6
LONG-TERM ADVERSE HEALTH EFFECTS

The long-term health effects associated with exposure to dioxins have been studied in a variety of populations, including Vietnam veterans and residents of Seveso, Italy, the site of an accidental release of dioxin. The biennial Institute of Medicine (IOM) Veterans and Agent Orange (VAO) reports have reviewed epidemiologic studies of Vietnam veterans, occupational studies, and population studies in an effort to determine whether Vietnam veterans are at increased risk for health effects from exposure to Agent Orange and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (also referred to as TCDD) during the Vietnam War. The literature is voluminous, and the VAO reports have been updated through 2008. A few of the studies include veterans who served in the Blue Water Navy in Vietnam, but most of the studies do not distinguish Navy veterans, let alone Blue Water Navy veterans, from other Vietnam-veteran populations.

In compliance with the congressional legislation that mandated the biennial reports, the VAO committees have examined the available evidence of a positive association between Agent Orange and health outcomes from epidemiologic studies in which chance, bias, and confounding can be ruled out with reasonable confidence. The committees have assigned the association to the following categories: sufficient evidence of association, limited or suggestive evidence of association, inadequate or insufficient evidence to determine association, and limited or suggestive evidence of no association (see Table 6-1). The reviews of the literature can be found in the eight VAO reports and are not repeated here; Table 6-1 summarizes these findings. The findings by the VAO committees regarding health effects for which there is sufficient evidence of an association are not identical to the list of diseases that the Department of Veterans Affairs (VA) recognizes as



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6 LONG-TERM ADVERSE HEALTH EFFECTS The long-term health effects associated with exposure to dioxins have been studied in a variety of populations, including Vietnam veterans and residents of Seveso, Italy, the site of an accidental release of dioxin. The biennial Institute of Medicine (IOM) Veterans and Agent Orange (VAO) reports have reviewed epidemiologic studies of Vietnam veterans, occupational studies, and population studies in an effort to determine whether Vietnam veterans are at increased risk for health effects from exposure to Agent Orange and its contaminant 2,3,7,8- tetrachlorodibenzo-p-dioxin (also referred to as TCDD) during the Vietnam War. The literature is voluminous, and the VAO reports have been updated through 2008. A few of the studies include veterans who served in the Blue Water Navy in Vietnam, but most of the studies do not distinguish Navy veterans, let alone Blue Water Navy veterans, from other Vietnam-veteran populations. In compliance with the congressional legislation that mandated the biennial reports, the VAO committees have examined the available evidence of a positive association between Agent Orange and health outcomes from epidemiologic studies in which chance, bias, and confounding can be ruled out with reasonable confidence. The committees have assigned the association to the following categories: sufficient evidence of association, limited or suggestive evidence of association, inadequate or insufficient evidence to determine association, and limited or suggestive evidence of no association (see Table 6-1). The reviews of the literature can be found in the eight VAO reports and are not repeated here; Table 6-1 summarizes these findings. The findings by the VAO committees regarding health effects for which there is sufficient evidence of an association are not identical to the list of diseases that the Department of Veterans Affairs (VA) recognizes as 109

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110 BLUE WATER NAVY VIETNAM VETERANS AND AGENT ORANGE EXPOSURE TABLE 6-1 Summary of Seventh Biennial Update of Findings of Occupational, Environmental, and Veteran Studies Regarding Associations Between Exposure to Herbicides and Specific Health Outcomesa Sufficient Evidence of an Association Epidemiologic evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between exposure to herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence.b For example, if several small studies that are free of bias and confounding show an association that is consistent in magnitude and direction, there could be sufficient evidence of an association. There is sufficient evidence of an association between exposure to the chemicals of interest and the following health outcomes: Soft-tissue sarcoma (including heart), 1994 (year of IOM finding), 1990 (year of VA service-connection decision) Non-Hodgkin’s lymphoma, 1994, 1990 Chronic lymphocytic leukemia (including hairy-cell leukemia and other chronic B-cell leukemias) (category clarification since Update 2006), 2003, 2004 Hodgkin’s disease, 1994, 1995 Chloracne, 1994, 1985 Limited or Suggestive Evidence of an Association Epidemiologic evidence suggests an association between exposure to herbicides and the outcome, but a firm conclusion is limited because chance, bias, and confounding could not be ruled out with confidence. For example, a well-conducted study that had strong findings in accord with less compelling results from studies of populations with similar exposures could constitute such evidence. There is limited or suggestive evidence of an association between exposure to the chemicals of interest and the following health outcomes: Laryngeal cancer, 1994, 1995 Cancer of the lung, bronchus, or trachea, 1994, 1995 Prostatic cancer, 1994, 1997 Multiple myeloma, 1994, 1995 AL amyloidosis, 2007, 2009 Early-onset transient peripheral neuropathy, 1996, 1997 Parkinson’s disease (category change from Update 2006), 2009, 2009 Porphyria cutanea tarda, 1994; sufficient, 1996; changed to limited or suggestive, 1995

