia)

Colon

nr 14.1 (nr)

Rectum

nr 10.3 (nr)

Mortality—1995–1998 (SMR vs regional rates)

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)

FINLAND

Finnish community exposed to chlorophenol contamination (men and women)

Chlorophenol Lampi et al., 1992

Colon—men, women

    9 1.1 (0.7–1.8)

Finnish fishermen (n = 6,410) and spouses (n = 4,260) registered between 1980 and 2002 compared to national statistics

Serum dioxin Turunen et al., 2008

Fisherman

SMRs

Colon

    8 0.5 (0.2–1.0)

Rectum

    8 0.8 (0.4–1.6)

Spouses

Colon

  10 1.3 (0.6–2.4)

Rectum

    8 2.1 (0.9–4.2)
SWEDEN

Swedish fishermen (high consumption of fish with persistent organochlorines)

Organochlorine compounds Svensson et al., 1995

Incidence

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)

Mortality

East coast

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)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
CASE-CONTROL STUDIES

International Case-Control Studies

421 Egyptian colorectal cancer cases and 439 hospital controls

nr Herbicides 5.5 (2.4–12.3) Lo et al., 2010

Swedish patients (1970–1977)

Phenoxy acids, chlorophenols Hardell, 1981

Colon

Exposed to phenoxy herbicides

  11 1.3 (0.6–2.8)

Exposed to chlorophenols

    6 1.8 (0.6–5.3)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; 2,5-DCP, 2,5-dichlorophenol; 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; JEM, job-exposure matrix; MCPA, methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PMR, proportionate mortality ratio; SIR, standardized incidence ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; 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.

cancer overall. In the most restrictively defined cohort, the SIR for colon cancer was 0.95 (95% CI 0.55–1.55), and the SIR for rectal cancer was 0.78 (95% CI 0.29–1.70). For both cancer types, the results were similar in the two more inclusive, but potentially more biased, cohorts.

Manuwald et al. (2012) reported a 23-year update of mortality in a cohort of chemical workers in Hamburg, Germany, who were exposed to dioxin. Compared to national rates, male workers had an increase in mortality from rectal cancer (SMR = 1.95, 95% CI 0.98–3.51) but not from colon cancer (SMR = 0.64, 95% CI 0.26–1.32). An increase in colorectal-cancer deaths was not seen in exposed women (SMR = 0.90, 95% C.I 0.29–2.12 for colon cancer and SMR = 1.01, 95% CI 0.11–3.65 for rectal cancer).

Ruder and Yiin (2011) reported mortality for 1940–2005 separately for intestinal cancer (ICD-9 152–153) and colon cancer in the NIOSH PCP cohort of 2,122 workers in the four US plants that had been involved in PCP production. PCP production entailed exposure to PCDDs and PCDFs but not to the most toxic 2,3,7,8 dioxin congener. A subcohort of 720 workers (all men, the PCP-plus-

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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TCDD group) had also been employed in TCP production and so had also been exposed to TCDD. Relative to US referent rates, deaths from intestinal cancer were not substantially changed in the entire cohort (26 deaths, SMR = 1.07, 95% CI 0.70–1.57), the PCP-only group (15 deaths, SMR = 0.90, 95% CI 0.50–1.49), or the PCP-plus-TCDD group (11 deaths, SMR = 1.44, 95% CI 0.72–2.57). Only two deaths from rectal cancer were reported in the entire cohort—one in each subcohort—which was in accord with expectations.

The participants in the AHS are known to have had extensive exposure to the phenoxy herbicides, but the analyses of updated mortality (Waggoner et al., 2011) and cancer incidence (Koutros et al., 2010a) address only exposure to pesticides in general. The updated cancer incidence in the AHS (Koutros et al., 2010a) revealed no increase in SIR of colon cancer in private applicators (339 cases, SIR = 0.87, 95% CI 0.78–0.97) or their spouses (144 cases, SIR = 0.83, 95% CI 0.70–0.98). Cancer of the rectum also was not increased in these populations of private applicators (117 cases, SIR = 0.90, 95% CI 0.74–1.08) or their spouses (30 cases, SIR = 0.69, 95% CI 0.47–0.99). In the study by Waggoner et al. (2011), mortality from both intestinal and rectal cancer in the applicators (private and commercial combined) was significantly lower than expected.

The association between obesity and cancer risk was examined (Andreotti et al., 2010) in pesticide applicators and their spouses on the basis of data from the AHS. A small increase in the risk of colon cancer in men was the only statistically significant association with increased body -mass index (BMI; trend in HR with BMI = 1.05, 95% CI 1.02–1.09, p = 0.005); no such relationship was apparent in the women. Of the many pesticides tested for an interactive role in the BMI–colon cancer relationship in men, the only one that had any bearing on the COIs and on which results were reported is dicamba (2-methoxy-3,6-dichlorobenzoic acid), which showed no evidence of interaction. The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Biologic Plausibility

Long-term animal studies examining the effect of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004) have reported no increase in the incidence of colorectal cancer. Recently, Xie et al. (2012) reported that AHR activation by TCDD induces robust proliferation in two human colon-cancer cell lines through Src-mediated epidermal growth factor receptor activation. That novel finding suggests that TCDD and other AHR ligands may contribute to colon carcinogenesis, but more studies are needed to understand the potential role of AHR activation in intestinal carcinogenesis.

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

The generic findings on the applicators and their spouses in the AHS showed indications of increased mortality from both colon and intestinal cancer in agricultural workers, but earlier assessment of colorectal cancer in this study population had found no increase in risks in association with exposure to individual phenoxy herbicides (Lee WJ et al., 2007). None of the epidemiologic studies reviewed that specifically addressed the COIs, however, yielded evidence of an association between the COIs and colorectal cancer. There is no evidence of biologic plausibility of an association between exposure to any of the COIs and tumors of the colon or rectum. Overall, the available evidence does not support an association between the COIs 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 COIs 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 21,370 men and 7,350 women would receive diagnoses of liver cancer or intrahepatic bile duct cancer in the United States in 2012 and that 13,980 men and 6,570 women would die from these cancers (Siegel et al., 2012). 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

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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greater in blacks than in whites. The average annual incidence of hepatobiliary cancers is shown in Table 8-4.

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 COIs 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.

Update 2010 considered followup reports on three previously studied populations. Collins et al. (2009a,b) examined mortality in workers employed in a Dow Chemical Company plant in Midland, Michigan, during 1937–1980. They found two cases of cancer of the hepatobiliary tract in 1,615 TCP workers (SMR = 0.5, 95% CI 0.1–1.6) but no observed deaths from that cancer in 773 PCP workers. The second occupational-mortality study was of workers in the Dow AgroSciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD; SMRs for hepatobiliary cancer calculated on the basis of national mortality figures were 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 (McBride et al., 2009a). The update of cancer incidence in the Seveso cohort did not find systematic evidence of hepatic or biliary cancers in any of the exposure zones (Pesatori et al., 2009).

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

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies No Vietnam-veteran studies, environmental studies, or case-control studies of exposure to the COIs and hepatobiliary cancer have been published since Update 2010.

Occupational Studies Malignant neoplasms of the hepatobiliary tract were not specifically reported in Boers et al. (2012), Burns et al. (2011), or Manuwald et al. (2012).

An update of cancer incidence in US PCP workers through 2005 reported no increase in cancers of the hepatobiliary tract (Ruder and Yiin, 2011). There were nine deaths from liver or biliary cancer for an SMR of 1.21 (95% CI 0.56–2.31) in all the workers, but they all occurred in the workers that had only PCP exposure and resulted in a somewhat higher but still nonsignificant risk estimate (SMR = 1.76, 95% CI 0.81–3.35).

Koutros et al. (2010a) published an update of cancer incidence in the AHS. In private applicators, there were 32 cases of liver cancer (SIR = 0.73, 95% CI 0.50–1.03) and eight cases of gallbladder cancer (SIR = 1.33, 95% CI 0.57–2.61).

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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TABLE 8-8 Selected Epidemiologic Studies—Hepatobiliary Cancers (Shaded Entries Are New Information for This Update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS

US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

All COIs

Mortality

1965–2000—liver, intrahepatic bile ducts (ICD-9 155)

    5 nr Boehmer et al., 2004 CDC, 1990a

US CDC Selected Cancers Study—case-control study of incidence (12/1/1984–11/30/1989) among US males born 1929–1953

    8 All COIs 1.2 (0.5–2.7)

US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973

All COIs

1965–1982—liver, bile duct

Breslin et al., 1988

Army, deployed (n = 19,708) vs nondeployed (n = 22,904)

  34 1.0 (0.8–1.4)

Marine Corps, deployed (n = 4,527) vs nondeployed (n = 3,781)

    6 1.2 (0.5–2.8)
State Studies of US Vietnam Veterans

923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans

    0 nr Anderson et al., 1986a,b

International Vietnam-Veteran Studies

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

Incidence

All branches, 1982–2000

  27 0.7 (0.4–1.9) ADVA, 2005a

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)

Mortality

All branches, return–2001

  48 0.9 (0.6–1.1) ADVA, 2005b

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)

1980–1994

CDVA, 1997a

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

All COIs

18,940 deployed vs 24,642 nondeployed

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Incidence

1982–2000

    2 2.5 (0.1–147.2) ADVA, 2005c

Mortality

1966–2001 (liver, gallbladder)

    4 2.5 (0.4–27.1) ADVA, 2005c

1982–1994

    1 nr CDVA, 1997b

OCCUPATIONAL—INDUSTRIAL

IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates

Mortality 1939–1992

  15 0.7 (0.4–1.2) Kogevinas et al., 1997

13,831 exposed to highly chlorinated PCDDs

  12 0.9 (0.5–1.5)

7,553 not exposed to highly chlorinated PCDDs

    3 0.4 (0.1–1.2)

Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort

Saracci et al., 1991

Liver, gallbladder, bileduct (ICD-8 155–156)

    4 0.4 (0.1–1.1)

Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)

Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP

Incidence 1943–1982

Lynge, 1985

Men

    3 1.0 (nr)

Women

    0 nr

German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 month in 1951–1976) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4,5-TCP

Mortality 1951–1992

    0 Becher et al., 1996

German Production Workers at Bayer Plant in Dormagen (520 men working > 1 month in 1965–1989) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1965–1989

    0 Becher et al., 1996

German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 month in 1957–1987) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Mortality 1956–1989

    1 1.2 (0.0–6.9) Becher et al., 1996

BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)

Focus on TCDD

Incidence

1960–1992—liver, gallbladder, bile duct

    2 2.1 (0.3–7.5) Ott and Zober, 1996

TCDD < 0.1 μg/kg of body weight

    1 2.8 (0.1–15.5)

TCDD 0.1–0.99 μg/kg of body weight

    0 0.0 (0.0–15.4)

TCDD > 1 μg/kg of body weight

    1 2.8 (0.1–15.5)

German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)

Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP

Mortality 1952–1989

    0 Becher et al., 1996

New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram

Mortality 1969–2004

McBride et al., 2009a

Ever-exposed workers

    2 1.4 (0.2–5.1)

Never-exposed workers

    0 0.0 (0.0–8.2)

Production Workers (713 men and 100 women worked > 1 month in 1969–1984)

Mortality 1969–2000—ICD-9 155

’t Mannetje et al., 2005

Phenoxy herbicide producers (men and women)

    1 1.6 (0.0–8.8)

Phenoxy herbicide sprayers (> 99% men)

    0 0.0 (0.0–4.2)

NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

Through 1993

Steenland et al., 1999

Liver, biliary tract (ICD-9 155–156)

    7 0.9 (0.4–1.6)

Through 1987 (liver, biliary tract)

    6 1.2 (0.4–2.5) Fingerhut et al., 1991

≥ 1-year exposure, ≥ 20-year latency

    1 0.6 (0.0–3.3)

Mortality—754 Monsanto workers, among most highly exposed workers from Fingerhut et al. (1991); liver, biliary tract

    2 1.4 (0.2–5.2) Collins et al., 1993
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts)

2,4,5-T; 2,4,5-TCP

1942–2003 (n = 1,615)

    2 0.5 (0.1–1.6) Collins et al., 2009a

March 1949–1978 (n = 121); 121 TCP workers with chloracne

    0 nr Zack and Suskind, 1980

Through 1982 (n = 878); liver, biliary tract (ICDA-8 155–156)

    0 1.2 (nr) Bond et al., 1988

All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

1940–2005 (n = 2,122) (liver and biliary; ICD–9 155–156)

    9 1.2 (0.6–2.3)

PCP and TCP (n = 720)

    0 – (0.0–1.6)

PCP (no TCP) (n = 1,402)

    9 1.8 (0.8–3.4)

Dow PCP Production Workers (1937–1989 in Midland, Michigan) (not in IARC and NIOSH cohorts)

Low chlorinated dioxins, 2,4-D

Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) Mortality 1940–1989 (n = 770); liver, primary (ICDA-8 155–156)

    0 0.0 (0.0–1.7) Collins et al., 2009b Ramlow et al., 1996

0-yr latency

    0 nr

15-yr latency

    0 nr

OCCUPATIONAL—PAPER AND PULP

TCDD

WORKERS

IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM

McLean et al., 2006

Exposure to nonvolatile organochlorine compounds

Never

  27 0.9 (0.6–1.3)

Ever

  16 0.7 (0.4–1.1)

Danish paper workers

Rix et al., 1998

Men

Liver

  10 1.1 (0.5–2.0)

Gallbladder

    9 1.6 (0.7–3.0)

Women

Liver

    1 0.6 (0.0–3.2)

Gallbladder

    4 1.4 (0.4–3.7)
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Pulp and Paper cohorts independent of IARC cohort

United Paperworkers International, 201 white men employed ≥ 10 yrs and dying 1970–1984

    2 2.0 (0.2–7.3) Solet et al., 1989
OCCUPATIONAL—HERBICIDE-USING
WORKERS (not related to IARC sprayer cohorts)

DENMARK

Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)

Herbicides Ronco et al., 1992

Men

Liver

   

Self-employed

  23 0.4 (p < 0.05)
   

Employee

    9 0.8 (nr)

Gallbladder

   

Self-employed

  35 0.8 (nr)
   

Employee

    7 0.8 (nr)

Women

Liver

   

Family workers

    5 0.5 (nr)

Gallbladder

   

Self-employed

    7 2.7 (p < 0.05)
   

Employee

    1 0.7 (nr)
   

Family workers

  17 1.0 (nr)

FINNISH Phenoxy Herbicide Sprayers (1,909

Phenoxy

men working 1955–1971 ≥ 2 wks) not IARC

herbicides

(liver, biliary tract)

Incidence

    3 0.9 (0.2–2.6) Asp et al., 1994

Mortality 1972–1989

    2 0.6 (0.1–2.2)

ITALIAN Licensed Pesticide Users—male

farmers in southern Piedmont licensed 1970–1974

Mortality 1970–1986 (n = 23,401)

  15 0.6 (0.3–0.9) Torchio et al., 1994

Italian rice growers with documented phenoxy use (n = 1,487)

    7 Phenoxy herbicides Gambini et al., 1997
1.3 (0.5–2.6)

NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident hepatobiliary cancer cases vs remainder of 19,904 men with any incident cancer

