ORGANIZATION OF CANCER GROUPS

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

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

BIOLOGIC PLAUSIBILITY

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

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

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

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

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

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

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

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

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

THE COMMITTEE'S VIEW OF “GENERAL” HUMAN CARCINOGENS

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

In classic experiments based on the induction of cancer in mouse skin that were conducted over 40 years ago, carcinogens were categorized as initiators, those capable of causing an initial genetic insult to the target tissue, and 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 chemical in humans are based heavily on the results of epidemiologic studies, especially on the question of whether there is evidence of excess cancer risk at multiple organ sites. As the evaluations of specific types of cancer in the remainder of this chapter indicate, the committee finds that TCDD appears to be a multisite carcinogen. That finding is in agreement with the International Agency for Research on Cancer (IARC), which has determined that TCDD is a category 1 “known human carcinogen” (Baan et al., 2009); with the US Environmental Protection Agency (EPA), which has concluded that TCDD is “likely to be carcinogenic to humans” (http://www.epa.gov/ttn/atw/hlthef/dioxin.html; updated Januarary 2000; accessed September 21, 2013); and with the National Toxicology Program (NTP), which regards TCDD as “known to be a human carcinogen” (NTP, 2011). It is important to emphasize that the goals and methods of IARC and EPA in making their determinations were different from those of the present committee: the missions of those organizations focus on evaluating risk to minimize future exposure, whereas this committee focuses on risk after exposure. Furthermore, recognition that TCDD and cacodylic acid are multisite carcinogens does not imply that they cause human cancer at every organ site.

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

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

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

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

A number of studies of populations that received potentially relevant exposures were identified in the literature search for this review but did not characterize exposure with sufficient specificity for their results to meet the committee's criteria for inclusion in the evidentiary database. For instance, the British Pesticide Users Health Study has followed almost 60,000 men and 4,000 women who were certified for agricultural pesticide use in Great Britain since 1987. Frost et al. (2011) reported cancer incidence and mortality in this cohort up to 2004 for the full array of anatomic sites, but exposure was defined only as being a member of this cohort. Therefore, the cancer-specific findings of Frost et al. (2011) will not be repeatedly noted in the individual sections below. That is also the case for the mortality followup of Japanese Americans in the Honolulu Heart Program reported by Charles et al. (2010). Technically, this rubric would apply to the mortality and morbidity results reported by Waggoner et al. (2011) and >Koutrous et al. (2010a); because of the context provided by the extensive pesticide-specific results that have been published on individual cancers in the Agricultural Health Study (AHS) and the knowledge that 2,4-D was one of the most frequently used pesticides in this large prospective cohort, however, those results are presented below, but not given full evidentiary weight. Numerous cancer studies of the case-control design addressing particular cancers had exposure characterizations that were not more specific than job titles, farm residence, or pesticide exposure; therefore, their results are not regarded as fully relevant for the purpose of this review, and such studies are mentioned only in passing in a discussion of the cancer investigated.

ORAL, NASAL, AND PHARYNGEAL CANCER

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

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

The average annual incidences reported in Table 8-2 show that men are at greater risk than are women for those cancers and that the incidences increase with age—but there are few cases, and care should be exercised in interpreting the numbers. Tobacco and alcohol use are established risk factors for oral and pharyngeal cancers. Reported risk factors for nasal cancer include occupational exposure to nickel and chromium compounds (d'Errico et al., 2009; Feron et al., 2001; Grimsrud and Peto, 2006), wood dust (d'Errico et al., 2009), leather dust (Bonneterre et al., 2007), and high doses of formaldehyde (Nielsen and Wolkoff, 2010).

TABLE 8-2

Average Annual Incidence (per 100,000) of Nasal, Nasopharyngeal, Oral-Cavity and Pharyngeal, and Oropharyngeal Cancers in the United States.

Conclusions from VAO and Previous Updates

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

In Update 2006, at the request of the Department of Veterans Affairs (VA), the committee attempted to evaluate tonsil-cancer cases separately, but it was able to identify only three cohort studies that provided the number of tonsil-cancer cases in their study populations and concluded that the studies did not provide sufficient evidence to determine whether an association existed between exposure to the COIs and tonsil cancer. No new studies have offered any important additional insight into the question. The committee responsible for Update 2006 recommended that VA evaluate the possibility of studying health outcomes, including tonsil cancer, in Vietnam-era veterans by using existing administrative and health-services databases. Anecdotal evidence provided to that committee suggested a potential association between the exposures in Vietnam and tonsil cancer. Increasing evidence indicating that some cancers of the oropharynx and oral cavity can have a viral (HPV) etiology is consistent with the mechanistic hypothesis explaining an excess of these cancers in Vietnam veterans: immune alterations associated with Agent Orange exposure may have increased susceptibility to HPV infection in the oral cavity and tonsils of Vietnam veterans, thereby making them more prone to the development of squamous-cell carinomas in these tissues. The present committee strongly reiterates the 2006, 2008, and 2010 recommendation that VA develop a strategy that uses existing databases to evaluate tonsil cancer in Vietnam-era veterans.

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

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

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

TABLE 8-3

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

CANCERS OF THE DIGESTIVE ORGANS

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

Esophageal cancer (ICD-9 150), stomach cancer (ICD-9 151), colon cancer (ICD-9 153), rectal cancer (ICD-9 154), and pancreatic cancer (ICD-9 157) are among the most common cancers. ACS estimated that about 226,160 people would receive diagnoses of those cancers in the United States in 2012 and that 114,690 people would die from them (Siegel et al., 2012). Other digestive cancers (for example, small intestine, anal, and hepatobiliary cancers) added about 58,520 new diagnoses and 27,820 deaths to the 2012 estimates for the United States (Siegel et al., 2012). Collectively, tumors of the digestive organs were expected to account for 17% of new cancer diagnoses and 25% of cancer deaths in 2012. The average annual incidences of gastrointestinal cancers are presented in Table 8-4.

TABLE 8-4

Average Annual Incidence (per 100,000) of Selected Gastrointestinal Cancers in the United States.

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

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

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

Esophageal Cancer

Epithelial tumors of the esophagus (squamous-cell carcinomas and adenocarcinomas) are responsible for more than 95% of all esophageal cancers (ICD-9 150); 17,460 newly diagnosed cases and 15,070 deaths were estimated for 2012 (Siegel et al., 2012). The considerable geographic variation in the incidence of esophageal tumors suggests a multifactorial etiology. Rates of esophageal cancer have been increasing in the last 2 decades. Adenocarcinoma of the esophagus has slowly replaced squamous-cell carcinoma as the most common type of esophageal malignancy in the United States and western Europe (Blot and McLaughlin, 1999). Squamous-cell esophageal carcinoma rates are higher in blacks than in whites and higher in men than in women. Smoking and alcohol ingestion are associated with the development of squamous-cell carcinoma; these risk factors have been less thoroughly studied for esophageal adenocarcinoma, but they appear to be associated. The rapid increase in obesity in the United States has been linked to increasing rates of gastroesophageal reflux disease (GERD), and the resulting rise in chronic inflammation has been hypothesized as explaining the link between GERD and esophageal adenocarcinoma. The average annual incidence of esophageal cancers is shown in Table 8-4.

Conclusions from VAO and Previous Updates

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

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

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

TABLE 8-5

Selected Epidemiologic Studies—Esophageal Cancer (Shaded Entries Are New Information for This Update).

Update of the Epidemiologic Literature

Vietnam-Veteran and Environmental Studies

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

Occupational Studies

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

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

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

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

Case-Control Studies

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

Biologic Plausibility

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

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

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

Synthesis

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

Conclusion

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

Stomach Cancer

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

Conclusions from VAO and Previous Updates

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

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

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

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

TABLE 8-6

Selected Epidemiologic Studies—Stomach Cancer (Shaded Entries Are New Information for This Update).

Update of the Epidemiologic Literature

Vietnam-Veteran and Environmental Studies

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

Occupational Studies

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

Boers et al. (2012) provided a quantified, TCDD-based analysis, updated through 2006, of mortality in male workers in two Dutch phenoxy-herbicide factories, which were considered in Update 2010 (Boers et al., 2010). The 1,020 workers in factory A had been involved in production of 2,4,5-T with its associated TCDD contamination; the 1,036 in factory B had produced only phenoxy herbicides that would not have had TCDD contamination. Contemporary TCDD concentrations measured in a subsample of 187 workers were used to derive a model incorporating job history to estimate serum TCDD concentrations of all the men at the end of their employment. Using the estimated TCDD concentrations of the workers in both factories did not indicate an increased risk of stomach cancer posed by TCDD (hazard ratio [HR] = 1.06, 95% CI 0.77–1.47). The dose–response modeling applied only to the workers in factory A, however, found a significantly increased risk of stomach cancer (HR = 1.52, 95% CI 1.05–2.20), whereas the qualitative exposure analysis in Boers et al. (2010) had not (HR = 2.23, 95% CI 0.38–13.20).

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

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

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

Case-Control Studies

In a Spanish study, Santibanez et al. (2012) explored the relationship between 399 stomach cancers of varied histology and occupational exposures estimated by application of a job—exposure matrix to work histories. Of chemicals that might have been of interest, only the category of “pesticides” was used, which is not specific enough for the results to be regarded as informative for the present review.

Biologic Plausibility

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

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

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

Synthesis

Boers et al. (2012) derived a predictive model based on job histories and current TCDD concentrations in a subset of the workers in two Dutch phenoxy-herbicide factories. Using estimates of each man's serum TCDD at the end of his employment, they found a significant increase in the risk of death from stomach cancer in the workers in the factory that had TCDD contamination, whereas an earlier categorical analysis of the same data found an increase risk with a very wide confidence interval (Boers et al., 2010); when the workers in the factory that did not have TCDD contamination were added to the continuous analysis, the risk did not remain significant (Boers et al., 2012). Several case-control studies addressing agricultural exposures reported evidence of an association of stomach cancer: both Ekström et al. (1999) and Mills and Yang (2007) found an association with herbicides, and with phenoxy herbicides in particular; Cocco et al. (1999) found a relationship with herbicide exposure, but the results were not specific as to type of herbicide. There has been no suggestion of an association between TCDD and stomach cancer in the Seveso population (Consonni et al., 2008; Pesatori et al., 2009) nor has there been any suggestion of an association between the COIs and stomach cancer in the studies of Vietnam-veteran cohorts or in the AHS.

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

Conclusion

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

Colorectal Cancer

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

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

Conclusions from VAO and Previous Updates

Update 2006 considered colorectal cancer independently for the first time. Prior updates developed tables of results on colon and rectal cancer, but 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 COIs to sustain that negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Colorectal cancer was thus reclassified into the default category of inadequate or insufficient evidence to determine whether there is an association. The information considered in Update 2008 did not provide evidence to support moving colorectal cancers out of the category of inadequate or insufficient evidence.

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

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

TABLE 8-7

Selected Epidemiologic Studies—Colon and Rectal Cancer (Shaded Entries Are New Information for This Update).

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies

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

Occupational Studies

Burns et al. (2011) updated, through 2007, cancer incidence in workers who were alive on January 1, 1985, and had been employed at any time from 1945 to 1994 in 2,4-D production by the Dow Chemical Company in Midland, Michigan. They found no evidence of significantly increased rates of cancer overall. In the most restrictively defined cohort, the SIR for colon cancer was 0.95 (95% CI 0.55–1.55), and the SIR for rectal cancer was 0.78 (95% CI 0.29–1.70). For both cancer types, the results were similar in the two more inclusive, but potentially more biased, cohorts.

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

Ruder and Yiin (2011) reported mortality for 1940–2005 separately for intestinal cancer (ICD-9 152–153) and colon cancer in the NIOSH PCP cohort of 2,122 workers in the four US plants that had been involved in PCP production. PCP production entailed exposure to PCDDs and PCDFs but not to the most toxic 2,3,7,8 dioxin congener. A subcohort of 720 workers (all men, the PCP-plus-TCDD group) had also been employed in TCP production and so had also been exposed to TCDD. Relative to US referent rates, deaths from intestinal cancer were not substantially changed in the entire cohort (26 deaths, SMR = 1.07, 95% CI 0.70–1.57), the PCP-only group (15 deaths, SMR = 0.90, 95% CI 0.50–1.49), or the PCP-plus-TCDD group (11 deaths, SMR = 1.44, 95% CI 0.72–2.57). Only two deaths from rectal cancer were reported in the entire cohort—one in each subcohort—which was in accord with expectations.

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

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

Biologic Plausibility

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

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

Synthesis

The generic findings on the applicators and their spouses in the AHS showed indications of increased mortality from both colon and intestinal cancer in agricultural workers, but earlier assessment of colorectal cancer in this study population had found no increase in risks in association with exposure to individual phenoxy herbicides (Lee WJ et al., 2007). None of the epidemiologic studies reviewed that specifically addressed the COIs, however, yielded evidence of an association between the COIs and colorectal cancer. There is no evidence of biologic plausibility of an association between exposure to any of the COIs and tumors of the colon or rectum. Overall, the available evidence does not support an association between the COIs and colorectal cancer.

Conclusion

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

Hepatobiliary Cancers

Hepatobiliary cancers include cancers of the liver (ICD-9 155.0, 155.2) and the intrahepatic bile duct (ICD-9 155.1). ACS estimated that 21,370 men and 7,350 women would receive diagnoses of liver cancer or intrahepatic bile duct cancer in the United States in 2012 and that 13,980 men and 6,570 women would die from these cancers (Siegel et al., 2012). Gallbladder cancer and extrahepatic bile duct cancer (ICD-9 156) are fairly uncommon and are often grouped with liver cancers when they are addressed.

In the United States, liver cancers account for about 1.5% of new cancer cases and 3.3% of cancer deaths. Misclassification of metastatic cancers as primary liver cancer can lead to overestimation of the number of deaths attributable to liver cancer (Percy et al., 1990). In developing countries, especially those in sub-Saharan Africa and Southeast Asia, liver cancers are common and are among the leading causes of death. Known risk factors for liver cancer include chronic infection with hepatitis B or hepatitis C virus and exposure to the carcinogens aflatoxin and vinyl chloride. Alcohol cirrhosis and obesity-associated metabolic syndrome may also contribute to the risk of liver cancer. In the general population, the incidence of liver and intrahepatic bile duct cancer increases slightly with age; at the ages of 50–64 years, it is greater in men than in women and greater in blacks than in whites. The average annual incidence of hepatobiliary cancers is shown in Table 8-4.

Conclusions from VAO and Previous Updates

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

Update 2010 considered followup reports on three previously studied populations. Collins et al. (2009a,b) examined mortality in workers employed in a Dow Chemical Company plant in Midland, Michigan, during 1937–1980. They found two cases of cancer of the hepatobiliary tract in 1,615 TCP workers (SMR = 0.5, 95% CI 0.1–1.6) but no observed deaths from that cancer in 773 PCP workers. The second occupational-mortality study was of workers in the Dow AgroSciences plant in New Plymouth, New Zealand, who were potentially exposed to TCDD; SMRs for hepatobiliary cancer calculated on the basis of national mortality figures were 1.4 (95% CI 0.2–5.1) in exposed workers and 0.0 (95% CI 0.0–8.2) in the never-exposed group (McBride et al., 2009a). The update of cancer incidence in the Seveso cohort did not find systematic evidence of hepatic or biliary cancers in any of the exposure zones (Pesatori et al., 2009).

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

TABLE 8-8

Selected Epidemiologic Studies—Hepatobiliary Cancers (Shaded Entries Are New Information for This Update).

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies

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

Occupational Studies

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

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

Koutros et al. (2010a) published an update of cancer incidence in the AHS. In private applicators, there were 32 cases of liver cancer (SIR = 0.73, 95% CI 0.50–1.03) and eight cases of gallbladder cancer (SIR = 1.33, 95% CI 0.57–2.61). In their spouses, there were six liver-cancer cases (SIR = 0.76, 95% CI 0.28–1.66) and seven gallbladder-cancer cases (SIR = 1.09, 95% CI 0.44–2.25). Waggoner et al. (2011) compared deaths from hepataboliary from the time of enrollment (1993–1997) through 2007 to state mortality rates. Rates of hepatobiliary cancers (liver and gallbladder) in applicators was less than expected (50 deaths, SMR = 0.70, 95% CI 0.52–0.93), but not in their spouses (18 deaths, SMR = 0.81, 95% CI 0.48–1.28). The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee's task.