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LONG-TERM ADVERSE HEALTH EFFECTS 111 TABLE 6-1 Summary of Seventh Biennial Update of Findings of Occupational, Environmental, and Veteran Studies Regarding Associations Between Exposure to Herbicides and Specific Health Outcomesa Hypertension 2007, not VA service connected Ischemic heart disease (category change from Update 2006), 2009, 2009 Type 2 diabetes (mellitus), 2000, 2001 Spina bifida in offspring of exposed people, 1996, 1996 Inadequate or Insufficient Evidence to Determine an Association The available epidemiologic studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to control for confounding, have inadequate exposure assessment, or fail to address latency. There is inadequate or insufficient evidence to determine an association between exposure to the chemicals of interest and the following health outcomes that were explicitly reviewed: Cancers of the oral cavity (including lips and tongue), pharynx (including tonsils), or nasal cavity (including ears and sinuses) Cancers of the pleura, mediastinum, and other unspecified sites in the respiratory system and intrathoracic organs Esophageal cancer Stomach cancer Colorectal cancer (including small intestine and anus) Hepatobiliary cancers (liver, gallbladder, and the bile ducts) Pancreatic cancer Bone and joint cancer Melanoma Nonmelanoma skin cancer (basal-cell and squamous-cell) Breast cancer Cancers of the reproductive organs (cervix, uterus, ovary, testis, and penis; excluding prostate) Urinary bladder cancer Renal cancer (kidney and renal pelvis) Cancers of brain and nervous system (including eye) Endocrine cancers (thyroid, thymus, and other endocrine organs) Leukemia (other than all chronic B-cell leukemias, such as chronic lymphocytic leukemia and hairy-cell leukemia) Cancers at other and unspecified sites Infertility

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112 BLUE WATER NAVY VIETNAM VETERANS AND AGENT ORANGE EXPOSURE TABLE 6-1 Summary of Seventh Biennial Update of Findings of Occupational, Environmental, and Veteran Studies Regarding Associations Between Exposure to Herbicides and Specific Health Outcomesa Spontaneous abortion (other than after paternal exposure to TCDD, which appears not to be associated) Neonatal or infant death and stillbirth in offspring of exposed people Low birth weight in offspring of exposed people Birth defects (other than spina bifida) in offspring of exposed people Childhood cancer (including acute myelogenous leukemia) in offspring of exposed people Neurobehavioral disorders (cognitive and neuropsychiatric) Neurodegenerative diseases, excluding Parkinson’s disease Chronic peripheral nervous system disorders Respiratory disorders (wheeze or asthma, chronic obstructive pulmonary disease, and farmer’s lung) Gastrointestinal, metabolic, and digestive disorders (changes in hepatic enzymes, lipid abnormalities, and ulcers) Immune system disorders (immune suppression, allergy, and autoimmunity) Circulatory disorders (other than hypertension and ischemic heart disease) Endometriosis Effects on thyroid homeostatis The VAO committees used a classification that spans the full array of cancers. However, reviews for nonmalignant conditions were conducted only if they were found to have been the subjects of epidemiologic investigation or at the request of the VA. By default, any health outcome on which no epidemiologic information has been found falls into this category.

