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Veterans and Agent Orange: Update 2014 (2016)

Chapter: 8 Cancers

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Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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8

Cancers

Chapter Overview

Based on new evidence and a review of prior studies, the committee for Update 2014 determined that epidemiologic results concerning an association between exposure to the chemicals of interest (COIs) and bladder cancer had accrued to now constitute limited or suggestive evidence of an association. No other new significant associations between the relevant exposures and particular types of cancer were found. Aside from the conclusion concerning bladder cancer, current evidence supports the findings of earlier updates. Thus the current findings on cancer can be summarized as follows:

  • There is sufficient evidence of an association with the COIs and soft tissue sarcomas and B-cell lymphomas (Hodgkin lymphoma, non-Hodgkin lymphomas, chronic lymphocytic leukemia, hairy cell leukemia).
  • There is limited or suggestive evidence of an association between the COIs and bladder cancer; laryngeal cancer; cancers of the lung, bronchus, or trachea; prostate cancer; multiple myeloma, and amyloid light-chain (AL) amyloidosis.
  • There is inadequate or insufficient evidence to determine whether there is an association between the COIs and any other specific type of cancer.

Cancers are the second-leading cause of death in the United States. However, among men 60–75 years old, the group that includes most Vietnam veterans, the risk of dying from cancer exceeds the risk of dying from heart disease, the leading cause of death in the United States, and it does not fall to second place

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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until after the age of 75 years (Heron et al., 2009). About 589,430 Americans of all ages were expected to die from cancer in 2015—more than 1,500 per day. In the United States, one-fourth of all deaths are from cancer (Siegel et al., 2015).

This chapter summarizes—and presents conclusions about—the strength of the evidence from epidemiologic studies regarding associations between exposure to the COIs—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), picloram, and cacodylic acid—and various types of cancer. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals (DLCs) informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners of DLCs. 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 because mono-ortho PCBs typically contribute less than 10 percent to total TEQs, based on the World Health Organization (WHO) revised toxicity equivalency factors (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, then 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 to provide an 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 the risk of cancer, the approach used to assess the exposure of study subjects is of critical importance in determining the overall relevance and usefulness of findings. As noted in Chapters 3 and 6, there is great variation in the detail and the accuracy of exposure assessments 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 an individual’s presence in a locale when herbicides were used. As noted in Chapter 2, an 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 the 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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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reported are for 2008–2012 and are from the most recent dataset available (NCI, 2015). Incidence data are given for all races combined and also separately for blacks and whites. The age range of 60–74 years now includes about 80 percent of Vietnam-era veterans, and the incidences are presented for three 5-year age groups: 60–64 years, 65–69 years, and 70–74 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 70–74 years old as in men 60–64 years old and about 75 percent higher in blacks 60–64 years old than in whites in the same age group (NCI, 2015). 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 Orange1 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); Update 2010 (IOM, 2011a); and Update 2012 (IOM, 2014). That is followed by a discussion of the most recent scientific literature, a discussion of biologic plausibility, and a synthesis of the material reviewed. When it is appropriate, the literature is discussed by exposure type (service in Vietnam, occupational exposure, or environmental exposure). Each section ends with the committee’s conclusion regarding the strength of the evidence from epidemiologic studies. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

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

Information on biologic mechanisms by which exposure to TCDD could contribute to the generic (rather than tissue-specific or organ-specific) carcinogenic potential of the other COIs is summarized in Chapter 4. It distills toxicologic

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1Despite loose usage of “Agent Orange” by many people, in numerous publications, and even in the title of this series, this committee uses “herbicides” to refer to the full range of herbicide exposures experienced in Vietnam, while “Agent Orange” is reserved for a specific one of the mixtures sprayed in Vietnam.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 through 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 the 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 in the summary of this report, but the point is not reiterated for every health outcome addressed.

ORGANIZATION OF CANCER GROUPS

For Update 2006, the committee developed a system for addressing cancer types to clarify how specific cancer diagnoses had been 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 the 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, 9th 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 represents a marked change from the previous four revisions that evolved into ICD-9. ICD-9 was in effect from 1979 to 1998; because ICD-9 is the version most prominent in the research reviewed in this series, it 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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 WHO’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. The 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. A 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 by the committee that speak 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 in cultured cells.

Concerning 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 a question 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 findings on genotoxic effects in assays conducted primarily in vitro. The results of such studies indicate that 2,4-D and 2,4,5-T are genotoxic only at very high concentrations.

There is 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), bladder (Arnold et al., 2006; Cohen et al., 2007b; Wang et al., 2009; Wei et al., 2002; Yamamoto et al., 1995), liver, and thyroid gland (Yamamoto et al., 1995). Treatment with cacodylic acid induced the formation of neoplasms of the lung when administered to mouse strains that are genetically susceptible to developing these tumors (Hayashi et al., 1998; Yamanaka et al., 2009). 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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

as a tumor-promoter with respect to lung cancer (Yamanaka et al., 1996). These studies are further discussed in Chapter 4.

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 TCDD-induced cancers (Androutsopoulos et al., 2009; Barouki and Coumoul, 2010; Dietrich and Kaina, 2010; Murray et al., 2014; Ray and Swanson, 2009; Rysavy et al., 2013; Tsay et al., 2013). On the basis of these data, the biologic plausibility of an association between TCDD exposure and cancer has been firmly established in a mechanistic sense, and TCDD is considered a nongenotoxic carcinogen, as reviewed by Hernández et al. (2009). TCDD can disrupt circadian rhythms via the AHR, and chronic disruption of circadian rhythms is associated with an increased incidence of cancer, suggesting a potential additional pathway by which TCDD increases cancer risk (Wang C et al., 2014; Xu et al., 2013).

Studies in laboratory animals in which only TCDD has been administered have shown 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 increases 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. Work with a mouse lung cancer model suggests that in addition to increasing cell division, the tumor-promoting activity of TCDD includes decreasing apoptosis (Chen et al., 2014a). 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, in most cases via its interaction with AHR (Murray et al., 2014; Rysavy et al., 2013). Thus, it may be that TCDD increases the incidence or progression of human cancers through the interplay of multiple cellular mechanisms. Tissue-specific protective cellular mechanisms may also be important to the response to TCDD and may 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 because it increases the incidence of tumors, including tumors at sites distant from the site of treatment, at doses well below the maximum tolerated dose (Rysavy et al., 2013). TCDD has frequently been characterized as a nongenotoxic carcinogen. TCDD is non-mutagenic because it does not produce

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

changes in DNA sequences, but because of the oxidative stress it produces, TCDD does have some genotoxic potential. This may contribute to its recognized activity as 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 two orders of magnitude more potent than the “classic” promoter tetradecanoyl phorbol acetate (TPA) and that its skin-tumor promotion depends on the AHR.

A number of potential pathways for TCDD carcinogenesis have been proposed. TCDD may contribute to tumor progression by inhibiting p53 regulation (phosphorylation and acetylation) triggered by genotoxic agents through the increased expression of the metastasis marker AGR2 (Ambolet-Camoit et al., 2010) and through a functional interaction between the AHR and FHL2—the “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 finding supports the hypothesis that TCDD acts as a tumor promoter by preventing initiated cells from undergoing apoptosis (Chen et al., 2014b; Chopra et al., 2009). AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the cytokine interleukin-6, which has tumor-promoting effects in numerous tissues—including breast, prostate, and ovary—and opens up the possibility that TCDD would promote carcinogenesis in these and possibly 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, perhaps via an epigenetic effect of interfering with DNA methylation levels (Davis and Uthus, 2004; Williams, 2012). Recent work has shown an interaction between the AHR and the ADM (adrenomedullin) oncogene in cell lines and lung tissue (Portal-Nunez et al., 2012), and AHR repression experiments in gastric and head and neck cancers suggest that AHR expression leads to increased cancer cell growth and invasion (DiNatale et al., 2012; Yin et al., 2013)

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 a marker of DNA damage. The induction of cytochrome P4501A1 (CYP1A1) in these cells 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) and involves AHR-dependent uncoupling of mitochondrial respiration (Senft et al., 2002). Mitochondrial reactive-oxygen

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

production depends on the AHR. Other than these observations of 8-OHdG formation and oxidative stress, there is little evidence that TCDD is genotoxic, and it appears likely that some of its mechanisms of action may involve epigenetic modifications 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 these compounds (Wen et al., 2008). Clastogenic genetic disturbances arising as a consequence of confirmed exposure to herbicides were determined by analyzing sister-chromatid exchanges (SCEs) in lymphocytes from a group of 24 New Zealand 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 group of veterans and the control group. These Vietnam War veterans also had a much higher proportion of cells with SCE frequencies above the 95th percentile than the controls (11.0 percent and 0.07 percent, respectively). A study of SCE frequencies in blood samples taken from Vietnamese women from high and moderate TCDD-sprayed areas also showed increased SCE frequencies of 2.40 per cell and 2.19 per cell, respectively, for these women compared with Vietnamese women from unexposed areas (1.48 per cell, p < 0.001) (Suzuki et al., 2014).

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 mechanistic mode-of-action data. Although the specific mechanisms by which dioxin causes cancer remain to be definitively established, the intracellular factors and mechanistic pathways involved in dioxin’s cancer-promoting activity all have parallels in both 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. The International Agency on Cancer Research (IARC) has classified TCDD in group 1 as carcinogenic to humans and found the strongest evidence for carcinogenicity for all cancers combined and a positive association between exposure to TCDD and soft-tissue sarcomas, non-Hodgkin lymphomas, and lung cancer (IARC, 2012b). The combination of a positive association with TCDD exposure for these specific cancer sites no doubt contributes to the association with all cancers combined being the strongest, as reports of increased risks for several other cancers in TCDD-exposed workers and in the TCDD-exposed population in Seveso were only sporadic and not fully consistent.

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 carcinogenic potential

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

contributes to an 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 the presence or 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 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 (non-mutational) 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 more than 40 years ago, carcinogens were categorized as initiators, those capable of causing an initial genetic insult to the target tissue, and promoters, those capable of promoting the growth of initiated tumor cells, generally through non-mutational events. Some carcinogens, such as those found in tobacco smoke, were considered “whole carcinogens” or “complete 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 the overall susceptibility of various organs to cancer development and in organ-specific responses to particular putative carcinogens. Therefore, judgments

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

about the “general” carcinogenicity of a chemical in humans are based heavily on the results of epidemiologic studies, especially on the issue of whether there is evidence of an 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 IARC, which has determined that TCDD is a category 1 “known human carcinogen” (Baan et al., 2009; IARC, 2012b); with the US Environmental Protection Agency (EPA), which has concluded that TCDD is “likely to be carcinogenic to humans”2; 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: Those organizations focus on anticipating hazards in order to minimize future exposure, whereas this committee focuses on risk after exposure. Furthermore, the 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 not provided in the report of a cohort study, a statistical test for an increase in all cancers is not meaningless, but it is usually less scientifically supportable than analyses based on specific sites, for which more substantial biologically based hypotheses can often be developed. The size of a cohort and the length of the observation period often constrain the number of cancer cases that are observed and which specific types of cancer have enough observed cases to permit analysis. For instance, an analysis of the cumulative results on diabetes and cancers 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 herbicides increases the risk of every variety of cancer, but rather as an indication that the agent is carcinogenic to humans. The committee acknowledges that the results of the highly stratified analyses conducted suggest that the incidence of some cancers did increase in the Ranch Hand subjects, but it views the “all cancers” results as a conglomeration of information on specific cancers—most important, melanoma and prostate cancer, for which elevated results have been published (Akhtar et al., 2004; Pavuk et al., 2006)—and as meriting individual longitudinal analysis to resolve outstanding questions.

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2See http://www.epa.gov/ttn/atw/hlthef/dioxin.html, updated January 2000, accessed September 21, 2013.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

The literature search for this update identified several publications on populations with relevant exposures that included risk statistics for overall cancer incidence (McBride et al., 2013; Yi and Ohrr, 2014) or mortality (Kang et al., 2014; Lin et al., 2012; Wang et al., 2013), which were all somewhat elevated, although not necessarily significantly so. The most substantial elevation (standardized mortality ratio [SMR] = 1.70, 95% confidence interval [CI] 1.35–2.13) was seen among workers at a Chinese automobile foundry factory, where TCDD was only one of several toxic agents, but there was no consistent indication of elevated cancer risk associated with exposure to the VAO COIs specifically (Wang et al., 2013).

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 era 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 percent. A follow-up 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; that study found mortality among Vietnam veterans to be 11.7 percent, which may be fairly comparable with that of their American fellows. The recent update on mortality among female US Vietnam veterans (Kang et al., 2014) stated that at the end of 2010, 20.2 percent of the deployed women in the cohort had died compared to 24.6 percent of those who remained in the United States. Because of considerable differences in mortality profiles for men and women, however, this does not provide a particularly accurate estimate for the large majority of American Vietnam veterans who are male.

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 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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 follow-up 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 Koutros et al. (2010a); however, 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, 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 no 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 CANCERS

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). Although the above cancers are classified together in the same category, the epidemiological risk factors for cancers that occur in the oral cavity and pharynx are very different from the risk factors for cancer of the nasopharynx. We now recognize that, in addition to cigarette smoking and alcohol consumption, infection with human papilloma virus (HPV), particularly alpha HPV16, is an important risk factor for squamous-cell carcinoma of the head and neck, and risk estimates are highest for cancers of the base of the tongue, tonsils, and oropharynx (collectively classified as oropharyngeal cancers) (Gillison et al. 2000; Marur et al., 2010; Oliveira et al., 2012).