Reif et al., 1989

Forestry workers (n = 134)

Herbicides

Liver

    1 0.8 (0.1–5.8)

Gallbladder

    3 4.1 (1.4–12.0)

Aged 20–59

    1 6.3 (1.1–36.6)

Aged ≥ 60

    2 3.5 (0.9–13.3)
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Sawmill workers (n = 139)

Herbicides, chlorophenols

Gallbladder

    2 2.3 (0.6–9.1)

SWEDEN

Incident stomach cancer cases 1961–1973 with agriculture as economic activity in 1960 census

Wiklund, 1983
99% CI

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)

THE NETHERLANDS

Dutch Licensed Herbicide Sprayers—1,341 certified before 1980

Through 2000

    0 nr Swaen et al., 2004

UNITED STATES

US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states

Herbicides PCMRs Blair et al., 1993

Men

Whites (n = 119,648)

326 1.0 (0.9–1.1)

Nonwhites (n = 11,446)

  24 0.7 (0.5–1.1)

Women

Whites (n = 2,400)

    6 0.7 (0.3–1.6)

Nonwhites (n = 2,066)

    2 0.4 (0.0–1.3)

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides

Incidence

Enrollment through 2006—SIRs for participants

Koutros et al., 2010a

Liver

Private applicators

  32 0.7 (0.5–1.0)

Commercial applicators

    1 nr

Spouses

    6 0.8 (0.3–1.7)

Gallbladder

Private applicators

    8 1.3 (0.6–2.6)

Commercial applicators

    0 nr

Spouses

Enrollment through 2002

    7 1.1 (0.4–2.3) Alavanja et al., 2005

Liver

Private applicators (men, women)

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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Spouses of private applicators (> 99% women)

  35 1.0 (0.7–1.4)

Commercial applicators (men, women)

    3 0.9 (0.2–2.5)

Gallbladder

nr 0.0 (0.0–4.2)

Private applicators (men, women)

Spouses of private applicators (> 99% women)

    8 2.3 (1.0–4.5)

Commercial applicators (men, women)

    3 0.9 (0.2–2.5)

Mortality

nr 0.0 (0.0–35.8)

Enrollment through 2007, vs state rates (liver and gallbladder)

Waggoner et al., 2011

Applicators (n = 1,641)

  50 0.7 (0.5–0.9)

Spouses (n = 676)

  18 0.8 (0.5–1.3)

Enrollment through 2000, vs state rates

Blair et al., 2005a

Liver

Private applicators (men, women)

    8 0.6 (0.2–1.1)

Spouses of private applicators (> 99%

    4 1.7 (0.4–4.3)

women)

Rectum

Private applicators (men, women)

    3 2.0 (0.4–5.7)

Spouses of private applicators (> 99% women)

    2 1.3 (0.1–4.6)
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171) TCDD

Incidence

20-yr followup to 1996—men and women

Pesatori et al., 2009

Zone A

Liver

    0

Biliary

    0

Zone B

Liver

  14 1.3 (0.8–2.2)

Biliary

    6 2.3 (1.0–5.2)

Zone R

Liver

  56 0.7 (0.6–1.0)

Biliary

  16 0.8 (0.5–1.4)

10-yr followup to 1991—men

Bertazzi et al., 1993

Zone B

Liver

    4 2.1 (0.8–5.8)

Gallbladder (ICD-9 156)

    1 2.3 (0.3–17.6)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Zone R

Liver

    3 0.2 (0.1–0.7)

Gallbladder (ICD-9 156)

    3 1.0 (0.3–3.4)

10-yr followup to 1991—women

Bertazzi et al., 1993

Zone B

Gallbladder (ICD-9 156)

    4 4.9 (1.8–13.6)

Zone R

Liver

    2 0.5 (0.1–2.1)
    Gallbladder (ICD-9 156)     7 1.0 (0.5–2.3)

Mortality

25-yr followup to 2001—men and women

Consonni et al., 2008

Zone A

Liver

    3 1.0 (0.3–3.2)

Biliary

    0 0.0 (nr)

Zone B

Liver

  16 0.9 (0.5–1.4)

Biliary

    2 0.6 (0.1–2.3)

Zone R

Liver

107 0.8 (0.7–1.0)

Biliary

  31 1.2 (0.8–1.7)

20-yr followup to 1996

Bertazzi et al., 2001

Zones A and B—men

Liver, gallbladder

    6 0.5 (0.2–1.0)

Liver

    6 0.5 (0.2–1.1)

Zones A and B—women

Liver, gallbladder

    7 1.0 (0.5–2.2)

Liver

    6 1.3 (0.6–2.9)

15-yr followup to 1991—men

Bertazzi et al., 1997

Zone B

Liver, gallbladder

    4 0.6 (0.2–1.4)

Liver

    4 0.6 (0.2–1.6)

Zone R

Liver, gallbladder

  35 0.7 (0.5–1.0)

Liver

  31 0.7 (0.5–1.0)

15-yr followup to 1991—women

Bertazzi et al., 1997

Zone B

Liver, gallbladder

    4 1.1 (0.3–2.9)

Liver

    3 1.3 (0.3–3.8)

Zone R

Liver, gallbladder

  25 0.8 (0.5–1.3)

Liver

  12 0.6 (0.3–1.1)

10-yr followup to 1986—men

Bertazzi et al., 1989b

Zone B—liver

    3 1.2 (0.4–3.8)

Zone R—liver

    7 0.4 (0.2–0.8)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

10-yr followup to 1986—women

Bertazzi et al., 1989b

Zone A—gallbladder (ICD-9 156)

    1 12.1 (1.6–88.7)

Zone B—gallbladder (ICD-9 156)

    2 3.9 (0.9–16.2)

Zone R

Liver

    3 0.4 (0.1–1.4)

Gallbladder (ICD-9 156)

    5 1.2 (0.5–3.1)
Quail Run Mobile Home Cohort TCDD Hoffman et al., 1986

154 exposed residents vs 155 unexposed area residents

    0 nr

SWEDEN

Swedish fishermen (high consumption of fish with persistent organochlorines)

Organochlorine compounds Svensson et al., 1995

Incidence

East coast

    1 0.5 (0.0–2.7)

West coast

    9 0.9 (0.4–1.7)

Mortality

East coast

    6 1.3 (0.5–2.9)

West coast

  24 1.0 (0.6–1.5)

VIETNAM

Risk factor for hepatocellular carcinoma in Hanoi

Herbicides Cordier et al., 1993

Military service in South Vietnam for ≥ 10 yrs after 1960

  11 8.8 (1.9–41.0)

CASE-CONTROL STUDIES

International Case-Control Studies

Swedish patients (25–80 yrs of age) diagnosed with liver cancer (ICD-7 155, 156) between 1974–June 1981 vs national rates

102 Phenoxy acids, chlorophenols 1.8 (0.9–4.0) Hardell, 1984

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 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; JEM, job-exposure matrix; MCPA, methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCP, pentachlorophenol; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; 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:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

In their spouses, there were six liver-cancer cases (SIR = 0.76, 95% CI 0.28–1.66) and seven gallbladder-cancer cases (SIR = 1.09, 95% CI 0.44–2.25). Waggoner et al. (2011) compared deaths from hepataboliary from the time of enrollment (1993–1997) through 2007 to state mortality rates. Rates of hepatobiliary cancers (liver and gallbladder) in applicators was less than expected (50 deaths, SMR = 0.70, 95% CI 0.52–0.93), but not in their spouses (18 deaths, SMR = 0.81, 95% CI 0.48–1.28). The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker 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. 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 can be heavily involved in the development and progression of many cancers, including liver cancers (Mantovani et al., 2008). 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).

Bile duct hyperplasia (but not tumors) has been reported in rodents following chronic treatment with TCDD (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 interleu-kin-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 through the increased expression of the metastasis marker AGR2 (Ambolet-Camoit et al., 2010) and 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 proposed cross-talk between the AHR and the mitogen-activated protein kinase signaling pathway in chemically induced hepatocarcinogenesis (Borlak and Jenke, 2008).

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TCDD inhibits ultraviolet-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).

Elyakim et al. (2010) found that human microRNA miR-191 was upregulated in hepatocellular carcinoma and that miR-191 was upregulated after TCDD treatment and may contribute to the mechanism of the carcinogenic activity of TCDD. Ovando et al. (2010) used toxicogenomics to identify genomic responses that may be contributing to the development of hepatotoxicity in rats treated chronically with the AHR ligands, TCDD or PCB 126. They identified 24, 17, and 7 genes that were differentially expressed in the livers of rats exposed to those AHR ligands and in human cholangiocarcinoma, human hepatocellular adenoma, and rat hepatocellular adenoma, respectively. That finding may help to elucidate the mechanisms by which dioxin-like compounds induce their hepatotoxic and carcinogenic effects.

In rodents, TCDD may promote hepatocarcinogenesis through cytotoxicity, chronic inflammation, and liver regeneration and through hyperplastic and hypertrophic growth due to sustained activation of the AHR (Köhle and Bock, 2007; Köhle et al., 2008). Species differences associated with AHR activation are demonstrated 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 the in vitro human hepatocyte studies may not reflect the in vivo response of human liver to TCDD. In vitro studies with transformed cell lines 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).

In a recent study, gene-expression changes were compared in adult female primary human and rat hepatocytes exposed to TCDD in vitro (Black et al., 2012). Whole-genome microarrays found that TCDD produced differing gene-expression profiles in rat and human hepatocytes both on an ortholog basis (conserved genes in different species) and on a pathway basis. For commonly affected orthologs or signaling pathways, the human hepatocytes were about one-fifteenth as sensitive as rat hepatocytes. Such findings are consistent with epidemiologic studies that show humans to be less sensitive to TCDD-induced hepatotoxicity.

Chronic exposure of rats to TCDD was associated with fatty liver degeneration and necrosis (Chen X et al., 2012). Another group reported that the hepatotoxic effects of TCDD were exacerbated in mice that had glutathione deficiency (Chen YJ et al., 2012). The combined exposure to PCBs and TCDD induced significant hepatotoxicity in rats (Lu C et al., 2010). Studying the effects of environmental chemicals on nuclear hormone receptors, Shah et al. (2011) demonstrated that in vitro assays for stratifying environmental contaminants can serve as surrogates in combination with rodent toxicity evaluations.

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

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

Synthesis

The marginally significant rSMRs of hepatobiliary cancer in applicators and their spouses in the AHS (Waggoner et al., 2011) assessed exposure only to pesticides in general, so they cannot be considered fully informative for the purpose of the present review. Even in combination with the previously reported isolated finding of a barely significant increase in mortality from biliary cancer in the moderate-exposure zone at Seveso (Pesatori et al., 2009), a consistent pattern of increased risk of biliary cancer is not established. Despite the evidence of TCDD’s activity as a hepatocarcinogen in animals, the evidence from epidemiologic studies remains inadequate to link the COIs 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 COIs and hepatobiliary cancer.

Pancreatic Cancer

The incidence of pancreatic cancer (ICD-9 code 157) increases with age. ACS estimated that 22,090 men and 21,830 women would receive a diagnosis of pancreatic cancer in the United States in 2012 and that 18,850 men and 18,540 women would die from it (Siegel et al., 2012). 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. Chronic pancreatitis, obesity, and type 2 diabetes are also associated with an increased risk of pancreatic cancer (ACS, 2013a). The average annual incidence of pancreatic cancer is shown in Table 8-4.

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

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

responsible for Update 2006 concluded that there was not enough evidence on each of the COIs 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. 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 followup 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.

Collins et al. (2009a,b) reported on Dow Chemical Company PCP workers in Midland, Michigan, and did not find evidence of increased mortality from pancreatic cancer, whether or not they had also been engaged in TCP production, which would have provided an opportunity for exposure to TCDD and other chlorinated dioxins. McBride et al. (2009a) found no evidence of increased pancreatic-cancer deaths in either exposed workers or the never-exposed group in the Dow AgroSciences plant in New Plymouth, New Zealand. A nested case-control study of pancreatic cancer in the AHS cohort found no statistically significant associations with exposure to 2,4-D or dicamba (Andreotti et al., 2009). A followup study of two Dutch cohorts of chlorophenoxy-herbicide production workers did not find the risk of death from pancreatic cancer to be increased in either factory (Boers et al., 2010). Pesatori et al. (2009) did not find the incidence of pancreatic cancer to be increased in the Seveso cohort 20 years after the accident.

Table 8-9 summarizes the results of the relevant studies concerning pancreatic cancer.

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies No Vietnam-veteran studies, environmental studies, or case-control studies of exposure to the COIs and pancreatic cancer have been published since Update 2010.

Occupational Studies Burns et al. (2011) published an update examining cancer incidence through 2007 in workers who were alive on January 1, 1985, and had been employed at any time from 1945 to 1994 in 2,4-D production by the Dow Chemical Company in Midland, Michigan. They found no evidence of significantly increased rates of cancer overall. With two cases observed, the incidence of pancreatic cancer in the most restrictively defined cohort was not

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 8-9 Selected Epidemiologic Studies—Pancreatic Cancer (Shaded Entries Are New Information for This Update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans

US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

All COIs

Mortality

1965–2000

    5 1.0 (0.3–3.5) Boehmer et al., 2004

US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973

All COIs

1965–1982

Breslin et al., 1988

Army, deployed (n = 19,708) vs nondeployed (n = 22,904)

  82 0.9 (0.6–1.2)

Marine Corps, deployed (n = 4,527) vs nondeployed (n = 3,781)

  18 1.6 (0.5–5.8)

US VA Cohort of Female Vietnam Veterans

All COIs

Mortality

Through 2004

Cypel and Kang, 2008

US Vietnam veterans

  17 2.1 (1.0–4.5)

Vietnam-veteran nurses

  14 2.5 (1.0–6.0)

Through 1991

Dalager et al., 1995

US Vietnam veterans

    7 2.8 (0.8–10.2)
   

Vietnam-veteran nurses

    7 5.7 (1.2–27.0)

Through 1987

Thomas et al., 1991

US Vietnam veterans

    5 2.7 (0.9–6.2)

State Studies of US Vietnam Veterans

Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs nondeployed

  14 1.0 (0.6–1.7) Visintainer et al., 1995

Non-black

    9 0.7 (0.3–1.3)

Black

    5 9.1 (2.9–21.2)

923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans

    4 nr Anderson et al., 1986

International Vietnam-Veteran Studies

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

Incidence

All branches, 1982–2000

  86 1.2 (0.9–1.4) ADVA, 2005a

Navy

  14 0.9 (0.5–1.5)

Army

  60 1.2 (0.9–1.5)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Air Force

  12 1.3 (0.7–2.3)

Mortality

All branches, return–2001

101 1.2 (1.0–1.5) ADVA, 2005b

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)

1980–1994

  38 1.4 (0.9–1.8) CDVA, 1997a

Australian Conscripted Army National Service (18,940 deployed vs 24,642 nondeployed)

