7

Cancer

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

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

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

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

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

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

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

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

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

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

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

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

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

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

ORGANIZATION OF CANCER GROUPS

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

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

BIOLOGIC PLAUSIBILITY

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

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

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

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

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

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

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

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

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

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

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

THE COMMITTEE’S VIEW OF “GENERAL” HUMAN CARCINOGENS

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

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

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

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

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

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

ORAL, NASAL, AND PHARYNGEAL CANCER

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

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

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

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

Conclusions from VAO and Previous Updates

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

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

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

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

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

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

Update of the Epidemiologic Literature

Vietnam-Veteran Studies

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

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

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

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

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

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

Occupational Studies

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

Environmental Studies

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

Biologic Plausibility

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

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

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

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

Synthesis

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

Conclusion

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

CANCERS OF THE DIGESTIVE ORGANS

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

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

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

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

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

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

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

Esophageal Cancer

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

Conclusions from VAO and Previous Updates

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

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

Update of the Epidemiologic Literature

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

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

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

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

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

TABLE 7-5 Selected Epidemiologic Studies—Esophageal Cancer

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

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

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

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

Biologic Plausibility

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

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

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

Synthesis

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

Conclusion

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

Stomach Cancer

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

Conclusions from VAO and Previous Updates

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

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

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

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

Update of the Epidemiologic Literature

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

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

TABLE 7-6 Selected Epidemiologic Studies—Stomach Cancer

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

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

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

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

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

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

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

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

Biologic Plausibility

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

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

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

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

Synthesis

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

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

Conclusion

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

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

Colorectal Cancer

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

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

Conclusions from VAO and Previous Updates

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

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

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