The American Cancer Society (ACS) estimated that about 45,780 men and women would receive diagnoses of oral cavity or pharyngeal cancers in the United States in 2015 and that 8,650 men and women would die from these cancers (Siegel et al., 2015). Almost 90 percent 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 incidence rates reported in Table 8-1 show that men are at greater risk than women to be diagnosed with these cancers and that the incidence rates increase with age. However, because of the small number of cases, incidence rates should

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 8-1 Average Annual Incidence (per 100,000) of Nasal, Oral Cavity, and Pharyngeal Cancers in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Nose, Nasal Cavity, and Middle Ear:
Men 2.3 2.3 2.2 2.8 2.8 2.2 3.8 3.8 3.8
Women 1.3 1.3 0.8 1.5 1.5 1.3 2.1 2.2 0.9
Oral Cavity and Pharynx:
Men 53.5 55.9 52.3 59.8 62.2 59.4 61.5 64.5 53.6
Women 15.9 16.7 13.5 19.8 21.0 16.4 24.2 25.7 18.0

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

be interpreted with caution. Tobacco and alcohol use are well-established risk factors and also contribute synergistically to the incidence of oral cavity and pharyngeal cancers, and, as mentioned above, infection with HPV is a major risk factor for oropharygeal cancers (Hashibe et al., 2007, 2009; Kreimer et al., 2013; Michaud et al., 2014; Oliveira et al., 2012). Ecological studies in the United States have shown that between 2001 and 2010 the incidence rates for cancers of the oral cavity went down (possibly because of decreasing prevalence of smoking), whereas incidence rates for oropharyngeal cancers have increased annually by 2.9 percent, which has been attributed to HPV infection (Chaturvedi et al., 2011).

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), as well as infection with Epstein–Barr virus.

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 cavity, 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, Update 2010, and Update 2012 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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

to the COIs and tonsil cancer. No new published studies have offered any important additional insight into this specific 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 potential mechanistic hypothesis explaining an excess of these cancers in Vietnam veterans: Immune alterations associated with herbicide 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 carcinomas of these tissues. The present committee strongly reiterates the 2006, 2008, 2010, and 2012 recommendation that VA develop a strategy that uses existing databases to evaluate tonsil cancer in Vietnam-era veterans.

In Update 2010, Cypel and Kang (2010) reported on a follow-up study of Vietnam-era Army Chemical Corps (ACC) veterans, comparing mortality through 2005 in ACC veterans by Vietnam service. They reported a non-significant increase in oral cavity and pharyngeal cancers in the deployed cohort compared with cases in the non-deployed 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 non-significant excess in mortality from buccal cavity and pharyngeal cancers, but there were no deaths from nasopharyngeal cancers in either group.

In Update 2012, several occupational cohort studies reported on cancers of the oral cavity or pharynx, but the evidence was inconsistent. Studies of workers at Dow’s plant in Midland, Michigan, and in the NIOSH pentachlorophenol (PCP) cohort reported no increases in incidence (Burns CJ et al., 2011) or mortality (Ruder and Yiin, 2011) from oral cavity and pharyngeal cancers. By contrast, Manuwald et al. (2012) reported significantly increased mortality from cancers of the lip, oral cavity, or pharynx (SMR = 2.17, 95% CI 1.08–3.87) in a cohort of male and female chemical plant workers versus Hamburg’s general population.

The existing evidence from all published studies conducted among Vietnam veterans or various occupational cohorts reporting on the incidence of or mortality from cancers of the nose, oral cavity, or pharynx is largely inconclusive. The majority of these studies have reported no association or non-significant modest excesses in risk, while not characterizing exposure as specifically as needed for the committee’s decision making. In addition, the small numbers of oral, nasal, or pharyngeal cancer cases reported, in combination with a general lack of information on the smoking and drinking habits or HPV exposure status of the study participants, limit the interpretation of the data.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Studies evaluated previously and in the present report are summarized in Table 8-2.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

There have been no studies of US Vietnam veterans evaluating exposure to the COIs and oral, nasal, or pharyngeal cancers since Update 2012. However, two recent cohort studies of Vietnam War veterans (a majority of them males) from New Zealand and Korea reported on cancer incidence and mortality for cancers of the oral cavity, nasal cavity, and pharynx.

McBride and colleagues (2013) followed 2,783 male veterans from New Zealand who served in Vietnam from 1964 through 1972 for cancer incidence and mortality from 1988 through 2008 and compared them with the general population of New Zealand. With regard to incident head and neck cancers (n = 19), which by their definition excluded cancers of the larynx and esophagus, there was a modestly increased risk, albeit not a statistically significant one (standardized incidence ratio [SIR] = 1.34, 95% CI 0.81–2.09). A similar increase (SIR = 1.32, 95% CI 0.78–2.08) was observed when the analysis was restricted to cancers of the oral cavity, pharynx, and larynx (excluding cancers of lip, sinus cavities, or salivary glands) (n = 18). There were five incident cases and two deaths from laryngeal cancer in this cohort. Using the same groupings for cancer mortality, McBride et al. (2013) reported substantial and significant increased risks of death from head and neck cancers (SMR = 2.20, 95% CI 1.09–3.93) and from cancers of the oral cavity, pharynx, and larynx (SMR = 2.13, 95% CI 1.06–3.81) among the New Zealand Vietnam veterans based on 11 deaths in each grouping. McBride et al. (2013) did not report on nasal cancer separately.

Although the follow-up of the cohort of New Zealand Vietnam veterans was relatively long (20 years), the study did not have information on cancer incidence and mortality in the time period immediately after the service. In addition, information on potential confounding factors including smoking, drinking habits, and HPV status was not available, which limits the interpretation of the data, particularly regarding incident cancers. However, the greater than two-fold excess risks of mortality from head and neck cancers as well as from cancers of the oral cavity, pharynx, and larynx cannot be completely attributed to confounding by smoking, because excess risks were not found in this cohort for deaths from other smoking-related diseases such as lung cancer, chronic obstructive pulmonary disease (COPD), or coronary heart disease. Finally, because of the small sample size, the study did not report on tonsillar cancers specifically.

Several recent publications examined incidence (Yi, 2013; Yi and Ohrr, 2014) and mortality (Yi et al., 2014b) for cancers of the oral cavity, nasal cavity, and pharynx in the Korean Veterans Health Study, a large prospective cohort of

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-2 Selected Epidemiologic Studies—Oral, Nasal, and Pharyngeal 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 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 non-deployed) serving during Vietnam era (July 1, 1965–March 28, 1973)      
Mortality—Oral cavity and pharyngeal cancer      
Through 2005     Cypel and Kang, 2010
Deployed (2,872) vs non-deployed (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 non-deployed   All COIs  
Mortality      
1965–2000 (ICD-9 140–149) 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 non-deployed (lip, oral cavity, pharynx) 12 1.0 (0.5–1.8) Visintainer et al., 1995
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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 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, 2005b
Navy 56 1.6 (1.1–2.0)  
Army 174 1.6 (1.3–1.8)  
Air Force 17 0.9 (0.5–1.5)  
Mortality      
All branches, return–2001     ADVA, 2005a
Head and neck 101 1.4 (1.2–1.7)  
Navy 22 1.5 (0.9–2.1)  
Army 69 1.5 (1.1–1.8)  
Air Force 9 1.1 (0.5–2.0)  
Nasal 3 0.8 (0.2–2.2)  
1980–1994     CDVA, 1997a
Lip (ICD-9 140) 0 nr  
Nasopharyngeal cancer (ICD-9 147) 2 0.5 (0.1–1.7)  
Nasal cavities (ICD-9 160) 2 1.2 (0.1–4.1)  
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence      
1982–2000     ADVA, 2005c
Head and neck 44 2.0 (1.2–3.4)  
Mortality      
1966–2001     ADVA, 2005c
Head and neck 16 1.8 (0.8–4.3)  
Nasal 0 0.0 (0.0–48.2)  
1982–1994     CDVA, 1997b
Nasopharyngeal cancer (ICD-9 147) 1 1.3 (0.0– > 10)  
Nasal cavities (ICD-9 160) 0 0.0 (0.0– > 10)  
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008)      
Head and neck 19 1.3 (0.8–2.1)  
Oral cavity, pharynx and larynx 18 1.3 (0.8–2.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality (1988–2008)      
Head and neck 11 2.2 (1.1–3.9)  
Oral cavity, pharynx and larynx 11 2.1 (1.1–3.8)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)     Yi and Ohrr, 2014
Lip (C00) 1 vs 2 1.4 (0.1–26.2)
Tongue (C01–C02) 17 vs 14 1.0 (0.5–2.2)  
Mouth (C03–C06) 23 vs 9 2.5 (1.1–5.7)  
Salivary gland (C07–C08) 13 vs 2 7.0 (1.5–32.3)  
Tonsil (C09) 10 vs 12 0.9 (0.4–2.2)  
Other oropharynx (C10) 6 vs 3 2.0 (0.5–8.2)  
Nasopharynx (C11) 21vs 29 0.7 (0.4–1.2)  
Hypopharynx (C12–C13) 18 vs 12 1.0 (0.5–2.2)  
Nose, sinuses, etc. (C30–C31) 11 vs 8 1.8 (0.7–4.7)  
Mortality (1992–2005)     Yi et al., 2014b
Oral cavity cancer (C00–C14)      
Categorized high vs low 45 vs 37 1.1 (0.7–1.7)  
HR per unit of log EOI (n = 180,639) 82 1.1 (0.9–1.2)  
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 PCDDs 22 1.3 (0.8–2.0)  
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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 et al., 1986
Lip (ICD-9 140) 0 nr
Tongue (ICD-9 141) 1 1.1 (0.0–6.2)  
Pharynx (ICD-9 146–149) 1 0.5 (0.0–3.0)  
Nose (ICD-9 160) 3 4.9 (1.0–14.4)  
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 et al., 1998
All working anytime in 1955–1985 1 2.3 (0.1–12.4)
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 mo 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 mo 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 mo 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  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality      
Through 1987   90% CI Zober et al., 1990
Buccal cavity, pharynx 1 4.8 (0.3–22.9)
Squamous-cell carcinoma of tonsil 1 nr  
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo 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 et al., 2012
Men 9 2.0 (0.9–3.8)
Women 2 3.4 (0.4–12.5)  
Mortalilty 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 (ICD-9)     ’t Mannetje et al., 2005
2 2.8 (0.3–9.9)
Lip (140) 0 nr  
Mouth (141–145) 2 5.4 (0.7–20.0)  
Oropharynx (146) 0 nr  
Nasopharynx (147) 0 0.0 (0.0–41.8)  
Hypopharynx, other (148–149) 0 nr  
Phenoxy herbicide sprayers (> 99% men) 1 1.0 (0.0–5.7) ’t Mannetje et al., 2005
Lip (140) 0 nr
Mouth (141–145) 0 0.0 (0.0–7.5)  
Oropharynx (146) 0 nr  
Nasopharynx (147) 1 8.3 (0.2–46.3)  
Hypopharynx, other (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, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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, MI) (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 CJ 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., 1998
Buccal cavity (ICD-7 140–144)      
Men 24 1.0 (0.7–1.5)  
Women 4 1.5 (0.4–3.8)  
Pharynx (ICD-7 145–149)      
Men 15 2.0 (1.1–3.3)  
Women 2 2.1 (0.2–7.6)  
Tonsil cancers among pharyngeal cancers 11 nr  
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
  90% CI  
Buccal cavity, pharynx (ICD-7 140–148) 1 0.1 (0.0–0.7)  
Nasal (ICD-7 160) 0 nr  
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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 follow-up (1975–1984) reported in Hansen et al. (1992)      
6 1.1 (0.4–2.5)  
25-yr follow-up (1975–2001)      
Born before 1915 (high exposure) 3 0.7 (0.2–2.3)  
Born 1915–1934 (medium exposure) 6 0.7 (0.3–1.4)  
Born after 1934 (low exposure) 0 0.0 (0.0–1.0)  
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
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
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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     Wiklund, 1983
(male, female)   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 et al., 2004
Nose 0
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  
Women      
Whites (n = 2,400) 1 12.2 (0.2–68.0)  
Nonwhites (n = 2,066) 0 0.0 (0.0–103.6)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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; follow-ups 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     Alavanja et al., 2005
Private applicators (men and women) 66 0.7 (0.5–0.8)
Lip 25 1.4 (0.9–2.1)  
Spouses of private applicators (> 99% women) 14 0.7 (0.4–1.2)  
Lip 2 1.4 (0.2–5.1)  
Commercial applicators 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) 5 0.3 (0.1–0.7)  
Spouses of private applicators (> 99% women) 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)   TCDD  
Incidence      
10-yr follow-up to 1991—men     Bertazzi et al., 1993
Buccal cavity (140–149)    
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Zone B 6 1.7 (0.8–3.9)  
Zone R 28 1.2 (0.8–1.7)  
Nose, nasal cavities (160)      
Zone R 0 nr  
10-yr follow-up to 1991—women     Bertazzi et al., 1993
Buccal cavity (140–149)    
Zone B 0 nr  
Zone R 0 nr  
Nose, nasal cavities (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 (carcinomas, 11 lymphomas, 5 sarcomas) in   Herbicides, pesticides Caplan et al., 2000
CDC (1990a) study population      
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; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; 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); PCP, pentachlorophenol; PCMR, proportionate cancer mortality ratios; PM, proportionate mortality; PMR, proportionate mortality ratio; SEA, Southeast Asia; SIR, standardized incidence ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; VA, US Department of Veteran Affairs.

aSubjects are male and outcome is mortality unless otherwise noted.

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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

185,265 male Vietnam veterans who were alive in 1992 and were followed for cancer incidence through 2003 and for mortality through 2005. For the internal comparison analysis of high- versus low-exposure categories derived from the Exposure Opportunity Index (EOI) scores generated by the EOI model, Yi and Ohrr (2014) reported statistically significant increased hazard ratios (HRs) for cancers of the mouth [ICD-10 C03–C06] (HR = 2.54, 95% CI 1.13–5.70) and salivary glands [ICD-10 C07–C08] (relative risk [RR] = 6.98, 95% CI 1.50–32.3), and a non-significant increase in the risk of oropharyngeal cancer [ICD-10 C10] (HR = 1.98, 95% CI 0.48–8.17). Tonsil cancer [ICD-10 C09], which is rarely reported separately, has been the object of some focused attention in VAO updates, but no difference between the high- and low-exposure groups was found (HR = 0.88, 95% CI 0.35–2.20). Differences in incidence also were not observed for the other head and neck cancers analyzed separately: lip [ICD-10 C10], tongue [ICD-10 C01–C02], nasopharynx [ICD-10 C11], hypopharynx [ICD-10 C12–C13], and nose and sinuses [ICD-10 C30–C31]. In contrast to the incidence analyses of separate head and neck cancers, Yi et al. (2014b) reported only on these cancers as a group defined by ICD-10 codes C00–C14 and found no association when comparing the high- versus low-exposure categories (HR = 1.07, 95% CI 0.68–1.68, based on a total of 82 deaths, with 45 of them in high-exposure category) nor in the analysis based on the logarithms of the individual EOI scores (HR = 1.05, 95% CI 0.94–1.17).