All COIs

Incidence

1982–2000

  17 2.5 (1.0–6.3) ADVA, 2005c

Mortality

1966–2001

  19 3.1 (1.3–8.3) ADVA, 2005c

1982–1994

    6 1.5 (nr) CDVA, 1997b

OCCUPATIONAL—INDUSTRIAL

IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates

Mortality 1939–1992

  47 0.9 (0.7–1.3) Kogevinas et al., 1997

13,831 exposed to highly chlorinated PCDDs

  30 0.9 (0.5–1.4)

7,553 not exposed to highly chlorinated PCDDs

  16 1.0 (0.7–1.4)

Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort

  26 1.1 (0.7–1.6) Saracci et al., 1991

British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)

MCPA

Mortality through 1983

    9 0.7 (0.3–1.4) Coggon et al., 1986

Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)

Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP

Incidence

Incidence 1943–1982

Lynge, 1985

Men

    3 0.6 (nr)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Women

    0 nr

Mortality

Mortality 1955–2006

    7 1.2 (0.8–1.7) Boers et al., 2012

Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)

Dioxins, 2,4,5-T, 2,4,5-TCP

Mortality 1955–2006 (hazard ratios for lagged TCDD plasma levels)

    6 0.9 (0.5–1.6) Boers et al., 2012

Mortality 1955–2006

    4 0.9 (0.2–4.2) Boers et al. 2010

Mortality 1955–1991

    4 2.5 (0.7–6.3) Hooiveld et al., 1998

Mortality 1955–1985

    3 2.9 (0.6–8.4) Bueno de Mesquita et al., 1993

Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)

2,4-D; MCPA; MCP; highly chlorinated dioxins unlikely

Mortality 1965–2006

    1 nr Boers et al., 2010

Mortality 1965–1986

    0 0.0 (0.0–10.9) Bueno de Mesquita et al., 1993

German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 month in 1951–1976) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4,5-TCP

Mortality 1951–1992

    0 Becher et al., 1996

German Production Workers at Bayer Plant in Dormagen (520 men working > 1 month in 1965–1989) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1965–1989

    0 Becher et al., 1996

German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 month in 1957–1987) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1956–1989

    2 1.7 (0.2–6.1) Becher et al., 1996
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)

Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP

Mortality 1952–2007 (ICD-9 157)

  10 0.9 (0.4–1.7) Manuwald et al., 2012

Men

    7 0.9 (0.4–1.9)

Women

    3 1.0 (0.2–2.9)

Mortality 1952–1989

    2 0.6 (0.1–2.3) Becher et al., 1996

New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram

Mortality 1969–2004

McBride et al., 2009a

Ever-exposed workers

    3 1.3 (0.3–3.9)

Never-exposed workers

    0 0.0 (0.0–4.9)

Production Workers (713 men and 100 women worked > 1 month in 1969–1984)

Mortality 1969–2000

’t Mannetje et al., 2005

Phenoxy herbicide producers (men, women)

    3 2.1 (0.4–6.1)

Phenoxy herbicide sprayers (> 99% men)

    0 0.0 (0.0–2.1)

NIOSH Mortality Cohort (12 US plants, 5,172

Dioxins, phenoxy

male production and maintenance workers

herbicides

1942–1984) (included in IARC cohort as of 1997)

Through 1993

  16 1.0 (0.6–1.6) Steenland et al., 1999

Through 1987

  10 0.8 (0.4–1.6) Fingerhut et al., 1991

≥ 1-year exposure, ≥ 20-year latency

    4 1.0 (0.3–2.5)

All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts)

2,4,5-T; 2,4,5-TCP

1942–2003 (n = 1,615)

    6 0.7 (0.2–1.4) Collins et al., 2009a
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

1940–2005 (n = 2,122)

  18 1.3 (0.8–2.0)

PCP and TCP (n = 720)

    6 1.4 (0.5–3.0)

PCP (no TCP) (n = 1,402)

  12 1.3 (0.7–2.2)

Dow 2,4-D Production Workers (1945–1982 in Midland, Michigan) (subset of all TCP-exposed workers)

2,4-D, lower chlorinated dioxins

Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3)

    2 0.4 (0.1–1.5) Burns et al., 2011

Dow PCP Production Workers (1937–1989 in Midland, Michigan) (not in IARC and NIOSH cohorts)

Low chlorinated dioxins, 2,4-D

Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) Mortality 1940–1989 (n = 770)

    5 1.1 (0.3–2.5) Collins et al., 2009b Ramlow et al., 1996

0-yr latency

    2 0.7 (0.1–2.7)

15-yr latency

    2 0.9 (0.1–3.3)

Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohorts)

1,412 white male US flavor and fragrance chemical plant workers (1945–1965)

Dioxin, 2,4,5-T Thomas, 1987
    6 1.4 (nr)

OCCUPATIONAL—PAPER AND PULP WORKERS

TCDD

IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM

McLean et al., 2006

Exposure to nonvolatile organochlorine compounds

Never

  67 0.8 (0.7–1.1)

Ever

  69 1.1 (0.9–1.4)

Danish paper workers

Rix et al., 1998

Men

  30 1.2 (0.8–1.7)

Women

    2 0.3 (0.0–1.1)

New Hampshire pulp and paper workers, 883 white men working ≥ 1 yr, mortality through July 1985

    9 1.9 (0.9–3.6) Henneberger et al., 1989
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×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

United Paperworkers International, 201 white men employed ≥ 10 yrs and dying 1970–1984

    1 0.4 (0.0–2.1) Solet et al., 1989

Northwestern US paper and pulp workers—5 mills in Washington, Oregon, and California, 3,523 worked ≥ 1 yr 1945–1955, mortality through March 1977

    4 90% CI 0.3 (0.1–0.8) Robinson et al., 1986
OCCUPATIONAL—HERBICIDE-USING
WORKERS (not related to IARC sprayer cohorts)

DENMARK

Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)

Herbicides Ronco et al., 1992

Men

Self-employed

137 0.6 (p < 0.05)

Employee

  23 0.6 (p < 0.05)

Women

Self-employed

    7 1.2 (nr)

Employee

    4 1.3 (nr)

Family workers

  27 0.7 (p < 0.05)

ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974

Mortality 1970–1986 (n = 23,401)

  32 0.7 (0.5–1.0) Torchio
et al., 1994

Italian rice growers with documented phenoxy use (n = 1,487)

Phenoxy herbicides Gambini et al., 1997
    7 0.9 (0.4–1.9)

NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident pantreatic cancer cases vs remainder of 19,904 men with any incident cancer

Herbicides Reif et al., 1989

Forestry workers (n = 134)

    6 1.8 (0.8–4.1)

Aged 20–59

    0

Aged ≥ 60

    6 2.4 (1.1–5.4)

Sawmill workers (n = 139)

Herbicides, chlorophenols
    2 0.5 (0.1–1.8)

SWEDEN

Incident pancreatic cancer cases 1961–1973 with agriculture as economic activity in 1960 census

99% CI Wiklund, 1983
777 0.8 (0.8–0.9)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

THE NETHERLANDS

Dutch Licensed Herbicide Sprayers—1,341 certified before 1980

Through 2000

    5 1.2 (0.4–2.7) Swaen et al., 2004

Through 1987

    3 2.2 (0.4–6.4) Swaen et al., 1992

UNITED STATES

US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states

Herbicides PCMRs Blair et al., 1993

Men

Whites (n = 119,648)

1,133 1.1 (1.1–1.2)

Nonwhites (n = 11,446)

125 1.2 (1.0–1.4)

Women

Whites (n = 2,400)

  23 1.0 (0.6–1.5)

Nonwhites (n = 2,066)

  16 0.7 (0.4–1.2)

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides

Incidence

Enrollment through 2006—SIRs for participants

Koutros et al., 2010a

Private applicators

  80 0.7 (0.6–0.9)

Commercial applicators

    5 1.0 (0.3–2.3)

Spouses

  32 0.7 (0.5–1.0)

Nested case-control (applicators, spouses combined)

Andreotti et al., 2009

2,4-D

  48 0.9 (0.5–1.5)

Dicamba

  23 0.9 (0.6–1.6)

Enrollment through 2002

Alavanja et al., 2005

Private applicators

  46 0.7 (0.5–1.0)

Spouses of private applicators (> 99% women)

  20 0.9 (0.6–1.4)

Commercial applicators

    3 1.1 (0.2–3.2)

Mortality

Enrollment through 2007, vs state rates

Waggoner et al., 2011

Applicators (n = 1,641)

171 0.8 (0.7–1.0)

Spouses (n = 676)

    1 nr
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Enrollment through 2000, vs state rates

Blair et al., 2005a

Private applicators (men and women)

  29 0.6 (0.4–0.9)

Spouses of private applicators (> 99% women)

  10 0.7 (0.3–1.2)

US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of pancreatic cancer

Herbicides

Agricultural extension agents

  21 1.3 (0.8–1.9) Alavanja et al., 1988

Forest conservationists

  22 1.5 (0.9–2.3) Alavanja et al., 1989

Florida Licensed Pesticide Applicators (common phenoxy use assumed but not documented; had been listed by Blair et al., 1983)

Herbicides

Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976

Herbicides Blair et al., 1983

Any pesticide (dose-response by length of licensure)

Expected exposed cases
    4 4.0

White Male Residents of Iowa—pancreatic cancer on death certificate, usual occupation: farmers vs not

Herbicides

> 20 yrs old when died 1971–1978—PMR

416 1.1 (nr) Burmeister, 1981

ENVIRONMENTAL

Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group)

TCDD

Incidence

20-yr followup to 1996—men and women

Zone A

    1 1.2 (0.2–8.2) Pesatori et al., 2009

Zone B

    3 0.6 (0.2–1.7)

Zone R

  38 1.0 (0.7–1.4)

10-yr followup to 1991—men

Pesatori et al., 1992

Zone A, B

    2 1.0 (0.3–4.2)

10-yr followup to 1991—women

Pesatori et al., 1992

Zone A, B

    1 1.6 (0.2–12.0)

Mortality

25-yr followup to 2001—men and women

Consonni et al., 2008

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)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

20-yr followup to 1996

Bertazzi et al., 2001

Zones A and B—men

    4 0.7 (0.3–1.9)

Zones A and B—women

    1 0.3 (0.0–2.0)

15-yr followup to 1991—men

Bertazzi et al., 1997

Zone A

    1 1.9 (0.0–10.5)

Zone B

    2 0.6 (0.1–2.0)

Zone R

  20 0.8 (0.5–1.2)

15-yr followup to 1991—women

Bertazzi et al., 1997

Zone B

    1 0.5 (0.0–3.1)

Zone R

  11 0.7 (0.4–1.3)

10-yr followup to 1986—men

Bertazzi et al., 1989a,b

Zone A, B, R

    9 0.6 (0.3–1.2)

Zone B

    2 1.1 (0.3–2.7)

10-yr followup to 1986—women

Bertazzi et al., 1989a

Zone A, B, R

    4 1.0 (0.3–2.7)

SWEDEN

Swedish fishermen (high consumption of fish with persistent organochlorines)

Organochlorine compounds Svensson et al., 1995

Incidence

East coast

    4 0.6 (0.2–1.6)

West coast

  37 1.0 (0.7–1.4)

Mortality

East coast

    5 0.7 (0.2–1.6)

West coast

  33 0.8 (0.6–1.2)

CASE-CONTROL STUDIES

International Case-Control Studies

UK men, 18–35 yrs of age from counties with particular chemical manufacturing—mortality

Herbicides, chlorophenols Magnani et al., 1987

Herbicides

nr 0.7 (0.3–1.5)

Chlorophenols

nr 0.8 (0.5–1.4)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; 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; JEM, job-exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCDF, polychlorinated dibenzofuran; PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PM, proportionate mortality; PMR, proportionate mortality ratio; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; UK United Kingdom; 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:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

increased (SIR = 0.42, 95% CI 0.05–1.52), nor was it increased in the two successively more inclusive, but potentially more biased, cohorts.

Boers et al. (2012) published the results of analyses of serum TCDD concentrations in the recently updated Dutch chlorophenoxy-herbicide cohorts, which had been published earlier. Boers et al. (2010) had published less sophisticated exposed-vs-unexposed results, which showed no increase in pancreatic-cancer deaths (HR for factory A = 0.86, 95% CI 0.18–4.19; only one pancreatic-cancer death in the factory B cohort). When the predicted serum TCDD concentrations generated by the model developed from the blood sampling were used, the risks of pancreatic cancer were not increased in the entire cohort (HR = 1.17, 95% CI 0.82–1.65) or in the factory A cohort alone (HR = 0.89, 95% CI 0.50–1.57).

Manuwald et al. (2012) reported on mortality in 1,191 men and 398 women who had been employed for at least 3 months during 1952–1984 in a chemical plant in Hamburg (a subcohort of the IARC phenoxy-herbicide cohort). During that period, the plant produced insecticides and herbicides, including 2,4,5-T, so cohort members had the possibility of exposure to TCDD. Subjects entered the cohort on the date of their first employment in the plant, and vital status was sought through 2007. The observed numbers of deaths from pancreatic cancer were near expectation in men (SMR = 0.90, 95% CI 0.36–1.85), women (SMR = 1.0, 95% CI 0.20–2.93), and the entire cohort (SMR = 0.93, 95% CI 0.44–1.70).

Ruder and Yiin (2011) reported mortality in 1940–2005 for the NIOSH PCP cohort of 2,122 workers in the US four plants that had been involved in PCP production. Relative to US referent rates, there were slightly more deaths from pancreatic cancer in each group, but results were not substantially different in the entire cohort (18 deaths, SMR = 1.29, 95% CI 0.76–2.03), the PCP-only group (12 deaths, SMR = 1.25, 95% CI 0.65–2.19), or the PCP-plus-TCDD group (six deaths, SMR = 1.36, 95% CI 0.50–2.96).

Waggoner et al. (2011) reported on mortality rates in the AHS cohort and found fewer pancreatic cancers than expected in both applicators (103 deaths, SMR = 0.75, 95% CI 0.61–0.91) and in their spouses (38 cases, SMR = 0.72, 95% CI 0.51–0.99). Koutros et al. (2010a) updated cancer incidence through 2006 in the AHS cohorts of private applicators, their spouses, and commercial applicators. There was a significant decrease in the number of pancreatic-cancer cases observed in the private applicators (80 cases, SIR = 0.72, 95% CI 0.57–0.89). A nonsignificant decrease in mortality from pancreatic cancer was observed in spouses (32 cases, SIR = 0.72, 95% CI 0.49–1.01), but the incidences did not differ from expectation in the smaller groups of commercial applicators (five cases, SIR = 0.99, 95% CI 0.32–2.31). The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs 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 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, chronic inflammation and hyperproliferation are closely linked to the formation and progression of cancers, including cancer 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).

The biologic plausibility of the carcinogenicity of the COIs 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. In the 31 female and 62 male cases in the AHS case-control study considered in Update 2010 (Andreotti et al., 2009), however, the risk of pancreatic cancer was not associated with 2,4-D exposure, so the relative increase in the AHS cohort overall (Waggoner et al., 2011) would most certainly not be attributable to 2,4-D exposure. No increase in risk has been reported in US male Vietnam veterans or in IARC followup studies. The new updates on production cohorts and analyses from the AHS do not imply that exposures to the COIs are associated with the occurrence of pancreatic 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 COIs and pancreatic cancer.