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). Studies performed in laboratory animals have consistently demonstrated that long-term exposure to TCDD results in the formation of liver adenomas and carcinomas (Knerr and Schrenk, 2006; Walker et al., 2006). Furthermore, TCDD increases the growth of hepatic tumors that are initiated by treatment with a complete carcinogen. Pathologic liver changes have been observed after exposure to TCDD, including nodular hyperplasia and massive inflammatory cell infiltration (Kociba et al., 1978; NTP, 2006; Walker et al., 2006; Yoshizawa et al., 2007); inflammation can be heavily involved in the development and progression of many cancers, including liver cancers (Mantovani et al., 2008). In monkeys treated with TCDD, hyperplasia and an increase in cells that stain positive for alpha-smooth muscle actin have been observed (Korenaga et al., 2007). Postive staining for alpha-smooth muscle actin is thought to be indicative of a process (epithelial–mesenchymal transition) that is associated with the progression of malignant tumors (Weinberg, 2008).

Bile duct hyperplasia (but not tumors) has been reported in rodents following chronic treatment with TCDD (Knerr and Schrenk, 2006; Walker et al., 2006; Yoshizawa et al., 2007). Similarly, monkeys treated with TCDD developed metaplasia, hyperplasia, and hypertrophy of the bile duct (Allen et al., 1977). Hollingshead et al. (2008) showed that TCDD-activated AHR in human breast and endocervical cell lines induces sustained high concentrations of the interleu-kin-6 cytokine, which has tumor-promoting effects in numerous tissues, including cholangiocytes; thus, TCDD might promote carcinogenesis in biliary tissue.

TCDD may contribute to tumor progression by inhibiting p53 regulation (phosphorylation and acetylation) triggered by genotoxicants through the increased expression of the metastasis marker AGR2 (Ambolet-Camoit et al., 2010) and a functional interaction between the AHR and FHL2 (Kollara and Brown, 2009). The AHR was also shown to be a regulator of c-raf and proposed cross-talk between the AHR and the mitogen-activated protein kinase signaling pathway in chemically induced hepatocarcinogenesis (Borlak and Jenke, 2008). TCDD inhibits ultraviolet-C radiation-induced apoptosis in primary rat hepatocytes and Huh-7 human hepatoma cells, and this supports the hypothesis that TCDD acts as a tumor-promoter by preventing initiated cells from undergoing apoptosis (Chopra et al., 2009).

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

In rodents, TCDD may promote hepatocarcinogenesis through cytotoxicity, chronic inflammation, and liver regeneration and through hyperplastic and hypertrophic growth due to sustained activation of the AHR (Köhle and Bock, 2007; Köhle et al., 2008). Species differences associated with AHR activation are demonstrated by the divergence in the transcriptomic responses to TCDD in mouse, rat, and human liver (Boutros et al., 2008, 2009; Carlson et al., 2009; Kim et al., 2009), but it should be noted that the in vitro human hepatocyte studies may not reflect the in vivo response of human liver to TCDD. In vitro studies with transformed cell lines and primary hepatocytes cannot replicate the complexity of a tissue response that is important in eliciting the toxic responses observed in vivo (Dere et al., 2006).

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

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

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

Synthesis

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

Conclusion

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

Pancreatic Cancer

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

Conclusions from VAO and Previous Updates

Update 2006 considered pancreatic cancer independently for the first time. Prior updates developed tables of results for pancreatic cancer but reached conclusions about the adequacy of the evidence of its association with herbicide exposure in the context of gastrointestinal tract cancers. The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the herbicides used by the US military in Vietnam and gastrointestinal tract tumors, including pancreatic cancer. The committee responsible for Update 2006 concluded that there was not enough evidence on each of the COIs to sustain that negative conclusion for any of the cancers in the gastrointestinal group and that, because these various types of cancer are generally regarded as separate disease entities, the evidence on each should be evaluated separately. Pancreatic cancer was thus reclassified into the default category of inadequate or insufficient evidence of an association. The Update 2006 committee reviewed the increased rates of pancreatic cancer in Australian National Service Vietnam veterans but concluded that the increased rates could be attributed to the rates of smoking in the cohort (ADVA, 2005c). The committee also noted the report of increased rates of pancreatic cancer in US female Vietnam nurse veterans (Dalager et al., 1995). That increase persisted in the followup study of the American female veterans (Cypel and Kang, 2008) considered in Update 2008, but the update on mortality in the Seveso population (Consonni et al., 2008) did not support an association with pancreatic cancer.

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

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

TABLE 8-9

Selected Epidemiologic Studies—Pancreatic Cancer (Shaded Entries Are New Information for This Update).

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies

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

Occupational Studies

Burns et al. (2011) published an update examining cancer incidence through 2007 in workers who were alive on January 1, 1985, and had been employed at any time from 1945 to 1994 in 2,4-D production by the Dow Chemical Company in Midland, Michigan. They found no evidence of significantly increased rates of cancer overall. With two cases observed, the incidence of pancreatic cancer in the most restrictively defined cohort was not increased (SIR = 0.42, 95% CI 0.05–1.52), nor was it increased in the two successively more inclusive, but potentially more biased, cohorts.

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

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

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

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

Biologic Plausibility

Long-term animal studies have examined the effect of exposure to the COIs on tumor incidence (Charles et al., 1996; Stott et al., 1990; Walker et al., 2006; Wanibuchi et al., 2004). No increase in the incidence of pancreatic cancer in laboratory animals after the administration of cacodylic acid, 2,4-D, or picloram has been reported. A 2-year study of female rats reported increased incidences of pancreatic adenomas and carcinomas after treatment at the highest dose of TCDD (100 ng/kg per day) (Nyska et al., 2004). Other studies have observed chronic active inflammation, acinar-cell vacuolation, and an increase in proliferation of the acinar cells surrounding the vacuolated cells (Yoshizawa et al., 2005b). As previously discussed, chronic inflammation and hyperproliferation are closely linked to the formation and progression of cancers, including cancer of the pancreas (Hahn and Weinberg, 2002; Mantovani et al., 2008). Metaplastic changes in the pancreatic ducts were also observed in female monkeys treated with TCDD (Allen et al., 1977).

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

Synthesis

The large excess of pancreatic cancers in female Vietnam veterans vs their nondeployed counterparts observed by Thomas et al. (1991) and Dalager et al. (1995) prevailed in a study by Cypel and Kang (2008), who found a significant increase in all female Vietnam veterans and in the nurse subset. The committee responsible for Update 2006 reported a higher incidence of and mortality from pancreatic cancer in deployed Australian National Service veterans than in nondeployed veterans (ADVA, 2005c). A limitation of all the veteran studies considered has been the lack of control for the effect of smoking. In the 31 female and 62 male cases in the AHS case-control study considered in Update 2010 (Andreotti et al., 2009), however, the risk of pancreatic cancer was not associated with 2,4-D exposure, so the relative increase in the AHS cohort overall (Waggoner et al., 2011) would most certainly not be attributable to 2,4-D exposure. No increase in risk has been reported in US male Vietnam veterans or in IARC followup studies. The new updates on production cohorts and analyses from the AHS do not imply that exposures to the COIs are associated with the occurrence of pancreatic cancer.

Conclusion

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

LARYNGEAL CANCER

ACS estimated that 9,840 men and 2,520 women would receive diagnoses of cancer of the larynx (ICD-9 161) in the United States in 2012 and that 2,880 men and 770 women would die from it (Siegel et al., 2012). Those numbers constitute a little more than 0.9% of new cancer diagnoses and 0.7% of cancer deaths. The incidence of cancer of the larynx increases with age, and it is more common in men than in women, with a sex ratio in the United States of about 4:1 in people 50–64 years old. The average annual incidence of laryngeal cancer is shown in Table 8-10.

TABLE 8-10

Average Annual Cancer Incidence (per 100,000) of Laryngeal Cancer in the United States.

Established risk factors for laryngeal cancer are tobacco use and alcohol use, which are independent and act synergistically. Occupational exposures—long and intense exposures to wood dust, paint fumes, and some chemicals used in the metalworking, petroleum, plastics, and textile industries—also could increase risk (ACS, 2012a). An Institute of Medicine committee concluded that asbestos is a causal factor in laryngeal cancer (IOM, 2006); infection with human papilloma virus is also thought to raise the risk of laryngeal cancer (Baumann et al., 2009; Hobbs and Birchall, 2004).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to at least one of the COIs and laryngeal cancer on the basis of the evidence discussed below in the section “Synthesis.” Although the small number of laryngeal cancers included in most studies generally limits their statistical power to support strong conclusions, additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 did not change that conclusion.

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

TABLE 8-11

Selected Epidemiologic Studies—Laryngeal Cancer (Shaded Entries Are New Information for This Update).

LUNG CANCER

Lung cancer (carcinoma of the lung or bronchus, ICD-9 162.2–162.9) is the leading cause of cancer death in the United States. ACS estimated that 116,470 men and 109,690 women would receive diagnoses of lung cancer in the United States in 2012 and that about 87,750 men and 72,590 women would die from it (Siegel et al., 2012). Those numbers represent roughly 14% of new cancer diagnoses and 28% of cancer deaths in 2012. The principal types of lung neoplasms are identified collectively as bronchogenic carcinoma and carcinoma of the lung. Cancer of the trachea (ICD-9 162.0) is often grouped with cancer of the lung and bronchus under ICD-9 162. The lung is also a common site of metastatic tumors.

In men and women, the incidence of lung cancer increases greatly beginning at about the age of 40 years. The incidence in people 50–54 years old is double that in people 45–49 years old, and it doubles again in those 55–59 years old. The incidence is consistently higher in black men than in women or white men. The average annual incidence of lung cancer in the United States is shown in Table 8-12.

TABLE 8-12

Average Annual Incidence (per 100,000) of Lung and Bronchial Cancer in the United States.

ACS estimates that 87% of lung-cancer deaths are attributable to cigarette-smoking (ACS, 2011). Smoking increases the risk of all histologic types of lung cancer, but the associations with squamous-cell and small-cell carcinomas are strongest. Other risk factors include exposure to asbestos, uranium, vinyl chloride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, diesel exhaust, and inorganic arsenic. The latter statement does not imply that cacodylic acid, which is a metabolite of inorganic arsenic, can be assumed to be a risk factor. Important environmental risk factors include exposure to tobacco smoke and radon (ACS, 2013a).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to at least one COI and lung cancer on the basis of the evidence discussed below in the section “Synthesis.” Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 did not change that conclusion.

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

TABLE 8-13

Selected Epidemiologic Studies—Lung, Bronchus, or Trachea Cancer (Shaded Entries Are New Information for This Update).

BONE AND JOINT CANCER

ACS estimated that about 1,600 men and 1,290 women would receive diagnoses of bone or joint cancer (ICD-9 170) in the United States in 2012 and that 790 men and 620 women would die from these cancers (Siegel et al., 2012). Primary bone cancers are among the least common malignancies, but the bones are frequent sites of tumors secondary to cancers that have metastasized. Only primary bone cancer is considered here. The average annual incidence of bone and joint cancer is shown in Table 8-14.

TABLE 8-14

Average Annual Incidence (per 100,000) of Bone and Joint Cancer in the United States.

Bone cancer is more common in teenagers than in adults. It is rare among people in the age groups of most Vietnam veterans (50–64 years). Among the risk factors for bone and joint cancer in adults are exposure to ionizing radiation in treatment for other cancers and a history of some noncancer bone diseases, including Paget disease.

Conclusions from VAO and Previous Updates

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

Table 8-15 summarizes the results of the relevant studies.

TABLE 8-15

Selected Epidemiologic Studies—Bone and Joint Cancer (Shaded Entries Are New Information for This Update).

SOFT-TISSUE SARCOMA

Soft-tissue sarcoma (STS) (ICD-9 164.1, 171) arises in soft somatic tissues in and between organs. Three of the most common types of STS—liposarcoma, fibrosarcoma, and rhabdomyosarcoma—occur in similar numbers in men and women. Because of the diverse characteristics of STS, accurate diagnosis and classification can be difficult. ACS estimated that about 6,110 men and 5,170 women would receive diagnoses of STS in the United States in 2012 and that about 2,050 men and 1,850 women would die from it (Siegel et al., 2012). The average annual incidence of STS is shown in Table 8-16.

TABLE 8-16

Average Annual Incidence (per 100,000) of Soft-Tissue Sarcoma (Including Malignant Neoplasms of the Heart) in the United States.

Among the risk factors for STS are exposure to ionizing radiation during treatment for other cancers and some inherited conditions, including Gardner syndrome, Li-Fraumeni syndrome, and neurofibromatosis. Several chemical exposures have been identified as possible risk factors (Zahm and Fraumeni, 1997).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was sufficient epidemiologic data to support an association between exposure to the COIs and STS. Additional information available to the committees responsible for subsequent updates has not changed that finding.

As seen with Hodgkin lymphoma and non-Hodgkin lymphoma, the available epidemiologic evidence suggests that phenoxy herbicides rather than TCDD may be associated with developing STS. Some of the strongest evidence of an association between STS and exposure to phenoxy herbicides comes from a series of case-control studies conducted in Sweden (Eriksson et al., 1981, 1990; Hardell and Eriksson, 1988; Hardell and Sandstrom, 1979). The studies, involving a total of 506 cases, show an association between STS and exposure to phenoxy herbicides, chlorophenols, or both. The VAO committee concluded that although those studies had been criticized, there is insufficient justification to discount the consistent pattern of increased risks and the clearly described and sound methods used. In addition, a reanalysis of the data by Hardell (1981) to evaluate the potential influence of recall bias and interviewer bias confirmed the original results. Hansen et al. (2007) conducted a historical-cohort study of male gardeners who were members of the Danish Union; cancer incidence was ascertained from 1975 to 2001. Birth date served as a surrogate for potential exposure to pesticides and herbicides; older cohorts represented higher exposure potential. Men born before 1915 were much more likely to die from STS, although this finding was based on only three cases. Reif et al. (1989) performed a series of case-control analyses in a sample of specified occupations and found a significant association between STS and having recently been employed as a forestry worker.

Those findings are supported by a significantly increased risk in a NIOSH study of production workers most highly exposed to TCDD (Fingerhut et al., 1991); Steenland et al. (1999) published an update of the NIOSH cohort, but STS was not among the outcomes evaluated. A similar increased risk was seen in the IARC cohort in deaths that occurred 10–19 years after first exposure (Kogevinas et al., 1992; Saracci et al., 1991) according to a fairly crude exposure classification. An updated and expanded study of the IARC cohort by Kogevinas et al. (1997) found a nonsignificantly increased risk of STS when followup was extended to 1992. Then NIOSH and IARC cohorts are among the largest and the most highly exposed occupational cohorts. Smaller studies of workers that are included in the multinational IARC cohort—Danish herbicide manufacturers (Lynge et al., 1985, 1993) and Dow production workers in Midland, Michigan, and New Zealand (Collins et al., 2009a; 't Mannetje et al., 2005)—showed an increased risk of STS, but the results were commonly nonsignificant, possibly because of small samples (related to the relative rarity of STS in the population).

Several studies have reported on STS in relation to living near waste incinerators that release dioxin as a contaminant. Viel et al. (2000) reported on an investigation of apparent clusters of STS and non-Hodgkin lymphoma cases in the vicinity of a municipal solid waste incinerator in Doubs, France; Comba et al. (2003) and Costani et al. (2000) examined STS in the general population living near a chemical plant in the northern Italian city of Mantua; and Zambon et al. (2007) conducted a population-based case-control study in Venice, Italy, in an area that included 26 waste incinerators and other industrial plants. Each of those studies found a statistically significant excess of STS, but none showed any direct evidence of human exposure.

