Veterans and Agent Orange: Update 2012 (2014)

8


Cancer

Chapter Overview

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

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

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

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

Cancer is the second-leading cause of death in the United States. Among men 55–69 years old, the group that includes most Vietnam veterans (see Table 8-1), however, the risk of dying from cancer exceeds the risk of dying from heart disease, the leading cause of death in the United States, and does not fall to second place until after the age of 75 years (Heron et al., 2009). About 577,000 Americans of all ages were expected to die from cancer in 2010—more than 1,500 per day. In the United States, one-fourth of all deaths are from cancer (Siegel et al., 2012).

This chapter summarizes and presents conclusions about the strength of the

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

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

evidence from epidemiologic studies regarding associations between exposure to the chemicals of interest (COIs)—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlo-rodibenzo-p-dioxin (TCDD), picloram, and cacodylic acid—and various types of cancer. The committee also considers studies of exposure to polychlorinated biphenyls (PCBs) and other dioxin-like chemicals (DLCs) informative if their results were reported in terms of TCDD toxic equivalents (TEQs) or concentrations of specific congeners of DLCs. However, studies that report TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration since mono-ortho PCBs typically contribute less than 10% to total TEQs, based on the WHO revised TEFs of 2005 (La Rocca et al., 2008; Van den Berg et al., 2006). If a new study reported on only a single type of cancer and did not revisit a previously studied population, its design information is summarized here with its results; design information on all other new studies can be found in Chapter 6.

The objective of this chapter is assessment of whether the occurrence of various cancers in Vietnam veterans themselves may be associated with exposure they may have received during military service. Therefore, studies of childhood cancers in relation to parental exposure to the COIs are discussed in Chapter 10, which addresses possible adverse effects in the veterans’ offspring. Studies that consider only childhood exposure are not considered relevant to the committee’s charge.

In an evaluation of a possible connection between herbicide exposure and risk of cancer, the approach used to assess the exposure of study subjects is of critical importance in determining the overall relevance and usefulness of find-

ings. As noted in Chapters 3 and 6, there is great variety in detail and accuracy of exposure assessment among studies. A few studies used biologic markers of exposure, such as the presence of a chemical in serum or tissues; some developed an index of exposure from employment or activity records; and some used other surrogate measures of exposure, such as presence in a locale when herbicides were used. As noted in Chapter 2, inaccurate assessment of exposure, a form of measurement error, can obscure the relationship between exposure and disease.

Each section on a type of cancer opens with background information, including data on its incidence in the general US population and known or suspected risk factors. Cancer-incidence data on the general US population are included in the background material to provide a context for consideration of cancer risk in Vietnam veterans; the figures presented are estimates of incidence in the entire US population, not predictions for the Vietnam-veteran cohort. The data reported are for 2004–2008 and are from the most recent dataset available (NCI, 2010). Incidence data are given for all races combined and separately for blacks and whites. The age range of 55–69 years now includes about 80% of Vietnam-era veterans, and incidences are presented for three 5-year age groups: 55–59 years, 60–64 years, and 65–69 years. The data were collected for the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute and are categorized by sex, age, and race, all of which can have profound effects on risk. For example, the incidence of prostate cancer is about 2.6 times as high in men who are 65–69 years old as in men 55–59 years old and almost twice as high in blacks 55–64 years old as in whites in the same age group (NCI, 2010). Many other factors can influence cancer incidence, including screening methods, tobacco and alcohol use, diet, genetic predisposition, and medical history. Those factors can make someone more or less likely than the average to contract a given kind of cancer; they also need to be taken into account in epidemiologic studies of the possible contributions of the COIs.

Each section of this chapter pertaining to a specific type of cancer includes a summary of the findings described in the previous Agent Orange reports: Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994); Veterans and Agent Orange: Update 1996, referred to as Update 1996 (IOM, 1996); Update 1998 (IOM, 1999); Update 2000 (IOM, 2001); Update 2002 (IOM, 2003); Update 2004 (IOM, 2005); Update 2006 (IOM, 2007); Update 2008 (IOM, 2009); and Update 2010 (IOM, 2011). That is followed by a discussion of the most recent scientific literature, a discussion of biologic plausibility, and a synthesis of the material reviewed. When it is appropriate, the literature is discussed by exposure type (service in Vietnam, occupational exposure, or environmental exposure). Each section ends with the committee’s conclusion regarding the strength of the evidence from epidemiologic studies. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