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

LARYNGEAL CANCER

ACS estimated that 9,840 men and 2,520 women would receive diagnoses of cancer of the larynx (ICD-9 161) in the United States in 2012 and that 2,880 men and 770 women would die from it (Siegel et al., 2012). 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 8-10.

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, 2012a). 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).

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 COIs and laryngeal cancer on the basis of the evidence discussed below in the section “Synthesis.” Although the small number of laryngeal cancers included in most studies generally limits their statistical power to support strong conclusions, additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 did not change that conclusion.

Table 8-11 summarizes the results of the relevant studies.

TABLE 8-10 Average Annual Cancer Incidence (per 100,000) of Laryngeal Cancer in the 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
Men 12.0 11.3 24.5 19.2 17.8 41.2 26.5 25.9 50.6
Women 2.9 2.8 5.3 3.8 3.7 6.5 5.6 5.6 10.7

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2005–2009 (NCI, 2013).

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 8-11 Selected Epidemiologic Studies—Laryngeal Cancer (Shaded Entries Are New Information for This Update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans

US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

All COIs

Mortality

1965–2000

    0 0.0 (nr) Boehmer et al., 2004

US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973

All COIs

1965–1988

  50 1.3 (nr) Watanabe and Kang, 1996

Army, deployed (n = 27,596) vs nondeployed (n = 31,757)

  50 1.4 (p < 0.05)

Marine Corps, deployed (n = 6,237) vs nondeployed (n = 5,040)

    4 0.7 (nr)
International Vietnam-Veteran Studies

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

Incidence

All branches, 1982–2000

  97 1.5 (1.2–1.8) ADVA, 2005a

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)

Mortality

All branches, return–2001

  28 1.1 (0.7–1.5) ADVA, 2005b

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)

1980–1994

  12 1.3 (0.7–2.2) CDVA, 1997a

Australian Conscripted Army National Service

All COIs

(18,940 deployed vs 24,642 nondeployed)

Incidence

1982–2000

    8 0.7 (0.2–1.6) ADVA, 2005c

Mortality

1966–2001

    2 0.4 (0.0–2.4) ADVA, 2005c

1982–1994

    0 0 (0– > 10) CDVA, 1997b
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates

Mortality 1939–1992

  21 1.6 (1.0–2.5) Kogevinas et al., 1997

13,831 exposed to highly chlorinated PCDDs

  15 1.7 (1.0–2.8)

7,553 not exposed to highly chlorinated PCDDs

    5 1.2 (0.4–2.9)

Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort

Saracci et al., 1991
    8 1.5 (0.6–2.9)

British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)

MCPA

Mortality through 1983

    4 1.7 (0.5–4.5) Coggon et al., 1986

German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in

Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP

IARC cohort as of 1997)

Mortality 1952–2007

    7 3.5 (1.4–7.2) Manuwald et al., 2012

Men

    6 3.8 (1.4–8.2)

Women

    1 2.5 (0.0–13.9)

Mortality 1952–1989—stats on men only, 1,184 (tables all for 1,148 men, not necessarily German nationals)

    2 2.0 (0.2–7.1) Manz et al., 1991

vs national rates (also vs gas workers); same observation period as Becher et al., 1966

New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram

Mortality 1969–2004

McBride et al., 2009a

Ever-exposed workers

    1 2.5 (0.1–14.0)

Never-exposed workers

    1 9.7 (0.2–54.3)

Production Workers (713 men and 100 women worked > 1 month in 1969–1984)

Mortality 1969–2000

    0 nr ’t Mannetje et al., 2005
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

Through 1987

    7 2.1 (0.8–4.3) Fingerhut et al., 1991

≥ 1-year exposure, ≥ 20-year latency

    3 2.7 (0.6–7.8)

All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts)

2,4,5-T; 2,4,5-TCP

1942–2003 (n = 1,615)

    3 1.3 (0.3–3.9) Collins et al., 2009a

All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

1940–2005 (n = 2,122)

    5 1.5 (0.5–3.4)

PCP and TCP (n = 720)

    1 0.9 (0.0–5.1)

PCP (no TCP) (n = 1,402)

    4 1.7 (0.5–4.3)

Dow 2,4-D Production Workers (1945–1982 in Midland, Michigan) (subset of all TCP-exposed workers)

2,4-D, lower chlorinated dioxins

Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3)

    4 1.1 (0.3–2.9) Burns et al., 2011

Through 1982 (n = 878)

    1 3.0 (0.0–16.8) Bond et al., 1988

Dow PCP Production Workers (1937–1989 in Midland, Michigan) (not in IARC and NIOSH cohorts)

Low chlorinated dioxins, 2,4-D

Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP)

    2 1.7 (0.2–6.2) Collins et al., 2009b

Mortality 1940–1989 (n = 770)

    2 2.9 (0.3–10.3) Ramlow et al., 1996

0-yr latency

    2 2.9 (0.4–10.3)

15-yr latency

    1 nr
OCCUPATIONAL—PAPER AND PULP TCDD
WORKERS

IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM

McLean et al., 2006

Exposure to nonvolatile organochlorine compounds

Never

  18 0.9 (0.5–1.5)

Ever

  20 1.2 (0.8–1.9)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—HERBICIDE-USING
WORKERS (not related to IARC sprayer cohorts)

DENMARK

Danish gardeners (n = 3,124) exposed to pesticides

    9 0.7 (0.3–1.4) Kenborg et al., 2012

ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974

Mortality 1970–1986 (n = 23,401)

  25 0.5 (0.3–0.7) Torchio et al., 1994

Italian rice growers with documented phenoxy use (n = 1,487)

Phenoxy herbicides Gambini et al., 1997
7 0.9 (0.4–1.9)

NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 303 incident laryngeal cancer cases vs remainder of 19,904 men with any incident cancer

Herbicides Reif et al., 1989

Forestry workers (n = 134)

    2 1.1 (0.3–4.7)

SWEDEN

Swedish lumberjacks—used phenoxys 1954–1967, Incidence 1958–1992

Thörn et al., 2000

Exposed (n = 154)

Foremen (n = 15)

    0 nr

THE NETHERLANDS

Dutch Licensed Herbicide Sprayers—1,341 certified before 1980

Through 2000

    1 1.0 (0.0–5.1) Swaen et al., 2004

UNITED STATES

US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states

Herbicides PCMRs Blair et al., 1993

Men

Whites (n = 119,648)

162 0.7 (0.6–0.8)

Nonwhites (n = 11,446)

  32 1.1 (0.8–1.5)

Women

Whites (n = 2,400)

    0 nr (0.0–3.3)

Nonwhites (n = 2,066)

    0 nr (0.0–4.8)
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) TCDD

Mortality

25-yr followup to 2001—men and women, all respiratory cancers (ICD-9 160–165) excluding lung cancers (ICD-9 162)

Consonni et al., 2008
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Zone A

    0 nr

Zone B

≤     8 nr

Zone R

≤   49 nr

20-yr followup to 1996—men and women, all respiratory cancers (ICD-9 160–165) excluding lung cancers (ICD-9 162)

Bertazzi et al., 2001

Zone A

    0 nr

Zone B

    8 nr

15-yr followup to 1991—men

Bertazzi et al., 1997, 1998

Zone B

    6 nr

Zone R

    32 nr

15-yr followup to 1991—women

Bertazzi et al., 1997, 1998

Zone B

    0 nr

Zone R

    6 nr
Ecological Study of Residents of Chapaevsk, Russia Dioxin Revich et al., 2001

Incidence—Crude incidence rate in 1998 vs

Men

Regional (Samara)

    0

National (Russia)

11.3

Women

Regional (Samara)

0

National (Russia)

0.4

Mortality—1995–1998 (SMR vs regional rates)

Men

  13 2.3 (1.2–3.8)

Women

    1 0.1 (0.0–0.6)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; 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; JEM, job-exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; 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:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies

No Vietnam-veteran studies, environmental studies, or case-control studies of exposure to the COIs and laryngeal cancer have been published since Update 2010.

Occupational Studies

Burns et al. (2011) updated cancer incidence through 2007 in workers who were alive on January 1, 1985, and had been employed at any time from 1945 to 1994 in 2,4-D production by the Dow Chemical Company in Midland, Michigan. They found no evidence of significantly increased cancer rates overall. With four cases observed, the incidence of laryngeal cancer in the most restrictively defined cohort was not increased (SIR = 1.13, 95% CI 0.30–2.88), as was the case in the two successively more inclusive, but potentially more biased, cohorts.

Boers et al. (2012) did not report any deaths from laryngeal cancer in the updated Dutch chlorophenoxy-herbicide cohorts.

Manuwald et al. (2012) reported mortality in 1,191 men and 398 women who had been employed for at least 3 months during 1952–1984 in a chemical plant in Hamburg (a subcohort of the IARC phenoxy-herbicide cohort). During that period, the plant produced insecticides and herbicides, including 2,4,5-T, so cohort members had the possibility of exposure to TCDD. Subjects entered the cohort on the date of their first employment in the plant, and vital status was sought through 2007. SMRs calculated relative to the population of Hamburg showed that death from laryngeal cancer was increased in men (SMR = 3.75, 95% CI 1.37–8.16), and in the entire cohort the increase in risk was significant (SMR = 3.50, 95% CI 1.40–7.21), but a single death from laryngeal cancer did not constitute an increase in the women (SMR = 2.53, 95% CI 0.03–13.91). The prevalence of smoking was not controlled for in the study, but it has been suggested that it did not differ from that in the general population (Flesch-Janys et al., 1995).

Ruder and Yiin (2011) reported mortality in 1940–2005 in the NIOSH PCP cohort of 2,122 workers in the four US plants that had been involved in PCP production. PCP production entailed exposure to PCDDs and PCDFs but not to the most toxic 2,3,7,8 dioxin congener. A subcohort of 720 workers (all men, the PCP-plus-TCDD group) had also been employed in TCP production and so had also been exposed to TCDD. Only five deaths from laryngeal cancer were found in the entire cohort. Relative to US referent rates, that did not constitute a substantial increase (SMR = 1.45, 95% CI 0.47–3.38), nor did the four deaths in the PCP-only group (SMR = 1.69, 95% CI 0.46–4.32). There was only a single laryngeal-cancer death in the PCP-plus-TCDD group (SMR = 0.92, 95% CI 0.02–5.14).

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The new publications on the AHS (Koutros et al., 2010a; Waggoner et al., 2011) did not report separate findings on laryngeal cancers.

Kenborg et al. (2012) conducted a study that focused on Parkinson disease in a Danish cohort of 3,124 male union members who worked as professional gardeners in 1975. When studying that cohort previously, Hansen et al. (1992, 2007) had reported that herbicides (including phenoxy herbicides) constituted most of their exposure. In addressing the observation that smoking has repeatedly been found to be negatively associated with the occurrence of Parkinson disease, Kenborg et al. also investigated the incidence of several cancers that are recognized as being smoking-related. The incidence of cancer of the larynx in the gardeners was similar to the age-adjusted and calendar-period-adjusted incidence in the general male Danish population (nine cases, SIR = 0.72, 95% CI 0.33–1.37).

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs 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 COIs has been reported.

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

Synthesis

The original VAO committee reviewed five studies that presented data on laryngeal cancer separately (Bond et al., 1988; Coggon et al., 1986; Fingerhut et al., 1991; Manz et al., 1991; Sarracci et al., 1991). It concluded that “although the numbers are too small to draw strong conclusions, the consistency of a mild increase in relative risk is suggestive of an association for laryngeal cancer.” That 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 (the IARC Cohort of Phenoxy Herbicide Workers analyzed by Kogevinas et al., 1997) has shown significant effects in workers who were exposed to any phenoxyacetic acid herbicide or chlorophenol (21 deaths, RR = 1.6, 95% CI 1.0–2.5), especially workers who were exposed to TCDD or higher-chlorinated dioxins (15 deaths, RR = 1.7, 95% CI 1.0–2.8). 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 in that 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

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

studying pulp and paper workers also showed an increase in risk (20 deaths, RR = 1.2, 95% CI 0.8–1.9; 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 Operation 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 continuing updates on various occupational cohorts are largely consistent with the prior work, reporting a nonsignificant excess of laryngeal cancer. Some 10% of laryngeal cancers now being diagnosed are associated with HPV, but this small fraction is unlikely to have a substantial effect on studies over time. Most reports show an increased risk of laryngeal cancer that is not statistically significant, most likely because of the small number of cases in any individual study. In larger studies with exposure characterizations that focus on the COIs, the associations are generally strong for laryngeal cancer.

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 COI and laryngeal cancer.

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 116,470 men and 109,690 women would receive diagnoses of lung cancer in the United States in 2012 and that about 87,750 men and 72,590 women would die from it (Siegel et al., 2012). Those numbers represent roughly 14% of new cancer diagnoses and 28% of cancer deaths in 2012. The principal types of lung neoplasms are identified collectively as bronchogenic carcinoma and carcinoma of the lung. Cancer of the trachea (ICD-9 162.0) 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.

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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 8-12.

ACS estimates that 87% of lung-cancer deaths are attributable to cigarette-smoking (ACS, 2011). Smoking increases the risk of all histologic types of lung cancer, but the associations with squamous-cell 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, 2013a).

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 COI and lung 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, Update 2008, and Update 2010 did not change that conclusion.

Table 8-13 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies

No Vietnam-veteran studies, environmental studies, or case-control studies of exposure to the COIs and cancers of the lung, bronchus, or trachea have been published since Update 2010.

TABLE 8-12 Average Annual Incidence (per 100,000) of Lung and Bronchial Cancer in the 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
Men 99.7 93.6 175.7 177.3 168.5 302.9 302.2 294.6 465.8
Women 74.4 74.3 101.7 140.8 145.4 164.3 230.4 241.5 257.8

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2005–2009 (NCI, 2013).