No cases of STS have been reported in Zones A and B in the Seveso cohort (Consonni et al., 2008); the incidence of STS was slightly increased in Zone R but not significantly (Pesatori et al., 2009). Veteran studies have not found a significant increase in STS. No increase was seen in Operation Ranch Hand veterans (AFHS, 1996, 2000; Michalek et al., 1990) or in VA studies of US Vietnam veterans (Breslin et al., 1986, 1988; Bullman et al., 1990; Watanabe and Kang, 1995; Watanabe et al., 1991). A slight increase in the incidence of STS was seen in Australian Air Force veterans compared with the Australian population but not in Army or Navy personnel (ADVA, 2005a), and no increase in mortality was seen in Australian veterans who served in any of the military branches (ADVA, 2005b). A nonsignificant increase in mortality from STS was also seen in state studies of veterans in Massachusetts, Michigan, and New York.

Table 8-17 summarizes the relevant studies.

TABLE 8-17

Selected Epidemiologic Studies—Soft-Tissue Sarcoma (Shaded Entries Are New Information for This Update).

SKIN CANCERS

Skin cancers are generally divided into two broad categories: neoplasms that develop from melanocytes (malignant melanoma, or simply melanoma) and neoplasms that do not. Nonmelanoma skin cancers (primarily basal-cell and squamous-cell carcinomas) have a far higher incidence than melanoma but are considerably less aggressive and therefore more treatable. The average annual incidence of melanoma is shown in Table 8-18.

TABLE 8-18

Average Annual Cancer Incidence (per 100,000) of Skin Cancers (Excluding Basal-Cell and Squamous-Cell Cancers) in the United States.

The committee responsible for Update 1998 first chose to address melanoma studies separately from those of nonmelanoma skin cancer. Some researchers report results by combining all types of skin cancer without specifying type. The present committee believes that combined information is not interpretable (although there is a supposition that mortality figures refer predominantly to melanoma and that high incidence figures refer to nonmelanoma skin cancer); therefore, it is interpreting data only when results specify melanoma or nonmelanoma skin cancer.

ACS estimated that about 44,250 men and 32,000 women would receive diagnoses of cutaneous melanoma (ICD-9 172) in the United States in 2012 and that about 6,060 men and 3,120 women would die from it (Siegel et al., 2012). According to one report, more than 3 million cases of nonmelanoma skin cancer (ICD-9 173), primarily basal-cell and squamous-cell carcinomas, are diagnosed in the United States each year (ACS, 2013b); it is not required to report them to registries, so the numbers of cases are not as precise as those of other cancers. ACS reports that although melanoma accounts for less than 5% of skin-cancer cases, it is responsible for about 75% of skin-cancer deaths (ACS, 2012b). It estimates that 3,010 people die each year from nonmelanoma skin cancer (ACS, 2012b).

Melanoma occurs more frequently in fair-skinned people than in dark-skinned people; the risk in whites is roughly 20 times that in dark-skinned blacks. The incidence increases with age, more strikingly in males than in females. Other risk factors include the presence of particular kinds of moles on the skin, suppression of the immune system, and excessive exposure to ultraviolet (UV) radiation, typically from the sun. A family history of the disease has been identified as a risk factor, but it is unclear whether that is attributable to genetic factors or to similarities in skin type and sun-exposure patterns. In addition to the dermal forms of melanoma, these tumors occur much more infrequently in various tissues of the eye.

Excessive exposure to UV radiation is the most important risk factor for nonmelanoma skin cancer; some skin diseases and chemical exposures have also been identified as potential risk factors. Although exposure to inorganic arsenic is recognized as a risk factor for nonmelanoma skin cancer, this does not imply that exposure to cacodylic acid, which is a metabolite of inorganic arsenic, can be assumed to be a risk factor.

Melanoma

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and skin cancer. Additional information available to the committee responsible for Update 1996 did not change that conclusion. The committee responsible for Update 1998 considered the literature on melanoma separately from that of nonmelanoma skin cancer and found that there was inadequate or insufficient information to determine whether there is an association between the COIs and melanoma. The committees responsible for Update 2000, Update 2002, and Update 2004 concurred with the findings of Update 1998. The committee responsible for Update 2006 was unable to reach a consensus as to whether there was limited or suggestive evidence of an association between exposure to the COIs and melanoma or inadequate or insufficient evidence to determine whether there is an association, so melanoma was left in the latter category. The committee for Update 2008 determined that evidence of an association between exposure to the COIs and melanoma remained inadequate or insufficient to determine whether an association exists.

Cypel and Kang (2010) compared cause-specific mortality between deployed and nondeployed veterans in the Vietnam-era ACC cohort. In comparing the deployed with the nondeployed veterans, a moderate but not statistically significant increase in risk of malignant skin cancer was observed in the deployed cohort. Updates of mortality in TCP workers in New Zealand (McBride et al., 2009a) and in the Dow Chemical Company cohort in Midland, Michigan (Collins et al., 2009a) did not find evidence of an association between the COIs and melanoma. In evaluating the use of specific pesticides and melanoma in the AHS, Dennis et al. (2010) found that exposure only to arsenic-based pesticides, among the COIs, showed any increase in risk, which was weak and far from statistically significant. Updating cancer incidence in the Seveso cohort for the period 1977–1996 (Pesatori et al., 2009) continued to provide evidence that melanoma is associated with exposure to TCDD.

Table 8-19 summarizes the relevant melanoma studies.

TABLE 8-19

Selected Epidemiologic Studies—Melanoma (Shaded Entries Are New Information for This Update).

Update of the Epidemiologic Literature

Vietnam-Veteran and Environmental Studies

No Vietnam-veteran studies or environmental studies of exposure to the COIs and melanoma have been published since Update 2010.

Occupational Studies

Burns et al. (2011) updated cancer incidence through 2007 in workers who were alive on January 1, 1985, and had been employed at any time from 1945 to 1994 in 2,4-D production by the Dow Chemical Company in Midland, Michigan. They found no evidence of significantly increased rates of cancer overall. With eight cases observed, the incidence of melanoma in the most restrictively defined cohort was not increased (SIR = 1.18, 95% CI 0.51–2.33), as was the case for the two successively more inclusive, but potentially more biased, cohorts.

Boers et al. (2012) studied an occupational cohort of 187 Dutch workers who were employed in two phenoxy-herbicide factories. Individual estimates of exposure were derived from a newly developed predictive model that used serum TCDD concentrations recently measured in a subset of the cohort. Estimates of mortality from melanoma were slightly but nonsignificantly increased (entire cohort, seven deaths, HR = 1.29, 95% CI 0.90–1.84; factory A, five deaths, HR = 1.27, 95% CI 0.76–2.23). An earlier analysis of the data (Boers et al., 2010), which categorized the subjects as exposed or not exposed on the basis of job histories, found no suggestion of a relationship between exposure to COIs and melanoma in the workers in factory A, where 2,4,5-T had been produced.

In reporting mortality in the NIOSH PCP cohort updated through 2005, Ruder and Yiin (2011) grouped an unspecified number of melanoma deaths in a classification (ICD-9 170–173, 190–199) that had 38 deaths, of which 2 were identified as STS deaths and 6 as deaths from “brain and other nervous system” cancer. The study provided no useful information on the risk of melanoma mortality in these workers.

Koutros et al. (2010a) and Waggoner et al. (2011) updated cancer incidence and overall mortality, respectively, in the AHS. Koutros et al. limited exposure characterization to job (applicators and spouses). They reported 173 incident melanomas in private applicators, for an SIR of 0.89 (95% CI 0.76–1.03), and 13 incident melanomas in commercial applicators, for an SIR of 1.09 (95% CI 0.58–1.86). They reported 92 incident cases in spouses, for an SIR of 1.17 (95% CI 0.94–1.43).

Waggoner et al. (2011) updated the vital status of the AHS cohort through 2007 and presented mortality data that differed little from the incidence data in Koutros et al. (2010a). Using a similar job classification as a surrogate for exposure, they reported 38 deaths compared with 50 expected for an SMR of 0.76 (95% CI 0.54–1.05). In spouses, they reported 10 deaths compared with 13 expected for an SMR of 0.75 (95% CI 0.36–1.38). The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee's task.

Case-Control Studies

Gallagher et al. (2011) studied melanoma and its association with plasma concentrations of PCBs by using an unusual case-control design. They ascertained cases by using the resources (plasma specimens and sun-exposure data) from melanoma cases originally recruited for evaluating the effects of UV exposure and gene variants on risk of melanoma in the Genes, Environment & Melanoma (GEM) study (Begg et al., 2005; Berwick et al., 2006). Controls for that study were drawn from a different study, conducted at about the same time in the same geographic region (British Columbia), that was designed to investigate the effect of solar UV exposure and plasma organochlorine compounds on risk of non-Hodgkin lymphoma (Spinelli et al., 2007). The studies were similar in design: they both recruited participants by using the population-based BC Cancer Registry, and they used the same computer-assisted telephone interview protocol to collect information on sun exposure, phenotype, and sun sensitivity. Cases from the GEM study included 153 patients, of whom 86 (56%) were able to be recontacted for drawing of additional blood for this investigation. Blood was drawn in 2002–2005 for controls and in 2008 for cases. The laboratory analyses were well controlled to ensure comparability. Plasma samples from 460 controls were assayed for 14 PCB congeners and 11 chlorine-based pesticides or their metabolites; after matching on age and area of residence, 309 were available for use in the study. A total of three cases were not included in the study because of the inability to match with controls. The exposure assessment included 14 PCB congeners (dioxin-like mono-ortho PCBs 105, 118, and 156 and non-dioxin-like PCBs 28, 52, 99, 101, 128, 138, 153, 170, 180, 183, and 187) and 11 persistent pesticides.

Many of the accepted risk factors for melanoma were found to be associated with the disease in this study. Analysis showed significant associations between PCB congeners and melanoma although they were rather imprecise. Total PCB concentrations were associated with disease, with a significant dose–response relationship. The highest risk was in the highest PCB-exposure quartile (OR = 6.02, 95% CI 2.00–18.17). The dioxin-like mono-ortho PCBs, however, showed a significant association (OR = 2.84, 95% CI 1.01–7.97), which was less pronounced than that of the non-dioxin-like PCBs (OR = 7.02, 95% CI 2.30–21.43). There was some indication of an association of pesticide exposure with melanoma but it was limited to nonachlor, Mirex, and hexachlorobenzene.

Thus, the study provided evidence of an association between chemicals that have dioxin-like activity and melanoma but with important limitations. First, the number of cases was small, and participation was low, so there is a question of unmeasured bias. In addition, although the authors attempted to control for sun exposure, this is notoriously difficult. The cases and controls arose from different studies and, although every attempt was made to match them, they may not have been comparable in some respects (such as ethnicity). The presence of disease could alter the measured exposures. The confidence limits of the point estimates are imprecise, and this lessens confidence in their generalizability. In addition, there is little exposure specificity in the association, so it is difficult to interpret in light of the biologic data. Finally, only dioxin-like mono-ortho PCBs were reported, which typically contribute only a small percentage to total TEQs, making it difficult to accurately determine whether an association exists with total TEQs, and the largest associations were found for the non-dioxin-like compounds.

Behrens et al. (2012) conducted a case-control study of uveal (ocular) melanoma and pesticide exposure, but exposure to unspecified herbicides does not reach the level of specificity that the committee has regarded as necessary for full relevance. The significant finding in the category of 1–9 years of “application of any herbicide on farm where subject worked” is intriguing but contrary to expectations of a dose–response association. The results with respect to personal application and mixing of herbicides are more pertinent for the committee's purposes, and they are firmly not positive.

Biologic Plausibility

TCDD and related herbicides have not been found to cause melanoma in animal models. In general, rodents, which are used in most toxicology studies, are not a good model for studying melanoma. TCDD does produce nonmelanoma skin cancers in animal models (Wyde et al., 2004). As discussed elsewhere in this chapter, TCDD is a known tumor-promoter and could act as a promoter for skin-cancer initiators, such as UV radiation. Ikuta et al. (2009) examined the physiologic role of the AHR in human skin and theorized that overactivation can lead to skin cancers, but they provided no evidence that melanoma incidence is increased after TCDD exposure. Recent work in this field has shown that the AHR mediates UVB-induced skin-tanning in a murine model through action on melanocytes; this is evidence that skin pigmentation and potentially the regulatory action of the target cell for melanoma may be affected by TCDD. Studies of human cells have also confirmed a role of the AHR in regulation of keratinocytes and melanocytes. Kalmes et al. (2011) have shown that AHR signaling in immortalized HaCaT cells is associated with cell-cycle progression. In human melanocytes, Luecke et al. (2010) demonstrated that TCDD exposure induced tyrosinase and tyrosinase-related protein 2 gene expression—an indication that AHR signaling after TCDD exposure modulates melanogenesis. O'Donnell et al. (2012) further showed that the activity of the AHR was associated with proliferation of melanoma cells. Finally, it was recently shown in a Han Chinese population that normal genetic variants of the AHR are associated with the occurrence of vitiligo; this strongly suggests that the AHR is associated with melanocyte distribution in humans.

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

Synthesis

No compelling association between the COIs and melanoma was observed in any of the three new occupational studies.

The committee responsible for Update 2006 was unable to reach a consensus as to whether there was limited or suggestive evidence of an association between exposure to the COIs and melanoma or inadequate or insufficient evidence to determine whether there is an association. That committee considered the findings from the Air Force Health Study (AFHS) on melanoma, evaluated in terms of TCDD measurements (Akhtar et al., 2004; Pavuk et al., 2005), to be of prime interest. However, the data from the final AFHS examination cycle indicate that many more melanoma cases were diagnosed in the comparison veterans than in the Operation Ranch Hand veterans. Consequently, the committee responsible for Update 2006 recommended that the final data on the Ranch Hand and comparison veterans be analyzed in a uniform manner to document the full melanoma experience of the AFHS subjects and to permit definitive evaluation of the possible association between the COIs and melanoma. That request remains unaddressed.

This is the first update in which any information on ocular melanoma has been identified. The case-control study of Behrens et al. (2012) found some increases in the incidence of uveal melanoma in association with unspecified herbicides; this is not the degree of herbicide specificity required for results to be considered fully relevant. A Vietnam veteran submitted information (Data from Rutz [2012] available in the National Academies Public Access Records Office [http://www8.nationalacademies.org/cp/ManageRequest.aspx?key=49448]) received in response to a Freedom of Information Act request to VA about the frequency with which choroidal melanoma (a specific type of uveal melanoma) was diagnosed in VA facilities; the document indicated that a large number of such cases had been seen, but the lack of documentation explaining how the VA had gathered the data and exactly what they represented prevented the committee from being able to assess their import. Because literature searches did not identify any epidemiology studies of ocular melanoma in association with the COIs, the committee submitted an inquiry to Carol and Mark Shields, who responded (Data from Shields [2012] available in the National Academies Public Access Records Office [http://www8.nationalacademies.org/cp/ManageRequest.aspx?key=49448]) that their analyses of more than 2,000 cases of uveal melanoma had not revealed any association with the COIs.

Conclusion

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

Basal-Cell Cancer and Squamous-Cell Cancer (Nonmelanoma Skin Cancer)

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and skin cancer, and additional information available to the committee responsible for Update 1996 did not change that conclusion. The committee responsible for Update 1998 considered the literature on nonmelanoma skin cancer separately from that on melanoma and concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and basal-cell or squamous-cell cancer. The committees responsible for Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 did not change that conclusion.

Table 8-20 summarizes the relevant studies.

TABLE 8-20

Selected Epidemiologic Studies—Other Nonmelanoma (Basal-Cell and Squamous-Cell) Skin Cancer (Shaded Entries Are New Information for This Update).

Update of the Epidemiologic Literature

No epidemiology studies of exposure to the COIs and basal-cell or squamous-cell cancer have been published since Update 2010.

Biologic Plausibility

There are no new studies on animal models of skin cancer that are relevant to this update. TCDD has been shown to produce nonmelanoma skin cancer in animal models (Wyde et al., 2004). As discussed elsewhere in this chapter, TCDD is a known tumor-promoter and could act as a promoter for skin-cancer initiators, such as UV radiation, but no experiments have been conducted specifically to support this potential mechanism.