Occupational, Environmental, and Case-Control Studies

There have been no occupational, environmental, or case-control studies of exposure to the COIs and oral, nasal, or pharyngeal cancers published since Update 2012.

Biologic Plausibility

As noted above, evidence exists linking HPV to cancers of the head and neck (Marur et al., 2010; Szentirmay et al., 2005), to tonsillar and base-of-tongue cancers (Ramqvist et al., 2015), and to oropharyngeal cancers in particular (Gillison and Shah, 2001; Gillison et al., 2012). There is considerable evidence from laboratory studies that TCDD may increase susceptibility to viral infection, but to date it is unknown whether exposure to the other COIs contributes to susceptibility to viral infection or action, however, this potential link warrants further exploration. Moreover, 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 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). An NTP study (Yoshizawa et al., 2005a) reported

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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. (2012) utilized head and neck squamous-cell carcinoma cell lines to investigate mechanisms for tumor progression associated with 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 IL-6 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

Tonsil cancers, or more generally squamous-cell carcinomas, remain of interest to Vietnam veterans and the committee, but very limited new information on them with respect to possible herbicide exposure became available in this update. The Korean Health Study did not find an association between herbicide exposure and the risk of tonsillar cancers. However, the Korean study reported a statistically significant 2.5-fold increased risk for oral cancer and a suggestive increase for oropharyngeal cancers, excluding tonsils, associated with the herbicide exposure group (Yi and Ohrr, 2014). There is some uncertainty about the reliability of exposure estimates derived from EOI scores used in studying the Korean Vietnam veterans. Moreover, a lack of information on potential confounding factors such as smoking, alcohol, and HPV exposure limits the interpretation of the results for the few positive associations. Among New Zealand veterans there was modest increased risk for incident head and neck cancers, but a significant 2.2-fold increased risk of death from head and neck cancers in comparison to general population.

In combination with the previously reviewed literature, the inconsistent results of these two new cohort studies do not support an association between the cancers of oral cavity, nose, or pharynx 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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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. The findings on cancers of the digestive organs as a group (ICD-9 150–159) are too broad for useful etiologic analysis and will no longer be considered.

Esophageal cancer (ICD-9 150), stomach cancer (ICD-9 151), colon cancer (ICD-9 153), rectal cancer (ICD-9 154), and pancreatic cancer (ICD-9 157) are among the most common cancers. ACS estimated that about 223,230 people would receive diagnoses of those cancers in the United States in 2015 and that 116,570 people would die from them (Siegel et al., 2015). Other digestive cancers (for example, small intestine, anal, and hepatobiliary cancers) added about 67,920 new diagnoses and 32,730 deaths to the 2015 estimates for the United States (Siegel et al., 2015). Collectively, tumors of the digestive organs were expected to account for 18 percent of new cancer diagnoses and 25 percent of cancer deaths in 2015. The average annual incidences of gastrointestinal cancers are presented in Table 8-3.

The incidences of stomach, colon, rectal, and pancreatic cancers increase with age. In general, the incidences are higher in men than in women and higher in blacks than in whites. 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 (Maisonneuve and Lowenfels, 2015; Stewart et al., 2008). Infection with the bacterium Helicobacter pylori increases the risk of stomach and pancreatic cancers. 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 in general. The participant’s 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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 8-3 Average Annual Incidence (per 100,000) of Selected Gastrointestinal Cancers in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Stomach:
Men 23.8 22.0 35.3 35.8 32.0 52.8 47.9 42.7 77.7
Women 10.4 8.9 16.8 15.3 12.9 22.0 23.2 19.1 39.5
Esophagus:
Men 24.3 25.4 27.9 32.1 34.1 30.4 36.0 38.5 36.4
Women 4.0 4.0 6.7 6.0 5.8 9.8 8.7 8.4 13.3
Colon (excluding rectum):
Men 75.5 71.3 112.5 113.6 109.3 164.5 158.4 155.4 223.5
Women 54.4 51.0 86.6 82.2 78.5 119.6 120.7 119.1 157.5
Rectum and Rectosigmoid Junction:
Men 41.5 39.4 53.3 53.5 51.9 56.9 62.4 61.3 68.3
Women 23.0 22.1 28.6 30.3 29.0 35.3 35.1 34.7 34.2
Liver and Intrahepatic Bile Duct:
Men 46.5 40.0 87.5 42.8 37.2 62.8 49.8 44.0 51.7
Women 11.3 9.8 17.3 15.0 13.0 16.9 19.8 17.1 17.7
Pancreas:
Men 37.1 36.4 54.4 52.4 52.2 66.8 68.9 70.4 77.7
Women 25.1 24.5 35.0 38.2 37.1 55.3 54.0 53.1 68.3
Small Intestine:
Men 7.0 6.9 10.6 9.4 9.1 16.1 11.7 11.5 20.6
Women 5.5 5.3 9.6 6.5 6.4 10.9 7.9 7.7 13.9
Anus, Anal Canal, and Anorectum:
Men 3.5 3.7 3.9 4.4 4.9 3.7 4.8 5.0 5.1
Women 6.1 6.9 3.1 6.5 7.1 5.0 6.8 7.6 4.9
Other Digestive Organs:
Men 1.6 1.4 3.1 2.0 1.8 2.7 3.1 3.2 4.7
Women 1.2 1.1 1.8 1.6 1.6 1.9 2.3 2.3 2.2
Gallbladder:
Men 1.7 1.5 2.6 2.9 2.6 4.7 4.2 3.9 7.7
Women 3.3 3.0 5.1 5.2 4.9 7.3 6.9 6.9 8.0
Other Biliary:
Men 5.2 5.1 4.0 7.8 7.5 5.9 11.4 10.8 10.9
Women 3.2 2.9 4.3 5.1 4.9 4.5 7.4 7.2 7.7

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

cancers 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. CJ 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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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 percent of all esophageal cancers (ICD-9 150); 16,980 newly diagnosed cases and 15,590 deaths were estimated for 2015 (Siegel et al., 2015). The considerable geographic variation in the incidence of esophageal tumors suggests a multifactorial etiology. The rates of esophageal cancer have been increasing in the past two decades, and nearly 50 percent of all cases occur in northwest Europe and North America. In the United States, adenocarcinoma of the esophagus has slowly replaced squamous-cell carcinoma as the most common type of esophageal malignancy; although squamous-cell carcinoma continues to be the most common form of esophageal cancer worldwide (Rubenstein and Shaheen, 2015). Squamous-cell esophageal carcinoma rates are higher in blacks than in whites and higher in men than in women. Smoking and alcohol ingestion are associated with the development of squamous-cell carcinoma; these risk factors have been less thoroughly studied for esophageal adenocarcinoma, but they appear to be associated. The rapid increase in obesity in the United States has been linked to increasing rates of gastroesophageal reflux disease (GERD), and the resulting rise in chronic inflammation has been hypothesized as explaining the link between GERD and esophageal adenocarcinoma (Rubenstein and Shaheen, 2015). The average annual incidence of esophageal cancers is shown in Table 8-3.

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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

1937 to 1980. Collins et al. (2009b) 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 concurrent PCP exposure. Collins et al. (2009c) 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 follow-up 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 on 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 medium- and low-exposure areas.

In Update 2012, the strongest evidence came from an occupational cohort of workers at a chemical plant in Hamburg, which reported a significant increased esophageal-cancer mortality relative to men in the general population of Hamburg (SMR = 2.56, 95% CI 1.27–4.57), whereas no deaths from esophageal cancer were observed among female workers, who made up a smaller portion of this cohort (Manuwald et al., 2012). By contrast, in the NIOSH cohort Ruder and Yiin (2011) reported no excess mortality of esophageal cancer in comparison with the US population (SMR = 0.99, 95% CI 0.43–1.96). In the AHS study, 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) in comparison with the general population, which could indicate a healthy worker effect.

Table 8-4 summarizes the results of the relevant studies concerning esophageal cancer.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies Several recent publications examined esophageal cancer incidence (Yi, 2013; Yi and Ohrr, 2014) and cancer-specific mortality (Yi et al., 2014b) in the Korean Veterans Health Study, a large prospective cohort of 185,265 male Vietnam veterans alive in 1992, who were followed for cancer incidence through 2003 and for mortality through 2005. Comparing the Vietnam veterans to the general Korean population, Yi (2013) reported a statistically significant decrease in the incidence of esophageal cancer (SIR = 0.70, 95% CI 0.64–0.85), which may be due to a “healthy soldier” effect. However, in the internal comparison of those with high versus low EOI scores, Yi and Ohrr (2014) reported a statistically significant 36 percent increased risk for esophageal cancer (HR = 1.36, 95% CI 1.00–1.85). This result was based on a large number of incident esophageal cancers (n = 184) observed during follow-up, of which 113 cases

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 8-4 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 non-deployed   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 non-deployed 9 0.9 (0.4–1.6) Vistainer et al., 1995
International Studies of Vietnam Veterans      
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence      
All branches, 1982–2000 70 1.2 (0.9–1.5) ADVA, 2005b
Navy 19 1.6 (0.9–2.4)  
Army 40 1.1 (0.7–1.4)  
Air Force 11 1.5 (0.8–2.8)  
Mortality      
All branches, return–2001 67 1.1 (0.8–1.3) ADVA, 2005a
Navy 13 1.0 (0.5–1.7)  
Army 42 1.0 (0.7–1.3)  
Air Force 12 1.5 (0.8–2.6)  
1980–1994 23 1.2 (0.7–1.7) CDVA, 1997a
Australian Conscripted Army National Service (18,940 deployed vs 24,642 non-deployed)   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
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—esophagus (C15) categorized high (n = 113) vs low (n = 71) 113 1.4 (1.0–1.9) Yi and Ohrr, 2014
Mortality (1992–2005)—esophagus categorized high (n = 98) vs low (n = 64)   1.3 (0.9–1.8) Yi et al., 2014b
HR per unit of log EOI (n = 180,639) 162 1.0 (0.9–1.1)  
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 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 mo 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  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 mo 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, MI) (in IARC and   2,4,5-T; 2,4,5-TCP  
NIOSH cohorts)      
1942–2003 (n = 1,615)     Collins et al., 2009b
Trichlorophenol workers 5 1.0 (0.3–2.2)
Pentachlorophenol workers 2 0.8 (0.1–2.9)  
All Dow PCP-Exposed Workers—all workers from two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   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,     McLean et al., 2006
TCDD among 27 agents assessed by JEM      
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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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., 1994
Mortality 1972–1989 2 1.3 (0.2–4.7)  
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)  
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, 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; follow-ups 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)
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Spouses (n = 676) 3 nr  
Enrollment through 2000, vs state rates     Blair et al., 2005a
Private applicators (men and women) 16 0.5 (0.3–0.9)
Spouses of private applicators (> 99% women) 1 0.3 (0.1–1.9)  
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 follow-up to 1996—men and women      
Zone A 0   Pesatori et al., 2009
Zone B 1 0.3 (0.0–1.9)
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 Lee et al., 2004b
137 herbicides, 2.4-D
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; EOI, Exposure Opportunity Index; HR, hazard ratio; 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; SIR, standardized incidence ratio; 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 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

were among veterans in the high-exposure category. Yi et al. (2014b) reported a non-significant increase in mortality from esophageal cancer (HR = 1.26, 95% CI 0.91–1.75) when comparing those in the higher exposure category with those with lower estimated exposure; these results were based on 162 deaths due to esophageal cancer, of which 98 deaths occurred in the higher exposure category, Similarly, mortality from esophageal cancer was not found to be associated with the individual, log-transformed EOI scores (HR = 1.02, 95% CI 0.94–1.17) (Yi et al., 2014b). Information on smoking and alcohol consumption was not available, and thus some of the modest association could be due to confounding. Data from the self-reported questionnaires collected in a sub-cohort of Korean veterans who were alive in 2004 indicated that the prevalence of smoking was relatively high in this cohort (45 percent and 36 percent were former and current smokers, respectively), and 11 percent of veterans reported a high prevalence of drinking (> 5 drinks/week). However, the distributions of smoking and drinking habits were similar for veterans with high and low EOI scores (Yi et al., 2013b).

Occupational and Environmental Studies There have been no occupational or environmental studies of exposure to the COIs and esophageal cancers published since Update 2012.

Case-Control Studies There have been no case-control studies of exposure specifically to the COIs and esophageal cancers published since Update 2012.

However, a recently published hospital-based case-control study examined the risk of Barrett’s esophagus and occupational exposures to asbestos, metal dust, organic solvents, and pesticides (Qureshi et al., 2013). Barrett’s esophagus is a disorder characterized by intestinal metaplasia of the normally stratified squamous epithelium of the esophagus and is associated with an increased risk of adenocarcinoma of the esophagus. This study included 226 cases and 1,424 controls selected from among patients undergoing endoscopy at a VA medical center in Houston, Texas, from 2008 through 2010. They reported no association between self-reported use of pesticides and the risk of Barrett’s esophagus (odds ratio [OR] = 0.97, 95% CI 0.50–1.90). The major limitations include the potential for selection/referral bias as well as recall bias because pesticide exposure information was collected via a self-reported questionnaire. The authors did not address TCDD or the specific herbicides of interest, and thus this study is not regarded as being 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), and no increase in the incidence of esophageal cancer has been reported in laboratory animals after exposure to them. A previous biomarker

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 that had a family history of UGI cancer, but it was not associated with indoor air pollution, esophageal squamous-cell dysplasia category, age, sex, or smoking. These results might be interpreted to suggest that enhanced expression of the AHR in patients who had a family history of UGI cancer may contribute to UGI-cancer risk associated with AHR ligands—such as polycyclic aromatic hydrocarbons, which are found in cigarette smoke—and with TCDD.

In a small series of studies, AHR expression was found to be higher in esophageal tumors than in corresponding normal mucosa and, somewhat surprisingly, played a role in the suppression of metastatic potential, in contrast to many other cancers (Safe et al., 2013). The significance of these observations and the mechanism underlying increased AHR expression was not determined (Zhang et al., 2012).