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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TABLE 8-13 Selected Epidemiologic Studies—Lung, Bronchus, or Trachea Cancer (Shaded Entries Are New Information for This Update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US VietnamVeterans

US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)

All COIs

Incidence

1982–2003—White SEA comparison veterans only (n = 1,482). Serum TCDD (pg/g) based on model with exposure variable loge(TCDD)

Pavuk et al., 2005

Per unit increase of –loge(TCDD) (pg/g) Quartiles (pg/g):

  36 1.7 (0.9–3.2)

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)

Quartiles (years in SEA):

  36 1.1 (0.9–1.2)

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)

Through 1999—White subjects vs national rates

Akhtar et al., 2004

Ranch Hand veterans (n = 1,189)

  33 1.1 (0.8–1.6)

With tours between 1966–1970

  33 1.1 (0.8–1.6)

SEA comparison veterans (n = 1,776)

  48 1.2 (0.9–1.6)

With tours between 1966–1970

  37 1.2 (0.9–1.6)

Mortality

Through 1999—White subjects vs national rates

Akhtar et al., 2004

Ranch Hand veterans (n = 1,189)

  21 0.9 (0.6–1.3)

SEA comparison veterans (n = 1,776)

  38 1.1 (0.8–1.5)
US VA Cohort of Army Chemical Corps—Expanded as of 1997 to include all Army men with chemical MOS (2,872 deployed vs 2,737 nondeployed) serving during Vietnam era (7/01/1965–3/28/1973) All COIs

Mortality—Respiratory system cancers

Through 2005

Cypel and Kang, 2010

Deployed veterans (2,872) vs nondeployed (2,737)

60 vs 26 1.3 (0.8–2.1)

ACC deployed men in Kang et al. (2006) reported sprayed herbicide vs did not spray

  19 1.4 (0.5–3.4)
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Through 1991

  11 1.4 (0.4–5.4) Dalager and Kang, 1997

US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

All COIs

Mortality—trachea, bronchus, lung

1965–2000

  41 1.0 (0.6–1.5) Boehmer et al., 2004

Low grade pay at time of discharge

nr 1.6 (0.9–3.0)

US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973

All COIs

1965–1988 (lung)

Watanabe and Kang, 1996

Army, deployed (n = 27,596) vs nondeployed (n = 31,757)

1,139 1.1 (nr) (p < 0.05)

Marine Corps, deployed (n = 6,237) vs nondeployed (n = 5,040)

215 1.2 (1.0–1.3)

US VA Study of Marine Post-service Mortality—sample of Marines serving 1967–1969, deployed (n = 10,716) vs nondeployed (n = 9,346)

All COIs

Mortality (lung), earlier of discharge or April 1973 through 1991

  42 1.3 (0.8–2.1) Watanabe and Kang, 1995

US VA Cohort of Female Vietnam Veterans

All COIs

Mortality

Through 2004—lung

  50 1.0 (0.7–1.4) Cypel and Kang, 2008

Vietnam veteran nurses

  35 0.8 (0.5–1.2)

US VA using the Patient Treatment Files—329 Vietnam-era veterans and 269 noncancer controls and 111 colon cancer controls (1983–1990)

All COIs Mahan et al., 1997
134 1.4 (1.0–1.9)

State Studies of US Vietnam Veterans

Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs nondeployed

  80 0.9 (0.7–1.1) Visintainer et al., 1995

International Vietnam-Veteran Studies

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

Incidence

All branches, 1982–2000

576 1.2 (1.1–1.3) ADVA,

Navy

141 1.4 (1.2–1.7) 2005a

Army

372 1.2 (1.1–1.3)

Air Force

  63 1.0 (0.7–1.2)

Histologic type—all service branches combined

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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

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)

Large-cell

  79 1.1 (0.8–1.3)

Other

  70 1.1 (0.8–1.3)

Validation Study

Expected number of exposed cases AIHW, 1999
46   65 (49–81)

Men–self report

120 65 (49–89) CDVA, 1998a

Mortality

All branches, return–2001

544 1.2 (1.1–1.3) ADVA, 2005b

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)

1980–1994

CDVA, 1997a

Lung (ICD-9 162)

212 1.3 (1.1–1.4)

Respiratory systems (ICD-9 163–165)

  13 1.8 (1.0–3.0)

Australian Conscripted Army National Service (18,940 deployed vs 24,642 nondeployed)

All COIs

Incidence

1982–2000

  78 1.2 (1.0–1.5) ADVA, 2005c

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) ADVA, 2005c

1982–1994

  27 2.2 (1.1–4.3) CDVA, 1997b

OCCUPATIONAL—INDUSTRIAL IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates

Mortality 1939–1992

Kogevinas et al., 1997

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)

13,831 exposed to highly chlorinated PCDDs

Lung (ICD-9 162)

225 1.1 (1.0–1.3)

Other respiratory organs (ICD-9 163–165)

    9 3.2 (1.5–6.1)
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

7,553 not exposed to highly chlorinated

PCDDs

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)

Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort

Saracci et al., 1991

Trachea, bronchus, lung (ICD-9 162)

173 1.0 (0.9–1.2)

Mortality, incidence of women in production (n = 699) and spraying (n = 2) compared to national death rates and cancer incidence rates

TCDD Kogevinas et al, 1993
    2 1.4 (0.2–4.9)

(lung)

British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)

MCPA

Mortality through 1983 (lung, pleura, mediastinum, ICD-8 162–164)

117 1.2 (1.0–1.4) Coggon et al., 1986

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)

British Production Workers at 4 plants (included in IARC cohort) (lung)

Dioxins, but TCDD unlikely; MCPA Coggon et al., 1991
  19 1.3 (0.8–2.1)

Workers with exposure above background

  14 1.2 (0.7–2.1)

Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)

Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP

Incidence

Incidence 1943–1987 (lung, men only)

  13 1.6 (0.9–2.8) Lynge, 1993

Incidence 1943–1982

Lynge, 1985

Men

  38 1.2 (nr)

Women

    6 2.2 (nr)

Dutch production workers in Plant A and Plant B, combined (in IARC cohort)

Dioxins, 2,4,5-T, 2,4,5-TCP

Mortality 1955–2006 (Plant A, 1,020 workers; Plant B, 1,036 workers) (respiratory cancers)

  54 1.0 (0.9–1.2) Boers et al., 2012

TCDD plasma level (HRs, by tertile) (trachea, bronchus, lung)

  52 1.0 (0.8–1.2)

Background (≤ 0.4)

  24 Referent

Low (0.4–4.1)

  11 0.5 (0.3–1.1)

Medium (4.1–20.1)

  12 1.2 (0.6–2.3)

High (≥ 20.1)

    5 1.2 (0.5–3.1)
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

963 men exposed during production 1955–1985 vs 1,317 unexposed; mortality in 1986 (respiratory system cancers, ICD-8 160–163)

9 vs 3 1.7 (0.5–6.3) Bueno de Mesquita et al., 1993

Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)

Dioxins, 2,4,5-T, 2,4,5-TCP

Mortality 1955–2006 (hazard ratios for lagged TCDD plasma levels)

Boers et al., 2012

Respiratory cancer

  30 1.1 (0.9–1.3)

Trachea, bronchus, lung cancers

  28 1.1 (0.9–1.3)

Mortality 1955–2006

Boers et al., 2010

Respiratory cancer

  21 1.1 (0.5–2.5)

Trachea, bronchus, lung cancers

  20 1.2 (0.5–2.8)

Mortality 1955–1985

Bueno de Mesquita et al., 1993

Trachea, bronchus, lung cancers

    9 1.0 (0.5–1.9)

Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)

2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely

Mortality 1965–2006

Boers et al., 2010

Respiratory cancer

  12 1.2 (0.6–2.7)

Trachea, bronchus, lung cancers

  12 1.2 (0.6–2.7)

Mortality 1965–1986

Bueno de Mesquita et al., 1993

Trachea, bronchus, lung cancers

    0 0.0 (0.0–1.3)

German Production Workers—2,479 workers at 4 plants (in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

All for plants

  47 1.4 (1.1–1.9) Becher et al., 1996

German Production Workers at Bayer Plant in Uerdingen (135 men working > 1 month in 1951–1976) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4,5-TCP

Mortality 1951–1992

    2 0.7 (0.0–2.5) Becher et al., 1996

German Production Workers at Bayer Plant in Dormagen (520 men working > 1 month in 1965–1989) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1965–1989

    3 1.6 (0.3–4.6) Becher et al., 1996
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 month in 1957–1987) (in IARC cohort as of 1997) and women—no results

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPP; 2,4-DP

Mortality 1956–1989

  11 1.5 (0.7–2.6) Becher et al., 1996

BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)

Focus on TCDD

Mortality

1953–1992

Ott and Zober, 1996

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)

Through 1987

90% CI Zober et al., 1990
    4 2.0 (0.7–4.6)

German Production Workers at Boehringer–Ingelheim Plant in Hamburg—1,144 men working > 1 month in 1952–1984 (generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)

Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP

Mortality 1952–2007

  73 1.4 (1.1–1.8) Manuwald et al., 2012

Men

  68 1.5 (1.2–1.9)

Women

    5 0.8 (0.3–1.9)

Mortality 1952–1989

  31 1.5 (1.0–2.1) Becher et al., 1996

Mortality (lung) 1952–1989—stats on men only, 1,184 (tables all for 1,148 men, not necessarily German nationals) vs national rates (also vs gas workers); same observation period as Becher et al., 1966

  26 1.7 (1.1–2.4) Manz et al., 1991

New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram

Mortality 1969–2004

McBride et al., 2009a

Ever-exposed workers

Respiratory cancer

  13 0.9 (0.5–1.6)

Trachea, bronchus, lung

  11 0.8 (0.4–1.5)
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Never-exposed workers

Respiratory cancer

    5 1.2 (0.4–2.7)

Trachea, bronchus, lung

    4 1.0 (0.3–2.5)

Production Workers (713 men and 100 women worked > 1 month in 1969–1984); mortality (1969–2000)

Trachea, bronchus, lung (ICD-9 162)

  12 1.4 (0.7–2.4) ’t Mannetje et al., 2005

Other respiratory system sites (ICD-9 163–165)

    1 3.9 (0.1–21.5)

Sprayers (697 men and 2 women on register of New Zealand applicators, 1973–1984); mortality 1973–2000

Trachea, bronchus, lung (ICD-9 162)

    5 0.5 (0.2–1.1) ’t Mannetje et al., 2005

Other respiratory system sites (ICD-9 163–165)

    1 2.5 (0.1–13.7)

NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

Through 1993

125 1.1 (0.9–1.3) Steenland et al., 1999

Chloracne subcohort (n = 608)

  30 1.5 (0.98–2.1)

Through 1987 (Entire cohort)

Fingerhut et al., 1991

Trachea, bronchus, lung (ICD-9 162)

  89 1.1 (0.9–1.4)

Respiratory system (ICD-9 160–165

  96 1.1 (0.9–1.4)

≥ 1-year exposure, ≥ 20-year 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)

All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts)

2,4,5-T; 2,4,5-TCP

1942–2003 (n = 1,615) (bronchus, trachea, lung)

  46 0.7 (0.5–0.9) Collins et al., 2009a

1940–1994 (n = 2,187 men) (lung)

  54 0.8 (0.6–1.1) Bodner et al., 2003

All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

Respiratory cancer (ICD-9 160–165)

1940–2005 (n = 2,122)

133 1.4 (1.2–1.6)c

PCP and TCP (n = 720)

  28 0.9 (0.6–1.3)

PCP (no TCP) (n = 1,402)

105 1.6 (1.3–1.9)c
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Trachea, bronchus, lung (ICD-9 162)

1940–2005 (n = 2,122)

126 1.4 (1.1–1.6)c

PCP and TCP (n = 720)

  27 0.9 (0.6–1.3)

PCP (no TCP) (n = 1,402)

  99 1.6 (1.3–1.9)c

Dow 2,4-D Production Workers (1945–1982 in Midland, Michigan) (subset of all TCP-exposed workers)

2,4-D, lower chlorinated dioxins

Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) (lung, bronchus)

  36 0.9 (0.6–1.3) Burns et al., 2011

Through 1994 (n = 1,517) (respiratory system, ICD-8 160–163)

  31 0.9 (0.6–1.3) Burns et al., 2001

Through 1986 (n = 878) vs national vs 36,804 “unexposed” workers at same location

Bloemen et al., 1993

Respiratory system (ICD-8 162–163)

    9 0.8 (0.4–1.5)

Through 1982 (n = 878)

Bond et al., 1988

Lung (ICD-8 162–163)

    8 1.0 (0.5–2.0)

Respiratory (ICD-8 160–163) (exposure lagged 15 yrs)

Low cumulative exposure

    1 0.7 (nr)

Medium cumulative exposure

    2 1.0 (nr)

High cumulative exposure

    5 1.7 (nr)

Dow PCP Production Workers (1937–1989 in Midland, Michigan) (not in IARC and NIOSH cohorts)

Low chlorinated dioxins, 2,4-D

Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) (bronchus, trachea, lung)

  30 1.0 (0.6–1.4) Collins et al., 2009b

Mortality 1940–1989 (n = 770)

Ramlow et al., 1996

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)

15-yr latency

Respiratory system (ICD-8 160–163)

  17 1.1 (0.6–1.8)

Lung (ICD-8 162)

  16 1.1 (0.6–1.8)

OCCUPATIONAL—PAPER AND PULP WORKERS

TCDD

IARC cohort of pulp and paper workers—60,468 workers from 11 countries,

McLean et al., 2006

TCDD among 27 agents assessed by JEM

Exposure to nonvolatile organochlorine compounds

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

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)
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)

CANADA

Ontario Forestry Workers—1,222 men working ≥ 6 months 1950–1982

Herbicides

80 deaths through 1982; 18 cancers (lung greatest with 5)

    5 nr Green, 1991

DENMARK

Danish gardeners (n = 3,124) exposed to pesticides

139 1.0 (0.9–1.2) Kenborg et al., 2012

Danish gardeners—incidence from 3,156 male and 859 female gardeners

Hansen et al., 2007

25-year followup (1975–2001)

Herbicides

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)

10-year followup (1975–1984) of male gardeners

  41 1.0 (0.7–1.3) Hansen et al., 1992

FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC

Phenoxy herbicides

Incidence

Asp et al., 1994

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)

Mortality 1972–1989

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)

ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974

Mortality 1970–1986 (n = 23,401) (lung)

155 0.5 (0.4–0.5) Torchio et al., 1994

Italian rice growers with documented phenoxy use (n = 1,487

Phenoxy herbicides Gambini et al., 1997

Lung

  45 0.8 (0.6–1.1)

Pleura

    2 2.2 (0.2–7.9)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 4,224 incident lung cancer cases vs remainder of 19,904 men with any incident cancer

Herbicides Reif et al., 1989

Forestry workers (n = 134)

  30 1.3 (0.8–1.9)

SWEDEN

Swedish pesticide applicators—incidence

Wiklund et al., 1989a

Trachea, bronchus, lung

  38 0.5 (0.4–0.7)

348 Swedish railroad workers (1957–October, 1978)—total exposure to herbicides (lung)

    3 Phenoxy acids 1.4 (nr) Axelson et al., 1980

Swedish lumberjacks—used phenoxys 1954–1967, Incidence 1958–1992

Thörn et al., 2000

Exposed (n = 154)

Foremen (n = 15)

    1 4.2 (0.0–23.2)

Lumberjacks (n = 139)

    0

Unexposed lumberjacks (n = 241)

    5 1.2 (0.4–2.7)

THE NETHERLANDS

Dutch Licensed Herbicide Sprayers—1,341 certified before 1980

Through 2000 (trachea, lung)

  27 0.7 (0.5–1.0) Swaen et al., 2004

Through 1987(trachea, lung)

  12 1.1 (0.6–1.9) Swaen et al., 1992
UNITED STATES

US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states

Herbicides PCMRs Blair et al., 1993

Men

Whites (n = 119,648)

6,473 0.9 (0.9–0.9)

Nonwhites (n = 11,446)

664 1.0 (0.9–1.1)

Women

Whites (n = 2,400)

  57 0.8 (0.6–1.1)

Nonwhites (n = 2,066)

  24 0.6 (0.4–0.9)

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides

Incidence

Enrollment through 2006—SIRs for participants (lung, bronchus)

Koutros et al., 2010a

Private applicators

436 0.5 (0.4–0.5)

Commercial applicators

  26 0.8 (0.5–1.1)

Spouses

133 0.4 (0.4–0.5)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Enrollment through 2002