Biologic plausibility corresponds to the third element of the committee’s

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

Information on biologic mechanisms by which exposure to TCDD could contribute to the generic (rather than tissue-specific or organ-specific) carcinogenic potential of the COIs is summarized in Chapter 4. It distills toxicologic information concerning the mechanisms by which TCDD affects the basic process of carcinogenesis; such information, of course, applies to all the cancer sites discussed individually in this chapter. When biologic plausibility is discussed in this chapter’s sections on particular cancer types, the generic information is implicit, and only experimental data peculiar to carcinogenesis at the site in question are presented. A large literature indicates that carcinogenesis is a process that involves not only genetic changes but also epigenetic changes, which modify DNA and its expression without altering its sequence of bases (Johnstone and Baylin, 2010). There is increasing evidence that TCDD and the COIs may disturb cellular processes by epigenetic mechanisms (see Chapter 4), and reference to this evidence, as it applies to cancers is included where it exists, by cancer site.

Considerable uncertainty remains about the magnitude of risk posed by exposure to the COIs. Many of the veteran, occupational, and environmental studies reviewed by the committee did not control fully for important confounders. There is not enough information about the exposure experience of individual Vietnam veterans to permit combining exposure estimates for them with any potency estimates that might be derived from scientific research studies to quantify risk. The committee therefore cannot accurately estimate the risk to Vietnam veterans that is attributable to exposure to the COIs. The (at least currently) insurmountable problems in deriving useful quantitative estimates of the risks of various health outcomes in Vietnam veterans are explained in Chapter 1 and the summary of this report, but the point is not reiterated for every health outcome addressed.

ORGANIZATION OF CANCER GROUPS

For Update 2006, a system for addressing cancer types was described to clarify how specific cancer diagnoses were grouped for evaluation by the committee and to ensure that the full array of cancer types would be considered. The organization of cancer groups follows major and minor categories of cause of death related to cancer sites established by the National Institute for Occupational Safety and Health (NIOSH). The NIOSH groups map the full range of International Classification of Diseases, Ninth Revision (ICD-9) codes for malignant neoplasms (140–208). The ICD system is used by physicians and researchers to group related diseases and procedures in a standard form for statistical evaluation. Revision 10 (ICD-10) came into use in 1999 and constitutes a marked change from the previous four revisions that evolved into ICD-9. ICD-9 was in effect

from 1979 to 1998; because ICD-9 is the version most prominent in the research reviewed in this series, it is used when codes are given for a specific health outcome. Appendix C describes the correspondence between the NIOSH cause-of-death groupings and ICD-9 codes (see Table C-1); the groupings for mortality are largely congruent with those of the SEER program for cancer incidence (see Table C-2, which presents equivalences between the ICD-9 and ICD-10 systems). For the present update, the committee gave more attention to the World Health Organization’s classification of lymphohematopoietic neoplasms (WHO, 2008), which stresses partitioning of the disorders first according to the lymphoid or myeloid lineage of the transformed cells rather than into lymphomas and leukemias.

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

BIOLOGIC PLAUSIBILITY

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

With respect to 2,4-D, 2,4,5-T, and picloram, several studies have been performed in laboratory animals. In general, the results were negative, although some would not meet current standards of cancer bioassays; for instance, there is some question as to whether the highest doses (generally 30–50 mg/kg) in some of the studies reached a maximum tolerated dose. It is not possible to have absolute confidence that these chemicals have no carcinogenic potential. Further evidence of a lack of carcinogenic potential is provided, however, by negative

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

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

Studies in laboratory animals in which only TCDD has been administered have reported that it can increase the incidence of a number of neoplasms, most notably of the liver, lungs, thyroid, and oral mucosa (Kociba et al., 1978; NTP, 2006). Some studies have used the two-stage model of carcinogenesis and shown that TCDD can act as a tumor-promoter and increase the incidence of ovarian cancer (Davis et al., 2000), liver cancer (Beebe et al., 1995), and skin cancers (Wyde et al., 2004). In exerting its carcinogenic effects, TCDD is thought to act primarily as a tumor-promoter. In many of the animal studies reviewed, treatment with TCDD has resulted in hyperplasia or metaplasia of epithelial tissues. In addition, in both laboratory animals and cultured cells, TCDD has been shown to exhibit a wide array of effects on growth regulation, hormone systems, and other factors associated with the regulation of cellular processes that involve growth, maturation, and differentiation. Thus, it may be that TCDD increases the incidence or progression of human cancers through an interplay of multiple cellular factors. Tissue-specific protective cellular mechanisms may also affect the response to TCDD and complicate our understanding of its site-specific carcinogenic effects.