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

Synthesis

In accord with the results of reports previously assessed, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and basal-cell or squamous-cell cancer.

Conclusion

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

BREAST CANCER

Breast cancer (ICD-9 174 for females, ICD-9 175 for males) is the second-most common type of cancer (after nonmelanoma skin cancer) in women in the United States. ACS estimated that 226,870 women would receive diagnoses of breast cancer in the United States in 2012 and that 39,510 would die from it (Siegel et al., 2012). Overall, those numbers represent about 29% of the new cancers and 14% of cancer deaths in women. Incidence data on breast cancer are presented in Table 8-21.

TABLE 8-21

Average Annual Incidence (per 100,000) of Breast Cancer in the United States.

Breast-cancer incidence generally increases with age. In the age groups of most Vietnam veterans, the incidence is higher in whites than in blacks. Established risk factors other than age include personal or family history of breast cancer and some characteristics of reproductive history—specifically, early menarche, late onset of menopause, and either no pregnancies or first full-term pregnancy after the age of 30 years. A pooled analysis of six large-scale prospective studies of invasive breast cancer showed that alcohol consumption up to a daily average of 60 g (2.1 oz), which spanned the consumption reported by more than 99% of the women, was associated with a small linear increase in incidence in comparison with nondrinkers (Smith-Warner et al., 1998). It is generally accepted that breast-cancer risk is increased by prolonged use of hormone-replacement therapy, particularly preparations that combine estrogen and progestins (Chlebowski et al., 2003). The potential of other personal behavioral and environmental factors (including use of exogenous hormones) to affect breast-cancer incidence is being studied extensively.

Most of the roughly 10,000 female Vietnam veterans who were potentially exposed to herbicides in Vietnam are approaching or have reached menopause. Given the high incidence of breast cancer in older and postmenopausal women in general, it is expected on the basis of demographics alone that the breast-cancer burden in female Vietnam veterans will increase in the near future.

The vast majority of breast-cancer epidemiologic studies involve women, but the disease also occurs rarely in men, with 2,190 new cases expected in 2012 (Siegel et al., 2012). Reported instances of male breast cancer are noted below, but the committee's conclusions are based on the studies in women.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and breast cancer. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. After consideration of a new study with positive findings on an association between 2,4-D exposure and breast cancer in female farmworkers in California (Mills and Yang, 2005)—in conjunction with the earlier findings of Kang et al. (2000), Kogevinas et al. (1997), Revich et al. (2001), and Warner et al. (2002)—the committee responsible for Update 2006 was unable to reach consensus as to whether there might be limited or suggestive evidence of an association between the COIs and breast cancer. An increase in the incidence of breast cancer in the residents of Zone A in Seveso may be emerging with greater latency (Pesatori et al., 2009), but in light of null findings on mortality from breast cancer in the important cohorts of female Vietnam-era veterans (Cypel and Kang, 2008) and Seveso residents (Consonni et al., 2008), all members of the committees for Update 2008 and Update 2010 concurred that breast cancer should remain in the category of inadequate or insufficient evidence to determine whether there is an association.

Table 8-22 summarizes the relevant research.

TABLE 8-22

Selected Epidemiologic Studies—Breast Cancer (Shaded Entries Are New Information for This Update).

CANCERS OF THE FEMALE REPRODUCTIVE SYSTEM

This section addresses cancers of the cervix (ICD-9 180), endometrium (also referred to as the corpus uteri; ICD-9 182.0–182.1, 182.8), and ovary (ICD-9 183.0). Additional cancers of the female reproductive system that are infrequently reported separately are cancers of the uterus (ICD-9 179), placenta (ICD-9 181), fallopian tube and other uterine adnexa (ICD-9 183.2–183.9), and other female genital organs (ICD-9 184); findings on these cancers are included in this section. ACS estimates of the numbers of new female reproductive-system cancers in the United States in 2012 are presented in Table 8-23; they represent roughly 11% of new cancer cases and 11% of cancer deaths in women (Siegel et al., 2012).

TABLE 8-23

Estimates of New Cases of Deaths from Selected Cancers of the Female Reproductive System in the United States in 2012.

Cervical cancer occurs more often in blacks than in whites, but endometrial and ovarian cancers occur more often in whites. The incidence of endometrial and ovarian cancers is higher in older women and in those who have family histories of these cancers. Use of unopposed (without progestogen) estrogen-hormone therapy and obesity, which increases endogenous concentrations of estrogen, both increase the risk of endometrial cancer. HPV infection, particularly infection with HPV types 16 and 18, is the most important risk factor for cervical cancer. Use of oral contraceptives is associated with a substantial reduction in the risk of ovarian cancer.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the COIs and female reproductive cancers. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 has been sparse and has not changed that conclusion.

Tables 8-24, 8-25, and 8-26 summarize the results of the relevant studies on cancers of the cervix, uterus, and ovary, respectively.

TABLE 8-24

Selected Epidemiologic Studies—Cervical Cancer (Shaded Entries Are New Information for This Update).

TABLE 8-25

Selected Epidemiologic Studies—Uterine Cancer (Shaded Entries Are New Information for This Update).

TABLE 8-26

Selected Epidemiologic Studies—Ovarian Cancer (Shaded Entries Are New Information for This Update).

PROSTATE CANCER

ACS estimated that 241,740 new cases of prostate cancer (ICD-9 185) would be diagnosed in the United States in 2012 and that 28,170 men would die from it (Siegel et al., 2012). That makes prostate cancer the second-most common cancer in men (after nonmelanoma skin cancers); it is expected to account for about 29% of new cancer diagnoses and 9% of cancer deaths in men in 2012. The average annual incidence of prostate cancer is shown in Table 8-27.

TABLE 8-27

Average Annual Incidence (per 100,000) of Prostate Cancer in the United States.

The incidence of prostate cancer varies widely with age and race. The risk more than doubles from the ages of 50–54 years to the ages of 55–59 years, and it nearly doubles again from the ages of 55–59 years to the ages of 60–64 years. As a group, American black men have the highest recorded incidence of prostate cancer in the world (Miller et al., 1996); their risk is roughly twice that in whites in the United States, 5 times that in Alaska natives, and nearly 8.5 times that in Korean Americans. Little is known about the causes of prostate cancer. Other than race and age, risk factors include a family history of the disease and possibly some elements of the Western diet, such as high consumption of animal fats. The drug finasteride, which has been widely used to treat benign enlargement of the prostate, was found to decrease the prevalence of prostate cancer substantially in a major randomized trial (Thompson et al., 2003). Finasteride acts by decreasing the formation of potent androgen hormones in the prostate.

The study of the incidence of and mortality from prostate cancer is complicated by trends in screening for the disease. The widespread adoption of serum prostate-specific antigen (PSA) screening in the 1990s led to very large increases in prostate-cancer incidence in the United States, which have recently subsided as exposure to screening has become saturated. The long-term influence of better screening on incidence and mortality in any country or population is difficult to predict and will depend on the rapidity with which the screening tool is adopted, its differential use in men of various ages, and the aggressiveness of tumors detected early with this test (Gann, 1997). Because exposure to PSA testing is such a strong determinant of prostate-cancer incidence, epidemiologic studies must be careful to exclude differential PSA testing as an explanation of a difference in risk observed between two populations.

Prostate cancer tends not to be fatal, so mortality studies might miss an increase in incidence of the disease. Findings that show an association between an exposure and prostate-cancer mortality should be examined closely to determine whether the exposed group might have had poorer access to treatment that would have increased the likelihood of survival.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to the COIs and prostate cancer. 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.

Eight studies that addressed whether exposure to the COIs is associated with prostate cancer were considered in Update 2010, and they were all effectively neutral, small sample size being the primary limitation. The only strong result that was in any way related to prostate cancer was the finding by Shah et al. (2009) that of 1,495 veterans who had undergone radical prostatectomy and were followed for 5 years, those who were exposed to Agent Orange had an increased risk of biochemical progression of 1.47 (95% CI 1.08–2.00). Accordingly, the committee for Update 2010 agreed with the conclusion of its predecessors.

Table 8-28 summarizes results of the relevant studies, including both morbidity and mortality studies.

TABLE 8-28

Selected Epidemiologic Studies—Prostate Cancer (Shaded Entries Are New Information for This Update).

TESTICULAR CANCER

ACS estimated that 8,590 men would receive diagnoses of testicular cancer (ICD-9 186.0–186.9) in the United States in 2012 and that 360 men would die from it (Siegel et al., 2012). Other cancers of the male reproductive system that are infrequently reported separately are cancers of the penis and other male genital organs (ICD-9 187). The average annual incidence of testicular cancer is shown in Table 8-29.

TABLE 8-29

Average Annual Incidence (per 100,000) of Testicular Cancer in the United States.

Testicular cancer occurs more often in men under 40 years old than in older men. On a lifetime basis, the risk in white men is about four times that in black men. Cryptorchidism (undescended testes) is a major risk factor for testicular cancer. Family history of the disease also appears to be a risk factor. Several other hereditary, medical, and environmental risk factors have been suggested, but the results of research are inconsistent (Bosl and Motzer, 1997).

Conclusions from VAO and Previous Updates

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

Table 8-30 summarizes the results of the relevant studies.

TABLE 8-30

Selected Epidemiologic Studies—Testicular Cancer (Shaded Entries Are New Information for This Update).

BLADDER CANCER

Urinary bladder cancer (ICD-9 188) is the most common urinary tract cancer. Cancers of the urethra and paraurethral glands and other and unspecified urinary cancers (ICD-9 189.3–189.9) are infrequently reported separately; any findings on these cancers would be reported in this section. ACS estimated that 55,600 men and 17,910 women would receive a diagnosis of bladder cancer in the United States in 2012 and that 10,510 men and 4,370 women would die from it (Siegel et al., 2012). In males, in whom this cancer is about twice as common as it is in females, those numbers represent about 7% of new cancer diagnoses and 3% of cancer deaths. Overall, bladder cancer is fourth in incidence in men in the United States.

Bladder-cancer risk rises rapidly with age. In men in the age groups that characterize most Vietnam veterans, bladder-cancer incidence is about twice as high in whites as in blacks. The average annual incidence of urinary bladder cancer is shown in Table 8-31.

TABLE 8-31

Average Annual Incidence (per 100,000) of Bladder Cancer in the United States.

The most important known risk factor for bladder cancer is tobacco use, which accounts for about half the bladder cancers in men and one-third of them in women (Miller et al., 1996). Occupational exposure to aromatic amines (also called arylamines), polycyclic aromatic hydrocarbons, and some other organic chemicals used in the rubber, leather, textile, paint-products, and printing industries is associated with higher incidence. In some parts of Africa and Asia, infection with the parasite Schistosoma haematobium contributes to the high incidence.

Exposure to inorganic arsenic is also a risk factor for bladder cancer. Although cacodylic acid is a metabolite of inorganic arsenic, as discussed in Chapter 4, the data are insufficient to conclude that studies of inorganic-arsenic exposure are directly relevant to exposure to cacodylic acid, so the literature on inorganic arsenic is not considered in this section.

Conclusions from VAO and Previous Updates

The committees responsible for VAO and Update 1996 concluded that there was limited or suggestive evidence of no association between exposure to the COIs and urinary bladder cancer. Additional information available to the committee responsible for Update 1998 led it to change that conclusion to one of inadequate or insufficient information to determine whether there is an association. The committees responsible for Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 did not change that conclusion.

Table 8-32 summarizes the results of the relevant studies.

TABLE 8-32

Selected Epidemiologic Studies—Urinary Bladder Cancer (Shaded Entries Are New Information for This Update).

RENAL CANCER

Cancers of the kidney other than the renal pelvis (ICD-9 189.0) and cancer of the renal pelvis (ICD-9 189.1) are often grouped in epidemiologic studies; cancer of the ureter (ICD-9 189.2) is sometimes also included. Although diseases of those organs have different characteristics and could have different risk factors, there is some logic to grouping them: the structures are all exposed to filterable chemicals, such as polycyclic aromatic hydrocarbons, that appear in urine. ACS estimated that 40,250 men and 24,520 women would receive diagnoses of renal cancer (ICD-9 189.0, 189.1) in the United States in 2012 and that 8,650 men and 4,920 women would die from it (Siegel et al., 2012). Those figures represent 2–4% of all new cancer diagnoses and cancer deaths. The average annual incidence of renal cancer is shown in Table 8-33.

TABLE 8-33

Average Annual Incidence (per 100,000) of Kidney and Renal Pelvis Cancer in the United States.

Renal cancer is twice as common in men as in women. In the age groups that include most Vietnam veterans, black men have a higher incidence than do white men. With the exception of Wilms tumor, which is more likely to occur in children, renal cancer is more common in people over 50 years old.

Tobacco use is a well-established risk factor for renal cancer. People who have some rare syndromes—notably, von Hippel-Lindau syndrome and tuberous sclerosis—are at higher risk. Other potential risk factors include obesity, heavy acetaminophen use, kidney stones, and occupational exposure to asbestos, cadmium, and organic solvents. Firefighters, who are routinely exposed to numerous pyrolysis products, are in a known higher-risk group.

Conclusions from VAO and Previous Updates

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

Table 8-34 summarizes the results of the relevant studies.

TABLE 8-34

Selected Epidemiologic Studies—Renal Cancer (Shaded Entries Are New Information for This Update).

BRAIN CANCER

Nervous-system cancers (ICD-9 191–192) involve the central nervous system (CNS) and include tumors of the brain and spinal cord, the cranial nerves, and the meninges (the outer coverings of the brain and spinal cord). Any of the cell types in the CNS can develop into cancer. Tumors of the peripheral nervous system and autonomic nervous system are considered soft-tissue tumors (ICD-9 171). Most cancers in the CNS are not primary tumors arising from nervous system tissues, but originated in other parts of the body, such as the lung or breast, and have metastasized to the brain or spinal cord. This section focuses on cancers that originate in the CNS.

Cancer of the eye (ICD-9 190) was considered in Update 2006, but the present committee decided that findings concerning cancer of the eye would be tracked with results on brain cancer because when it is reported it is often grouped with brain cancer.

The average annual incidence of primary CNS cancer is shown in Table 8-35. About 95% of cases originate in the brain, cranial nerves, and cranial meninges. In people over 45 years old, about 90% of tumors that originate in the brain are gliomas—astrocytoma, ependymoma, oligodendroglioma, or glioblastoma multiforme. Astrocytoma is the most common; glioblastoma multiforme has the worst prognosis. Meningiomas make up 20–40% of CNS cancers; they tend to occur in middle age and are more common in women than in men. Most meningiomas are benign and can be removed surgically.

TABLE 8-35

Average Annual Incidence (per 100,000) of Brain and Other Nervous System Cancers in the United States.

ACS estimated that about 12,630 men and 10,280 women would receive diagnoses of brain and other nervous-system cancers in the United States in 2012 and that 7,720 men and 5,980 women would die from them (Siegel et al., 2012). Those numbers represent about 1.5% of new cancer diagnoses and 2.3% of cancer deaths. ACS estimated that 1,310 men and 1,300 women would receive diagnoses of cancers of the eye and orbit in the United States in 2012 and that 120 men and 150 women would die from them (Siegel et al., 2012).

In reviewing the descriptive epidemiology of these cancers, it is important to recognize the variation with which specific cancers are included in published reports, many of which distinguish between benign and malignant tumors. Another variation is whether cancers derived from related tissues (such as the pituitary or the eye) are included with CNS cancers. Various types of cancer are usually grouped; although this may bias results in unpredictable ways, the most likely consequence is dilution of risk estimates toward the null.

The only well-established environmental risk factor for brain tumors is exposure to high doses of ionizing radiation (ACS, 2012c; Wrensch et al., 2002). Other environmental exposures—such as to vinyl chloride, petroleum products, electromagnetic fields, and cell-phone use—are unproved as risk factors. The causes of most cancers of the brain and other portions of the nervous system are not known.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of no association between exposure to the COIs and brain cancer. The committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion.