Samanic et al., 2006

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

Enrollment through 2002

Alavanja et al., 2005

Private applicators

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

Lung

  12 0.6 (0.3–1.0)

Respiratory system

  14 0.6 (0.3–1.0)

Mortality

Enrollment through 2007, vs state rates

Waggoner et al., 2011

Respiratory

Applicators (n = 1,641)

422 0.4 (0.4–0.5)

Spouses (n = 676)

110 0.4 (0.3–0.5)

Trachea, bronchus, lung

Applicators (n = 1,641)

417 0.4 (0.4–0.5)

Spouses (n = 676)

108 0.4 (0.3–0.5)

Other respiratory system

Applicators (n = 1,641)

    5 0.2 (0.1–0.3)

Spouses (n = 676)

    2 nr

Enrollment through 2000, vs state rates

Blair et al., 2005a

Private applicators (men and women)

129 0.4 (0.3–0.4)

Years handled pesticides

≤ 10 yrs

  25 0.4 (nr) (p < 0.05)

≥ 10 yrs

  80 0.3 (nr) (p < 0.05)

Spouses of private applicators (> 99% women)

  29 0.3 (0.2–0.5)

Florida Licensed Pesticide Applicators (common phenoxy use assumed but not documented)

Herbicides

Pesticide applicators in Florida licensed 1965–1966 (n = 3,827)—mortality through 1976

Herbicides Blair et al., 1983

Any pesticide (dose-response by length of licensure)

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Only for lawn and ornamentals (lung, ICD-8 162–163)

    7 0.9 (nr)

Minnesota Highway Maintenance Workers (n = 4,849) who worked ≥ l day for the Department of Transportation and ≥ 1 day after January 1, 1945 (1984–1986)

Herbicides Bender et al., 1989

Trachea, bronchus, lung (ICD-9 162.0–162.8)

  54 0.7 (0.5–0.9)

All respiratory (ICD-9 160.0–165.9)

  57 0.7 (0.5–0.9)

ENVIRONMENTAL

Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171)

TCDD

Incidence

20-yr followup to 1996—men and women (lung ICD-9 162)

Pesatori et al., 2009

Zone A

    7 1.1 (0.5–2.4)

Zone B

  37 1.0 (0.7–1.3)

Zone R

280 1.0 (0.9–1.2)

10-yr followup to 1991—men

Bertazzi et al., 1993

Zone A

    2 0.8 (0.2–3.4)

Zone B

  18 1.1 (0.7–1.8)

Zone R

  96 0.8 (0.7–1.0)

10-yr followup to 1991—women

Bertazzi et al., 1993

Zone R

  16 1.5 (0.8–2.5)

Mortality

25-yr followup to 2001—men and women (lung ICD-9 162)

Consonni et al., 2008

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)

20-yr followup to 1996 (lung)

Bertazzi et al., 2001

Zones A, B—men

  57 1.3 (1.0–1.7)

Zones A, B—women

    4 0.6 (0.2–1.7)

15-yr followup to 1991—men (lung)

Bertazzi et al., 1998

Zone A

    4 1.0 (0.4–2.6)

Zone B

  34 1.2 (0.9–1.7)

Zone R

176 0.9 (0.8–1.1)

15-yr followup to 1991—women (lung)

Bertazzi et al., 1998

Zone A

    0 nr

Zone B

    2 0.6 (0.1–2.3)

Zone R

  29 1.0 (0.7–1.6)

Ecological Study of Residents of Chapaevsk, Russia

Dioxin Revich et al., 2001
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Incidence—Crude incidence rate in 1998 vs

Men

Regional (Samara)

nr 102.4 (nr)

National (Russia)

nr 89.4 (nr)

Women

Regional (Samara)

nr 11.1 (nr)

National (Russia)

nr 9.8 (nr)

Mortality—1995–1998 (SMR vs regional rates)

Men

168 3.1 (2.6–3.5)

Women

  40 0.4 (0.3–0.6)

Other International Environmental Studies

FINLAND

Finnish fishermen (n = 6,410) and spouses (n = 4,260) registered between 1980 and 2002 compared to national statistics (larynx, trachea, lung, combined)

Serum dioxin Turunen et al., 2008

Fisherman

  72 0.8 (0.6–1.0)

Spouses

    8 0.7 (0.3–1.4)

JAPAN

Residents of municipalities with and without waste incineration plants (cross-sectional)

Dioxin emissions age-adjusted mortality (per 100,000) Fukuda et al., 2003

Men

With

39.0 ± 6.7 vs

Without

41.6 ± 9.1 (p = 0.0001)

Women

With

13.7 ± 3.8 vs

Without

14.3 ± 4.6 (p = 0.11)

SWEDEN

Swedish fishermen (high consumption of fish with persistent organochlorines)

Organochlorine compounds Svensson et al., 1995

Incidence

East coast (lung)

  24 1.2 (0.8–1.8)

West coast (lung)

  73 0.9 (0.7–1.1)

Mortality

East coast

  16 0.8 (0.5–1.3)

West coast

  77 0.9 (0.7–1.1)

CASE-CONTROL STUDIES

International Case-Control Studies

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Saskatchewan, Canada farmers (604 men, 223 women) diagnosed with lung cancer between November, 1983, and July, 1986

Herbicides McDuffie et al., 1990

Interviews with lung cancer patients (273 men and 103 women) who sprayed herbicides

103 0.6 (nr)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; ACC, Army Chemical Corps; CATI, computer-assisted telephone interviewing; 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; JEM, job-exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; MOS, military occupational specialty; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PM, proportionate mortality; SEA, Southeast Asia; SIR, standardized incidence ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; 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.

c99% CI.

Occupational Studies

Burns et al. (2011) updated cancer incidence through 2007 in workers who were alive on January 1, 1985, and had been employed at any time from 1945 to 1994 in 2,4-D production by the Dow Chemical Company in Midland, Michigan. They found no evidence of significantly increased rates of cancer overall. With 36 cases observed, the incidence of lung or bronchial cancer in the most restrictively defined cohort was not increased (SIR = 0.92, 95% CI 0.65–1.28). The category of other respiratory cancers was significantly increased (SIR = 4.76, 95% CI 1.53–11.11), but this category consisted of only one carcinoma of the sinuses and four cases of mesothelioma, which could be attributed with some certainty to occupational asbestos exposure, although no documentation was provided.

Boers et al. (2012) updated mortality in workers in two chlorophenoxy herbicide plants in the Netherlands by using semiquantitative measures of TCDD exposure. Plasma concentrations of TCDD in a subset of 187 workers were used to develop a predictive model of TCDD exposure, and a Cox proportional-hazards model was used to investigate associations between time-varying TCDD exposure

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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and cause-specific mortality. No relationship was found between TCDD exposure and respiratory cancers. HRs for predicted TCDD concentrations and cancers of the trachea, bronchus, and lung were not increased in the entire cohort (HR = 0.98, 95% CI 0.84–1.15 for each unit increase in TCDD exposure on a log scale) or in only the workers in factory A (HR = 1.07, 95% CI 0.86–1.33). That study was a reanalysis of the mortality data on the cohort updated through 2006; using crude exposure estimates based on job classification, Boers et al. (2010) had found that respiratory-cancer risks were not significantly increased. That finding is in contrast with the excess mortality from respiratory cancers reported in the second followup of the cohort (Hooiveld et al., 1998).

Manuwald et al. (2012) updated mortality though 2007 in a cohort of 1,589 male and female workers employed for at least 3 months during 1952–1984 in a factory in Hamburg, Germany, that produced various herbicides and insecticides, including 2,4,5-T, which was contaminated with TCDD and other higher-chlorinated dioxins and furans. SMRs were calculated by using the population of Hamburg as a reference group. Deaths due to cancer of the trachea, bronchus, and lung were significantly increased in men (68 deaths, SMR = 1.52, 95% CI 1.18–1.93) and in the total cohort (SMR = 1.43, 95% CI 1.12–1.80) but were not increased in the smaller group of women (five deaths, SMR = 0.80, 95% CI 0.26–1.88). The prevalence of smoking was not controlled for but was suggested not to differ from that in the general population (Flesch-Janys et al., 1995). Although those findings are consistent with earlier mortality reports on this cohort (Becher et al., 1996; Manz et al., 1991), an exposure–response relationship was not found (p = 0.30) for respiratory-cancer mortality when estimated cumulative occupational exposure to TCDD was stratified into quartiles.

Ruder and Yiin (2011) reported mortality through 2005 in a cohort of 2,122 US PCP production workers in four plants in the NIOSH Dioxin Registry relative to US referent rates. The workers in all four plants were exposed to PCP and to PCDDs and PCDFs as contaminants during the production of PCP. Two plants were also involved in TCP production, so a subcohort of 720 men was also exposed to 2,3,7,8-TCDD, a contaminant of TCP, but not of PCP. A total of 1,165 deaths occurred in 1940–2005, and overall cancer mortality was significantly increased (326 deaths, SMR = 1.17, 95% CI 1.05–1.31). There were excess deaths from tracheal, bronchial, and lung cancer (126 deaths, SMR = 1.36, 95% CI 1.13–1.62) in the entire cohort and in the PCP-only group (99 deaths, SMR = 1.56, 95% CI 1.27–1.90) but no increase in the PCP-plus-TCDD group (27 deaths, SMR = 0.91, 95% CI 0.60–1.33). The increase in the SMR for lung-cancer mortality did not increase with duration (days of work in PCP operations); it reached the concentration of statistical significance in the lowest group (up to 57 days) and in the third of the four categories (182 to < 650 days). The study has merit in that it followed all US workers employed in PCP manufacturing through 1992 for an average of 39 years from first exposure. The lack of information on smoking greatly limits conclusions regarding the contribution of the agents to the

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

increase in mortality from tracheal, bronchial, and lung cancers. Although there was potential for occupational exposure to TEQs in the entire cohort, the smaller subcohort with potential for TCDD exposure did not have increased mortality due to tracheal, bronchial, and lung cancers. In addition, the authors noted that there was no difference in mortality between the 236 workers who had diagnoses of chloracne and other workers, as found earlier by Bodner et al. (2003).

Koutros et al. (2010a) updated cancer incidence as of 2006 in members of the large prospective AHS cohort. SIRs of lung and bronchial cancers were significantly lower in private applicators (436 cases, SIR = 0.48, 95% CI 0.43–0.53) and their spouses (133 cases, SIR = 0.42, 95% CI 0.35–0.50) and unchanged in commercial applicators (26 cases, SIR = 0.75, 95% CI 0.49–1.09) relative to the general population in Iowa and North Carolina, the states selected for the study. Lower rates of smoking and increased physical activity are factors that may contribute to the lower risk of cancer at these sites.

Waggoner et al. (2011) reported mortality in the same AHS cohort from the time of enrollment (1993–1997) through 2007 vs state-specific rates. Death from tracheal, bronchial, and lung cancer was significantly decreased in private and commercial applicators (417 deaths, SMR = 0.43, 95% CI 0.39–0.47) and their spouses (108 deaths, SMR = 0.38, 95% CI 0.31–0.45). The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee’s task.

Kenborg et al. (2012) conducted a study that focused on Parkinson disease in a Danish cohort of 3,124 male union members who worked as professional gardeners in 1975. When studying this cohort previously, Hansen et al. (1992, 2007) had reported that herbicides (including phenoxy herbicides) constituted most of their exposure. Kenborg et al. (2012) reported the incidence of several cancers recognized as being smoking-related. The incidence of lung cancer in the gardeners was similar to the age-adjusted and calendar-period–adjusted incidence in the general male Danish population (SIR = 1.02, 95% CI 0.86–1.20).

Biologic Plausibility

Long-term animal studies have examined the effects of exposure to the COIs 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 an 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 nonneoplastic 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 non-neoplastic lesions were bronchiolar metaplasia and squamous metaplasia of the alveolar epithelium. Cystic keratinizing epithelioma was the most commonly

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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observed neoplasm. The lung was also identified as a target organ in an NTP 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, results that were similar to what was observed in the earlier 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 COIs is discussed in general at the beginning of this chapter.

Synthesis

The evidence remains limited but suggestive of an association between exposure to at least one COI and the risk of developing or dying from lung cancer. In the present update, there are new supporting data from the followup studies of mortality in the Hamburg cohort of herbicide producers (Manuwald et al., 2012) and in US PCP workers (Ruder and Yiin, 2011). In the past, the most compelling evidence has come from studies of heavily exposed occupational cohorts, including British 2-methyl-4-chlorophenoxyacetic acid (MCPA) production workers (Coggon et al., 1986), German production workers (Becher et al., 1996), a BASF cohort (Ott and Zober, 1996), a NIOSH cohort (Fingerhut et al., 1991; Steenland et al., 1999), and Danish production workers (Lynge, 1993).

In the last update, Cypel and Kang (2010) found a significantly increased lung-cancer risk in Army Chemical Corps (ACC) veterans who used herbicides in Vietnam. The most recent findings from the Operation Ranch Hand study (Pavuk et al., 2005) suggested an increase in risk with serum TCDD concentration even in subjects who made up the comparison group, whose TCDD exposure was considerably lower than that of the Ranch Hand cohort (but not zero). 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 dif-

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

fered 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; however, although there was substantial 2,4-D exposure in this cohort (Blair et al., 2005b), dioxin exposure of the contemporary farmers was probably negligible.

In large part, the environmental studies have not been supportive of an 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.

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 COI and carcinomas of the lung, bronchus, and trachea.

BONE AND JOINT CANCER

ACS estimated that about 1,600 men and 1,290 women would receive diagnoses of bone or joint cancer (ICD-9 170) in the United States in 2012 and that 790 men and 620 women would die from these cancers (Siegel et al., 2012). 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 8-14.

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

TABLE 8-14 Average Annual Incidence (per 100,000) of Bone and Joint Cancer in the 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
Men 1.0 1.3 0.3 1.3 1.3 1.1 1.5 1.5 2.8
Women 0.8 0.9 0.4 1.5 1.5 1.5 1.2 1.4 0.4

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2005–2009 (NCI, 2013).

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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risk factors for bone and 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 COIs 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, Update 2008, and Update 2010 did not change that conclusion.

Table 8-15 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran and Case-Control Studies

No Vietnam-veteran studies or case-control studies of exposure to the COIs and bone or joint cancer have been published since Update 2010.

Occupational Studies

In an update of cancer incidence from 1985 through 2007 in 2,4-D production workers in the Dow Chemical Company in Midland, Michigan, Burns et al. (2011) found a single case of cancer of bone or soft tissue, with attendant nonsignificant estimates of exposure-related risk (SIR = 0.81, 95% CI 0.01–4.49 in the most restrictively defined cohort). Similarly, Waggoner et al. (2011) reported three deaths from cancer in the applicators in the AHS and two in their spouses. The numbers are too small to add significantly to the assessment of bone-cancer risk associated with exposure to the COIs.

Environmental Studies

One recent study (McNally et al., 2012) reported on the occurrence of bone cancer (Ewings sarcoma and osteosarcoma) in all of Great Britian in 1980–2005. The data on incidence from the cancer registries included 2,566 osteosarcoma cases and 1,650 Ewing sarcoma cases. There were essentially no exposure data, but the cases occurred in lower-socioeconomic areas, possibly indicating some association with agricultural exposures. This very large study has no exposure data and thus provides little information that is germane to the task of the present committee.