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

Synthesis

In this update, the only study that provided some evidence for a potential association between esophageal cancer and exposure to herbicides was the Korean Veterans Health Study, which reported a modestly increased risk for both incidence (RR = 1.36, 95% CI 1.00–1.85) and mortality from esophageal cancer (RR = 1.26, 95% CI 0.91–1.75) when comparing high- versus low-exposure categories. Despite several advantages, including the large sample size of this cohort and adequate numbers of cases both for incidence of and mortality from esophageal cancer, the difficulty in determining the validity and reliability of the herbicide exposure opportunity score developed by Stellman et al. (2003b) as well as a lack of information on smoking and alcohol consumption (two main risk factors for esophageal cancer) limit the interpretation of the results.

In combination with the studies reviewed previously, however, this 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.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Stomach Cancer

The incidence of stomach cancer (ICD-9 151) increases with age. ACS estimated that 15,540 men and 9,050 women would receive diagnoses of stomach cancer in the United States in 2015 and that 6,500 men and 4,220 women would die from it (Siegel et al., 2015). In general, the incidence is higher in men than in women and in blacks than in whites. Other risk factors include a family history of this cancer, some diseases of the stomach, and diet. Infection with Helicobacter pylori increases the risk of stomach cancer. Tobacco or alcohol use and the consumption of nitrite- and salt-preserved food may also increase the risk (Ang and Fock, 2014; Brenner et al., 2009; Key et al., 2004). The average annual incidence of stomach cancer is shown in Table 8-3.

Conclusions from VAO and Previous Updates

Update 2006 considered stomach cancer independently for the first time. Prior updates had developed a table of results for stomach cancer but drew 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 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. The conclusion that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and stomach cancer has been maintained by the committees responsible for subsequent updates.

Table 8-5 summarizes the results of the relevant studies concerning stomach cancer. Results new to this update are shaded.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies Since Update 2012, cohort studies of Vietnam veterans from New Zealand and Korea have reported on stomach cancer.

Mortality from (Yi et al., 2014b) and incidence of (Yi and Ohrr, 2014) stomach cancer were assessed among Korean veterans who had served in Vietnam between 1964 and 1973. In analyses of cancer incidence, Yi and Ohrr (2014) reported a modestly increased risk of stomach cancer (HR = 1.14, 95% CI 1.04–1.24) in the internal comparison of the high- and low-exposure groups based on

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-5 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) 24 1.8 (0.8–3.9)  
Quartiles (pg/g):      
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 from 1966 through 1970 14 0.6 (0.4–1.1)  
SEA comparison veterans (n = 1,776) 31 0.9 (0.6–1.2)  
With tours from 1966 through 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 non-deployed   All COIs  
Mortality      
1965–2000 5 nr Boehmer et al., 2004
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 non-deployed (n = 22,904) 88 1.1 (0.9–1.5)  
Marine Corps, deployed (n = 4,527) vs non-deployed (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., 1986a,b
International Vietnam-Veteran Studies      
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence      
All branches, 1982–2000 104 0.9 (0.7–1.1) ADVA, 2005b
Navy 28 1.1 (0.7–1.6)  
Army 66 0.9 (0.7–1.1)  
Air Force 10 0.7 (0.3–1.3)  
Mortality      
All branches, return–2001 76 0.9 (0.7–1.2) ADVA, 2005a
Navy 22 1.3 (0.8–1.8)  
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 non-deployed)   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
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 9 0.8 (0.4–1.6)  
Mortality (1988–2008) 9 1.3 (0.6–2.4)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—Stomach (C16) categorized high (n = 1,154) vs low (n = 973)   1.1 (1.0–1.2) Yi and Ohrr, 2014
Mortality (1992–2005)—Stomach (C16) categorized high (n = 613) vs low (n = 464)   1.2 (1.0–1.3) Yi et al., 2014b
HR per unit of log EOI (n =180,639) 1,077 1.1 (1.0–1.1)  
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 et al., 1997
13,831 exposed to highly chlorinated PCDDs 42 0.9 (0.7–1.2)
7,553 not exposed to highly chlorinated PCDDs 30 0.9 (0.6–1.3)  
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 1 TCDD 1.4 (nr) Kogevinas et al., 1993
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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1955–2006 14 1.1 (0.8–1.5) Boers et al., 2012
TCDD plasma level (HRs, 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
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 mo 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 mo 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 mo 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 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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, 1996a
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 > 1.0 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 mo 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  
Mortalilty 1952–1989 12 1.3 (0.7–2.2) Becher et al., 1996
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 mo 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)
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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 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-yr exposure, ≥ 20-yr 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, MI) (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., 2009b
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, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   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)  
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (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 CJ 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, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 4 1.2 (0.3–3.1) Collins et al., 2009c
Mortality 1940–1989 (n = 770)     Ramlow et al., 1996
0-yr latency 4 1.7 (0.5–4.3)  
15-yr latency 3 1.8 (0.4–5.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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) 6 Dioxin, 2,4,5-T Expected exposed cases Thomas, 1987
    4.2  
Automobile workers from Hubei province in China (worked 1 yr during 1980–1985)   PCDD/F Wang et al., 2013
Mortality (1980–2005) (n = 3,529) 15 1.3 (0.6–2.7)  
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 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 yr and dying 1970–1984 1 0.5 (0.1–3.0) 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 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–Dec 1987      
Linkage of records for ~70,000 male Saskatchewan farmers (1971–1985) 246 0.9 (0.8–1.0) Wigle et al., 1990
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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) 39 Phenoxy herbicides 1.0 (0.7–1.3) Gambini et al., 1997
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 3 Phenoxy acids 2.2 (nr) Axelson et al., 1980
Incident stomach cancer cases 1961–1973 with agriculture as economic activity in 1960 census 2,599 99% CI 1.1 (1.0–1.2) Wiklund, 1983
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
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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; follow-ups 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) 10 0.5 (0.2–1.0)
Spouses of private applicators (> 99% women) 4 1.1 (0.3–2.8)  
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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 9 p-trend < over yrs worked 0.7 (0.3–1.3) Alavanja et al., 1989
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)   TCDD  
Incidence      
20-yr follow-up to 1996—men and women      
Zone A 3 0.9 (0.3–2.7) Pesatori et al., 2009
Zone B 19 0.9 (0.6–1.4)
Zone R 131 0.8 (0.7–1.0)  
10-yr follow-up 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 follow-up 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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality      
25-yr follow-up 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 follow-up 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 follow-up 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 follow-up 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 follow-up to 1986—men     Bertazzi et al., 1989a
Zone A, B, R 40 0.8 (0.6–1.2)
10-yr follow-up to 1986—women     Bertazzi et al., 1989a
Zone A, B, R 22 1.0 (0.6–1.5)
10-yr follow-up 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)  
Spouses 2 0.3 (0.0–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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  
Without   39.0 ± 8.8 (p = 0.29)  
Women      
With   20.7 ± 5.0 vs  
Without   20.7 ± 5.8 (p = 0.92)  
SWEDEN      
Swedish fishermen (high consumption of fish with persistent organochlorines)   Organochlorine compounds Svensson et al., 1995a
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 170 Herbicides, pesticides Lee et al., 2004b
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      
Unexposed to all herbicides 490 1.0  
< 1 mo 11 1.6 (0.7–3.5)  
1–6 mo 30 1.9 (1.1–3.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
7–12 months 7 1.7 (0.6–4.7)  
> 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; EOI, Exposure Opportunity Index; HR, hazard ratio; 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; pg/g, picogram per gram; PMR, proportionate mortality ratio; SEA, Southeast Asia; SIR, standardized incidence ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorodibenzo-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.

the EOI scores. Similarly, for stomach cancer mortality, Yi et al. (2014b) reported a modestly increased risk for the high- versus low-exposure groups (HR = 1.17, 95% CI 1.03–1.33) and a positive association with the individual log-transformed EOI scores (HR = 1.05, 95% CI 1.02–1.08).

In a study of mortality and cancer incidence among 2,783 New Zealand Vietnam veterans who served in Vietnam between 1964 and 1975, McBride et al. (2013) reported that stomach cancer mortality was slightly elevated in the cohort (SMR = 1.27, 95% CI 0.58–2.42, based on nine deaths), while stomach cancer incidence was slightly less than expected (SIR = 0.82, 95% CI 0.38–1.56, based on nine cases).

Occupational Studies Wang et al. (2013) reported on mortality from 1980 to 2005 in a cohort of 3,529 workers, who had worked at least 1 year from 1980 through 1985 in an automobile foundry factory located in Hubei province in China with potential exposure to PCDD/Fs. When compared to the general population, the modest elevation in the risk of gastric cancers was not statistically significant (SMR = 1.28, 95% CI 0.60–2.74).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Environmental and Case-Control Studies No environmental or case-control studies of exposure to the COIs and stomach cancer have been published since Update 2012.

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 cancers 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., 2002); 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). Recent cell culture work consistent with the in vivo studies showed that decreased AHR expression in two human gastric cancer cell lines was associated with decreased cell growth, migration, and invasion, all of which are hallmarks of malignant potential (Yin et al., 2013).

In a biomarker study of cancer patients, AHR expression and nuclear translocation 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

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 the type of herbicide. In contrast,

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

in occupational cohort studies there was little evidence of an exposure-related increase in stomach cancer. Updated mortality findings from Seveso concerning TCDD exposure (Consonni et al., 2008; Pesatori et al., 2009) found no evidence of an increase in stomach cancer. There was a modestly increased risk of stomach cancer in Korean veterans but inconsistent evidence in New Zealand Vietnam veterans, as has been the case in previously reviewed studies of Vietnam veterans.

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 Cancers

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 percent of digestive tract tumors; ACS estimated that 132,700 people would receive diagnoses of colorectal cancer in the United States in 2015 and that 49,700 would die from it (Siegel et al., 2015). Excluding basal-cell and squamous-cell skin cancers, colorectal cancers are the third-most common form of cancer both in men and in women. The average annual incidence of colorectal cancers is shown in Table 8-3.

The incidence of colorectal cancers increases with age; it is higher in men than in women and in blacks than in whites. (Screening can affect the incidence, and screening is recommended for all persons over 50 years old). Other risk factors include a family history of this form of cancer, body weight, lack of physical exercise, and diet (Kamangar et al., 2006). Type 2 diabetes is associated with an increased risk of colorectal cancers (ACS, 2013a).

Conclusions from VAO and Previous Updates

Update 2006 considered colorectal cancers independently for the first time. Prior updates developed tables of results on colon and rectal cancers, but conclusions about the adequacy of the evidence of their association with herbicide exposure were reached only in the context of gastrointestinal tract cancers. The

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 cancers. 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 cancers were thus reclassified into the default category of inadequate or insufficient evidence to determine whether there is an association. The additional information considered in subsequent updates did not provide evidence to suggest that colorectal cancers be moved out of the category of inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and colorectal cancers.

The results of the relevant studies concerning colon and rectal cancers are summarized in Table 8-6, in which results new to this update are shaded.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies McBride et al. (2013) reported on mortality among 2,783 male New Zealand veterans who had served in Vietnam between 1964 and 1975 and were alive in 1988 (when the electronic mortality database started). Follow-up was through 2008, with those who emigrated or were lost to follow-up excluded. Colorectal cancer mortality was slightly elevated in the cohort (SMR = 1.04, 95% CI 0.64–1.61, based on 20 deaths), while all-cause mortality was significantly in deficit in the cohort (all-cause SMR = 0.85, 95% CI 0.77–0.94). Colorectal cancer incidence was slightly lower than expected (SIR = 0.95, 95% CI 0.73–1.21, based on 63 cases).