The committee responsible for Update 2006 changed the classification for brain cancer (formally expanding it to include cancers of the eye and orbit) to inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and brain cancer. That committee considered one study that suggested a relationship between phenoxy acid herbicides and adult gliomas (Lee et al., 2005); studies that reported slightly but not statistically significantly higher risks of brain cancer in deployed than in nondeployed Australian Vietnam-era veterans (ADVA, 2005a,b) and in pesticide applicators in the AHS (Alavanja et al., 2005); and several studies that had essentially neutral findings (Carreon et al., 2005; Magnani et al., 1987; McLean et al., 2006; Ruder et al., 2004; Torchio et al., 1994). Overall, the studies discussed in Update 2006 suggested that a conclusion of no association between exposure to the COIs and brain cancer had been too definitive.

The committee for Update 2008 agreed that brain cancers should remain in the inadequate or insufficient category after review of two new studies. The relevance of the largely null findings on association with occupational exposure to herbicides from a case-control study of gliomas and meningiomas (Samanic et al., 2008) was limited in that no specific compounds were addressed. In evaluating mortality through 2001 in the Seveso cohort, Consonni et al. (2008) found no increase in mortality from brain cancer in any of the three exposure zones with increasing exposure and no indication of a dose–response relationship.

Update 2010 considered several new studies. A study of Vietnam-era Army Chemical Corps veterans found no difference in brain cancer rates between deployed and nondeployed veterans (Cypel and Kang, 2010), and studies of TCP and 2,4,5-T production workers in two settings also found no difference in brain-cancer incidence (Collins et al., 2009a) or brain-cancer mortality (Collins et al., 2009b; McBride et al, 2009a) compared with general population rates. A 20-year followup of brain cancer after the Seveso exposure incident found a nonstatistically significantly increased rate of brain cancer in those in the closest zone (RR = 2.43, 95% CI 0.60–9.79), but not in Zones B and R (Pesatori et al., 2009).

Table 8-36 summarizes the results of the relevant studies.

TABLE 8-36

Selected Epidemiologic Studies—Brain Tumors (Shaded Entries Are New Information for This Update).

ENDOCRINE CANCERS

Cancers of the endocrine system as grouped by the Surveillance, Epidemiology, and End Results program (see Table B-2 in Appendix B) have a disparate group of ICD codes: thymus cancer (ICD-9 164.0), thyroid cancer (ICD-9 193), and other endocrine cancer (ICD-9 194).

ACS estimated that 13,250 men and 43,210 women would receive diagnoses of thyroid cancer in the United States in 2012 and that 780 men and 1,000 women would die from it, and it estimated that 1,350 men and 1,170 women would receive diagnoses of other endocrine cancers in 2012 and that 460 men and 460 women would die from them (Siegel et al., 2012). Incidence data on cancers of the endocrine system are presented in Table 8-37.

TABLE 8-37

Average Annual Incidence (per 100,000) of Endocrine System Cancer in the United States.

Thyroid cancer is the most prevalent endocrine cancer. Many types of tumors can develop in the thyroid, most of them benign. The thyroid contains two main types of cells: follicular cells make and store thyroid hormones and make thyroglobulin; C cells make the hormone calcitonin, which helps to regulate calcium metabolism. Different cancers of varied severity can develop from each kind of cell, and the classification of thyroid cancer is still evolving (Liu et al., 2006; Nikiforov, 2011). Papillary carcinoma is the most common and usually affects women of childbearing age; it metastasizes slowly and is the least malignant type of thyroid cancer. Follicular carcinoma accounts for about 15% of all cases and has greater rates of recurrence and metastasis. Medullary carcinoma is a cancer of parafollicular cells in the thyroid and tends to occur in families; it requires treatment different from other types of thyroid cancer. Anaplastic carcinoma (also called giant-cell cancer and spindle-cell cancer) is rare but is the most aggressive form of thyroid cancer; it does not respond to radioiodine therapy and metastasizes quickly, invading such nearby structures as the trachea and causing compression and breathing difficulties.

Thyroid cancer can occur in all age groups. Radiation exposure is recognized as a risk factor for thyroid cancer, so increased incidence is observed in people who received radiation therapy directed at the neck (a common treatment in the 1950s for enlarged thymus, adenoids, and tonsils and for skin disorders) or who were exposed to iodine-125 from the Chernobyl nuclear power plant accident. If radiation exposure occurred in childhood, the risk of thyroid cancer is further increased. Other risk factors are a family history of thyroid cancer and chronic goiter.

Conclusions from VAO and Previous Updates

The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not consider endocrine cancers separately and therefore reached no conclusion as to whether there was an association between exposure to the COIs and endocrine cancers. The committees responsible for Update 2006, Update 2008, and Update 2010 did consider endocrine cancers separately and concluded that there was inadequate or insufficient evidence to determine whether there is an association between the COIs and endocrine cancers.

Table 8-38 summarizes the pertinent results of the relevant studies.

TABLE 8-38

Selected Epidemiologic Studies—Endocrine Cancers (Thyroid, Thymus and Other) (Shaded Entries Are New Information for This Update).

LYMPHOHEMATOPOIETIC CANCERS

Lymphohematopoietic cancers (LHCs) constitute a heterogeneous group of clonal hematopoietic and lymphoid-cell disorders, including leukemias, lymphomas, and multiple myeloma. They are among the most common types of cancer induced by environmental and therapeutic agents. As in the case of other cancers that are subject to idiosyncratic grouping in reports of results of epidemiologic studies (notably, head and neck cancers and gastrointestinal cancers), the conclusions that the VAO committees have drawn about associations between herbicide exposure to the COIs and specific LHCs have been complicated and curtailed by the lack of specificity and by inconsistencies in groupings in the available evidence. For LHCs, that has been a function not only of epidemiologists' seeking to combine related cancers to produce categories that have enough cases to permit statistical analysis but also of alterations in the prevailing system used by the medical community to classify these malignancies. Categorization of cancers of the lymphatic and hematopoietic systems has continued to evolve, guided by growing information about gene expression and lineage of the clonal cancer cells that characterize each of a broad spectrum of neoplasms arising in these tissues (Jaffe, 2009). The World Health Organization (WHO) categorization presented in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue (WHO, 2008) bases its primary partition on whether the cancer cells are of myeloid or lymphoid origin (see Figure 8-1).

FIGURE 8-1

Hematopoiesis of stem cell differentiation. SOURCE: © Terese Winslow, 2007; US government has certain rights.

Stem cells arising in the bone marrow generate two major lineages of leukocytes: myeloid and lymphoid. Myeloid cells include monocytes and three types of granulocytes (neutrophils, eosinophils, and basophils). Lymphoid cells include T and B lymphocytes and a smaller set of cells called natural killer (NK) cells. All those cells circulate in the blood and are collectively referred to as white blood cells or leukocytes. Monocytes move out of the bloodstream into inflamed tissues, where they differentiate into macrophages or dendritic cells. Stem cells that are destined to become T lymphocytes migrate from the bone marrow to the thymus, where they acquire antigen-specific receptors. Antigen stimulation induces the T cells to differentiate into the several types involved in cell-mediated immunity. Progenitor or pre-B cells mature in the bone marrow into antigen-specific B cells. On encountering their cognate antigens, B cells differentiate into antibody-secreting plasma cells involved in humoral immunity; these result in multiple myeloma when they undergo malignant transformation.

LHCs originate in specific pluripotent or lineage-restricted cells at different stages in hematopoiesis and immune-cell development. The normal cells are transformed into a malignant tumor through multistep processes that involve genetic and epigenetic alterations. Traditionally, LHCs have been divided into leukemias, lymphomas, myelomas, and so on, according to their cell and site of origin (see Figure 8-1). That information and morphologic, cytochemical, and immunophenotypic data are used to characterize LHCs further by their distinct subtypes.

Leukemias occur when a cell residing in the bone marrow becomes cancerous and its daughter cells crowd normal cells in the bone marrow or are released from the bone marrow and circulate in the blood. Leukemias have generally been classified as myeloid or lymphoid, depending on the lineage of the original mutated cell. If the original mutated cell of a cancer of the blood arises in a lymphocytic cell line, the cancer is called lymphocytic leukemia; lymphocytic leukemias have been partitioned into acute lymphocytic leukemia (ALL) forms if they are derived from precursor B or T lymphoid cells, and indolent lymphoproliferative disorders (ILDs) derived from more mature lymphoid cells, which tend to replicate less rapidly. Although “chronic lymphocytic leukemia” is commonly used to refer to this group of ILDs, CLL is actually a specific form of ILD. Similarly, myeloid leukemias arise from a myeloid cell line and are classified into acute (AML) and chronic (CML) forms.

Lymphoma is a general term for cancers that arise from lymphocytes (B, T, or NK cells). Lymphomas generally present as solid tumors at lymphoid proliferative sites, such as lymph nodes and spleen. As stem cells mature into B or T cells, they pass through several developmental stages, each with unique functions. The developmental stage at which a cell becomes malignant defines the kind of lymphoma. About 85% of lymphomas are of B-cell origin, and 15% of NK-cell or T-cell origin, referred to as NKTCL by WHO (Jaffe et al., 2001) and Liao et al. (2012). There are two major types of B-cell lymphoma: Hodgkin lymphoma (HL), previously referred to as Hodgkin disease, and non-Hodgkin lymphoma (NHL). B cells give rise to a number of types of neoplasms that are given names based on the stage at which B-cell development was arrested when the cells became cancerous. Follicular, large-cell, and immunoblastic lymphomas result when a malignancy develops after a B cell has been exposed to antigens (such as bacteria and viruses). CLL is now believed to be a tumor of antigen-experienced (memory) B cells, not naïve B cells (Chiorazzi et al., 2005); small lymphocytic lymphoma (SLL), which presents primarily in lymph nodes rather than in the bone marrow and blood, is now considered to be the same disease as CLL at a different stage (Jaffe et al., 2008).

Myeloma is another type of lymphohematopoietic malignancy derived from antibody-secreting plasma cells, which also have a B-cell lineage, that accumulate in the marrow of various bones. In most cases (90%), tumors are formed at multiple sites, and the disease is called multiple myeloma (MM). The related premalignant condition AL amyloidosis also arises from B-cell–derived plasma cells. It occurs in 5–15% of patients who have MM and causes abnormal deposition of antibody fragments. Monoclonal gammopathy of undetermined significance (MGUS) is also recognized as a clonal condition that may progress to MM.

ICD partitions these malignancies into leukemias and lymphomas primarily on the basis of whether cancer cells circulated in the blood (disseminated) or appeared in the lymphatic system (solid tissue), respectively, before subdividing according to cell type. The emerging WHO classification of lymphohematopoietic malignancies (Campo et al., 2008; Jaffe, 2009) stratifies cancers of the blood and lymph nodes into disease categories according to their cell lineages—lymphoid or myeloid—as shown in Figure 8-1. It represents a substantial advance in understanding the biologic paths by which these cancers develop. The present committee decided, however, that it would not be productive to reformulate this entire section to correspond to the WHO categories. In practice, LHCs have routinely been reported in a variety of groupings, so it is a continuing challenge to parse out results, noting when results for broader groupings are presented in the results tables for several more specific diagnoses while recognizing that the specific results will be muted by being “misclassified” with other entities. Most epidemiologic studies already in the evidentiary database that did specify diseases precisely used ICD-9 or earlier versions, but some recent studies have applied ICD-10. Furthermore, the existing records that will serve as the basis of many current and even future studies will use earlier and evolving classifications, so this is likely to remain the case even in new literature for a considerable period. The nomenclature has become more uniform in recent studies, but the possibility of ambiguity remains if earlier researchers did not use a unique code in accordance with some established system.

Because it has been the objective of VAO committees to address disease entities in as great specificity as possible with the available data, overall results on the coarser grouping of LHCs are of little consequence for the conclusions of association that have been drawn for the more specific entities. The committee for Update 2010 noted, however, that the common biologic origin of LHCs that have been judged to have a substantial amount of evidence supporting association with the COIs (HL, NHL, CLL, hairy cell leukemia [HCL], MM, and AL amyloidosis) means that the WHO approach is supportive of and consistent with these decisions on the part of VAO committees.

VA has asked previous VAO committees to address CLL, AML, and HCL individually. Scrutiny of the entire body of epidemiologic results on leukemia for findings on particular types (as had been the most common manner of grouping) revealed several studies that showed increased risks specifically of CLL (or ILDs more generally), but did not provide support for an association of AML with exposure to the COIs. The committee for Update 2002 advised VA that CLL is recognized as a form of the already recognized-as-service-related condition NHL, whereas the committee for Update 2006 did not recognize an association between the COIs and AML. Later, the committee responsible for Update 2008 advised VA that HCL should be grouped with ILDs. In light of the history and in accord with the current WHO classification, the present committee has incorporated data specifically on CLL and HCL into the section on NHL. After a brief synopsis of biologic plausibility of the LHCs overall, the more common cancers of the lymphatic system are described in the sections below on HL, NHL, and MM (with a section on the related condition, AL amyloidosis), and then evidence on leukemias in general is discussed with a focus on information regarding those of myeloid origin.

Hodgkin Lymphoma

HL (ICD-9 201), also known as Hodgkin disease, is distinguished from NHL primarily on the basis of its neoplastic cells, mononucleated Hodgkin cells, and multinucleated Reed–Sternberg cells originating in germinal-center B cells (Küppers et al., 2002). HL's demographics and genetics are also characteristic. ACS estimated that 4,960 men and 4,100 women would receive diagnoses of HL in the United States in 2012 and that 670 men and 520 women would die from it (Siegel et al., 2012). The average annual incidence is shown in Table 8-39.

TABLE 8-39

Average Annual Incidence (per 100,000) of Hodgkin Disease in the United States.

The possibility that HL has an infectious etiology has been a topic of discussion since its earliest description. A higher incidence in people who have a history of infectious mononucleosis has been observed in some studies, and a link with Epstein–Barr virus has been proposed. In addition to the occupational associations discussed below, higher rates of the disease have been observed in people who have suppressed or compromised immune systems.

Conclusions from VAO and Previous Updates

The committee responsible for VAO determined that there were sufficient epidemiologic data to support an association between exposure to the COIs and HL. Additional studies available to the committees responsible for later updates have not changed that conclusion.

Of the 32 studies reviewed by the committee responsible for VAO, two well-conducted Swedish studies with good exposure characterization provide the most comprehensive information on the association between exposure to phenoxy herbicides (2,4-D and 2,4,5-T), picloram, or chlorophenols and HL. Hardell et al. (1981) considered NHL and HL together, and Hardell and Bengtsson (1983) considered HL separately; they found statistically significant associations with exposure to phenoxy acids (after excluding people who were exposed to chlorophenols) and with exposure to chlorophenols. In a study of 54 HL cases, Persson et al. (1989) found a large but not statistically significant risk associated with exposure to phenoxy acids. Several of the other case-control and occupational-cohort studies reviewed in VAO showed increased risk of HL, but only a few of the results were statistically significant. As with NHL, even the largest studies of production workers who were exposed to TCDD did not indicate an increased risk. The few studies of HL in Vietnam veterans tended to show increased risks, but only one (Holmes et al., 1986) was statistically significant.

Update 1996 reviewed studies that showed no excess of HL in the IARC phenoxy-herbicide cohort (Kogevinas et al., 1993) or in US farmers in 23 states (Blair et al., 1993). A smaller study of Finnish herbicide appliers (Asp et al., 1994) showed a nonsignificant increase, whereas Persson et al. (1993) reported a significant increase in Swedish farmers who were exposed to phenoxy acid herbicides. Studies of the Seveso cohort (Bertazzi et al., 1993) and of Vietnam-era veterans in Michigan (Visintainer et al., 1995) did not provide data that strengthened the association.