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 8-15 Selected Epidemiologic Studies—Bone and Joint Cancer (Shaded Entries Are New Information for This Update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans

US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973

All COIs

1965–1982

Breslin

Army, deployed (n = 19,708) vs nondeployed (n = 22,904)

  27 0.8 (0.4–1.7) et al., 1986, 1988

Marine Corps, deployed (n = 4,527) vs nondeployed (n = 3,781)

  11 1.4 (0.1–21.5)
State Studies of US Vietnam Veterans

Massachusetts Vietnam-era veterans

Veterans aged 35–64 years in 1993—cases diagnosed 1988–1993 vs nonexposed veterans with gastrointestinal cancers

    4 0.9 (0.1–11.3) Clapp, 1997

New York

Deployed vs nondeployed veterans

    8 1.0 (0.3–3.0) Lawrence et al., 1985

923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans

    1 nr Anderson et al., 1986
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates

Mortality 1939–1992

    5 1.2 (0.4–2.8) Kogevinas et al., 1997

13,831 exposed to highly chlorinated PCDDs

    3 1.1 (0.2–3.1)

7,553 not exposed to highly chlorinated

    2 1.4 (0.2–5.2)

PCDDs

British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)

MCPA

Mortality through 1983

    1 0.9 (0.0–5.0) Coggon et al., 1986

BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)

Focus on TCDD

Mortality

Through 1987

90% CI Zober et al., 1990
    0 0.0 (0.0–65.5)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram

Mortality 1969–2004

    0 0.0 (0.0–21.8) McBride et al., 2009a

Production Workers (713 men and 100 women worked > 1 month in 1969–1984)

Mortality 1969–2000

    0 nr ’t Mannetje et al., 2005

NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

Through 1987

    2 2.3 (0.3–8.2) Fingerhut et al., 1991

≥ 1-year exposure, ≥ 20-year latency

    1 5.5 (0.1–29.0)

Mortality—754 Monsanto workers, among most highly exposed workers from Fingerhut et al. (1991)

    2 5.0 (0.6–18.1) Collins et al., 1993

Dow 2,4-D Production Workers (1945–1982 in Midland, Michigan) (subset of all TCP-exposed workers)

2,4-D, lower chlorinated dioxins

Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) (bone, soft tissue)

    1 0.8 (0.0–4.5) Burns et al., 2011

Through 1982 (n = 878)

    0 nr (0.0–31.1) Bond et al., 1988

Dow PCP Production Workers (1937–1989 in Midland, Michigan) (not in IARC and NIOSH cohorts)

Low chlorinated dioxins, 2,4-D

Mortality 1940–1989 (n = 770)

    0 nr Ramlow et al., 1996

0-yr latency

    0 nr

15-yr latency

    0 nr
OCCUPATIONAL—PAPER AND PULP WORKERS TCDD

IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM

Danish paper workers

Rix et al., 1998

Men

    1 0.5 (0.0–2.7)

Women

    0 nr
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)

CANADA

Sawmill Workers in British Columbia—23,829 workers for ≥ 1 year at 11 mills using chlorophenates 1940–1985

Chlorophenates, not TCDD

Incidence 1969–1989

    4 1.1 (0.4–2.4) Hertzman et al., 1997

Mortality 1950–1989

    5 1.3 (0.5–2.7)

No exposed to highly chlorinated PCDDs

    2 1.4 (0.2–5.2)

DENMARK

Danish Farmers—incidence from linking farmers on 1970 census with national cancer registry (1970–1980)

Herbicides Ronco et al., 1992

Men

Self-employed

    9 0.9 (nr)

Employee

    0 nr

Women

Self-employed

    0 0.0

Employee

    1 6.3 (p < 0.05)

ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974

Mortality 1970–1986 (n = 23,401)

  10 0.8 (0.4–1.4) Torchio et al., 1994

Italian rice growers with documented phenoxy use (n = 1,487)

Phenoxy herbicides Gambini et al., 1997
    1 0.5 (0.0–2.6)

NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of incident bone cancer cases vs remainder of 19,904 men with any incident cancer

Herbicides Reif et al., 1989

Forestry workers (n = 134)

    1 1.7 (0.2–13.3)

SWEDEN

Incident bone cancer cases 1961–1973 with agriculture as economic activity in 1960 census

99% CI Wiklund, 1983
44 1.0 (0.6–1.4)

THE NETHERLANDS

Dutch Licensed Herbicide Sprayers—1,341 certified before 1980

Through 2000

    0 nr Swaen et al., 2004

UNITED STATES

US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states

Herbicides PCMRs Blair et al., 1993

Men

Whites (n = 119,648)

  49 1.3 (1.0–1.8)

Nonwhites (n = 11,446)

    4 1.0 (0.3–2.5)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Women

Whites (n = 2,400)

    1 1.2 (0.0–6.6)

Nonwhites (n = 2,066)

    0 0.0 (0.0–6.3)

White Male Residents of Iowa—bone cancer on death certificate, usual occupation: farmers vs not

Herbicides

> 20 yrs old when died 1971–1978—PMR

  56 1.1 (nr) Burmeister, 1981
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171) TCDD

Mortality

15-yr followup to 1991—men

Bertazzi et al., 1998

Zone R

    2 0.5 (0.1–2.0)

15-yr followup to 1991—women

Bertazzi et al., 1998

Zone B

    1 2.6 (0.3–19.4)

Zone R

    7 2.4 (1.0–5.7)
Ecological Study of Residents of Chapaevsk, Russia Dioxin Revich et al., 2001

Mortality—1995–1998 (SMR vs regional rates)

Men

    7 2.1 (0.9–4.4)

Women

    7 1.4 (0.6–3.0)
CASE-CONTROL STUDIES

International Case-Control Studies

European Multicentric study of association between occupational exposure and risk of bone sarcoma (96 cases, 35–69 yrs of age vs 2,632 hospital- and population-based controls

  18 Herbicides, pesticides 2.6 (1.5–4.6) Merletti et al., 2005

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CI, confidence interval; COI, chemical of interest; GI, gastrointestinal; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job-exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PMR, proportionate mortality ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; 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:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

No environmental studies with sufficiently specific characterization of exposure to the COIs and this health outcome have been published since Update 2010.

Biologic Plausibility

No animal studies have reported an increased incidence of bone and joint cancers after exposure to the COIs. The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Synthesis

The small amount of new data, in concert with the previous literature, summarized in Table 8-15 do not indicate an association between exposure to the COIs 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 COIs 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 6,110 men and 5,170 women would receive diagnoses of STS in the United States in 2012 and that about 2,050 men and 1,850 women would die from it (Siegel et al., 2012). The average annual incidence of STS is shown in Table 8-16.

TABLE 8-16 Average Annual Incidence (per 100,000) of Soft-Tissue Sarcoma (Including Malignant Neoplasms of the Heart) in the 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
Men 5.4 5.4 5.2 6.8 7.2 4.5 8.6 8.7 6.7
Women 4.5 4.4 6.3 5.4 5.2 7.7 7.0 7.6 3.4

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2005–2009 (NCI, 2013).

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

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).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was sufficient epidemiologic data to support an association between exposure to the COIs and STS. Additional information available to the committees responsible for subsequent updates has not changed that finding.

As seen with Hodgkin lymphoma and non-Hodgkin lymphoma, the available epidemiologic evidence suggests that phenoxy herbicides rather than TCDD may be associated with developing STS. Some of the strongest evidence of an association between STS and exposure to phenoxy herbicides comes from a series of case-control studies conducted in Sweden (Eriksson et al., 1981, 1990; Hardell and Eriksson, 1988; Hardell and Sandstrom, 1979). The studies, involving a total of 506 cases, show an association between STS and exposure to phenoxy herbicides, chlorophenols, or both. The VAO committee concluded that although those studies had been criticized, there is insufficient justification to discount the consistent pattern of increased risks and the clearly described and sound methods used. In addition, a reanalysis of the data by Hardell (1981) to evaluate the potential influence of recall bias and interviewer bias confirmed the original results. Hansen et al. (2007) conducted a historical-cohort study of male gardeners who were members of the Danish Union; cancer incidence was ascertained from 1975 to 2001. Birth date served as a surrogate for potential exposure to pesticides and herbicides; older cohorts represented higher exposure potential. Men born before 1915 were much more likely to die from STS, although this finding was based on only three cases. Reif et al. (1989) performed a series of case-control analyses in a sample of specified occupations and found a significant association between STS and having recently been employed as a forestry worker.

Those findings are supported by a significantly increased risk in a NIOSH study of production workers most highly exposed to TCDD (Fingerhut et al., 1991); Steenland et al. (1999) published an update of the NIOSH cohort, but STS was not among the outcomes evaluated. A similar increased risk was seen in the IARC cohort in deaths that occurred 10–19 years after first exposure (Kogevinas et al., 1992; Saracci et al., 1991) according to a fairly crude exposure classification. An updated and expanded study of the IARC cohort by Kogevinas et al. (1997) found a nonsignificantly increased risk of STS when followup was extended to 1992. Then NIOSH and IARC cohorts are among the largest and the most highly exposed occupational cohorts. Smaller studies of workers that are included in the multinational IARC cohort—Danish herbicide manufacturers (Lynge et al., 1985, 1993) and Dow production workers in Midland, Michigan, and New Zealand

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

(Collins et al., 2009a; ‘t Mannetje et al., 2005)—showed an increased risk of STS, but the results were commonly nonsignificant, possibly because of small samples (related to the relative rarity of STS in the population).

Several studies have reported on STS in relation to living near waste incinerators that release dioxin as a contaminant. Viel et al. (2000) reported on an investigation of apparent clusters of STS and non-Hodgkin lymphoma cases in the vicinity of a municipal solid waste incinerator in Doubs, France; Comba et al. (2003) and Costani et al. (2000) examined STS in the general population living near a chemical plant in the northern Italian city of Mantua; and Zambon et al. (2007) conducted a population-based case-control study in Venice, Italy, in an area that included 26 waste incinerators and other industrial plants. Each of those studies found a statistically significant excess of STS, but none showed any direct evidence of human exposure.

No cases of STS have been reported in Zones A and B in the Seveso cohort (Consonni et al., 2008); the incidence of STS was slightly increased in Zone R but not significantly (Pesatori et al., 2009). Veteran studies have not found a significant increase in STS. No increase was seen in Operation Ranch Hand veterans (AFHS, 1996, 2000; Michalek et al., 1990) or in VA studies of US Vietnam veterans (Breslin et al., 1986, 1988; Bullman et al., 1990; Watanabe and Kang, 1995; Watanabe et al., 1991). A slight increase in the incidence of STS was seen in Australian Air Force veterans compared with the Australian population but not in Army or Navy personnel (ADVA, 2005a), and no increase in mortality was seen in Australian veterans who served in any of the military branches (ADVA, 2005b). A nonsignificant increase in mortality from STS was also seen in state studies of veterans in Massachusetts, Michigan, and New York.

Table 8-17 summarizes the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran and Environmental Studies

No Vietnam-veteran studies or environmental studies of exposure to the COIs and STS have been published since Update 2010.

Occupational Studies

In an update of cancer incidence in 1985–2007 in 2,4-D production workers of Dow Chemical Company in Midland, Michigan, Burns et al. (2011) found a single case of cancer of the bone or soft tissue in the most restrictively defined cohort of exposed workers, with attendant nonsignificant estimates of exposure-related risk (SIR = 0.8, 95% CI 0.0–4.5). The numbers were too small to add substantially to the assessment of STS risk associated with exposure to Agent Orange–associated chemicals.

Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×

TABLE 8-17 Selected Epidemiologic Studies—Soft-Tissue Sarcoma (Shaded Entries Are New Information for This Update)

Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
VIETNAM VETERANS
US Vietnam Veterans

US Air Force Health Study—Ranch Hand veterans vs SEA veterans (unless otherwise noted)

All COIs

Mortality

Through 1987—Ranch Hand personnel (n = 1,261) vs SEA veterans (19,102)

    1 nr Michalek et al., 1990

US VA Proportionate Mortality Study—sample of deceased male Vietnam-era Army and Marine veterans who served 7/4/1965–3/1/1973

All COIs

1965–1984

Army, deployed (n = 24,145) vs nondeployed (n = 27,917)

  43 1.1 Watanabe et al., 1991

Served in I Corps (n = 6,668)

  10 0.9 (0.4–1.6) Bullman et al., 1990

Marine Corps, deployed (n = 5,501) vs nondeployed (n = 4,505)

  11 0.7 Watanabe et al., 1991

1965–1982

Breslin

Army, deployed (n = 19,708) vs nondeployed (n = 22,904)

  30 1.0 (0.8–1.2) et al.,1986, 1988

Marine Corps, deployed (n = 4,527) vs nondeployed (n = 3,781)

    8 0.7 (0.4–1.3)

US VA Study of Marine Post-service

All COIs

Mortality—sample of Marines serving 1967–1969, deployed (n = 10,716) vs nondeployed (n = 9,346)

Mortality, earlier of discharge or April 1973 through 1991

    0 nr Watanabe and Kang, 1995

US VA Case-control study

234 Vietnam veterans vs 13,496 Vietnam-era veterans

  86 0.8 (0.6–1.1) Kang et al., 1986
State Studies of US Vietnam Veterans

Massachusetts Vietnam-era veterans

Veterans aged 35–65 years in 1993—cases diagnosed 1988–1993 vs gastrointestinal cancers

  18 1.6 (0.5–5.4) Clapp, 1997

Diagnosed 1972–1983

    9 5.2 (2.4–11.1) Kogan and Clapp, 1988

Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs nondeployed

    8 1.1 (0.5–2.2) Visintainer et al., 1995
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

New York

—deployed vs nondeployed

    2 1.1 (0.2–6.7) Lawrence et al., 1985

281 STS cases with service in Vietnam vs live matched controls

  10 0.5 (0.2–1.3) Greenwald et al., 1984

923 White male Vietnam veterans with Wisconsin death certificate (1968–1978) vs proportions for Vietnam-era veterans

    4 nr Anderson et al., 1986
International Vietnam-Veteran Studies

Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters during 5/23/1962–7/1/1973 vs Australian population

All COIs

Incidence

All branches, 1982–2000

  35 1.0 (0.7–1.3) ADVA, 2005a

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)

Validation Study

Expected number of exposed cases AIHW, 1999
  14 27 (17–37)

Men

398 27 (17–37) CDVA, 1998a

Women

    2 0 (0–4) CDVA, 1998b

Mortality

All branches, return–2001

  12 0.8 (0.4–1.3) ADVA, 2005b

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)

1980–1994

    9 1.0 (0.4–1.8) CDVA, 1997a

Australian Conscripted Army National Service (18,940 deployed vs 24,642 nondeployed)

All COIs

Incidence

1982–2000

  10 1.0 (0.4–2.4) ADVA, 2005c

Mortality

1966–2001

    3 0.5 (0.1–2.0) ADVA, 2005c

1982–1994

    2 0.7 (0.6–4.5) CDVA, 1997b

1983–1985

    1 1.3 (0.1–20.0) Fett et al., 1987
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates