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

other tissues (Hollingshead et al., 2008). In rat liver, TCDD downregulates reduced folate carrier (Rfc1) mRNA and protein, whose normal levels are essential in maintaining folate homeostasis (Halwachs et al., 2010). Reduced Rfc1 activity and a functional folate deficiency may contribute to the risk of carcinogenesis posed by TCDD exposure.

Mechanisms by which TCDD induces G1 arrest in hepatic cells (Mitchell et al., 2006; Weiss et al., 2008) and decreases viability of endometrial endothelial cells (Bredhult et al., 2007), insulin-secreting beta cells (Piaggi et al., 2007), peripheral T cells (Singh et al., 2008), and neuronal cells (Bredhult et al., 2007) have been identified, and the results suggest possible carcinogenic mechanisms. TCDD may contribute to tumor progression by inhibiting p53 regulation (phosphorylation and acetylation) triggered by genotoxicants through the increased expression of the metastasis marker AGR2 (Ambolet-Camoit et al., 2010) and through a functional interaction between the AHR and FHL2—"four and a half LIM protein 2,” in which the LIM domain is a highly conserved protein structure (Kollara and Brown, 2009). Borlak and Jenke (2008) demonstrated that the AHR is a major regulator of c-raf and proposed that there is cross-talk between the AHR and the mitogen-activated protein kinase signaling pathway in chemically induced hepatocarcinogenesis. TCDD inhibits ultraviolet-C radiation-induced apoptosis in primary rat hepatocytes and Huh-7 human hepatoma cells, and this supports the hypothesis that TCDD acts as a tumor-promoter by preventing initiated cells from undergoing apoptosis (Chopra et al., 2009). Additional in vitro work with mouse hepatoma cells has shown that activation of the AHR results in increased concentrations of 8-hydroxy-2’-deoxyguanosine (8-OHdG), a product of DNA-base oxidation and later excision repair and a marker of DNA damage. Induction of cytochrome P4501A1 (CYP1A1) by TCDD or indolo(3,2-b) carbazole is associated with oxidative DNA damage (Park et al., 1996). In vivo experiments in mice corroborated those findings by showing that TCDD caused a sustained oxidative stress, as determined by measurements of urinary 8-OHdG (Shertzer et al., 2002) involving AHR-dependent uncoupling of mitochondrial respiration (Senft et al., 2002). Mitochondrial reactive-oxygen production depends on the AHR. Other than the occasional observation of 8-OHdG, there is little evidence that TCDD is genotoxic, and it appears likely that some of these mechanisms of action may be induced by epigenetic modifications (events that affect gene function but do not involve a change in gene coding sequence) of the genome.

Electronics-dismantling workers who experienced complex exposures, including exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs), had increased concentrations of urinary 8-OHdG indicative of oxidative stress and genotoxicity; this cannot, however, be ascribed directly to the DLCs (Wen et al., 2008). Clastogenic genetic disturbances arising as a consequence of confirmed exposure to Agent Orange were determined by analyzing sister-chromatid exchanges (SCEs) in lymphocytes from a group of 24 New Zea-

land Vietnam War veterans and 23 control volunteers (Rowland et al., 2007). The results showed a highly significant difference (p < 0.001) in mean SCE frequency between the experimental group and the control group. The Vietnam War veterans also had a much higher proportion of cells with SCE frequencies above the 95th percentile than did the controls (11.0% and 0.07%, respectively).

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

Thus, the toxicologic evidence indicates that a connection of TCDD and perhaps cacodylic acid with cancer in humans is, in general, biologically plausible, but (as discussed in The Committee’s View of “General” Human Carcinogens below) it must be determined case by case whether such potential contributes to each individual type of cancer. Experiments with 2,4-D, 2,4,5-T, and picloram in animals and cells have not provided a strong biologic basis for either the presence or the absence of carcinogenic effects.

THE COMMITTEE’S VIEW OF “GENERAL” HUMAN CARCINOGENS

To address its charge, the committee weighed the scientific evidence linking the COIs to specific individual cancer sites. That was appropriate given the different susceptibilities of various tissues and organs to cancer and the various genetic and environmental factors that can influence the occurrence of a particular type of cancer. Before considering each site in turn, however, it is important to address the concept that cancers share some characteristics among organ sites and to clarify the committee’s view regarding the implications of a chemical’s being a “general” human carcinogen. All cancers share phenotypic characteristics: uncontrolled cell proliferation, increased cell survival, invasion outside normal tissue boundaries, and eventually metastasis. The current understanding of cancer development holds that a cell or group of cells must acquire a series of sufficient genetic mutations to progress and that particular epigenetic events must occur to accelerate the mutational process and provide growth advantages for the more aggressive clones of cells. Both genetic (mutational) and epigenetic (nonmutational) activities of carcinogenic agents can stimulate the process of cancer development.