In Update 1998, a proportionate mortality ratio analysis that compared the experience of 33,833 US Army and Marine Corps Vietnam veterans who died during 1965–1988 with that of 36,797 deceased non-Vietnam veterans found a significant increase in Marine Corps veterans, but not Army veterans, who had served in Vietnam (Watanabe and Kang, 1996). Two studies of manufacturing workers found no association between TCDD and HL (Becher et al., 1996) or between PCP and HL (Ramlow et al., 1996). An update of the large IARC phenoxy herbicide cohort (Kogevinas et al., 1997) showed no association between phenoxy herbicides or chlorophenols and HL but did show a nonsignificant increase in HL in workers who were exposed to TCDD or higher-chlorinated hydrocarbons. Waterhouse et al. (1996) demonstrated a significant increase in the combined incidence of lymphopoietic neoplasms in a prospective study of a Michigan farming community. A 15-year followup study of the Seveso cohort (Bertazzi et al., 1997) found no deaths from HL in Zone A and a nonsignificant increase in deaths from HL in men and women in Zone B.

The committee responsible for Update 2000 reviewed the 15-year update of the Operation Ranch Hand study (AFHS, 2000), but the findings on HL were nonsignificant. In a retrospective cohort study of Dutch production and contract workers who were exposed to phenoxy herbicides, chlorophenols, and contaminants during 1950–1976, Hooiveld et al. (1998) reported increased but nonsignificant findings. Rix et al. (1998) compared mortality in a cohort of Danish paper-mill workers with that in the general Danish population and found a statistically significant increase in men but not women. In an update and expansion of cohorts involved in the NIOSH study, Steenland et al. (1999) found that the three deaths attributed to HL were consistent with the number expected. The 20-year mortality update after the Seveso accident reported no additional HL deaths in Zone A or B (Bertazzi et al., 2001).

The only new study reviewed in Update 2002 followed mortality to 1994 in a cohort of Dow Chemical Company workers (Burns et al., 2001); the single death attributed to HL resulted in a slight but nonsignificant increase.

Update 2004 reviewed a study by Akhtar et al. (2004) that found no excess of lymphopoietic cancers when comparing incidence and mortality between Ranch Hand veterans and veterans who had not served in Southeast Asia. Swaen et al. (2004) extended followup of mortality by 13 years in a cohort of Dutch herbicide appliers; with no additional deaths observed, the earlier increase in HL remained nonsignificant (Swaen et al., 1992).

Update 2006 reviewed reports on the cancer experience of Australian Vietnam veterans. In comparison with the general population, the incidence of HL was significantly higher when veterans from the different armed forces were combined (ADVA, 2005a); there was a significant association between HL and service in the Army, but Navy and Air Force veterans showed nonsignificant increases. Mortality from HL was nonsignificantly higher in the Army veterans but not in all veterans combined or in the other branches (ADVA, 2005b). A comparison of deployed and nondeployed Vietnam-era Australian conscripted Army National Service veterans (ADVA, 2005c) found no association between deployment and the incidence of or mortality from HL. In a multinational IARC cohort of 60,468 pulp and paper industry workers, McLean et al. (2006) found that death from HL was significantly higher in those who had ever been exposed to nonvolatile organochlorine compounds (which would include TCDD) but not in those who had never been exposed. Two reports from the US AHS (Alavanja et al., 2005; Blair et al., 2005a) found no excess risk of HL in pesticide applicators, commercial applicators, and their spouses. In the Cross-Canada Study of Pesticides and Health, Pahwa et al. (2006) found no association of any exposure to phenoxy herbicides, 2,4-D, Mecoprop, or MCPA and HL.

The committee responsible for Update 2008 reviewed a study by Cypel and Kang (2008) that compared mortality from lymphopoietic cancers in female Vietnam veterans with that of female era veterans and the US population; deaths from lymphopoietic cancers were not higher in those who served in Vietnam. Consonni et al. (2008) reported no statistically significant increase in deaths from HL in the Seveso cohort 25 years after the accident.

The committee for Update 2010 reviewed several occupational cohorts, a case-control study, and an update of cancer incidence in the Seveso cohort. No deaths from HL were identified in Dow PCP workers in Midland, Michigan (Collins et al., 2009b), but the TCP workers (Collins et al., 2009a) had an increased SMR of HL with a wide confidence interval. McBride et al. (2009a) examined mortality in TCP manufacturing workers in the Dow AgroSciences plant in New Plymouth, New Zealand, but a single observed HL death yielded inconclusive results. A French hospital-based case-control study of lymphoid neoplasms (Orsi et al., 2009) found a modest increase in the risk of HL after occupational exposure to herbicides in general and a greater increase after occupational exposure to phenoxy herbicides in particular, but neither was statistically significant; no association was observed with domestic use of herbicides. In the 20-year followup of cancer incidence in the Seveso cohort (Pesatori et al., 2009), there were still no cases of HL in Zone A, whereas a modest nonsignificant increase in HL risk was found in Zone R and a less clear increase in Zone B.

Table 8-40 summarizes the results of the relevant studies.

TABLE 8-40

Selected Epidemiologic Studies—Hodgkin Lymphoma (Shaded Entries Are New Information for This Update).

Update of the Epidemiologic Literature

Vietnam-Veteran and Environmental Studies

No Vietnam-veteran studies or environmental studies of exposure to the COIs and HL specifically have been published since Update 2010.

Occupational Studies

Only a single case of HL was diagnosed in the period January 1987–December 2007 in 1,316 men who had worked at any time during 1945–1994 at Dow Chemical Company's 2,4-D production plant in Midland, Michigan (Burns et al., 2011). That provides little information about whether HL is associated with 2,4-D exposure (SIR = 1.30, 95% CI 0.02–7.23) in the most restrictively defined cohort.

In the NIOSH cohort of 2,122 PCP workers, Ruder and Yiin (2011) reported a single death from HL (ICD-9 201), which occurred in the 1,402 people in the PCP-only group (SMR = 0.97, 95% CI 0.02–5.41); there were none in the 720 men in the PCP-plus-TCDD group.

In the update of cancer incidence through December 31, 2006, in participants in the AHS, Koutros et al. (2010a) did not find increases in the incidence of HL in the private applicators (SIR = 0.96, 95% CI 0.57–1.52) or in their spouses (SIR = 0.85, 95% CI 0.34–1.74). The preponderance of the HL cases occurred in the subsample drawn from Iowa (15 of 18 cases in applicators [SIR = 1.27, 95% CI 0.71–2.09] and 6 of 7 cases in their spouses [SIR = 1.02, 95% CI 0.37–2.21]). In the update of mortality in the AHS cohort through 2007, Waggoner et al. (2011) observed only five deaths from HL in the applicators (SMR = 1.03, 95% CI 0.34–2.41) and a single death from HL in their spouses. The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee's task.

Case-Control Studies

In an early report of the Cross-Canada Study of Pesticides and Health, Pahwa et al. (2003) had not found an increased risk of HL in those exposed to any type of herbicide for at least 10 hours/year. Karunanayake et al. (2012) presented results on exposure of any duration to individual pesticides. The 316 HL cases had been diagnosed during September 1, 1991–December 31, 1994, and age-matched to 1,506 controls randomly selected from provincial insurance, voter, or telephone lists. With adjustment for age, province, and several aspects of medical history, herbicides of interest in this review showed no statistically significant associations with the incidence of HL; for all phenoxy herbicides, 65 exposed cases, OR = 0.94, 95% CI 0.66–1.34; for 2,4-D, 57 exposed cases, OR = 0.88, 95% CI 0.61–1.34; for Mecoprop, 20 exposed cases, OR = 1.35, 95% CI 0.76–2.40; for MCPA, 11 exposed cases, OR = 0.97, 95% CI 0.42–2.22; for diclofop-methyl, 10 exposed cases, OR = 1.77, 95% CI 0.70–4.47; and for dicamba, 32 exposed cases, OR = 1.16, 95% CI 0.71–1.90.

Zakerinia et al. (2012) conducted an Iranian hospital-based case-control study of 200 cases of lymphoma (54 HL, 100 NHL, and 46 MM admitted from January 2007 through April 2008) and 200 controls admitted through the emergency room and matched on age, sex, and state of residence. A detailed job history gathered by interview was the source of information on exposure to pesticides (herbicides, insecticides, and fungicides). The analyses for the subtypes of pesticides were conducted only on the full set of lymphomas, so this study does not provide fully relevant information for the purpose of this review.

Biologic Plausibility

HL arises from the malignant transformation of a germinal-center B cell and is characterized by malignant cells that have a distinctive structure and phenotype; these binucleate cells are known as Reed–Sternberg cells (Jaffe et al., 2008). No animal studies have shown an increase in HL after exposure to the COIs. Reed-Sternberg cells have not been demonstrated in mice or rats, so there is no good animal model of HL. Thus, there are no specific animal data to support the biologic plausibility of an association between the COIs and HL.

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

Synthesis

The relative rarity of HL complicates the evaluation of epidemiologic studies because their statistical power is generally low. Earlier studies (Eriksson et al., 1992; Hardell et al., 1981; Holmes et al., 1986; LaVecchia et al., 1989; Persson et al., 1993; Rix et al., 1998; Waterhouse et al., 1996; Wiklund et al., 1988) were generally well conducted and included excellent characterization of exposure, and they formed the basis of previous VAO committees' conclusions. Later findings have not contradicted those conclusions, especially given that most studies have had low statistical power. Although it has not been demonstrated as clearly as for NHL, a positive association between the COIs and the development of HL is biologically plausible because of the common lymphoreticular origin of HL and NHL and their common risk factors.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the COIs and HL.

Non-Hodgkin Lymphoma

NHL (ICD-9 200.0–200.8, 202.0–202.2, 202.8–202.9) is a general name for cancers of the lymphatic system other than HL or MM. NHL consists of a large group of lymphomas that can be partitioned into acute and aggressive (fast-growing) or chronic and indolent (slow-growing) types of either B-cell or T-cell origin. B-cell NHL includes Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, large-cell lymphoma, precursor B-lymphoblastic lymphoma, and mantle-cell lymphoma. T-cell NHL includes mycosis fungoides and anaplastic large-cell lymphoma. Precursor T-lymphoblastic lymphoma is not considered a type of NHL; it is considered part of T-lymphoblastic lymphoma/leukemia, a precursor lymphoid neoplasm included with the broad group of “acute lymphoid leukemias,” which can be of either T-cell or B-cell origin.

As noted in earlier VAO updates, in response to requests from VA, CLL and HCL have been recognized as sharing many traits with NHL (including B-cell origin and immunohistochemical properties). The proposed WHO classification of NHL notes that CLL (ICD-9 204.1) and its lymphomatous form, SLL, are both derived from mature B cells (Chiorazzi et al., 2005; IARC, 2001). The present VAO committee has determined that it is more appropriate to consider those lymphatic malignancies with other forms of NHL. Therefore, discussion of CLL and HCL will no longer follow the general section on leukemia but has been moved into the NHL grouping.

ACS estimated that 38,160 men and 31,970 women would receive diagnoses of NHL in the United States in 2012 and that 10,320 men and 8,620 women would die from it (Siegel et al., 2012). The incidence of NHL is uniformly higher in men than in women and typically higher in whites than in blacks. In the groups that characterize most Vietnam veterans, incidence increases with age. In addition, ACS estimated that about 9,490 men and 6,570 women would receive diagnoses of CLL in the United States in 2012 and that 2,730 men and 1,850 women would die from it (Siegel et al., 2012). Nearly all cases occur after the age of 50 years. Average annual incidences of NHL are shown in Table 8-41 with the additional incidences of CLL.

TABLE 8-41

Average Annual Incidence (per 100,000) of Non-Hodgkin Lymphoma in the United States.

The causes of NHL are poorly understood. People who have suppressed or compromised immune systems are known to be at higher risk, and some studies show an increased incidence in people who have HIV, human T-cell leukemia virus type I, Epstein-Barr virus, or gastric Helicobacter pylori infections. The human retrovirus HTLV-1 causes adult T-cell lymphoma, but early reports that HTLV-2 might play a role in the etiology of HCL have not been substantiated. A broad spectrum of behavioral, occupational, and environmental risk factors have been proposed as contributors to the occurrence of NHL, but given the diversity of malignancies included under this name, it is not too surprising that—aside from infectious agents, immune problems, and particular chemotherapies—specific risk factors have not been definitively established (Morton et al., 2008; Wang and Nieters, 2010).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was sufficient evidence to support an association between exposure to at least one of the COIs and NHL. Additional information available to the committees responsible for later updates has not changed that conclusion.

As with HL, epidemiologic data reviewed by previous VAO committees suggest that the phenoxy herbicides (including 2,4-D) rather than TCDD may be associated with NHL. The original VAO committee concluded that a positive association existed between exposure to herbicides and the development of NHL, and studies reviewed by later committees have continued to support that finding. A large, well-conducted case-control study in Sweden by Hardell (1981) examined NHL and HL together and found a significantly increased risk associated with exposure to phenoxy acids or chlorophenols on the basis of 105 cases. Those results were replicated in further investigations of the validity of the exposure assessment and potential biases (Hardell, 1981). Another Swedish case-control study by Hardell et al. (1994) showed a statistically significant risk in a comparison of the occupational histories of 105 people who were exposed to phenoxy herbicides and chlorophenols and received diagnoses of NHL in 1974–1978 with 335 control subjects. Similar data by Persson et al. (1989) showed an increased risk of NHL in those exposed to phenoxy acids on the basis of a logistic regression analysis of 106 cases.

Studies of production workers have shown some association between TCDD exposure and NHL. A larger study of 21,863 workers in the IARC phenoxy-herbicide cohort by Kogevinas et al. (1997) found a nonsignificant increase in NHL risk. Subjects in that expanded multinational study were followed from 1939 to 1992. Other studies of Danish and Dutch phenoxy-herbicide workers who were part of the IARC cohort have shown a nonsignificant increased risk of NHL (Boers et al., 2010; Bueno de Mesquita et al., 1993; Hooiveld et al., 1998; Lynge, 1993). A cohort of 2,479 workers in four plants in Germany with exposure to phenoxy herbicide and contaminants (dioxins and furans) had significantly increased risk of NHL on the basis of five cases (Becher et al., 1996). A variety of herbicides were produced in the plants, including those known to have been contaminated with TCDD. Increases in risk—but nonsignificant ones—have also been found in the NIOSH mortality study (Steenland et al., 1999). Risks were not significantly increased in the Dow Chemical Company Midland, Michigan, or Plymouth, New Zealand, chemical production workers, phenoxy-herbicide sprayers, or 2,4-D production workers (Bloemen et al., 1993; Bodner et al., 2003; Burns et al., 2001; Collins et al., 2009a,b; McBride et al., 2009a,b; Ramlow et al., 1996; 't Mannetje et al., 2005). A multinational IARC cohort study of paper and pulp workers found a statistically significant increase in workers who were exposed to chlorophenols (McLean et al., 2006).

Studies of farmers and agricultural workers have been generally positive for an association between herbicides or TCDD and NHL; however, only a few were statistically significant. A meta-analysis of several studies of the association between employment as a farmer in the central United States and NHL showed a statistically significant risk (Keller-Bryne et al., 1997). All the studies of US agricultural workers reviewed showed increased RRs, and two NCI studies of farmers in Kansas and Nebraska (Hoar et al., 1986; Zahm et al., 1990) showed patterns of increased risk linked to use of 2,4-D. A study of a subcohort of Hispanic workers in a larger cohort of 139,000 California members of the United Farm Workers of America (Mills et al., 2005) and a population-based case-control study in Italy of NHL and CLL cases (combined) identified during 1991–1993 (Miligi et al., 2006) both showed statistically significant associations with 2,4-D.