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LONG-TERM ADVERSE HEALTH EFFECTS 113 TABLE 6-1 Summary of Seventh Biennial Update Findings of Occupational, Environmental, and Veteran Studies Regarding Associations Between Exposure to Herbicides and Specific Health Outcomesa Limited or Suggestive Evidence of No Association Several adequate studies, which cover the full range of human exposure, are consistent in not showing a positive association between any magnitude of exposure to the herbicides of interest and the outcome. A conclusion of “no association” is inevitably limited to the conditions, exposures, and length of observation covered by the available studies. In addition, the possibility of a very small increase in risk at the exposure studied can never be excluded. There is limited or suggestive evidence of no association between exposure to the herbicides of interest and the following health outcomes: Spontaneous abortion after paternal exposure to TCDD, 2002 a Herbicides indicates the following chemicals of interest: 2,4- dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), cacodylic acid, and picloram. The evidence regarding association was drawn from occupational, environmental, and veteran studies in which people were exposed to the herbicides used in Vietnam, to their components, or to their contaminant. b Evidence of an association is strengthened by experimental data that support biologic plausibility, but its absence would not detract from the epidemiologic evidence. SOURCE: Adapted from IOM (2009) and annotated to indicate the year of IOM finding and year of VA service connection. linked to herbicide exposure in Vietnam and for which compensation is provided. Decisions regarding compensation are made by the VA, which takes both the VAO reports and other factors into consideration. For example, the VA recognizes non-Hodgkin’s lymphoma (NHL) as a service-related condition in Vietnam veterans, including Blue Water Navy veterans, but does not link it to Agent Orange exposure, although the VA website on these diseases does (http://www.publichealth.va.gov/ exposures/diseases.asp). In addition to reviewing previous VAO reports, the present committee heard from a number of veterans and is aware that many veterans attribute their illnesses to exposure to Agent Orange in Vietnam. The committee valued these accounts for descriptive purposes but did not have a way to use that information effectively in its study. Without an

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114 BLUE WATER NAVY VIETNAM VETERANS AND AGENT ORANGE EXPOSURE appropriate control population and representative sample of Blue Water Navy veterans, the committee was unable to determine if these veterans’ diseases could be attributed to Agent Orange–associated TCDD exposure. This committee was asked to assess the potential long-term health effects of exposure to herbicides in Blue Water Navy Vietnam veterans as a population distinct from other Vietnam veterans, as the VA compensates veterans based on the presumption of exposure for specific groups such as ground troops. To do that, the committee examined only peer-reviewed epidemiologic studies that identified Blue Water Navy Vietnam veterans as a separate population. Since individual exposure to TCDD could not be estimated (see Chapter 5), the committee could not determine any dose-response relationships for health effects experienced by Blue Water Navy veterans. The committee attempted to determine whether adverse health outcomes among Blue Water Navy personnel were consistent with those associated with TCDD exposure in other Vietnam veterans and if their health effects occurred more or less frequently than those seen in other Vietnam veterans previously identified as exposed to TCDD. VIETNAM VETERAN STUDIES Although the subjects of many epidemiologic studies of Vietnam veterans include Navy veterans, the committee found only a few studies that examined Vietnam Navy personnel specifically as a study population (the methods of the literature search are described in Chapter 1). Whether the Navy population in question was Blue Water Navy, was Brown Water Navy, or served on land in Vietnam or elsewhere was rarely indicated. The studies are presented below alphabetically by author. Australian’s Vietnam Veteran Mortality and Cancer-Incidence Studies In 2005, the Australian Institute of Health and Welfare of the Department of Veterans’ Affairs released the results of a series of reports investigating mortality and cancer incidence in Australian veterans. Two of the reports focused specifically on the health of Vietnam veterans (Wilson et al., 2005a,b). The 59,179 male Australian veterans who