In classic experiments based on the induction of cancer in mouse skin that were conducted over 40 years ago, carcinogens were categorized as initiators, those capable of causing an initial genetic insult to the target tissue, and promot-

ers, those capable of promoting the growth of initiated tumor cells, generally through nonmutational events. Some carcinogens, such as those found in tobacco smoke, were considered “whole carcinogens"; that is, they were capable of both initiation and promotion. Today, cancer researchers recognize that the acquisition of important mutations is a continuing process in tumors and that promoters, or epigenetic processes that favor cancer growth, enhance the accumulation of genotoxic damage, which traditionally would be regarded as initiating activity.

As discussed above and in Chapter 4, 2,4-D, 2,4,5-T, and picloram have shown little evidence of genotoxicity in laboratory studies, except at very high doses, and little ability to facilitate cancer growth in laboratory animals. However, cacodylic acid and TCDD have shown the capacity to increase cancer development in animal experiments, particularly as promoters rather than as pure genotoxic agents. Extrapolating organ-specific results from animal experiments to humans is problematic because of important differences between species in overall susceptibility of various organs to cancer development and in organ-specific responses to particular putative carcinogens. Therefore, judgments about the “general” carcinogenicity of a chemical in humans are based heavily on the results of epidemiologic studies, especially on the question of whether there is evidence of excess cancer risk at multiple organ sites. As the evaluations of specific types of cancer in the remainder of this chapter indicate, the committee finds that TCDD appears to be a multisite carcinogen. That finding is in agreement with the International Agency for Research on Cancer (IARC), which has determined that TCDD is a category 1 “known human carcinogen” (Baan et al., 2009); with the US Environmental Protection Agency (EPA), which has concluded that TCDD is “likely to be carcinogenic to humans” (http://www.epa.gov/ttn/atw/hlthef/dioxin.html; updated Januarary 2000; accessed September 21, 2013); and with the National Toxicology Program (NTP), which regards TCDD as “known to be a human carcinogen” (NTP, 2011). It is important to emphasize that the goals and methods of IARC and EPA in making their determinations were different from those of the present committee: the missions of those organizations focus on evaluating risk to minimize future exposure, whereas this committee focuses on risk after exposure. Furthermore, recognition that TCDD and cacodylic acid are multisite carcinogens does not imply that they cause human cancer at every organ site.

The distinction between general carcinogen and site-specific carcinogen is more difficult to grasp in light of the common practice of beginning analyses of epidemiologic cohorts with a category of “all malignant neoplasms,” which is a routine first screen for any unusual cancer activity in the study population rather than a test of a biologically based hypothesis. When the distribution of cancers among anatomic sites is lacking in the report of a cohort study, a statistical test for an increase in all cancers is not meaningless, but it is usually less scientifically supportable than are analyses based on specific sites, for which more substantial biologically based hypotheses can be developed. The size of a cohort and the

length of the observation period often constrain the number of cancer cases observed and which specific types of cancer have enough observed cases to permit analysis. For instance, an analysis of cumulative results on diabetes and cancer in the prospective Air Force Health Study (Michalek and Pavuk, 2008) produced important information summarizing previous findings on the fairly common condition of diabetes, but the cancer analysis does not go beyond “all cancers.” The committee does not accept the cancer findings as an indication that exposure to Agent Orange increases the risk of every variety of cancer. It acknowledges that the results of the highly stratified analyses conducted suggest that the incidence of some cancers did increase in the Operation Ranch Hand veterans, but it views the “all cancers” results as a conglomeration of information on specific cancers—most important, melanoma and prostate cancer, on which provocative results have been published (Akhtar et al., 2004; Pavuk et al., 2006)—and as meriting individual longitudinal analysis to resolve outstanding questions.