In the internal comparison of high- versus low-exposure opportunity groups, Yi and Ohrr (2014) found a deficit of colon cancer [ICD-10 C18] among the higher exposed (HR = 0.87, 95% CI 0.72–1.08) and a small excess of rectal cancer [ICD-10 C19–C21] (HR = 1.14, 95% CI 0.95–1.38). With regard to mortality from colorectal cancers [ICD-10 C18–C21], Yi et al. (2014b) reported no evidence of an increase in mortality from these cancers combined for high- versus low-exposure opportunity groups (HR = 0.96, 95% CI 0.78–1.19) or in association with the individual log-transformed EOI scores (HR = 1.02, 95% CI 0.97–1.07). Results were presented separately for 30 incident cases of and 19 deaths from cancer of the small intestine [ICD-10 C17]. Comparing the high- versus low-exposure opportunity groups, Yi and Ohrr (2014) found a significant increase in the incidence of this rather uncommon cancer (HR = 2.30, 95% CI 1.03–5.15). For mortality from cancer of the small intestine, Yi et al. (2014b) found elevated risks for both the internal comparison (HR = 2.88, 95% CI 1.00–8.28) and for the analysis of the individual EOI scores (HR = 1.11, 95% CI 0.87–1.40).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-6 Selected Epidemiologic Studies—Colon and Rectal 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 Vietnam Veterans      
US CDC Vietnam Experience Study—Cross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 non-deployed   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 non-deployed (n = 22,904) 209 1.0 (0.7–1.3)  
Marine Corps, deployed (n = 4,527) vs non-deployed (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., 1995a
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., 1986a,b
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 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, 2005b
Navy 91 1.3 (1.0–1.5)  
Army 239 1.1 (0.9–1.2)  
Air Force 47 1.1 (0.8–1.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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, 2005a
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, 2005a
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 (18,940 deployed vs 24,642 non-deployed)   All COIs  
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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Rectum 3 0.7 (0.2–9.5)  
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) (colorectal) 63 1.0 (0.7–1.2)  
Mortality (1988–2008) (colorectal) 20 1.0 (0.6–1.6)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)     Yi and Ohrr, 2014
Small intestine (C17) (19 vs 11)   2.3 (1.0–5.2)
Colon cancer (C18) (210 vs 228)   0.9 (0.7–1.1)  
Rectal cancer (C19–C20) 265 vs 231)   1.1 (1.0–1.4)  
Anus (C21) (7 vs 2)   3.3 (0.6–17.1)  
Mortality (1992–2005)     Yi et al., 2014b
HR per unit of log EOI (n = 180,639)      
Small intestine (C17) 19 1.1 (0.9–1.4)  
Colorectal (C18–C21) 366 1.0 (1.0–1.1)  
High exposure vs low exposure      
Small intestine (C17) (14 vs 5)   2.9 (1.0–8.3)  
Colorectal (C18–C21) (187 vs 179)   1.0 (0.8–1.2)  
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates      
Non-cancer mortality     Vena et al., 1998
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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 Mesquita et al., 1993
Large intestine, except colon 3 2.4 (0.5–7.0)
Rectum 0 0.0 (0.0–5.6)
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 mo 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  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
German Production Workers at Bayer Plant in Dormagen (520 men working > 1 mo 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 mo 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     Ott and Zober, 1996a
1960–1992—colorectal 5 1.0 (0.3–2.3)
TCDD < 0.1 µg/kg of body weight 2 1.1 (0.1–3.9)
TCDD 0.1–0.99 µg/kg of body weight 2 1.4 (0.2–5.1)  
TCDD > 1.0 µg/kg of body weight 1 0.5 (0.0–3.0)  
Mortality      
Through 1987—colon, rectum 2 90% CI 2.5 (0.4–7.8) Zober et al., 1990
Through 1970—(n = 74; 70 initially exposed, 4 involved with cleaning and testing procedures) 1 0.4 (nr) Theiss et al., 1982
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo 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) (ICD-9)   Dioxins; 2,4,5-T; 2,5-DCP; 2,4,5-TCP  
Mortality 1952–2007 (140–149)     Manuwald et al., 2012
Colon (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 (154) 13 1.7 (0.9–2.9)  
Men 11 2.0 (0.98–3.5)  
Women 2 1.0 (0.1–3.7)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortalilty 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 mo in 1969–1984)      
Mortality 1969–2000     ’t Mannetje et al., 2005
Phenoxy herbicide producers (men and women)    
Colon 2 0.6 (0.0–2.3)  
Rectum, rectosigmoid junction, anus 5 2.5 (0.8–5.7)  
Phenoxy herbicide sprayers (> 99% men)      
Colon 8 1.9 (0.8–3.8)  
Rectum, rectosigmoid junction, anus 4 1.5 (0.4–3.8)  
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-yr exposure, ≥ 20-yr latency      
Small intestine, colon 13 1.8 (1.0–3.0)  
Rectum 2 1.2 (0.1–4.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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, MI) (in IARC and NIOSH cohorts)   2,4,5-T; 2,4,5-TCP  
1942–2003 (n = 1,615)     Collins et al., 2009b
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, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   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, MI) (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 CJ et al., 2011
Colon 16 1.0 (0.6–1.6)  
Rectum 6 0.8 (0.3–1.7)  
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, MI) (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., 2009c
Large intestine 10 1.2 (0.6–2.3)  
Rectum 1 0.5 (0.0–2.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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)  
Pulp and paper cohorts independent of IARC cohort      
United Paperworkers International, 201 white men employed ≥ 10 yr and dying 1970–1984     Solet et al., 1989
Colon 7 1.5 (0.6–3.0)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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     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)  
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)
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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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 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)  
Small intestine 2 5.2 (1.4–18.9)  
Aged 20–59 2 11.2 (3.4–36.4)  
Aged ≥ 60 0  
Sawmill 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)  
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)  
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; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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)  
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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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) 56 0.7 (0.6–1.0)  
Spouses of private applicators (> 99% women) 31 1.2 (0.8–1.6)  
Rectum      
Private applicators (men, women) nr nr  
Spouses of private applicators (> 99% women) 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 yrs 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)  
Rectum 2 nr  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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)   TCDD  
Incidence      
20-yr follow-up 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 follow-up 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 follow-up 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 follow-up 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 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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 follow-up 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 follow-up 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 follow-up 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 follow-up 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 follow-up 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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Rectum nr 16.6 (nr)  
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., 1995a
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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
West coast      
Colon 58 1.0 (0.8–1.3)  
Rectum 31 1.0 (0.7–1.5)  
CASE-CONTROL STUDIES
International Case-Control Studies      
421 Egyptian colorectal cancer cases and 439 hospital controls   Herbicides 5.5 (2.4–12.3) Lo et al., 2010
Swedish patients (1970–1977) nr 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-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,4,5-TP, 2-(2,4,5-trichlorophenoxy) propionic acid; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; 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.

Environmental, Occupational, and Case-Control Studies No occupational, environmental, or case-control studies of exposure to the COIs and colorectal cancers have been published since Update 2012.

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 cancers. 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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

that TCDD and other AHR ligands may contribute to increased proliferation of colonic cells, but more studies are needed to understand the relation of increased proliferation of these cells to colorectal cancers, if any, and the potential role of AHR activation in colorectal and intestinal carcinogenesis.

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

Synthesis

Epidemiologic findings for colorectal cancers have not been particularly suggestive of an association with exposure to the COIs. The exceptionally large cohort of Korean Vietnam veterans generated results for cancer of the small intestine that presented a pattern of increased risk for both incidence and mortality, but no other epidemiologic findings for cancer of the small intestine have been encountered in these updates that could be used to appraise consistency.

There is no evidence of biologic plausibility of an association between exposure to any of the COIs and tumors of the colon or rectum or the small intestine. Overall, the available evidence does not support an association between the COIs and colorectal cancers.

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 cancers.

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 25,510 men and 10,150 women would receive diagnoses of liver cancer or intrahepatic bile duct cancer in the United States in 2015 and that 17,030 men and 7,520 women would die from these cancers (Siegel et al., 2015). Gallbladder cancer and extrahepatic bile duct cancer (ICD-9 156) are fairly uncommon and, when they are addressed, are often grouped with liver cancer.

In the United States, liver cancers account for about 2 percent of new cancer cases and 4 percent of cancer deaths. Misclassification of metastatic cancers as primary liver cancer can lead to an overestimation of the number of deaths attributable to liver cancer (Chuang et al., 2009). In developing countries, especially those in sub-Saharan Africa and Southeast Asia, liver cancers are common and are among the leading causes of death (Kamangar et al., 2006). Known risk factors for liver cancer include chronic infection with hepatitis B or hepatitis C virus

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 (Chuang et al., 2009; Farazi et al., 2006). In the general population, the incidence of liver and intrahepatic bile duct cancers is higher in men than in women and higher in blacks than in whites (NCI, 2015). The average annual incidence of hepatobiliary cancers is shown in Table 8-3.

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 subsequent updates did not change that conclusion.

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

Update of the Epidemiologic Literature

Vietnam-Veteran Studies McBride et al. (2013) did not report results for this outcome.

Recent publications examined incidence of (Yi, 2013; Yi and Ohrr, 2014) and mortality from (Yi et al., 2014b) cancers among 185,265 Korean male Vietnam veterans in the Korean Veterans Health Study. When compared to the general Korean population, there was no evidence of excess liver cancer risk (SIR = 1.00, 95% CI 0.96–1.05) (Yi, 2013). In the internal comparison of the high- versus low-exposure opportunity group, Yi and Ohrr (2014) reported a marginal elevation in liver cancer for the higher group (RR = 1.09, 95% CI 0.99–1.20). Yi et al. (2014b) reported modestly increased risk of liver cancer mortality in the internal comparison (RR = 1.12, 95% CI 1.02–1.23) and from the analysis of the individual EOI scores (RR = 1.03, 95% CI 1.00–1.05).

Occupational Studies Among 3,529 employees of a Chinese automobile foundry, Wang et al. (2013) found a significantly elevated risk of liver cancer mortality (SMR = 1.71, 95% CI 1.21–2.42, based on 32 cancer deaths).

Environmental and Case-Control Studies No environmental or case-control studies of exposure to the COIs and liver cancer have been published since Update 2012.

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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-7 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 non-deployed   All COIs  
Mortality      
1965–2000—liver, intrahepatic bile ducts (ICD-9 155) 5 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 8 All COIs
1.2 (0.5–2.7)
CDC, 1990a
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 non-deployed (n = 22,904) 34 1.0 (0.8–1.4)  
Marine Corps, deployed (n = 4,527) vs non-deployed (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 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence      
All branches, 1982–2000 27 0.7 (0.4–1.9) ADVA, 2005b
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, 2005a
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
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 18,940 deployed vs 24,642 non-deployed   All COIs  
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
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual E4 exposure opportunity scores) (HRs)   All COIs  
Incidence (1992–2003)—categorized high (n = 85,809) vs low (n = 94,442)     Yi and Ohrr, 2014
Liver (C22) 1,023 1.1 (1.0–1.2)  
Gall bladder, etc. (C23–C24) 125 1.2 (0.9–1.6)  
Mortality (1992–2005)—categorized high (n = 85,809) vs low (n = 94,442)     Yi et al., 2014b
HR per unit of log EOI (n = 2,053)      
Liver (C22) 2,053 1.0 (1.0–1.1)  
Gallbladder (C23–C24) 215 1.1 (1.0–1.1)  
High exposure vs low exposure      
Liver (C22) (1,107 vs 946)   1.1 (1.0–1.2)  
Gallbladder (C23–C24) (120 vs 95)   1.2 (0.9–1.6)  
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, bile duct (ICD-8 155–156) 4 0.4 (0.1–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 mo 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 mo 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 mo 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 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, 1996a
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 > 1.0 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 mo 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  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortalilty 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 mo 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-yr exposure, ≥ 20-yr latency 1 0.6 (0.0–3.3)
Mortality—754 Monsanto workers, among most highly exposed workers from     Collins et al., 1993
Fingerhut et al. (1991); liver, biliary tract 2 1.4 (0.2–5.2)  
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production 1948–1982 in Midland, MI) (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., 2009b
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, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP Ruder and Yiin, 2011
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 0 0.0 (0.0–1.7) Collins et al., 2009c
Mortality 1940–1989 (n = 770); liver, primary (ICDA-8 155–156)     Ramlow et al., 1996
0-yr latency 0 nr  
15-yr latency 0 nr  
Other Studies of Industrial Workers (not related to IARC or NIOSH phenoxy cohort)      
Automobile workers from Hubei province in China (worked 1 yr during 1980–1985)   PCDD/F Wang et al., 2013
Mortality (1980–2005) (n = 3,529) 32 1.7 (1.2–2.4)  
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 0.9 (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)  
Pulp and paper cohorts independent of IARC cohort      
United Paperworkers International, 201 white men employed ≥ 10 yr and dying 1970–1984 2 2.0 (0.2–7.3) Solet et al., 1989
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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
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)  
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 0 nr Swaen et al., 2004
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC (liver, biliary tract)   Phenoxy herbicides  
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)   Phenoxy herbicides Gambini et al., 1997
  7 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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Aged 20–59 1 6.3 (1.1–36.6)  
Aged ≥ 60 2 3.5 (0.9–13.3)  
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   99% CI Wiklund, 1983
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)  
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; follow-ups 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 7 1.1 (0.4–2.3)  
Enrollment through 2002     Alavanja et al., 2005
Liver    
Private applicators (men, women) 35 1.0 (0.7–1.4)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Spouses of private applicators (> 99% women) 3 0.9 (0.2–2.5)  
Commercial applicators (men, women) nr 0.0 (0.0–4.2)  
Gallbladder      
Private applicators (men, women) 8 2.3 (1.0–4.5)  
Spouses of private applicators (> 99% women) 3 0.9 (0.2–2.5)  
Commercial applicators (men, women) nr 0.0 (0.0–35.8)  
Mortality      
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% women) 4 1.7 (0.4–4.3)  
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)   TCDD  
Incidence      
20-yr follow-up 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 follow-up 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 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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 follow-up 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 follow-up 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 follow-up 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 follow-up 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 follow-up 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 follow-up 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 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
10-yr follow-up 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., 1995a
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 et al., 1984

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; CATI, computer-assisted telephone interview; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; EOI, Exposure Opportunity Index; HR, hazard ratio; 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); PCMR, proportionate cancer mortality ratio; 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 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 (the epithelial–mesenchymal transition) that is associated with the progression of malignant tumors (Weinberg, 2008). Zucchini-Pascal et al. (2012) showed that TCDD exposure induced an epithelial-to-mesenchymal transition in primary cultured human hepatocytes.

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 IL-6 cytokine, which has tumor-promoting effects in numerous tissues, including cholangiocytes; thus, TCDD might promote carcinogenesis in biliary tissue.

TCDD may contribute to tumor progression by inhibiting p53 regulation (phosphorylation and acetylation) triggered by genotoxicants 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). TCDD inhibits ultraviolet-C radiation-induced apoptosis in primary rat hepatocytes and Huh-7 human hepatoma cells, which supports the hypothesis that TCDD acts as a tumor promoter by preventing initiated cells from undergoing apoptosis (Chopra et al., 2009). TCDD inhibited the proliferation of isolated mouse oval cells, which are liver precursor cells, via an AHR-dependent pathway, suggesting that these cells are not the precursor for TCDD-induced tumors in the mouse (Faust et al., 2013a).

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 contribute to the development of hepatotoxicity in rats treated chronically with the AHR ligands, TCDD, or PCB 126. The researchers identified 24, 17, and 7

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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genes that were differentially expressed in the livers of rats exposed to those AHR ligands and in, respectively, human cholangiocarcinoma, human hepatocellular adenoma, and rat hepatocellular adenoma. These findings may help 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 the sustained activation of the AHR (Köhle and Bock, 2007; Köhle et al., 2008). For example, dioxin (TCDD) exposure was reported to increase liver fibrosis in mice via an AHR-dependent pathway. A recent study by Kennedy et al. (2014) addressed two of these issues by using transgenic mouse strains to measure dioxin-induced liver cancers in a model in which TCDD was used as a tumor promoter. One set of experiments showed that the number of TCDD-induced liver tumors was significantly higher in mice that expressed AHR with high binding affinity to TCDD than in an isogenic strain that expressed a low-binding-affinity AHR. A second set of experiments showed that the genetic ablation of inflammatory cytokines reduced significantly TCDD-induced liver tumors. Likewise, genetic ablation of AHR reduced TCDD-induction of the inflammatory cytokines (Pierre et al., 2014). 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). Finally, a recent study showed that AHR expression is significantly elevated in human liver cancers, although the absolute level of increase is only about 30 to 40 percent, but the biological significance of this observation is not known (Liu et al., 2013).

In a study of gene-expression changes in adult female primary human and rat hepatocytes exposed to TCDD in vitro, Black et al. (2012) used whole-genome microarrays to show that TCDD produced different 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. A more recent study of gene-expression changes in cultured rat liver cells (the WB-F344 cell line) showed that the AHR agonist PCB126 identified hundreds of dysregulated genes that increased in number as a function of time after exposure from 6 to 72 hours; these included the Wnt and TGF-b signaling pathways, which are involved in tumorogenesis (Faust et al., 2013b).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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.