Mortality 1939–1992

Kogevinas et al., 1997

13,831 exposed to highly chlorinated PCDDs

    6 2.0 (0.8–4.4)

7,553 not exposed to highly chlorinated PCDDs

    2 1.4 (0.2–4.9)

Mortality 1955–1988 of 12,492 production workers and 5,898 sprayers exposed—13,482 in exposed subcohort

    4 2.0 (0.6–5.2) Saracci et al., 1991

Nested case-control study

IARC cohort (men and women)—incidence

Kogevinas et al., 1995

   Exposed to 2,4,5-T

    5 4.3 (0.7–26.3)

   Exposed to TCDD

    5 5.2 (0.9–31.9)

Mortality—IARC cohort (16,863 men and 1,527 women) 10–19 years since first exposure

    4 6.1 (1.7–15.5) Kogevinas et al., 1992

British MCPA Plant—Production 1947–1982 (n = 1,545) (included in IARC cohort) and spraying 1947–1972 (n = 2,561) (not included in IARC cohort)

MCPA

Mortality through 1983

    1 1.1 (0.0–5.9) Coggon et al., 1986

Danish Production Workers (3,390 men and 1,069 women involved in production of phenoxy herbicides unlikely to contain TCDD at 2 plants in 1947–1987) (in IARC cohort)

Dioxins, but TCDD unlikely; 2,4-D, 2,4-DP, MCPA, MCPP

Incidence 1943–1987 (men only)

    5 2.0 (0.7–4.8) Lynge, 1993

Incidence 1943–1982

Lynge, 1985

Men

    5 2.7 (0.9–6.3)

Women

    0 nr

Dutch production workers in Plant A (549 men exposed during production 1955–1985; 594 unexposed) (in IARC cohort)

Dioxins, 2,4,5-T, 2,4,5-TCP

Mortality 1955–1991

    0 nr Hooiveld et al., 1998

Mortality 1955–1985

    0 0.0 (0.0–18.4) Bueno de Mesquita et al., 1993
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Dutch production workers in Plant B (414 men exposed during production 1965–1986; 723 unexposed) (in IARC cohort)

2,4-D; MCPA; MCPP; highly chlorinated dioxins unlikely

Mortality 1965–1986

    0 0.0 (0.0–73.8) Bueno de Mesquita et al., 1993

German Production Workers—2,479 workers at 4 plants (in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

BASF Cleanup Workers from 1953 accident (n = 247); 114 with chloracne, 13 more with erythema; serum TCDD levels (not part of IARC)

Focus on TCDD

Incidence

1960–1992

Ott and Zober, 1996

TCDD < 0.1 μg/kg of body weight

    0 nr

TCDD 0.1–0.99 μg/kg of body weight

    0 nr

TCDD > 1 μg/kg of body weight

    0 nr

Mortality

Through 1987

90% CI Zober et al., 1990
    0 nr

German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) and women—no results (some additions to observed cancers over Manz et al., 1991) (in IARC cohort as of 1997)

Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP

Mortality 1952–1989—stats on men only, 1,184 (tables all for 1,148 men, not necessarily German nationals) vs national rates (also vs gas workers); same observation period as Becher et al., 1966

    0 nr Manz et al., 1991

New Zealand Phenoxy Herbicide Production Workers and Sprayers (1,599 men and women working any time in 1969–1988 at Dow plant in New Plymouth) (in IARC cohort)

Dioxins; 2,4-D; 2,4,5-T; MCPA; MCPB; 2,4,5-TCP; Picloram

Mortality 1969–2004

McBride et al., 2009a

Ever-exposed workers

    1 3.4 (0.1–19.5)

Never-exposed workers

    0 0.0 (0.0–34.9)

Production Workers (713 men and 100 women worked > 1 month in 1969–1984)

Mortality 1969–2000

    0 0.0 (0.0–19.3) ’t Mannetje et al., 2005
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Sprayers (697 men and 2 women registered any time 1973–1984)

Mortality 1973–2000

    1 4.3 (0.1–23.8) ’t Mannetje et al., 2005

NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)

Dioxins, phenoxy herbicides

Through 1993

    4 2.3 (0.6–5.9) Steenland et al., 1999

Chloracne subcohort (n = 608)

    3 11.3 (2.3–33.1)

Through 1987

    4 3.4 (0.9–8.7) Fingerhut et al., 1991

≥ 1-year exposure, ≥ 20-year latency

    3 9.2 (1.9–27.0)

All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, Michigan) (in IARC and NIOSH cohorts)

2,4,5-T; 2,4,5-TCP

1942–2003 (n = 1,615)

    4 4.1 (1.1–10.5) Collins et al., 2009a

1940–1994 (n = 2,187 men)

    2 2.4 (0.3–8.6) Bodner et al., 2003

All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, Washington, and Wichita, Kansas) and workers who made PCP and TCP at two additional plants (in Midland, Michigan, and Sauget, Illinois) (connective tissue and soft tissue)

2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011

1940–2005 (n = 2,122) (connective tissue and soft tissue)

    2 1.5 (0.2–5.5)

PCP and TCP (n = 720)

    1 2.3 (0.1–12.6)

PCP (no TCP) (n = 1,402)

    1 1.1 (0.0–6.4)

Dow 2,4-D Production Workers (1945–1982 in Midland, Michigan) (subset of all TCP-exposed workers)

2,4-D, lower chlorinated dioxins

Cancer incidence through 2007 in Dow workers (n = 1,256) vs comparisons from state cancer registries (n = 23,354) (Cohort 3) (bone, soft tissue)

    1 0.8 (0.0–4.5) Burns et al., 2011

Through 1982 (n = 878)

    0 nr Bond et al., 1988
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Dow PCP Production Workers (1937–1989 in Midland, Michigan) (not in IARC and NIOSH cohorts)

Low chlorinated dioxins, 2,4-D

Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP)

    1 2.2 (0.0–12.1) Collins et al., 2009b

Mortality 1940–1989 (n = 770)

    0 Expected number of exposed cases Ramlow et al., 1996
0.2
OCCUPATIONAL—PAPER AND PULP TCDD
WORKERS

IARC cohort of pulp and paper workers—60,468 workers from 11 countries, TCDD among 27 agents assessed by JEM

McLean et al., 2006

Exposure to nonvolatile organochlorine compounds

Never

    8 1.2 (0.5–2.4)

Ever

    4 0.8 (0.2–2.0)

Danish paper-mill workers

Rix et al., 1998

Men employed in sorting and packing

  12 1.2 (0.6–2.0)

Women employed in sorting and packing

    8 4.0 (1.7–7.8)
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)

CANADA

Sawmill Workers in British Columbia—23,829 workers for ≥ 1 year at 11 mills using chlorophenates 1940–1985

Chlorophenates, not TCDD

Incidence 1969–1989

  11 1.0 (0.6–1.7) Hertzman et al., 1997

Mortality 1950–1989

    6 1.2 (0.5–2.3)

DENMARK

Danish gardeners—incidence from 3,156 male and 859 female gardeners

Hansen et al., 2007

25-year followup (1975–2001)

Herbicides

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)

10-year followup (1975–1984) of male gardeners

    3 5.3 (1.1–15.4) Hansen et al., 1992

ITALIAN Licensed Pesticide Users—male farmers in southern Piedmont licensed 1970–1974

Mortality 1970–1986 (n = 23,401)

    2 1.0 (0.1–3.5) Torchio et al., 1994
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

NEW ZEALAND National Cancer Registry (1980–1984)—case-control study of 142 incident STS cases vs remainder of 19,904 men with any incident cancer

Forestry workers (n = 134)

Herbicides Reif et al., 1989

Aged 20–59

    4 3.2 (1.2–9.0)

Aged ≥ 60

    0

SWEDEN

Swedish pesticide applicators—incidence (n = 20,245)

    7 99% CI 0.9 (0.8–1.1) Wiklund et al., 1988, 1989a

354,620 Swedish agricultural and forestry workers identified from 1960 census, followed 1961–1979; compared to reference population

331 0.9 (0.8–1.0) Wiklund and Holm, 1986

Incident STS cases 1961–1973 with agriculture as economic activity in 1960 census (connective tissue and muscle)

162 1.1 (0.9–1.3) Wiklund, 1983

UNITED STATES

US farmers—usual occupation of farmer and industry of agriculture on death certificates 1984–1988 from 23 states

Herbicides PCMRs Blair et al., 1993

Men

Whites (n = 119,648)

  98 0.9 (0.8–1.1)

Nonwhites (n = 11,446)

  10 1.5 (0.7–2.8)

Women

Whites (n = 2,400)

    3 1.2 (0.2–3.5)

Nonwhites (n = 2,066)

    0 0.0 (0.0–1.9)

US Agricultural Health Study—prospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993–1997; followups with CATIs 1999–2003 and 2005–2010

Phenoxy herbicides

Incidence

Enrollment through 2002

Alavanja et al., 2005

Private applicators

  10 0.7 (0.3–1.2)

Spouses of private applicators (> 99% women)

    3 0.5 (0.1–1.4)

Commercial applicators

nr 0.0 (0.0–3.8)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Mortality

Enrollment through 2007, vs state rates (connective tissue)

Waggoner et al., 2011

Applicators (n = 1,641)

    9 0.7 (0.3–1.5)

Spouses (n = 676)

    6 1.0 (0.4–2.2)

Enrollment through 2000, vs state rates

Blair et al., 2005a

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)

US Department of Agriculture Workers—nested case-control study of white men dying 1970–1979 of STS

Herbicides

USDA forest and soil

    2 1.0 (0.1–3.6) Alavanja et al., 1989

Florida Pesticide Applicators licensed 1965–1966 (n = 3,827)—mortality through 1976

Herbicides Blair et al., 1983

Any pesticide (dose-response by length of licensure)

    0 nr
ENVIRONMENTAL
Seveso, Italy Residential Cohort—Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group) (ICD-9 171) TCDD

Incidence

20-yr followup to 1996—men and women

Zone A

    0 nr Pesatori et al., 2009

Zone B

    0 nr

Zone R

    9 1.3 (0.6–2.7)

10-yr followup to 1991—men

Bertazzi et al., 1993;

Zone A

    0 nr

Zone B

    0 nr Pesatori et al., 1992

Zone R

    6 2.8 (1.0–7.3)

10-yr followup to 1991—women

Bertazzi et al., 1993;

Zone A

    0 nr

Zone B

    0 nr Pesatori et al., 1992

Zone R

    2 1.6 (0.3–7.4)

Mortality

25-yr followup to 2001—men and women

Consonni et al., 2008

Zone A

    0 nr

Zone B

    0 nr

Zone R

    4 0.8 (0.3–2.1)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

20-yr followup to 1996

Bertazzi et al., 2001

Zone A—men and women

    0 nr

Zone B—men and women

    0 nr

Zones A and B—men

    0 nr

Zones A and B—women

    0 nr

15-yr followup to 1991—men

Bertazzi et al., 1997, 1998

Zone A

nr

Zone B

    0 nr

Zone R

    4 2.1 (0.7–6.5)

15-yr followup to 1991—women

Bertazzi et al., 1997, 1998

Zone A

nr

Zone B

    0 nr

Zone R

    0 nr

10-yr followup to 1986—men

Bertazzi et al., 1989a

Zone A, B, R

    2 5.4 (0.8–38.6)

Zone R

    2 6.3 (0.9–45.0) Bertazzi et al., 1989b

10-yr followup to 1986—women

Bertazzi et al., 1989a

Zone A, B, R

    1 2.0 (0.2–1.9)

Zone B

    1 17.0 (1.8–163.6) Bertazzi et al., 1989b

FINLAND

Finnish community exposed to chlorophenol contamination (men and women)

    6 Chlorophenol 1.6 (0.7–3.5) Lampi et al., 1992

FRANCE

Residents near French solid-waste incinerator—incidence

Dioxin Viel et al., 2000

Spatial cluster

  45 1.4 (p = 0.004)

1994–1995

  12 3.4 (p = 0.008)

ITALY

Italian rice growers

Chlorophenoxy acids, chlorophenols Gambini et al., 1997
    1 4.0 (0.1–22.3)

NEW ZEALAND

Residents of New Plymouth Territorial Authority, New Zealand near plant manufacturing 2,4,5-T in 1962–1987

2,4,5-T Read et al., 2007

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)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Mortality

  27 1.2 (0.8–1.8)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)

SWEDEN

Swedish fishermen (high consumption of fish with persistent organochlorines)

Organochlorine compounds Svensson et al., 1995

Incidence

East coast

    0 0.0 (0.0–2.6)

West coast

    3 0.5 (0.1–1.4)

Mortality

East coast

    0 nr

West coast

    0 nr
CASE-CONTROL STUDIES

US Case-Control Studies

Kansas residents–duration and frequency of herbicide use—incidence

Phenoxy herbicides, 2.4-D Hoar et al., 1986

All farmers

  95 1.0 (0.7–1.6)

Farm-use of herbicides

  22 0.9 (0.5–1.6)

Washington state residents—incidence (1983–1985)

Phenoxy herbicides, chlorinated phenols Woods et al., 1987

High phenoxy exposure

nr 0.9 (0.4–1.9)

Self-reported chloracne

nr 3.3 (0.8–14.0)

International Case-Control Studies

Australian residents in Victorian Cancer Registry (1982–1987)

Phenoxy compounds Smith and Christophers, 1992
  30 1.0 (0.3–3.1)

British agricultural workers

Herbicides Balarajan and Acheson, 1984

Overall

  42 1.7 (1.0–2.9)

Under 75 yrs old

  33 1.4 (0.8–2.6)
Suggested Citation:"8 Cancer." Institute of Medicine. 2014. Veterans and Agent Orange: Update 2012. Washington, DC: The National Academies Press. doi: 10.17226/18395.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference

Cross-Canada Study of Pesticides and Health—Men (≥ 19 yrs of age) diagnosed September 1991–December 1994 (n = 357) vs matched population-based controls (n = 1,506); exposure to:

Pahwa et al., 2011

Phenoxy herbicides

80 vs 321 1.1 (0.8–1.5)

2,4-D

69 vs 293 1.0 (0.7–1.4)

Mecoprop

26 vs 81 1.3 (0.8–2.2)

MCPA

13 vs 46 1.1 (0.6–2.2)

Diclofop-methyl

8 vs 25 1.2 (0.4–2.9)

Cross-Canada Study of Pesticides and Health—Men (≥ 19 yrs of age) diagnosed September 1991–December 1994 (n = 357) vs matched population-based controls (n = 1,506); exposure to:

Phenoxy herbicides Pahwa et al., 2006

Any phenoxyherbicide

80 vs 321 1.1 (0.7–1.5)

2,4-D

69 vs 293 1.0 (0.6–1.5)

Mecoprop

26 vs 81 1.0 (0.5–1.9)

MCPA

13 vs 46 1.1 (0.5–2.2)

Finnish STS patients vs controls within quintiles based on TEQ in subcutaneous fat—incidence

110 Dioxin Tuomisto et al., 2004

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)

Italy

Population-based Veneto Tumour Registry, Italy, average exposure based on duration and distance of residence from 33 industrial sources—incidence

Dioxin Zambon et al., 2007

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