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

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

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

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

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

ORAL, NASAL, AND PHARYNGEAL CANCER

Oral, nasal, and pharyngeal cancers are found in many anatomic sites: the structures of the mouth (inside lining of the lips, cheeks, gums, tongue, and hard and soft palate—ICD-9 codes 140–145); oropharynx (ICD-9 146); nasopharynx (ICD-9 147); hypopharynx (ICD-9 148); other buccal cavity and pharynx (ICD-9 149); and nasal cavity and paranasal sinuses (ICD-9 160). Until recently, cancers that occur in the oral cavity and pharynx have been thought to be similar in descriptive epidemiology and risk factors, and cancer of the nasopharynx is thought to have a different epidemiologic profile. However, we now recognize that human papilloma virus (HPV) is an important risk factor for squamous-cell carcinoma of the head and neck, and risk estimates are highest for the base of the tongue and tonsils (oropharynx) (Marur et al., 2010).

The American Cancer Society (ACS) estimated that about 40,250 men and women would receive diagnoses of oral, nasal, or pharyngeal cancer in the United States in 2012 and that 7,850 men and women would die from these diseases (Siegel et al., 2012). Almost 91% of those cancers originate in the oral cavity or oropharynx. Most oral, nasal, and pharyngeal cancers are squamous-cell carcinomas. Nasopharyngeal carcinoma (NPC) is the most common malignant epithelial tumor of the nasopharynx but is relatively rare in the United States. There are three types of NPC: keratinizing squamous-cell carcinoma, nonkeratinizing carcinoma, and undifferentiated carcinoma.

The average annual incidences reported in Table 8-2 show that men are at greater risk than are women for those cancers and that the incidences increase

TABLE 8-2 Average Annual Incidence (per 100,000) of Nasal, Nasopharyngeal, Oral-Cavity and Pharyngeal, and Oropharyngeal Cancers in the United States^a

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

with age—but there are few cases, and care should be exercised in interpreting the numbers. Tobacco and alcohol use are established risk factors for oral and pharyngeal cancers. Reported risk factors for nasal cancer include occupational exposure to nickel and chromium compounds (d’Errico et al., 2009; Feron et al., 2001; Grimsrud and Peto, 2006), wood dust (d’Errico et al., 2009), leather dust (Bonneterre et al., 2007), and high doses of formaldehyde (Nielsen and Wolkoff, 2010).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COI and oral, nasal, and pharyngeal cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 did not change that conclusion.

In Update 2006, at the request of the Department of Veterans Affairs (VA), the committee attempted to evaluate tonsil-cancer cases separately, but it was able to identify only three cohort studies that provided the number of tonsil-cancer cases in their study populations and concluded that the studies did not provide sufficient evidence to determine whether an association existed between exposure to the COIs and tonsil cancer. No new studies have offered any important

additional insight into the question. The committee responsible for Update 2006 recommended that VA evaluate the possibility of studying health outcomes, including tonsil cancer, in Vietnam-era veterans by using existing administrative and health-services databases. Anecdotal evidence provided to that committee suggested a potential association between the exposures in Vietnam and tonsil cancer. Increasing evidence indicating that some cancers of the oropharynx and oral cavity can have a viral (HPV) etiology is consistent with the mechanistic hypothesis explaining an excess of these cancers in Vietnam veterans: immune alterations associated with Agent Orange exposure may have increased susceptibility to HPV infection in the oral cavity and tonsils of Vietnam veterans, thereby making them more prone to the development of squamous-cell carinomas in these tissues. The present committee strongly reiterates the 2006, 2008, and 2010 recommendation that VA develop a strategy that uses existing databases to evaluate tonsil cancer in Vietnam-era veterans.

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

McBride et al. (2009a) reported on mortality through 2004 in the New Zealand cohort of 1,599 workers who had been employed in manufacturing phenoxy herbicides from trichlorophenol (TCP); picloram was also produced in the plant. They reported a nonsignificant excess in mortality from buccal cavity and pharyngeal cancer and no deaths from nasopharyngeal cancer in either group.

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

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

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

Occupational Studies

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

TABLE 8-3 Selected Epidemiologic Studies—Oral, Nasal, and Pharyngeal Cancer (Shaded Entries Are New Information for This Update)

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

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

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

in the most restrictively defined cohort was not increased (standardized incidence ratio [SIR] = 1.09, 95% confidence interval [CI] 0.44–2.24), as was the case for the two more inclusive but potentially more biased cohorts.

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

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

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

Environmental Studies

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

Case-Control Studies

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

Biologic Plausibility

As noted above, there is increasing evidence that HPV contributes causally to cancers of the head and neck (Marur et al., 2010; Szentirmay et al., 2005) and to pharyngeal cancers in particular (Gillison and Shah, 2001; Gillison et al., 2012). It is unknown whether Agent Orange exposure contributes to a susceptibility to viral infection or action, but it warrants further exploration. The sparseness of data on the specific tumor site and a general lack of information on smoking, drinking, and viral exposure status in the few available epidemiologic studies preclude exploration of this hypothesis in the current literature.