Cacodylic acid (DMAIII and DMAV) is carcinogenic and has been shown to induce renal cancer. In F344/DuCrj rats treated with a mixture of carcinogens for 4 weeks, subsequent exposure to DMA (not indicated whether this was DMAIII or V) via the drinking water for 24 weeks caused tumor promotion in the liver, kidney, urinary bladder, and thyroid gland but inhibited induction of tumors of the nasal passages (Yamamoto et al., 1995). Recent studies have also found that oral exposure of adult mice to 200 ppm DMAV in addition to fetal arsenic exposure can act as a promoter of renal and hepatocellular carcinoma, markedly increasing tumor incidence beyond that produced by fetal arsenic exposure alone (Tokar et al., 2012).

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

Synthesis

Since the previous report the additional literature provides modest evidence of excess liver cancer among Korean veterans and among Chinese foundry workers, although confounding remains a concern. The lack of evidence of association between exposure and this outcome in most occupational and environmental studies does not support this association. 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 cancers, 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 cancers.

Pancreatic Cancer

The incidence of pancreatic cancer (ICD-9 157) increases with age. ACS estimated that 24,840 men and 24,120 women would receive a diagnosis of

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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pancreatic cancer in the United States in 2015 and that 20,710 men and 19,850 women would die from it (Siegel et al., 2015). The incidence is higher in men than in women and 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 8-3.

Conclusions from VAO and Previous Updates

Update 2006 considered pancreatic cancer independently for the first time. Prior updates developed tables of results for pancreatic cancer but reached conclusions about the adequacy of the evidence of its association with herbicide exposure in the context of gastrointestinal tract cancers. The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the herbicides used by the US military in Vietnam and gastrointestinal tract tumors, including pancreatic cancer. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the 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.

In reviewing the existing evidence concerning an association between herbicide exposure and pancreatic cancer, the committee for Update 2006 noted a report of increased rates of pancreatic cancer in US female Vietnam nurse veterans (Dalager et al., 1995a) but concluded that it alone did not constitute limited or suggestive evidence of an association. That increase persisted in the follow-up study of the American female veterans (Cypel and Kang, 2008), but committees for subsequent updates have concurred with the decision of the committee for Update 2006. Table 8-8 summarizes the results of the relevant studies concerning pancreatic cancer.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies Among 2,783 New Zealand veterans who served in Vietnam between 1964 and 1975, McBride et al. (2013) reported that pancreatic cancer mortality was in deficit in the cohort in comparison to the general population of New Zealand (SMR = 0.67, 95% CI 0.22–1.56, based on five deaths). Pancreatic cancer incidence was also lower than expected (SIR = 0.72, 95% CI 0.26–1.57, based on six cases). The wide confidence intervals resulting from the small number of observed cases make these results largely uninformative.

Kang et al. (2014) updated the vital status of 4,734 women who served in the US Army, Navy, Air Force, or Marines in Vietnam between July 4, 1965,

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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TABLE 8-8 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 non-deployed   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 non-deployed (n = 22,904) 82 0.9 (0.6–1.2)  
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 18 1.6 (0.5–5.8)  
US VA Cohort of Female Vietnam-era Veterans served in Vietnam (n = 4,586; nurses only = 3,690); non-deployed (n = 5,325; nurses only = 3,282)   All COIs  
Mortality
Through 2010—Vietnam-era veterans 50 1.7 (1.0–3.1) Kang et al., 2014
Vietnam nurses only 35 2.1 (1.0–4.3)
Through 2004—Vietnam-era veterans 17 2.1 (1.0–4.5) Cypel and Kang, 2008
Vietnam-veteran nurses 14 2.5 (1.0–6.0)
Through 1991—Vietnam-era veterans 7 2.8 (0.8–10.2) Dalager et al., 1995a
Vietnam nurses only 7 5.7 (1.2–27.0)
Through 1987—Vietnam-era veterans (Vietnam nurses not reported separately) 5 2.7 (0.9–6.2) Thomas et al., 1991
State Studies of US Vietnam Veterans
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed 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., 1986a,b
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 86 1.2 (0.9–1.4) ADVA, 2005b
Navy 14 0.9 (0.5–1.5)  
Army 60 1.2 (0.9–1.5)  
Air Force 12 1.3 (0.7–2.3)  
Mortality
All branches, return–2001 101 1.2 (1.0–1.5) ADVA, 2005a
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 non-deployed)   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
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 6 0.7 (0.3–1.6)  
Mortality (1988–2008) 5 0.7 (0.2–1.6)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—pancreas (C25) categorized high (n = 100) vs low (n = 84) 100 1.1 (0.8–1.5) Yi and Ohrr, 2014
Mortality (1992–2005)—pancreas (C25) categorized high (n = 141) vs low (n = 114)     Yi et al., 2014b
HR per unit of log EOI (n = 180,639) 255 1.0 (1.0–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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 47 0.9 (0.7–1.3) Kogevinas et al., 1997
13,831 exposed to highly chlorinated PCDDs 30 1.0 (0.7–1.4)
7,553 not exposed to highly chlorinated PCDDs 16 0.9 (0.5–1.4)  
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)  
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 (HRs 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
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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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; 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 mo 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 mo 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 mo 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
German Production Workers at Boehringer–Ingelheim Plant in Hamburg (1,144 men working > 1 mo 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  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
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Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 mo 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 male production and maintenance workers 1942–1984) (included in IARC cohort as of 1997)   Dioxins, phenoxy herbicides  
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-yr exposure, ≥ 20-yr 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, MI) (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., 2009b Ruder and Yiin, 2011
All Dow PCP-Exposed Workers—all workers from the two plants that only made PCP (in Tacoma, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   2,4,5-T; 2,4,5-TCP
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, MI) (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 CJ et al., 2011
Dow PCP Production Workers (1937–1989 in Midland, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 196 also having exposure to TCP) 5 1.1 (0.3–2.5) Collins et al., 2009c
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality 1940–1989 (n = 770)     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) 6 Dioxin, 2,4,5-T
1.4 (nr)
Thomas, 1987
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
United Paperworkers International, 201 white men employed ≥ 10 yr 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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Women      
Self-employed 7 1.2 (nr)  
Employee 4 1.3 (nr)  
Family workers 27 0.7 (p < 0.05)  
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
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 777 99% CI 0.8 (0.8–0.9) 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) 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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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; follow-ups 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  
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  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 follow-up 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 follow-up to 1991—men     Pesatori et al., 1992
Zone A, B 2 1.0 (0.3–4.2)
10-yr follow-up to 1991—women     Pesatori et al., 1992
Zone A, B 1 1.6 (0.2–12.0)
Mortality      
25-yr follow-up 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)  
20-yr follow-up 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 follow-up 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 follow-up 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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
10-yr follow-up 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 follow-up 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., 1995a,b
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; EOI, Exposure Opportunity Index; HR, hazard ratio; 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; 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 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

and March 28, 1973. Using the cohort of Vietnam-era veterans who remained in the United States as the referent yielded an increased risk of pancreatic cancer mortality (RR = 1.74, 95% CI 0.97–3.14) for those deployed to Vietnam. Further analyses restricted to female nurses, again using the non-deployed cohort as the referent, yielded a slightly higher risk of mortality from pancreatic cancer (RR = 2.07, 95% CI 1.00–4.25) for those nurses deployed to Vietnam.

Among 185,265 Korean male Vietnam veterans, Yi (2013) found no evidence of excess pancreatic cancer [ICD-10 C25] risk in comparison to the general population (SIR = 0.92, 95% CI 0.80–1.06). In the internal comparison analysis of high- versus low-exposure opportunity groups, Yi and Ohrr (2014) reported a small excess of pancreatic cancer incidence (RR = 1.12, 95% CI 0.83–1.51). Yi et al. (2014b) reported little indication of increased risk of mortality from pancreatic cancers in association with herbicide exposure from either the internal comparison of the high- and low-exposure opportunity groups (RR = 1.15, 95% CI 0.89–1.48) or the analysis of the individual EOI scores (RR = 1.03, 95% CI 0.97–1.09).

Occupational, Environmental, and Case-Control Studies No occupational, environmental, or case-control studies of exposure to the COIs and pancreatic cancer have been published since Update 2012.

Biologic Plausibility

Long-term animal studies have examined the effect on tumor incidence of exposure to each of the COIs: 2,4-D and 2,4,5-T (Charles et al., 1996), TCDD (Walker et al., 2006), picloram (Stott et al., 1990), and DMA (Wanibuchi et al., 1996, 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 the 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 cancers 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 versus their non-deployed counterparts that was observed by Thomas et al. (1991) and

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Dalager et al. (1995a) was replicated in a study by Cypel and Kang (2008), who found a significant increase in all female Vietnam veterans and in the nurse subset. The recent report by Kang et al. (2014) was also consistent with these findings. The committee responsible for Update 2006 reported a higher incidence of and mortality from pancreatic cancer in deployed Australian National Service veterans than in non-deployed veterans (ADVA, 2005c). The current update notes no excess among New Zealand veterans (McBride et al., 2013). The Korean study of Vietnam veterans suggests a small and insignificant association between estimated herbicide exposure and pancreatic cancer (Yi et al., 2014b). 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), 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. The studies of production cohorts provide limited support for an association. Overall, however, the existing evidence does not support a conclusion 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.

LARYNGEAL CANCER

ACS estimated that 10,720 men and 2,840 women would receive diagnoses of cancer of the larynx (ICD-9 161) in the United States in 2015 and that 2,890 men and 750 women would die from it (Siegel et al., 2015). Those numbers constitute a little more than 0.8 percent of new cancer diagnoses and 0.6 percent 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 to 64 years old. The average annual incidence of laryngeal cancer is shown in Table 8-9.

Exposure to tobacco smoke, paint fumes, metalworking fluids, and asbestos have been associated with laryngeal cancer, as has alcohol and occupational exposures to wood dust and employment in the petroleum, plastics, and textile industries (ACS, 2012a; IOM, 2006a).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-9 Average Annual Cancer Incidence (per 100,000) of Laryngeal Cancer in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 19.9 19.3 36.5 24.7 24.5 41.1 29.9 30.1 45.1
Women 3.7 3.7 5.5 4.7 4.8 7.6 5.2 5.5 7.4

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

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.” Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change that conclusion.

Table 8-10 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

There have been no studies of US Vietnam veterans that have evaluated exposure to the COIs and laryngeal cancer since Update 2012. However, two cohort studies of Vietnam War veterans (a majority of them male) from New Zealand and Korea have recently reported on cancer incidence and mortality for larynx cancer.

Among 2,783 New Zealand veterans who served in Vietnam between 1964 and 1975, McBride et al. (2013) reported a total of five incident cases and two deaths from larynx cancers, which were ascertained during the follow-up of this cohort from 1988 through 2008. The risk of mortality from cancer of the larynx (SMR = 2.00, 95% CI 0.23–7.39, based on two deaths) was increased compared to expectations based on national rates. Laryngeal cancer incidence was slightly greater than expected (SIR = 1.18, 95% CI 0.38–2.77, based on five cases). The CIs for both point estimates were wide and imprecise due to the few cases observed. The study lacked information on potential confounding factors, including smoking and alcohol. However, both the incidence of and mortality from lung cancer were not elevated in this cohort, and thus potential confounding by smoking is unlikely.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-10 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 non-deployed   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 non-deployed (n = 31,757) 50 1.4 (p < 0.05)
Marine Corps, deployed (n = 6,237) vs non-deployed (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 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 97 1.5 (1.2–1.8) ADVA, 2005b
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, 2005a
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 (18,940 deployed vs 24,642 non-deployed)   All COIs  
Incidence
1982–2000 8 0.7 (0.2–1.6) ADVA, 2005c
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality
1966–2001 2 0.4 (0.0–2.4) ADVA, 2005c
1982–1994 0 0 (0– > 10) CDVA, 1997b
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 5 1.2 (0.4–2.8)  
Mortality (1988–2008) 2 2.0 (0.2–7.4)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—larynx (C32) categorized high (n = 87) vs low (n = 67) 87 1.2 (0.9–1.7) Yi and Ohrr, 2014
Mortality (1992–2005)—larynx (C32) categorized high (n = 50) vs low (n = 32)   1.3 (0.8–2.0) Yi et al., 2014b
HR per unit of log EOI (n = 180,639) 82 1.1 (1.0–1.3)  
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 8 1.5 (0.6–2.9) 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 4 1.7 (0.5–4.5) Coggon et al., 1986
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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 mo 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 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)
vs national rates (also vs gas workers); same observation period as Becher et al., 1966
2 2.0 (0.2–7.1) 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 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 mo 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 7 2.1 (0.8–4.3) Fingerhut et al., 1991
≥ 1-yr exposure, ≥ 20-yr 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, MI) (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., 2009b
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   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, MI) (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 CJ 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, MI) (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., 2009c
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)  
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      
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 follow-up to 2001—men and women, all respiratory cancers (ICD-9 160–165) excluding lung cancers (ICD-9 162)     Consonni et al., 2008
Zone A 0 nr  
Zone B ≤ 8 nr  
Zone R ≤ 49 nr  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
20-yr follow-up 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 follow-up to 1991—men     Bertazzi et al., 1997, 1998
Zone B 6 nr
Zone R 32 nr  
15-yr follow-up 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; EOI, Exposure Opportunity Index; HR, hazard ratio; 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 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Several recent publications examined larynx cancer incidence (Yi, 2013; Yi and Ohrr, 2014) and cancer mortality (Yi et al., 2014b) in the Korean Veterans Health Study. A total of 157 incident cases of larynx cancer [ICD-10 C32] were identified in this cohort during follow-up. When compared to the general Korean population, the cohort showed no excess larynx cancer risk (SIR = 0.90, 95% CI 0.77–1.06) (Yi, 2013). Yi and Ohrr (2014) reported a modest increased risk of larynx cancer (RR = 1.21, 95% CI 0.87–1.69), albeit not statistically significant, despite the large number of cases (n = 87) in the high exposure category. The mortality experience of this cohort of Korean veterans of the Vietnam War was also studied. Deaths due to cancer of the larynx were positively associated with the log of EOI scores (HR = 1.13, 95% CI 1.0–1.28, based on 82 deaths), and a comparison of the high- to low-exposure groups yielded a modestly elevated risk (HR = 1.28, 95% CI 0.80–2.03, based on 50 deaths from larynx cancer in the high-exposure category). Adjustments were not made for smoking or drinking habits, but an analysis of the survey data from much of the cohort established that these behaviors did not differ systematically with opportunity for herbicide exposure (Yi et al., 2013b).