A large, well-conducted, population-based, Cross-Canada Study of Pesticides and Health reported on pesticide use and NHL incidence in men identified from cancer registries of six Canadian provinces in 1991–1994. Statistically significant associations were found between exposure to phenoxy herbicides, 2,4-D, or Mecocrop and NHL. A reanalysis of the data from that study confirmed the findings on phenoxy herbicides but found that the association with 2,4-D, although still increased, was no longer significantly so (McDuffie et al., 2001). A population-based case-control study in 2000–2001 in men and women 20–74 years old living in New South Wales, Australia, found an increased risk of NHL associated with “substantial” exposure to phenoxy herbicides (Fritschi et al., 2005). Spinelli et al. (2007) reported on a population-based case-control study in Vancouver and Victoria, British Columbia, and found strong monotonic increases in serum concentrations of two dioxin-like PCBs (PCB 118 and 156). Chiu et al. (2004) and Lee et al. (2004b) conducted a pooled (combined) analysis of two case-control studies that were carried out in three Midwestern US states—Iowa and Minnesota (Cantor et al., 1992) and Nebraska (Zahm et al., 1990)—and found that risks were increased in farmers by use of herbicides, including 2,4-D and 2,4,5-T. In a study of NHL incidence in people who lived in the vicinity of 13 French municipal waste incinerators, Viel et al. (2008) found a small but statistically significant increase in the risk of NHL and evidence of a dose–response relationship with increased exposure to dioxin. A case-control study of NHL rates in people who lived near a municipal solid-waste incinerator in Bensaçon, France, found that incidence of NHL was significantly increased in the area determined to have the highest dioxin contamination, but no increases were found in the low and intermediate categories (Floret et al., 2003). A French hospital-based case-control study of lymphoid neoplasms (Orsi et al., 2009) did not find the occurrence of NHL to be associated with occupational or domestic use of pesticides or phenoxy herbicides in particular.

Evidence of an association between the COIs and NHL in Vietnam veterans, the primary population of interest in the VAO updates, has been lacking. The Centers for Disease Control and Prevention (CDC) Selected Cancers Study (CDC, 1990a) showed a significantly increased risk of NHL in all Vietnam veterans; however, in analysis according to branch of service, Army and Air Force personnel were not at increased risk. Marine Corps veterans had higher mortality in the CDC Selected Cancers Study and significantly increased risks in several other studies (Breslin et al., 1988; Burt et al., 1987; Watanabe and Kang, 1996; Watanabe et al., 1991), but the implications of these findings are unclear. No increased risk has been seen in Operation Ranch Hand veterans (AFHS, 2000; Akhtar et al., 2004; Michalek et al., 1990; Wolfe et al., 1990) or in members of the Army Chemical Corps (Boehmer et al., 2004).

With 25 years of followup of the Seveso population and a relatively small number of observed cases, evidence of an increased incidence of NHL is emerging in the subgroup in the most highly exposed zones (Bertazzi et al., 1989b, 1993, 1997, 2001; Consonni et al., 2008; Pesatori et al., 1992, 2009).

The findings of several PCB-focused studies (Bertrand et al., 2010; Engel et al., 2007; Laden et al., 2010) are consistent with the associations with NHL repeatedly observed in connection with the COIs in the VAO series, but the extent of intercorrelation of these persistent organic pollutants greatly curtails the degree to which any effect can be specifically attributed to dioxin-like activity.

Table 8-42 summarizes the results of the relevant studies of all forms of NHL.

TABLE 8-42

Selected Epidemiologic Studies—Non-Hodgkin Lymphoma (Shaded Entries Are New Information for This Update).

Update 2002 was the first to discuss CLL separately from other leukemias. The epidemiologic studies indicated that farming, especially with exposure to 2,4-D and 2,4,5-T, is associated with significant mortality from CLL. Many more studies support the hypothesis that herbicide exposure can contribute to NHL risk. Most cases of CLL and NHL reflect malignant transformation of germinal-center B cells, so these diseases could have a common etiology.

Studies concerning CLL reviewed in Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 are summarized in Table 8-43.

TABLE 8-43

Selected Epidemiologic Studies—Chronic Lymphocytic Leukemia (Shaded Entries Are New Information for This Update).

Update of the Epidemiologic Literature

Vietnam-Veteran and Environmental Studies

No Vietnam-veteran studies or environmental studies of exposure to the COIs and NHL have been published since Update 2010.

Occupational Studies

Burns et al. (2011) published an update of cancer incidence through 2007 in workers who were alive on January 1, 1985, and had been employed at any time from 1945 to 1994 in 2,4-D production by the Dow Chemical Company in Midland, Michigan. They found no evidence of significantly increased rates of cancer overall. With 14 cases observed, the increase in risk of NHL in the most restrictively defined cohort did not reach statistical significance (SIR = 1.71, 95% CI 0.93–2.87), as was the case in the two successively more inclusive, but potentially more biased, cohorts.

Boers et al. (2012) provided a quantified, TCDD-based analysis of the mortality data updated through 2006 in male workers in two Dutch phenoxy-herbicide factories, which were considered in Update 2010 (Boers et al., 2010). The 1,020 workers in factory A had been involved in production of 2,4,5-T with its associated TCDD contamination, whereas the 1,036 working in factory B had produced only phenoxy herbicides that would not have had TCDD contamination. Contemporary TCDD concentrations measured in a subsample of 187 workers were used to derive a model incorporating job history to estimate serum TCDD concentrations of all the men at the end of their employment. Use of the estimated TCDD concentrations of the workers in both factories showed a significant increase in death due to NHL in association with TCDD exposure (HR = 1.36, 95% CI 1.06–1.74). Dose-response modeling applied only to the workers in factory A estimated an increased risk of NHL mortality that neared significance (HR = 1.27, 95% CI 0.95–1.71), whereas an increase in risk had not been evident (HR = 0.98, 95% CI 0.19–4.47) in the qualitative exposure analysis by Boers et al. (2010).

Manuwald et al. (2012) reported mortality in 1,191 men and 398 women who had been employed for at least 3 months during 1952–1984 in a chemical plant in Hamburg (a subcohort of the IARC phenoxy-herbicide cohort). During that period, the plant produced insecticides and herbicides, including 2,4,5-T, so cohort members had the possibility of exposure to TCDD. Subjects entered the cohort on the date of their first employment in the plant, and vital status was sought through 2007. SMRs that were calculated relative to the population of Hamburg showed that mortality from NHL was not increased in men (five deaths, SMR = 1.56, 95% CI 0.50–3.65) or in women (two deaths, SMR = 1.67, 95% CI 0.19–6.02), but for the entire cohort the increase in risk was significant (SMR = 1.59, 95% CI 0.64–3.28).

Ruder and Yiin (2011) reported mortality in 1940–2005 in the NIOSH PCP cohort of 2,122 workers in the four US plants that had been involved in PCP production. PCP production entailed exposure to PCDDs and PCDFs but not to the most toxic 2,3,7,8 dioxin congener. A subcohort of 720 workers (all men, the PCP-plus-TCDD group) had also been employed in TCP production and so had also been exposed to TCDD. Relative to US referent rates, deaths from NHL were significantly increased in the entire cohort (17 deaths, SMR = 1.77, 95% CI 1.03–2.84) and in the PCP-plus-TCDD group (eight deaths, SMR = 2.50, 95% CI 1.08–4.93) but not in the PCP-only group (nine deaths, SMR = 1.41, 95% CI 0.64–2.67).

Koutros et al. (2010a) and Waggoner et al. (2011) assessed cancer incidence and mortality, respectively, in private applicators, commercial applicators, and their spouses in the AHS cohort vs the general population of Iowa and North Carolina. Koutros et al. (2010a) updated their previously reported incidence study through December 31, 2006, and found no association between pesticide exposure and NHL incidence in private applicators (195 cases, SIR = 0.99, 95% CI 0.86–1.14), commercial applicators (9 cases, SIR = 0.82, 95% CI 0.38–1.56) and their spouses (86 cases, SIR = 0.99, 95% CI 0.79–1.22). Waggoner et al. (2011) reported similar findings in applicators (90 cases, SMR = 0.84, 95% CI 0.67–1.03) and in their spouses (42 cases, SMR = 1.11, 95% CI 0.80–1.50). The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee's task.

Case-Control Studies

Using information assembled in the Cross-Canada Study of Pesticides and Health, Hohenadel et al. (2011) tested for interaction effects on the risk of NHL when exposures involved various combinations of pesticides. Men who had NHL (513) were compared with the studywide control group (1,506) to assess NHL risk associated with exposure to multiple pesticides. When exposure to multiple herbicides (144 cases exposed to any herbicide) was considered, there was a trend (p = 0.02) in those who had been exposed to more herbicides to have a higher risk of NHL. When the analysis was limited to phenoxy-herbicide exposures (129 cases exposed to any phenoxy herbicide), the trend was a bit stronger (p = 0.01). When 36 combinations of differing types of pesticides were assessed, five pairs (all including the insecticide malathion) showed higher risk when exposure was to both, but none of the interaction terms was statistically significant; two of the combinations with malathion involved the phenoxy herbicides 2,4-D and Mecoprop. That is consistent with results on associations between NHL and individual pesticides published previously (McDuffie et al., 2001), in which exposure to the two phenoxy herbicides individually increased the risk of NHL significantly, whereas this was not the case for the two other phenoxy herbicides considered (MCP and diclofop-methyl). For the subsets of those exposed to the particular phenoxy herbicide, but not to malathion, the risk remained significant for Mecoprop (23 cases exposed only to phenoxy herbicide, OR = 2.09, 95% CI 1.23–3.54) but not for 2,4-D (49 cases exposed only to phenoxy herbicide, OR = 0.94, 95% CI 0.67–1.3).

Bräuner et al. (2012) measured the concentrations of 10 PCBs and eight organochlorine pesticides in adipose tissues and examined their relationship with NHL risk. There were no associations between PCBs and other organochlorine pesticides tested except DDT, which was associated with an increased NHL risk.

Viel et al. (2011) found a strong and consistent association between serum concentrations of PCDDs, PCDFs, and dioxin-like PCBs and NHL risk in people who lived in the vicinity of a municipal solid-waste incinerator that had high dioxin emission concentrations (Viel et al., 2011).

The literature search for the present update identified two additional case-control studies in which the exposures considered were not sufficiently specific for this review's COIs. In an Iranian hospital-based case-control study of exposure to pesticides, Zakerinia et al. (2012) found a significant increase in NHL incidence in people who were exposed (OR = 3.9, 95% CI 2.2–6.8). Similarly, a case-control study in the Shanghai Health Watch project reported statistically significant increases in NHL risks in agriculture and farmworkers and in workers who were exposed to general herbicides (OR = 1.77, 95% CI 1.02–3.05) (Wong et al., 2010).

Biologic Plausibility

The diagnosis of NHL encompasses a wide variety of lymphoma subtypes. In humans, about 85% are of B-cell origin and 15% of T-cell origin. In commonly used laboratory mice, the lifetime incidence of spontaneous B-cell lymphomas is about 30% in females and about 10% in males. Although researchers seldom note the subtypes of B-cell lymphomas observed, lymphoblastic, lymphocytic, follicular, and plasma-cell lymphomas are seen in mice and are similar to types of NHL seen in humans. Laboratory rats, however, are less prone to develop lymphomas, but Fisher 344 rats do have an increased incidence of spontaneous mononuclearcell leukemia of nonspecific origin. The lifetime incidence of leukemia is about 50% in male rats and about 20% in female rats. Neither mice nor rats develop T-cell lymphomas spontaneously at a predictable incidence, but T-cell-derived tumors can be induced by exposure to some carcinogens.

Several long-term feeding studies of various strains of mice and rats have been conducted over the last 30 years to determine the effects of TCDD on cancer incidence. Few of them have shown effects of TCDD on lymphoma or leukemia incidence. The NTP (1982a) reported no increase in overall incidence of lymphoma in female B6C3F1 mice exposed to TCDD at 0.04, 0.2, or 2.0 pg/kg per week for 104 weeks but found that histiocytic lymphomas (now considered to be equivalent to large B-cell lymphomas) were more common in the high-dose group. No effects on lymphoma incidence were seen in Osborne-Mendel rats treated with TCDD at 0.01, 0.05, or 0.5 μg/kg per week. Sprague-Dawley rats treated with TCDD at 0.003, 0.010, 0.022, 0.046, or 0.100 μg/kg per day showed no change in incidence of malignant lymphomas. Long-term exposure to phenoxy herbicides or cacodylic acid also has not resulted in an increased incidence of lymphomas in laboratory animals. Thus, few laboratory animal data support the biologic plausibility of promotion of NHL by TCDD or other COIs, but it should be noted that standard rodent models are not particularly sensitive for detection of chemicals that cause lymphohematopoietic cancers.

In contrast, more recent studies at the cellular level indicate that activation of the AHR by TCDD inhibits apoptosis, a mechanism of cell death that controls the growth of cancer cells. Vogel et al. (2007) studied human cancer cells in tissue culture and showed that addition of TCDD inhibited apoptosis in histiocytic-lymphoma cells, Burkitt-lymphoma cells, and NHL cell lines. The reduction in apoptosis was associated with an increase in the expression of Cox-2, C/EBP β, and Bcl-xL mRNA in the cells. Those genes code for proteins that protect cells from apoptosis. The effects of TCDD on apoptosis were blocked when an AHR antagonist or a Cox-2 inhibitor was added to the culture; this demonstrated the underlying AHR-dependent mechanism of the effects. More important, when C57Bl/10J mice were given multiple doses of TCDD over a period of 140 days, premalignant lymphoproliferation of B cells was induced before the appearance of any spontaneous lymphomas in the control mice. When the B cells were examined, they were found to manifest changes in gene expression similar to those induced by TCDD in the human cell lines, which provided support for this mechanism of lymphoma promotion by TCDD.

Recent evidence has shown that AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the interleu-kin-6 (IL-6) cytokine, which has tumor-promoting effects in numerous tissues (Hollingshead et al., 2008). IL-6 plays a roll in B-cell maturation and induces a transcriptional inflammatory response. It is known to be increased in B-cell neoplasms, including MM and various lymphomas, especially diffuse large B-cell lymphomas (Hussein et al., 2002; Kato et al., 1998; Kovacs, 2006).

An alternative link that could help to explain the association between TCDD and NHL has been explored in human studies. Chromosomal rearrangements, with consequent dysregulation of expression of various genes, are prevalent in B-cell lymphomas, and the t(14;18) reciprocal translocation, which juxtaposes the BCL2 with the locus of the immunoglobin heavy chain, is found in tumor cells in most cases of follicular lymphoma. Roulland et al. (2004) investigated the prevalence of the t(14;18) translocation that is characteristic of most cases of follicular lymphoma in 53 never-smoking and pesticide-using men in a cohort of French farmers whose pesticide exposures and confounding information had previously been well characterized; blood samples had been gathered from 21 during periods of high pesticide use and samples from the other 32 during a period of low pesticide use. The authors found a higher prevalence of cells carrying the translocation in the farmers whose blood had been drawn during a period of high pesticide use than in those whose blood had been drawn during a low-use period. Baccarelli et al. (2006) reported an increase in t(14;18) chromosomal translocation in lymphocytes from humans who were exposed to TCDD in the Seveso accident. In most cases of follicular lymphoma, tumor cells carry the t(14;18) chromosomal translocation, and there is evidence that an increased frequency of lymphocytes from the peripheral blood carrying this tumor marker may be a necessary but not sufficient step toward development of follicular lymphoma (Roulland et al., 2006).

Synthesis

The first VAO committee found the evidence to be sufficient to support an association between exposure to at least one of the COIs and NHL. The evidence was drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. As has generally been the case in previous updates, the new studies were largely concordant with the conclusion that there is an association with the COIs. Of the seven studies newly evaluated for this update that investigated the association between NHL and adequately specified exposures to the COIs, three found statistically significant positive associations (Boers et al., 2012; Ruder and Yiin, 2011; Viel et al., 2011).

Individual findings on CLL are fairly few compared with the considerable number of studies supporting an association between exposure to the COIs and NHL. Results of some high-quality studies show that exposure to 2,4-D and 2,4,5-T appears to be associated with CLL, including the incidence study of Australian veterans (ADVA, 2005a); the case-control study by Hertzman et al. (1997) of British Columbia sawmill workers who were exposed to chlorophenates; the Danish-gardener study (Hansen et al., 1992); and the population-based case-control study in two US states by Brown et al. (1990) that showed increased risks associated with any herbicide use and specifically use of 2,4,5-T for at least 20 years before the subjects were interviewed. Other studies that showed positive associations but do not contribute greatly to the overall conclusion include the population-based case-control study by Amadori et al. (1995) that used occupational titles but did not include specific assessments of exposure to the chemicals; the cancer-incidence study in Tecumseh County, Michigan, in which no exposure assessments were available (Waterhouse et al., 1996); and proportionate-mortality studies by Blair and White (1985) and Burmeister et al. (1982).