Long-term animal studies have examined the effect of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). A National Toxicology Program study (Yoshizawa et al., 2005a) reported an increase in the incidence of gingival squamous-cell carcinoma in female rats treated orally (by gavage) with TCDD at 100 ng/kg 5 days/week for 104 weeks. The incidence of gingival squamous-cell hyperplasia was significantly increased in all groups treated at 3–46 ng/kg. In addition, squamous-cell carcinoma of the oral mucosa of the palate was increased. This NTP study did not, however, find any pathologic effect of TCDD on nasal tissues (Nyska et al., 2005). Increased neoplasms of the oral mucosa were previously observed and described as carcinomas of the hard palate and nasal turbinates (Kociba et al., 1978). Kociba et al. (1978) also reported a small increase in the incidence of tongue squamous-cell carcinoma.

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

with this AHR activation. This tumor type typically produces large amounts of cytokines, and its IL6 expression levels correlate with disease aggressiveness. In this model, AHR activation by TCDD enhances IL6 production induced by another cytokine (IL 1β), so TCDD may promote head and neck squamous-cell carcinoma.

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

Synthesis

Most of the new studies that reported results on oral, nasal, and pharyngeal cancers noted estimated reductions or nonsignificant excesses in mortality from oral and pharyngeal cancers. With a total of 11 oral, pharyngeal, or lip cancers, however, a significantly increased risk was reported for the Hamburg cohort overall; but with nine and two cases, respectively, the increased estimates of risk for men and women did not achieve the traditional level (p = 0.05) of statistical significance. In the AHS, the incidence of oral and pharyngeal cancers was significantly decreased for both private applicators and their spouses. Those data are not sufficient, taken in combination with the previously reviewed literature, to suggest an association with the herbicides sprayed in Vietnam.

Conclusion

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

CANCERS OF THE DIGESTIVE ORGANS

Until Update 2006, VAO committees had reviewed “gastrointestinal tract tumors” as a group consisting of stomach, colorectal, and pancreatic cancers; esophageal cancer has been formally included only since Update 2004. With more evidence from occupational studies available, VAO updates now address cancers of the digestive organs individually. Findings on cancers of the digestive organs as a group (ICD-9 150–159) are too broad for useful etiologic analysis and will no longer be considered.

Esophageal cancer (ICD-9 150), stomach cancer (ICD-9 151), colon cancer (ICD-9 153), rectal cancer (ICD-9 154), and pancreatic cancer (ICD-9 157) are among the most common cancers. ACS estimated that about 226,160 people would receive diagnoses of those cancers in the United States in 2012 and that 114,690 people would die from them (Siegel et al., 2012). Other digestive cancers (for example, small intestine, anal, and hepatobiliary cancers) added about 58,520

new diagnoses and 27,820 deaths to the 2012 estimates for the United States (Siegel et al., 2012). Collectively, tumors of the digestive organs were expected to account for 17% of new cancer diagnoses and 25% of cancer deaths in 2012. The average annual incidences of gastrointestinal cancers are presented in Table 8-4.

The incidences of stomach, colon, rectal, and pancreatic cancers increase with age. In general, the incidences are higher in men than in women and higher

TABLE 8-4 Average Annual Incidence (per 100,000) of Selected Gastrointestinal Cancers in the United States^a

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

in blacks than in whites. Risk factors for the cancers vary but always include family history of the same form of cancer, some diseases of the affected organ, and diet. Tobacco use is a risk factor for pancreatic cancer and possibly stomach cancer (Miller et al., 1996). Infection with the bacterium Helicobacter pylori increases the risk of stomach and pancreatic cancer. Type 2 diabetes is associated with an increased risk of colorectal and pancreatic cancers (ACS, 2013a).

