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



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8 Cancer Chapter Overview Based on new evidence and a review of prior studies, the committee for did not find any new significant associations between the relevant exposures and particu- lar 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 dis- ease, 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 Ameri- cans 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 299

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300 VETERANS AND AGENT ORANGE: UPDATE 2012 TABLE 8-1  Age Distribution of Vietnam-Era and Vietnam-Theater Male Veterans, 2009–2010 (Numbers in Thousands) Vietnam Era Vietnam Theater Age Group (Years) n (%) n (%) All ages 7,805 3,816 ≤ 54 133 (1.8) 32 (0.9) 55–59 1,109 (15.1) 369 (10.4) 60–64 3,031 (41.3) 1,676 (47.0) 65–69 2,301 (31.3) 1,090 (30.6) 70–74 675 (9.2) 280 (7.9) 75–84 511 (6.9) 322 (9.0) ≥ 85 178 (2.4) 83 (2.4) SOURCE: IOM, 1994, Table 3-3, updated by 20 years. 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 concentra- tions 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-

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CANCER 301 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, includ- ing 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: Veter- ans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994); Veterans and Agent Orange: Update 1996, re- ferred 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 discus- sion 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 epidemio- logic 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

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302 VETERANS AND AGENT ORANGE: UPDATE 2012 congressionally mandated statement of task. In fact, the degree of biologic plau- sibility 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) carcino- genic potential of the COIs is summarized in Chapter 4. It distills toxicologic information concerning the mechanisms by which TCDD affects the basic pro- cess 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 ex- posure 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 esti- mates 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 com- mittee 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 Interna- tional 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

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CANCER 303 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 my- eloid 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 identifi- cation 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 “inad- equate evidence” of association with exposure to the COIs, which in principle is applicable to specific cancers. Failure to review a specific cancer or other condi- tion 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 associa- tions 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 hydro- carbon 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 mecha- nisms 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

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304 VETERANS AND AGENT ORANGE: UPDATE 2012 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 per- formed in laboratory animals have shown that it can induce neoplasms of the kid- ney (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 sus- pected 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, treat- ment 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 car- cinogenic 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

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CANCER 305 other tissues (Hollingshead et al., 2008). In rat liver, TCDD downregulates re- duced 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 (phos- phorylation 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 initi- ated 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 dam- age. 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 de- pends 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 con- sequence of confirmed exposure to Agent Orange were determined by analyzing sister-chromatid exchanges (SCEs) in lymphocytes from a group of 24 New Zea-

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306 VETERANS AND AGENT ORANGE: UPDATE 2012 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 carcinogen- esis and biologic plausibility based on mode-of-action data. Although the specific mechanisms by which dioxin causes cancer remain to be established, the intra- cellular 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 dif- ferent from the multiple animal species in which bioassays have demonstrated dioxin-induced neoplasia. Thus, the toxicologic evidence indicates that a connection of TCDD and per- haps 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 link- ing 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 be- ing 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 ag- gressive 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-

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CANCER 307 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 acquisi- tion 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. How- ever, cacodylic acid and TCDD have shown the capacity to increase cancer de- velopment 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 spe- cific 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 deter- mined 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

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308 VETERANS AND AGENT ORANGE: UPDATE 2012 length of the observation period often constrain the number of cancer cases ob- served 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 con- dition 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 occu- pational 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 expecta- tion (Boers et al., 2012). The committee notes that current information on overall mortality in US Viet- nam 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 expo- sures were identified in the literature search for this review but did not character- ize exposure with sufficient specificity for their results to meet the committee’s criteria for inclusion in the evidentiary database. For instance, the British Pesti- cide Users Health Study has followed almost 60,000 men and 4,000 women who

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CANCER 309 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 de- scriptive 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 carcino- mas. 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 car- cinoma, 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

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