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one of the COIs and NHL.

Multiple Myeloma

MM (ICD-9 203.0) is characterized by proliferation of bone-marrow stem cells that results in an excess of neoplastic plasma cells and in the production of excess abnormal proteins, usually fragments of immunoglobulins. MM is sometimes grouped with other immunoproliferative neoplasms (ICD-9 203.8). ACS estimated that 12,190 men and 9,510 women would receive diagnoses of MM in the United States in 2012 and that 6,020 men and 4,690 women would die from it (Siegel et al., 2012). The average annual incidence of MM is shown in Table 8-44.

TABLE 8-44

Average Annual Incidence (per 100,000) of Multiple Myeloma in the United States.

The incidence of MM is highly age-dependent and is relatively low in people under 40 years old. The incidence is slightly higher in men than in women, and the difference becomes more pronounced with age.

An increased incidence of MM has been observed in several occupational groups, including farmers and other agricultural workers and those with workplace exposure to rubber, leather, paint, and petroleum (Riedel et al., 1991). People who have high exposure to ionizing radiation and those who suffer from other plasma-cell diseases, such as monoclonal gammopathy of unknown significance or solitary plasmacytoma, are also at greater risk.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was limited or suggestive evidence of an association between exposure to the COIs and MM. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 did not change that conclusion.

Table 8-45 summarizes the results of the relevant studies.

TABLE 8-45

Selected Epidemiologic Studies—Multiple Myeloma.

Update of the Epidemiologic Literature

Vietnam-Veteran and Environmental Studies

No Vietnam-veteran studies or environmental studies of exposure to the COIs and MM have been published since Update 2010.

Occupational Studies

Burns et al. (2011) updated cancer incidence through 2007 in workers who were alive on January 1, 1985, and had been employed at any time from 1945 to 1994 in 2,4-D production by the Dow Chemical Company in Midland, Michigan. They found no evidence of significantly increased rates of cancer overall. With two cases observed, the incidence of MM in the most restrictively defined cohort was not increased (SIR = 0.79, 95% CI 0.09–2.87), as was the case for the two successively more inclusive, but potentially more biased, cohorts.

Ruder and Yiin (2011) reported mortality in 1940–2005 in the NIOSH PCP cohort of 2,122 workers in the four US plants that had been involved in PCP production. PCP production entailed exposure to PCDDs and PCDFs but not to the most toxic 2,3,7,8 dioxin congener. A subcohort of 720 workers (all men, the PCP-plus-TCDD group) had also been employed in TCP production and so had also been exposed to TCDD. In the total cohort, seven deaths attributed to MM were identified, which was consistent with the mortality experience of the US population (SMR = 1.50, 95% CI 0.60–3.10). The results were similar for the 1,402 workers in the PCP-only group (six deaths, SMR = 1.84, 95% CI 0.68–4.00). Only one of the deaths occurred in the PCP-plus-TCDD group (SMR = 0.72, 95% CI 0.02–3.99).

Koutros et al. (2010a) and Waggoner et al. (2011) assessed cancer incidence and mortality, respectively, in private and commercial pesticide applicators and their spouses in the AHS cohort vs the general population of Iowa and North Carolina. Koutros et al. (2010a) updated their previously reported incidence study through December 31, 2006, and found nonsignificant associations for MM in private pesticide applicators (71 cases, SIR = 1.2, 95% CI 0.93–1.51) and their spouses (21 cases, SIR = 0.94, 95% CI 0.58–1.44). Similarly, in an analysis of MM mortality in agricultural applicators and their spouses in 1993–2007 in this AHS cohort, Waggoner et al. (2011) reported a nonsignificant SMR in applicators (52 cases, SMR = 1.01, 95% CI 0.76–1.33) and their spouses (10 cases, SMR = 0.56, 95% CI 0.27–1.04). The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee's task.

Case-Control Studies

The Cross-Canada Study of Pesticides and Health is a population-based case-control study of several rare cancers conducted in men who lived in six Canadian provinces. Pahwa et al. (2012) assessed the effect of exposure to several specific phenoxy herbicides on 342 MM cases in comparison with the study's standard set of 1,506 controls with adjustment for age, province of residence, and several aspects of personal and family history. Mecoprop was found to be positively associated with the risk of MM (OR = 1.89, 95% CI 1.15–3.12), whereas this was not the case for 2,4-D (OR = 1.23, 95% CI 0.93–1.76) or for the less frequently used phenoxy herbicides MCPA (OR = 0.68, 95% CI 0.30–1.53) and diclofop-methyl (OR = 1.49, 95% CI 0.60–3.72).

Additional studies identified in the literature search for the present update presented results on MM in association with exposures that were not sufficiently specific with respect to the COIs in the VAO reviews. Perrotta et al. (2012) published findings from the EPILYMPH study, which applied a detailed occupational exposure-assessment approach to a large multicenter case-control study conducted in six European countries. The study included 227 MM cases and four age-matched controls per case, and ORs and 95% CIs were calculated for MM risk associated with level of education, individual occupations, and specific exposures. An increased risk was observed in general farmers (OR = 1.77, 95% CI 1.05–2.99) after adjustment for level of education. Pesticide exposure over a period of 10 years or more increased MM risk (OR = 1.62, 95% CI 1.01–2.58). In an Iranian hospital-based case-control study of exposure to pesticides, Zakerinia et al. (2012) found a significant increase in MM incidence (OR = 2.48, 95% CI 1.16–5.20).

Biologic Plausibility

No animal studies have reported an association between exposure to the COIs and MM. Thus, there are no specific animal data to support the biologic plausibility of such an association between the COIs and MM.

Recent evidence has shown that AHR activation by TCDD in human breast and endocervical cell lines induces sustained high concentrations of the IL-6 cytokine, which has tumor-promoting effects in numerous tissues (Hollingshead et al., 2008). IL-6 plays a roll in B-cell maturation and induces a transcriptional inflammatory response. It is known to be increased in B-cell neoplasms, including MM and various lymphomas (Hussein et al., 2002; Kovacs, 2006).

In comparing the frequency of specific variants of several metabolic genes between MM cases and controls, Gold et al. (2009) found some indication of differences, particularly in CYP1B1 and AHR alleles, that might reflect increased suspectibility to MM after exposure to particular chemicals. A biochemical link to the COIs, however, is far from being established.

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

Synthesis

Previous VAO reports found limited or suggestive evidence of an association between exposure to at least one of the COIs and MM. MM is a type of lymphohematopoietic malignancy that is derived from antibody-secreting plasma cells from the B-cell lineage. The evidence of an association between the COIs and lymphomas (NHL, HL, and CLL/HCL) has been classified as sufficient. Most of these cancers also arise from B cells, so the committee hypothesized that it would be etiologically plausible for the association with MM to belong with the lymphomas in the sufficient category. Although many studies of exposure to pesticides in general and MM found strong or at least positive associations, review of studies that addressed an association between the specific COIs and MM found that the results were considerably weaker than those for the other B-cell neoplasms and did not justify advancing MM out of the limited or suggestive category.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one of the COIs and MM.

Leukemia

Leukemias (ICD-9 202.4, 203.1, 204.0–204.9, 205.0–205.9, 206.0–206.9, 207.0–207.2, 207.8, 208.0–208.9) have traditionally been divided into four primary types: acute and chronic lymphocytic leukemia and acute and chronic myeloid leukemia. There are numerous subtypes of AML (ICD-9 205), which is also called acute myelogenous leukemia, granulocytic leukemia, or acute non-lymphocytic leukemia.

ACS estimated that 26,380 men and 20,320 women would receive diagnoses of some form of leukemia in the United States in 2012 and that 13,500 men and 10,040 women would die from it (Siegel et al., 2012). Collectively, leukemia was expected to account for 2.9% of all new diagnoses of cancer and 4.1% of deaths from cancer in 2012. The different forms of leukemia have different patterns of incidence and in some cases different risk factors. The incidences of the various forms of leukemia are presented in Table 8-46.

TABLE 8-46

Average Annual Incidence (per 100,000) of Leukemias in the United States.

Myeloid Leukemias

In adults, acute leukemia is nearly always in the form of AML (ICD-9 205.0, 207.0, 207.2). ACS estimated that about 7,350 men and 6,430 women would receive new diagnoses of AML in the United States in 2012 and that 5,790 men and 4,410 women would die from it (Siegel et al., 2012). In the age groups that include most Vietnam veterans, AML makes up roughly one-fourth of cases of leukemia in men and one-third in women. Overall, AML is slightly more common in men than in women. Risk factors associated with AML include high doses of ionizing radiation, occupational exposure to benzene, and exposure to some medications used in cancer chemotherapy (such as melphalan). Fanconi anemia and Down syndrome are associated with an increased risk of AML, and tobacco use is thought to account for about 20% of AML cases.

Vietnam veterans have expressed concern about whether myelodysplastic syndromes, most often precursors to AML, are associated with Agent Orange exposure. However, no results on those conditions in conjunction with the COIs have been found in VAO literature searches. Epidemiologic research on those hematologic disorders has been undertaken fairly recently; for instance, the LATIN case-control study (Maluf et al., 2009) has undertaken investigation of aplastic anemia in South America, but the reported exposures have been only as specific as “herbicides” and “agricultural pesticides.”

The incidence of CML increases steadily with age in people over 30 years old. Its lifetime incidence is roughly equal in whites and blacks and is slightly higher in men than in women. CML accounts for about one-fifth of cases of leukemia in people in the age groups that include most Vietnam veterans. It is associated with an acquired chromosomal abnormality known as the Philadelphia chromosome, for which exposure to high doses of ionizing radiation is a known risk factor.

Lymphoid Leukemias

ALL is a disease of young children (peak incidence at the age of 2–5 years) and of people over 70 years old. It is relatively uncommon in the age groups that include most Vietnam veterans. The lifetime incidence of ALL is slightly higher in whites than in blacks and higher in men than in women. Exposure to high doses of ionizing radiation is a known risk factor for ALL, but there is little consistent evidence on other factors.

CLL shares many traits with lymphomas (such as immunohistochemistry, B-cell origin, and progression to an acute, aggressive form of NHL), so the committee now considers it in the section above on NHL, as classified in the WHO system.

Conclusions from VAO and Previous Updates

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

The committee responsible for Update 2002, however, considered CLL separately and judged that there was sufficient evidence of an association with the herbicides used in Vietnam and CLL alone, and Update 2008 noted that HCL is closely related to CLL.

The committee responsible for Update 2006 considered AML individually but did not find evidence to suggest that its occurrence is associated with exposure to the COIs, and there is still not sufficient evidence to support such an association, so AML has been retained with other non-CLL leukemias in the category of inadequate and insufficient evidence.

Table 8-47 summarizes the results of the relevant studies.

TABLE 8-47

Selected Epidemiologic Studies—Leukemia (Shaded Entries Are New Information for This Update).

Update of the Epidemiologic Literature

Vietnam-Veteran, Environmental, and Case-Control Studies

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

Occupational Studies

Burns et al. (2011) updated cancer incidence through 2007 in workers who were alive on January 1, 1985, and had been employed at any time from 1945 to 1994 in 2,4-D production by the Dow Chemical Company in Midland, Michigan. They found no evidence of significantly increased rates of cancer overall. With five cases observed, the incidence of leukemia in the most restrictively defined cohort was not increased (SIR = 0.86, 95% CI 0.28–2.02), as was the case for the two successively more inclusive, but potentially more biased, cohorts.

Boers et al. (2012) provided a quantified, TCDD-based analysis of mortality updated through 2006 in male workers in two Dutch phenoxy-herbicide factories, which were considered in Update 2010 (Boers et al., 2010). The 1,020 workers in factory A had been involved in production of 2,4,5-T with its associated TCDD contamination, whereas the 1,036 working in factory B had produced only phenoxy herbicides that would not have had TCDD contamination. Contemporary TCDD concentrations measured in a subsample of 187 workers were used to derive a model incorporating job history to estimate serum TCDD concentrations of all the men at the end of their employment. The estimated TCDD concentrations in the workers in both factories did not indicate an increased risk of leukemia mortality in association with TCDD (HR = 0.90, 95% CI 0.59–1.37). The dose–response modeling, applied only to the workers in factory A, also did not find an increased risk of death from leukemia (HR = 0.74, 95% CI 0.38–1.42), whereas the qualitative exposure analysis in Boers et al. (2010) had found an HR of 0.28 (95% CI 0.03–2.61).

Ruder and Yiin (2011) reported mortality in 1940–2005 in the NIOSH PCP cohort of 2,122 workers in the four US plants that had been involved in PCP production. PCP production entailed exposure to PCDDs and PCDFs but not to the most toxic 2,3,7,8 dioxin congener. A subcohort of 720 workers (all men, the PCP-plus-TCDD group) had also been employed in TCP production and so had also been exposed to TCDD. Relative to US referent rates, deaths from leukemia were not substantially altered in the entire cohort (nine deaths, SMR = 0.89, 95% CI 0.41–1.68), the PCP-only group (seven deaths, SMR = 1.03, 95% CI 0.41–2.12), or the PCP-plus-TCDD group (two deaths, SMR = 0.60, 95% CI 0.07–2.16). Of the nine leukemia deaths, four occurred in the small group of 277 nonwhite males and resulted in a significant increase in SMR (4.57, 95% CI 1.25–11.7).

Koutros et al. (2010a) updated cancer incidence data in the AHS through 2006 and found nonsignificant associations with leukemia in the private pesticide applicators (133 cases, SIR = 0.96, 95% CI 0.81–1.14) and their spouses (37 cases, SIR = 0.83, 95% CI 0.58–1.14). Similarly, in an analysis of leukemia mortality in agricultural pesticide applicators and their spouses (1993–2007), Waggoner et al. (2011) reported no increased risk of leukemia in applicators (91 deaths, SMR = 0.85, 95% CI 0.68–1.04) or in their spouses (33 deaths, SMR = 1.09, 95% CI 0.75–1.53). The AHS has been generating valuable information on the COIs for a number of years, but these results are not herbicide-specific and so are not regarded as being fully informative for the committee's task.

In the British PUHS cohort of 62,960 subjects, neither leukemia incidence nor leukemia mortality was significantly increased by pesticide exposure in men or women (Frost et al., 2011).

Biologic Plausibility

Leukemia is a relatively rare spontaneous neoplasm in mice, but it is less rare in some strains of rats. A small study reported that five of 10 male rats fed TCDD at 1 ng/kg per week for 78 weeks showed an increased incidence of various cancers, one of which was lymphocytic leukemia (Van Miller et al., 1977). Later studies of TCDD's carcinogenicity have not shown an increased incidence of lymphocytic leukemia in mice or rats.

Two studies that used cells in tissue culture suggested that TCDD exposure does not promote leukemia. Proliferation of cultured human bone marrow stem cells (the source of leukemic cells) was not influenced by addition of TCDD to the culture medium (van Grevenynghe et al., 2005). Likewise, Mulero-Navarro et al. (2006) reported that the AHR promoter is silenced in ALL—an effect that could lead to reduced expression of the receptor, which binds TCDD and mediates its toxicity. No reports of animal studies have noted an increased incidence of leukemia after exposure to the phenoxy herbicides or other COIs.

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

Synthesis

The new findings from three cohorts of production workers (Boers et al., 2012; Burns et al., 2011; Ruder and Yiin, 2011) provide no evidence to support an association between exposure to the COIs and the occurrence of leukemia. The committee has some concern about misclassification of leukemia types and finds the correspondence between intensity of exposure and magnitude of risk for leukemias (other than CLL) to be erratic.

Conclusion

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and leukemias in general. An exception is the specific leukemia subtypes of chronic B-cell hematoproliferative diseases, including CLL and HCL, which are more appropriately grouped with lymphomas.

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