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

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

Esophageal Cancer

Epithelial tumors of the esophagus (squamous-cell carcinomas and adenocarcinomas) are responsible for more than 95% of all esophageal cancers (ICD-9 150); 17,460 newly diagnosed cases and 15,070 deaths were estimated for 2012 (Siegel et al., 2012). The considerable geographic variation in the incidence of esophageal tumors suggests a multifactorial etiology. Rates of esophageal cancer have been increasing in the last 2 decades. Adenocarcinoma of the esophagus has slowly replaced squamous-cell carcinoma as the most common type of esophageal malignancy in the United States and western Europe (Blot and McLaughlin, 1999). Squamous-cell esophageal carcinoma rates are higher in blacks than in whites and higher in men than in women. Smoking and alcohol ingestion are associated with the development of squamous-cell carcinoma; these risk factors have been less thoroughly studied for esophageal adenocarcinoma, but they appear to be associated. The rapid increase in obesity in the United States has been linked to increasing rates of gastroesophageal reflux disease (GERD), and the resulting rise in chronic inflammation has been hypothesized as explaining

the link between GERD and esophageal adenocarcinoma. The average annual incidence of esophageal cancers is shown in Table 8-4.

Conclusions from VAO and Previous Updates

The committee responsible for VAO explicitly excluded esophageal cancer from the group of gastrointestinal tract tumors, for which it was concluded that there was limited or suggestive evidence of no association with exposure to the herbicides used by the US military in Vietnam. Esophageal cancer was not separately evaluated and was not categorized with this group until Update 2004, so by default it fell into the category of inadequate or insufficient evidence of an association. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the COIs to sustain that negative conclusion for any of the cancers in the gastrointestinal group, and that because these various types of cancer are generally regarded as separate disease entities the evidence on each should be evaluated separately. Esophageal cancer was thus formally placed into the inadequate or insufficient category. No additional studies of esophageal cancer were reviewed in Update 2008.

Update 2010 considered a series of papers on mortality in TCP and PCP workers employed by Dow Chemical Company in Midland, Michigan, from 1937 to 1980. Collins et al. (2009a) followed 1,615 workers who worked at least 1 day in a department that had potential TCDD exposure, among whom five esophageal-cancer deaths were observed, for an SMR of 1.0 (95% CI = 0.3–2.2); none of the five had had concurrent PCP exposure. Collins et al. (2009b) described mortality in 773 PCP workers who were exposed to chlorinated dioxins that did not include TCDD; there were two observed deaths from esophageal cancer (SMR = 0.8, 95% CI 0.1–2.9). McBride et al. (2009a) reported on a mortality followup of the workers in the Dow AgroSciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD. The SMR for esophageal-cancer deaths in exposed workers was 2.5 (95% CI 0.7–6.4) compared with an SMR of 2.1 (95% CI 0.1–12.2) in the never-exposed group. In following up cancer incidence in the men and women exposed to dioxin in the Seveso accident, Pesatori et al. (2009) observed no esophageal cancers in the high-exposure zone and no exposure-related pattern in the occurrence of esophageal cancer in the moderate- and low-exposure areas.

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

Update of the Epidemiologic Literature

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

TABLE 8-5 Selected Epidemiologic Studies—Esophageal Cancer (Shaded Entries Are New Information for This Update)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DCP, 2,4-dichlorophenol; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job-exposure matrix; MCPA, 2 methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PM, proportionate mortality; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCP, pentachlorophenol; TCDD, 2,3,7,8-tetra-chlorodibenzo-p-dioxin; TCP, trichlorophenol.

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

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

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

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

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

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

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

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004), and no increase in the incidence of esophageal cancer has been reported in laboratory animals after exposure to them. A previous biomarker study analyzed esophageal-cell samples from patients who had been exposed to indoor air pollution of different magnitudes and did or did not have high-grade squamous-cell dysplasia or a family history of upper gastrointestinal-tract (UGI) cancer (Roth et al., 2009). AHR expression was higher in patients who had a family history of UGI cancer but was not associated with indoor air pollution, esophageal squamous-cell dysplasia category, age, sex, or smoking. The results suggest that enhanced expression of the AHR in patients who had a family his-

tory of UGI cancer may contribute to UGI-cancer risk associated with AHR ligands—such as polycyclic aromatic hydrocarbons, which are found in cigarette smoke—and with TCDD.