Occupational, Environmental, and Case-Control Studies

No occupational and environmental cohort studies, or case-control studies of exposure to the COIs and laryngeal cancer have been published since Update 2012.

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 cancers separately (Bond et al., 1988; Coggon et al., 1986; Fingerhut et al., 1991; Manz et al., 1991; Saracci 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.” The weight of evidence with regard to laryngeal cancer has increased since the original VAO committee review. Notable among epidemiological studies

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

contributing to the evidence are studies of workers employed in manufacturing herbicides potentially contaminated with TCDD. An IARC study (Kogevinas et al., 1997) that included essentially all of the phenoxy herbicide production workers who previously had been studied found an elevated rate of laryngeal cancers in workers who were exposed to any phenoxyacetic acid herbicide or chlorophenol (SMR = 1.6, 95% CI 1.0–2.5, based on 21 deaths), especially workers who were exposed to TCDD or higher-chlorinated dioxins (SMR = 1.7, 95% CI 1.0–2.8, based on 15 deaths). Ongoing updates have continued to indicate an increase in larynx cancer in the occupational cohorts making up this IARC cohort.

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). Analyses of Seveso have not reported findings for laryngeal cancer.

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 non-deployed soldiers (ADVA, 2005c). In contrast, Watanabe and Kang (1996) found a significant 40 percent excess of mortality from laryngeal cancer in Army personnel deployed to the Vietnam theater. The Ranch Hand study was not large enough to have sufficient power to detect an association if one existed. The Korean Vietnam Veterans Health Study reviewed in this update identified a large number of incident cases (n = 157) and deaths (n = 82) from larynx cancer during a 20-year follow-up (Yi, 2013; Yi and Ohrr, 2014b; Yi et al., 2014a,b). Despite the large sample size, the modestly increased risks of both incidence and mortality from larynx cancer were not statistically significant.

Overall, the majority of reports suggest an increased risk of laryngeal cancer although individual studies often are based on small numbers of cases and are not controlled for smoking. In addition, there is evidence of an excess risk of laryngeal cancer among those who experienced chloracne—a marker of high exposure. The literature provides a reasonable level of consistency with regard to evidence of a moderate increase in relative risk of laryngeal cancer. In larger occupational studies with good exposure characterizations that focus on the COIs, the associations are generally strong for laryngeal cancer, while studies of Vietnam veterans provide modest associations.

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.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

LUNG CANCER

Lung cancer (carcinoma of the lung or bronchus, ICD-9 162.2–162.9) is the second most common diagnosed non-skin cancer and the leading cause of cancer deaths in the United States. ACS estimated that 115,610 men and 105,590 women would receive diagnoses of lung cancer in the United States in 2015 and that about 86,380 men and 71,660 women would die from it (Siegel et al., 2015). Those numbers represent roughly 13 percent of new cancer diagnoses and 27 percent of cancer deaths in 2015. 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 cancers of the lung and bronchus under ICD-9 16.2, but it is a rare cancer. The lung is also a common site of metastatic tumors from other organ sites; in this chapter, however, we are only addressing primary lung cancer. The incidence of lung cancer increases with age and there is a racial/ethnic disparity of lung cancer risk; the incidence is consistently higher in black men than in white men or in women (either black or white) (NCI, 2015). The average annual incidence of lung cancer in the United States is shown in Table 8-11.

The Centers for Disease Control and Prevention’s (CDC’s) 2014 Surgeon General report estimates that 82 percent of lung cancer deaths are attributable to cigarette smoking (CDC, 2014). Smoking is a major risk factor for lung cancer and increases the risk of all histologic types of this disease, but the associations with squamous-cell and small-cell carcinomas are the 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 for lung cancer. Important environmental risk factors include exposure to secondary 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

TABLE 8-11 Average Annual Incidence (per 100,000) of Lung and Bronchial Cancers in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 167.6 163.7 261.6 288.0 289.7 390.4 401.4 409.7 494.9
Women 123.9 129.8 138.9 216.8 230.3 222.2 290.8 311.2 269.5

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, Update 2010, and Update 2012 did not change that conclusion.

Table 8-12 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Kang et al. (2014) reported on lung cancer mortality in an update of vital status through 2010 of female Vietnam-era veterans who served in Vietnam (n = 4,734) or who remained in the United States (n = 5,313). A total of 95 and 100 deaths from respiratory cancers were ascertained in these two groups of female veterans, respectively, during follow-up. In comparison to the non-deployed women (internal comparison analysis), respiratory cancer mortality was not associated with service in Vietnam for all the women (RR = 1.12, 95% CI 0.84–1.50) or for just the nurses (RR = 0.94, 95% CI 0.66–1.32).

McBride et al. (2013) reported on 2,783 male veterans from New Zealand, who served in Vietnam between 1964 and 1972 and were followed for lung cancer incidence and mortality through 2008. A total of 58 incident cases and 50 deaths from lung cancers were identified in this cohort. When compared to the general male population of New Zealand, there were no excess risks for lung cancer incidence (SIR = 1.13, 95% CI 0.86–1.47) or lung cancer mortality (SMR = 1.15, 95% CI 0.85–1.51).

In the Korean Veterans Health Study, a total of 1,223 incident cases and 1,170 deaths from cancers of the lung and bronchus were identified during follow-up. Compared to the general Korean population, there was no excess lung cancer risk (SIR = 0.99, 95% CI 0.93–1.05) in the entire cohort (Yi, 2013). Comparing veterans with higher opportunity scores to those in the group with lower scores, Yi and Ohrr (2014) reported a modest elevation in lung cancer incidence (HR = 1.12, 95% CI 1.00–1.27, based on 649 incident cases in the higher exposure category). With regard to cancer mortality for lung and bronchus, Yi et al. (2014b) also reported modestly increased lung cancer mortality for the high- versus low-exposure opportunity groups (HR = 1.15, 95% CI 1.02–1.30, based on 673 lung cancer deaths in the higher herbicide exposure category). Information on smoking habits was not available for this cohort during follow-up through 2003, and thus the modest associations could be due to confounding by smoking. Yi et al. (2013b) collected information on cigarette smoking via self-reported questionnaires from 114,562 Korean Vietnam veterans who were alive in July 2004 and found that the prevalence of smoking was relatively high in this cohort (45 percent and 36 percent were former or current smokers, respectively). The distribution of smoking, however, was similar between veterans in the high- and low-exposure groups (Yi et al., 2013b).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-12 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 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): 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 26 1.1 (0.7–1.6)  
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 non-deployed) serving during Vietnam era (July 1, 1965–March 28, 1973)   All COIs  
Mortality—Respiratory system cancers      
Through 2005     Cypel and Kang, 2010
Deployed veterans (2,872) vs non-deployed (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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
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 non-deployed   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 non-deployed (n = 31,757 ) 1,139 1.1 (nr) (p < 0.05)
Marine Corps, deployed (n = 6,237) vs non-deployed (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 non-deployed (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-era Veterans served in Vietnam (n = 4,586; nurses only = 3,690); non-deployed (n = 5,325; nurses only = 3,282)   All COIs  
Mortality
Through 2004—lung 195 1.1 (0.8–1.5) Kang et al., 2014
Vietnam nurses only 137 0.9 (0.7–1.3)
Through 2004—lung 50 1.0 (0.7–1.4) Cypel and Kang, 2008
Vietnam veteran nurses 35 0.8 (0.5–1.2)
Through 1991—lung 15 0.9 (0.4–1.7) Dalager et al., 1995a
Vietnam veteran nurses 9 0.5 (0.2–1.2)
Through 1987—lung (Vietnam veteran nurses not reported separately) 8 0.6 (0.3–1.5) Thomas et al., 1991
US VA using the Patient Treatment Files—329 Vietnam-era veterans and 269 non-cancer controls and 111 colon cancer controls (1983–1990) 134 All COIs
1.4 (1.0–1.9)
Mahan et al., 1997
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
State Studies of US Vietnam Veterans
Michigan Vietnam-era veterans, PM study of deaths (1974–1989)—deployed vs non-deployed 80 0.9 (0.7–1.1) Vistainer et al., 1995
International Vietnam-Veteran Studies
Australian Vietnam Veterans—58,077 men and 153 women served on land or in Vietnamese waters 5/23/1962–7/1/1973 vs Australian population   All COIs  
Incidence
All branches, 1982–2000 576 1.2 (1.1–1.3) ADVA, 2005b
Navy 141 1.4 (1.2–1.7)
Army 372 1.2 (1.1–1.3)  
Air Force 63 1.0 (0.7–1.2)  
Histologic type—all service branches combined
Adenocarcinoma 188 1.5 (1.2–1.7)  
Squamous 152 1.2 (1.0–1.4)  
Small-cell 87 1.2 (0.97–1.5)  
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, 2005a
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 non-deployed)   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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Mortality      
1966–2001 67 1.8 (1.2–2.7) ADVA, 2005c
1982–1994 27 2.2 (1.1–4.3) CDVA, 1997b
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence (1988–2008) 58 1.1 (0.9–1.5)  
Mortality (1988–2008) 50 1.2 (0.9–1.5)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—Lung cancer (C33–C34) categorized high (n = 649) vs low (n = 505)   1.1 (1.0–1.3) Yi and Ohrr, 2014
Mortality (1992–2005)—Lung cancer (C33–C34) categorized high (n = 673) vs low (n = 497)   1.2 (1.0–1.3) Yi et al., 2014b
HR per unit of log EOI (n = 180,639) 1,170 1.0 (1.0–1.1)  
OCCUPATIONAL—INDUSTRIAL
IARC Phenoxy Herbicide Cohort—Workers exposed to any phenoxy herbicide or chlorophenol (production or spraying) vs respective national mortality rates (ICD-9)      
Mortality 1939–1992     Kogevinas et al., 1997
Lung (162) 380 1.1 (1.0–1.2)
Other respiratory organs (163–165) 12 2.3 (1.2–3.9)  
13,831 exposed to highly chlorinated PCDDs      
Lung (162) 225 1.1 (1.0–1.3)  
Other respiratory organs (163–165) 9 3.2 (1.5–6.1)  
7,553 not exposed to highly chlorinated PCDDs      
Lung (162) 148 1.0 (0.9–1.2)  
Other respiratory organs (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 (ICD-9)     Saracci et al., 1991
Trachea, bronchus, lung (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 (lung) 2 TCDD
1.4 (0.2–4.9)
Kogevinas et al, 1993
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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) (ICD-8)   MCPA  
Mortality through 1983 (lung, pleura, mediastinum) (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)  
Chinese Automobile Foundry Factory Workers (n = 3,529)   PCDD/F Wang et al., 2013
Lung cancer mortality (1980–2005); comparison with Chinese general population 43 2.1 (1.6–2.9)  
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)  
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
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 mo 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 mo 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
German Production Workers at BASF Ludwigshafen Plant (680 men working > 1 mo 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
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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, 1996a
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 ≥ 1.0 µg/kg of body weight 8 2.2 (1.0–4.3)  
Through 1987 4 90% CI 2.0 (0.7–4.6) Zober et al., 1990
German Production Workers at Boehringer–Ingelheim Plant in Hamburg—1,144 men working > 1 mo 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)  
Mortalilty 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)  
Never-exposed workers      
Respiratory cancer 5 1.2 (0.4–2.7)  
Trachea, bronchus, lung 4 1.0 (0.3–2.5)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Production Workers (713 men and 100 women worked > 1 mo in 1969–1984); mortality (1969–2000) (ICD-9)      
Trachea, bronchus, lung (162)
Other respiratory system sites (163–165)
12
1
1.4 (0.7–2.4)
3.9 (0.1–21.5)
’t Mannetje et al., 2005
Sprayers (697 men and 2 women on register of New Zealand applicators, 1973–1984); mortality 1973–2000 (ICD-9)      
Trachea, bronchus, lung (162) Other respiratory system sites (163–165) 5
1
0.5 (0.2–1.1)
2.5 (0.1–13.7)
’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 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) (ICD-9)     Fingerhut et al., 1991
Trachea, bronchus, lung (162) 89 1.1 (0.9–1.4)
Respiratory system (160–165) 96 1.1 (0.9–1.4)  
≥ 1-yr exposure, ≥ 20-yr latency      
Trachea, bronchus, lung (162) 40 1.4 (1.0–1.9)  
Respiratory system (160–165) 43 1.4 (1.0–1.9)  
All Dow TCP-Exposed Workers (TCP production 1942–1979 or 2,4,5-T production   2,4,5-T;
2,4,5-TCP
 
1948–1982 in Midland, MI) (in IARC and NIOSH cohorts)      
1942–2003 (n = 1,615) (bronchus, trachea, lung) 46 0.7 (0.5–0.9) Collins et al., 2009b
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, WA, and Wichita, KS) and workers who made PCP and TCP at two additional plants (in Midland, MI, and Sauget, IL)   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  
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  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Dow 2,4-D Production Workers (1945–1982 in Midland, MI) (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 CJ 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, MI) (not in IARC and NIOSH cohorts)   Low chlorinated dioxins, 2,4-D  
Mortality 1940–2004 (n = 577, excluding 30 1.0 (0.6–1.4) Collins et al., 2009c
196 also having exposure to TCP) (bronchus, trachea, lung)      
Mortality 1940–1989 (n = 770) (ICD-8)     Ramlow et al., 1996
0-yr latency    
Respiratory system (160–163) 18 1.0 (0.6–1.5)  
Lung (162) 16 0.9 (0.5–1.5)  
15-yr latency      
Respiratory system (160–163) 17 1.1 (0.6–1.8)  
Lung (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, TCDD among 27 agents assessed by JEM (ICD-9)     McLean et al., 2006
Exposure to nonvolatile organochlorine compounds      
Lung (162)      
Never 356 1.0 (0.9–1.1)  
Ever 314 1.0 (0.9–1.2)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Pleura (163)      
Never 17 2.8 (1.6–4.5)  
Ever 4 0.8 (0.2–2.0)  
Other respiratory (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 mo 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-yr follow-up (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-yr follow-up (1975–1984) of male gardeners 41 1.0 (0.7–1.3) Hansen et al., 1992
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
FINNISH Phenoxy Herbicide Sprayers (1,909 men working 1955–1971 ≥ 2 wks) not IARC (ICD-8)   Phenoxy herbicides  
Incidence     Asp et al., 1994
Trachea, bronchus, lung (162) 39 0.9 (0.7–1.3)
Other respiratory (160, 161, 163) 4 1.1 (0.7–1.3)  
Mortality 1972–1989      
Trachea, bronchus, lung (162) 37 1.0 (0.7–1.4)  
Other respiratory (160, 161, 163) 1 0.5 (0.0–2.9)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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)  
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)  
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; follow-ups with CATIs 1999–2003 and 2005–2010   Phenoxy herbicides  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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)  
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  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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)      
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) (ICD-9)   Herbicides Bender et al., 1989
Trachea, bronchus, lung (162.0–162.8) 54 0.7 (0.5–0.9)  
All respiratory (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)   TCDD  
Incidence
20-yr follow-up 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 follow-up 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 follow-up to 1991—women     Bertazzi et al., 1993
Zone R 16 1.5 (0.8–2.5)  
Mortality      
25-yr follow-up 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 follow-up 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 follow-up 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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
15-yr follow-up 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
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., 1995a
Incidence
East coast (lung) 24 1.2 (0.8–1.8)  
West coast (lung) 73 0.9 (0.7–1.1)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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
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; EOI, Exposure Opportunity Index; HR, hazard ratio; 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); PCDF, polychlorinated dibenzofuran; PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; pg/g, picogram per gram; 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

Wang et al. (2013) followed a cohort of 3,529 workers who had worked at least 1 year in 1980–1985 at an automobile foundry located in Hubei province in China. When compared to the general population, there was a 2.1-fold increased risk of lung cancer mortality in this cohort (SMR = 2.13, 95% CI 1.58–2.88; based on 43 deaths). Although there were several measurements of PCDD/Fs in samples collected from six sites of this factory, the authors did not link these exposure estimates with lung cancer mortality in order to do an exposure–response analysis.

Environmental and Case-Control Studies

No environmental studies or case-control studies of exposure to the COIs and cancers of the lung, bronchus, or trachea have been published since Update 2012.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Biologic Plausibility

Long-term animal studies have examined the effect on tumor incidence of exposure to each of the COIs: 2,4-D and 2,4,5-T (Charles et al., 1996), TCDD (Walker et al., 2006), picloram (Stott et al., 1990), and DMA (Wanibuchi et al., 1996, 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 non-neoplastic lung lesions was found in female rats exposed to TCDD for 2 years (Kociba et al., 1978; NTP, 1982a,b, 2006; Walker et al., 2006, 2007). The most common non-neoplastic lesions were bronchiolar metaplasia and squamous metaplasia of the alveolar epithelium. Cystic keratinizing epithelioma was the most commonly observed neoplasm. The lung was also identified as a target organ in 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 NTP studies (Tritscher et al., 2000). A recent study with female mice in the lung cancer sensitive A/J strain background showed that estrogen exposure increased lung tumor incidence significantly in ovariectomized mice treated with a chemical carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), known to induce these tumors. However, TCDD exposure did not increase lung tumor formation further in these ovariectomized and estrogen-treated mice (Chen et al., 2014a). TCDD by itself had little lung tumor–promoting activity in intact female A/J mice, but it exhibited a significant synergistic effect when combined with a low dose of NNK. Cell culture experiments suggested that the TCDD effect was via inhibition of apoptosis (Chen et al., 2014b). The AHR has been implicated in the chemical induction of lung tumors but not linked specifically at this time to TCDD or the other COIs (Tsay et al., 2013).

Cacodylic acid (DMAIII and DMAV) is carcinogenic, but results from studies of DMA exposure and lung cancer in laboratory animals have not been consistent. In the mouse lung, cacodylic acid (DMAV) was been shown to act as a tumor initiator (Yamanaka et al., 1996, 2009) and as a tumor promoter (Mizoi et al., 2005). DMAV can also act as a complete carcinogen, inducing lung tumors in susceptible strains of mice, including those with deficient DNA-repair activity (Hayashi et al., 1998; Kinoshita et al., 2007). However, 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). 2,4-D causes lung damage, and a recent report provided evidence that this effect occurs via disruption of the microtubule network (Ganguli et al., 2014).

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

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

Synthesis

The recent evidence is consistent with and further strengthens the conclusion that there is limited but suggestive evidence of an association between exposure to at least one COI and the risk of developing or dying from lung cancer. 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, 1996a), a NIOSH cohort (Fingerhut et al., 1991; Steenland et al., 1999), and Danish production workers (Lynge, 1993). The occupational study of Wang and colleagues reviewed in this update also reported a statistically significant two-fold increased risk of lung cancer mortality in this cohort in comparison to the general population (Wang et al., 2013). However, there was no exposure–response analysis conducted despite the fact that concentrations of PCDD/Fs were collected from six sites in the foundry factory. The methodologically sound AHS did not show any increased risk of lung cancer, but, although there was substantial 2,4-D exposure in this cohort (Blair et al., 2005b), dioxin exposure of the contemporary farmers was probably negligible.

In large part, the environmental studies have not been supportive of an association, although in the cancer-incidence update from Seveso (Pesatori et al., 2009), the highest risks of lung cancer occurred in the most exposed.

In veterans’ studies, Cypel and Kang (2010) found a significantly increased lung-cancer risk in ACC veterans who used herbicides in Vietnam. The findings from the 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 differed greatly between the two cohorts of veterans, so confounding by smoking is probably minimal. The studies therefore lend support to the findings of the Ranch Hand study.

In this update, however, data from the US veteran women showed no excess lung cancer mortality in comparison to the US cohort of non-deployed women or those from the US general population. Similar results were observed also among male Vietnam veterans in New Zealand, although that cohort study was rather small and also lacked information on smoking. In contrast, the Korean Vietnam Veterans Health Study (Yi, 2013; Yi and Ohrr, 2014; Yi et al., 2014b) found

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

modestly elevated relative risks of both lung cancer incidence and mortality. The results were not adjusted for smoking, but earlier self-reported information from a large portion of the cohort indicated that smoking behavior did not appear related to the extent of a veteran’s exposure to herbicides. Despite their limitations, these new studies of Vietnam veterans are largely suggestive of modest associations between herbicide exposure and lung cancer incidence and mortality.

Finally, the several lines of mechanistic activity discussed in the section on biologic plausibility 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 the exposure to at least one COI and carcinomas of the lung, bronchus, and trachea.

BONE AND JOINT CANCERS

ACS estimated that about 1,640 men and 1,330 women would receive diagnoses of bone or joint cancer (ICD-9 170) in the United States in 2015 and that 850 men and 640 women would die from these cancers (Siegel et al., 2015). 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 8-13.

Bone cancer is more common in teenagers than in adults. It is rare among people in the age groups of most Vietnam veterans (55–69 years). Among the risk factors for bone and joint cancer in adults are gender, ethnicity, genetic and familial factors, exposure to ionizing radiation in treatment for other cancers and a history of some non-cancer bone diseases, including Paget disease (Chung and Van Hul, 2012; Ottaviani and Jaffe, 2009).

TABLE 8-13 Average Annual Incidence (per 100,000) of Bone and Joint Cancers in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 1.3 1.4 0.9 1.6 1.7 0.9 2.2 2.3 1.5
Women 1.0 1.1 0.5 1.1 1.2 1.1 1.4 1.3 1.9

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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, Update 2010, and Update 2012 did not change that conclusion.

Table 8-14 summarizes the results of the relevant studies.

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

Since the Update 2012, two studies of Vietnam veterans from countries other than the United States have generated publications addressing exposure to the COIs and bone cancer (McBride et al., 2013; Yi and Ohrr, 2014; Yi et al., 2014b).

Mortality from (Yi et al., 2014b) and incidence of (Yi and Ohrr, 2014) bone cancer were assessed among Korean Veterans who had served in Vietnam between 1964 and 1973. In analyses of cancer incidence, Yi and Ohrr (2014) reported a decreased risk of bone cancer (HR = 0.70, 95% CI 0.27–1.82) in the internal comparison of the high- and low-exposure groups based on the EOI scores. Similarly for bone cancer mortality, Yi et al. (2014b) reported a decreased risk for the high- versus low-exposure groups (HR = 0.48, 95% CI 0.16–1.49) and a negative association with the individual log-transformed EOI scores (HR = 0.81, 95% CI 0.64–1.04).

Cancer incidence and mortality from 1998 to 2008 were determined for 2,783 male veterans from New Zealand who had survived service in Vietnam between 1964 and 1972 (McBride et al., 2013). Based upon only two deaths, a comparison with the general male population of New Zealand was largely uninformative for an association with bone and cartilage cancers (SIR = 2.78, 95% CI 0.31–10.0).

Occupational, Environmental, and Case-Control Studies

No occupational, environmental, or case-control studies with sufficiently specific characterization of exposure to the COIs and bone or joint cancers have been published since Update 2012.

Biologic Plausibility

No animal studies have reported an increased incidence of bone and joint cancer after exposure to the COIs. The biologic plausibility of the carcinogenicity of the COIs is discussed in general at the beginning of this chapter.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-14 Selected Epidemiologic Studies—Bone and Joint 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 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 et al., 1986, 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 27 0.8 (0.4–1.7)
Marine Corps, deployed (n = 4,527) vs non-deployed (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 unexposed veterans with gastrointestinal cancers 4 0.9 (0.1–11.3) Clapp, 1997
New York
Deployed vs non-deployed 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., 1986a,b
International Vietnam-Veteran Studies
New Zealand Vietnam War Veterans (2,783 male survivors of deployment in 1964–1975)   All COIs McBride et al., 2013
Incidence–bone and cartilage (1988–2008) 2 2.8 (0.3–10.0)  
Korean Vietnam Veterans Health Study—entire population categorized with high exposure (n = 85,809) vs low exposure (n = 94,442) (individual EOI scores) (HRs; ICD-10)   All COIs  
Incidence (1992–2003)—bone cancer (C40–C41) categorized high (n = 8) vs low (n = 11) 8 0.7 (0.3–1.8) Yi and Ohrr, 2014
Mortality (1992–2005)—bone cancer (C40–C41) categorized high (n = 5) vs low (n = 11)   0.5 (0.2–1.5) Yi et al., 2014b
HR per unit of log EOI (n = 180,639) 16 0.8 (0.6–1.0)  
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 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 PCDDs 2 1.4 (0.2–5.2)  
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 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 0 90% CI 0.0 (0.0–65.5) Zober et al., 1990
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 mo 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-yr exposure, ≥ 20-yr 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, MI) (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
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
Through 1982 (n = 878) 0 nr (0.0–31.1) Bond et al., 1988
Dow PCP Production Workers (1937–1989 in Midland, MI) (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  
OCCUPATIONAL—HERBICIDE-USING WORKERS (not related to IARC sprayer cohorts)      
CANADA
Sawmill Workers in British
Columbia
—23,829 workers for ≥ 1 yr 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)  
Dutch Licensed Herbicide Sprayers—1,341 certified before 1980      
Through 2000 0 nr Swaen et al., 2004
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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 44 99% CI 1.0 (0.6–1.4) 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) 49 1.3 (1.0–1.8)  
Nonwhites (n = 11,446) 4 1.0 (0.3–2.5)  
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)   TCDD  
Mortality
15-yr follow-up to 1991—men     Bertazzi et al., 1998
Zone R 2 0.5 (0.1–2.0)
15-yr follow-up 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)  
Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×
Study Populationa Exposed Casesb Exposure of Interest/Estimated Relative Risk (95% CI)b Reference
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; EOI, Exposure Opportunity Index; HR, hazard ratio; 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.

Synthesis

The small amount of new data, in concert with the previous literature, summarized in Table 8-14 does 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 cancer.

SOFT-TISSUE SARCOMAS

Soft-tissue sarcomas (STSs) (ICD-9 164.1, 171) arise in soft somatic tissues in and between organs. Three of the most common types of STS—liposarcomas,

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

fibrosarcomas, and rhabdomyosarcomas—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 5,320 women would receive diagnoses of STS in the United States in 2015 and that about 4,870 men and 2,600 women would die from it (Siegel et al., 2015). The average annual incidence of STS is shown in Table 8-15.

Among the risk factors for STS are exposure to ionizing radiation during treatment for other cancers, some inherited genetic conditions (including Ewing’s sarcoma and Li-Fraumeni syndrome), and several chemical exposures (Cormier and Pollock, 2004).

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 have 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 potential 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; the cancer incidence was ascertained from 1975 to 2001. Birth date served as a surrogate for potential exposure to pesticides and herbicides, with older cohorts representing higher exposure potential. Men born before 1915 were

TABLE 8-15 Average Annual Incidence (per 100,000) of Soft-Tissue Sarcomas (Including Malignant Neoplasms of the Heart) in the United Statesa

  60–64 Years Old 65–69 Years Old 70–74 Years Old
All Races White Black All Races White Black All Races White Black
Men 7.2 7.3 7.4 9.8 10.4 6.9 12.3 12.9 8.3
Women 5.2 4.9 7.1 6.3 6.4 6.3 7.8 8.0 7.2

aSurveillance, Epidemiology, and End Results program, nine standard registries, crude age-specific rates, 2008–2012 (NCI, 2015).

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

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 to 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 non-significantly increased risk of STS when follow-up was extended to 1992. The 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 (Collins et al., 2009b; ’t Mannetje et al., 2005)—showed an increased risk of STS, but the results were commonly non-significant, possibly because of the 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 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 non-significant increase in mortality from STS was also seen in state studies of veterans in Massachusetts, Michigan, and New York.

Table 8-16 summarizes the relevant studies.

Suggested Citation:"8 Cancers." National Academies of Sciences, Engineering, and Medicine. 2016. Veterans and Agent Orange: Update 2014. Washington, DC: The National Academies Press. doi: 10.17226/21845.
×

TABLE 8-16 Selected Epidemiologic Studies—Soft-Tissue Sarcomas (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 non-deployed (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 non-deployed (n = 4,505) 11 0.7 Watanabe et al., 1991
1965–1982     Breslin et al., 1986, 1988
Army, deployed (n = 19,708) vs non-deployed (n = 22,904) 30 1.0 (0.8–1.2)
Marine Corps, deployed (n = 4,527) vs non-deployed (n = 3,781) 8 0.7 (0.4–1.3)  
US VA Study of Marine Post-service Mortality—sample of Marines serving 1967–1969, deployed (n = 10,716) vs non-deployed (n = 9,346)   All COIs  
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 gastrointestina