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

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

Synthesis

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

Conclusion

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

Stomach Cancer

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

Conclusions from VAO and Previous Updates

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

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

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

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

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

TABLE 8-6 Selected Epidemiologic Studies—Stomach Cancer (Shaded Entries Are New Information for This Update)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4-DP, dichlorprop; 2,4,5-T, 2,4,5-trichlorophenoxy-acetic acid; 2,4,5-TCP, 2,4,5-trichlorophenol; 2,5-DCP, 2,5-dichlorophenol; CATI, computer-assisted telephone interviewing; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; JEM, job-exposure matrix; MCPA, 2-methyl-4-chlorophenoxyacetic acid; MCPB, 4-(4-chloro-2-methylphenoxy)butanoic acid; MCPP, methylchlorophenoxypropionic acid; NIOSH, National Institute for Occupational Safety and Health; nr, not reported; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines); PCMR, proportionate cancer mortality ratios; PCP, pentachlorophenol; PMR, proportionate mortality ratio; SEA, Southeast Asia; SIR, standardized incidence ratio; SMR, standardized mortality ratio; TCDD, 2,3,7,8-tetrachlorod-ibenzo-p-dioxin; TCP, trichlorophenol; UFW, United Farm Workers of America; VA, US Department of Veterans Affairs.

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

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

Update of the Epidemiologic Literature

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

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

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

tions of the workers in both factories did not indicate an increased risk of stomach cancer posed by TCDD (hazard ratio [HR] = 1.06, 95% CI 0.77–1.47). The dose–response modeling applied only to the workers in factory A, however, found a significantly increased risk of stomach cancer (HR = 1.52, 95% CI 1.05–2.20), whereas the qualitative exposure analysis in Boers et al. (2010) had not (HR = 2.23, 95% CI 0.38–13.20).

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

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

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

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

exposures estimated by application of a job—exposure matrix to work histories. Of chemicals that might have been of interest, only the category of “pesticides” was used, which is not specific enough for the results to be regarded as informative for the present review.

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs (2,4-D and TCDD) on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of gastrointestinal cancer has been reported in laboratory animals. However, studies of laboratory animals have observed dose-dependent increases in the incidence of squamous-cell hyperplasia of the forestomach or fundus of the stomach after administration of TCDD (Hebert et al., 1990; Walker et al., 2006). Similarly, in a long-term TCDD-treatment study in monkeys, hypertrophy, hyperplasia, and metaplasia were observed in the gastric epithelium (Allen et al., 1977). A transgenic mouse bearing a constitutively active form of the AHR has been shown to develop stomach tumors (Andersson et al., 2002a); the tumors are neither dysplastic nor metaplastic but are indicative of both squamous-cell and intestinal-cell metaplasia (Andersson et al., 2005). The validity of the transgenic-animal model is indicated by the similarities in the phenotype of the transgenic animal (increased relative weight of the liver and heart, decreased weight of the thymus, and increased expression of AHR target gene CYP1A1) and animals treated with TCDD (Brunnberg et al., 2006).

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

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

Synthesis

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

the risk did not remain significant (Boers et al., 2012). Several case-control studies addressing agricultural exposures reported evidence of an association of stomach cancer: both Ekström et al. (1999) and Mills and Yang (2007) found an association with herbicides, and with phenoxy herbicides in particular; Cocco et al. (1999) found a relationship with herbicide exposure, but the results were not specific as to type of herbicide. There has been no suggestion of an association between TCDD and stomach cancer in the Seveso population (Consonni et al., 2008; Pesatori et al., 2009) nor has there been any suggestion of an association between the COIs and stomach cancer in the studies of Vietnam-veteran cohorts or in the AHS.

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

Conclusion

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

Colorectal Cancer

Colorectal cancers include malignancies of the colon (ICD-9 153) and of the rectum and anus (ICD-9 154); less prevalent tumors of the small intestine (ICD-9 152) are often included. Findings on cancers of the retroperitoneum and other unspecified digestive organs (ICD-9 159) are considered in this category. Colorectal cancers account for about 55% of digestive tract tumors; ACS estimated that 157,760 people would receive diagnoses of colorectal cancer in the United States in 2012 and that 53,620 would die from it (Siegel et al., 2012). Excluding basal-cell and squamous-cell skin cancers, colorectal cancer is the third-most common form of cancer both in men and in women. The average annual incidence of colorectal cancers is shown in Table 8-4.

The incidence of colorectal cancer increases with age; it is higher in men than in women and higher in blacks than in whites. (Screening can affect the incidence, and it is recommended for all persons over 50 years old.) Other risk factors include family history of this form of cancer, some diseases of the intestines, and diet. Type 2 diabetes is associated with an increased risk of colorectal cancer (ACS, 2013a).

Conclusions from VAO and Previous Updates

Update 2006 considered colorectal cancer independently for the first time. Prior updates developed tables of results on colon and rectal cancer, but conclus-

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

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

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

Update of the Epidemiologic Literature

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

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

TABLE 8-7 Selected Epidemiologic Studies—Colon and Rectal Cancer (Shaded Entries Are New Information for This Update)