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LONG-TERM ADVERSE HEALTH EFFECTS 115 served in Vietnam between 1962–1973, were retrospectively followed to assess mortality and cancer outcomes. Data were provided by the Australian Department of Veterans’ Affairs Nominal Roll of Vietnam Veterans. Cancers diagnosed from 1982 through 2000 and deaths occurring after service in Vietnam through 2001 were compared with those in the general population of Australian men. Mortality and incidence were standardized for age and calendar year. The 57,864 veterans included in the analysis had 4,590 cancers. Overall, the incidence of all cancers in the entire Australian Vietnam veteran population was increased by 13–15% compared to the general male population; the highest rates were found in the 12,935 Navy veterans, in whom the overall incidence of cancer (1,073 cancers) was 22–26% higher than in the control population. With regard to specific cancers, in the Navy veteran population, the incidences of the following cancers were found to be statistically significantly higher: lung cancer 1 (relative risk [RR] 1.4, 95% CI 1.2–1.7), head and neck cancers (RR 1.6, 95% CI 1.1–2.0), melanoma (RR 1.4, 95% CI 1.2–1.6), and colon cancer (RR 1.3, 95% CI 1.0–1.5). The incidences of leukemia,1 brain cancer, laryngeal cancer,1 Hodgkin’s disease,1 prostatic cancer,1 and esophageal cancer were also higher but the difference was not statistically significant. The incidence of one cancer linked to Agent Orange exposure, NHL,1 was found to be lower than that in the control population (RR 0.8, 95% CI 0.5–1.0) (Wilson et al., 2005a). A ship-by-ship analysis found no significant differences in cancer rates between specific ships or types of ships or compared with a control ship, the HMAS Melbourne, which was in the Vietnam theater but never served near the coast. Time spent on ships in Vietnamese waters also did not correlate with a difference in cancer incidence. The study authors concluded that “this study did not, therefore, provide any evidence to support the hypothesis that the increased cancer rates seen among Navy personnel could be attributable to exposure to contaminated water” (Wilson et al., 2005c). The analysis of standardized incidence ratios (SIRs) included only the larger ships due to power considerations. The Australian Vietnam veterans had an overall mortality that was 6% lower (on the basis of 6,166 deaths) than that in the general male population, but the disparity in rates was present for only the first 20 1 The IOM VAO reports have found sufficient or limited/suggestive evidence of association between this condition and exposure to herbicides.

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116 BLUE WATER NAVY VIETNAM VETERANS AND AGENT ORANGE EXPOSURE years after the war and was comparable in the two populations as of 2001. Mortality in Navy veterans (1,435 deaths) was also comparable with that in the general population except for cancer deaths—overall mortality from cancer was 19% higher. The greatest differences were seen in lung cancer (RR 1.4, 95% CI 1.2–1.6), melanoma (RR 1.6, 95% CI 1.0–2.1), and mesothelioma (RR 2.53, 95% CI 1.11–4.94). Mortality from NHL was 48% lower (RR 0.5, 95% CI 0.3–0.9). Several other causes of mortality were significantly lower, including, diabetes, mental and behavioral disorders, and respiratory disorders. For lung cancer, oral cancer, head and neck cancer, and prostatic cancer, both incidence and mortality were higher; for NHL, they were lower (Wilson et al., 2005b). The studied cohort of Australian Vietnam veterans is large and included a long follow-up period; the cohort is fairly homogeneous (male, mostly white, and able to meet military physical, medical, and educational standards), and only 2.5% were lost to follow-up. However, some degree of error is expected with the probabilistic matching used to ascertain outcomes from cancer and death registries linked to the Nominal Roll of Vietnam Veterans (rather than exact matching between veteran data and registries), possibly causing cancer and death outcomes to have been missed or wrongly assigned to veterans. Individual data pertaining to specific exposures in the military or before or after active duty were not available, so the results described represent an overall average exposure scenario for veterans. The authors also note the potential for a healthy-warrior effect inasmuch as the military actively screens personnel for health problems, so they are healthier than the general population, and risk estimates are lower. The healthy-worker effect is not seen in Navy veterans as the all-cause mortality rate is similar to that of the general population. Finally, the Australian analyses did not control for confounding variables, such as smoking. Bullman et al. This case–control study compared the incidence of testicular cancer in Vietnam veterans with different probable exposures to Agent Orange (Bullman et al., 1994). Ninety-seven veteran cases were identified from voluntary VA Agent Orange Registry medical examinations in 1982– 1991 and matched with 311 controls: 67 Army cases with 218 controls, 10 Air Force cases with 22 controls, eight Marines cases with 56 controls, and 12 Navy cases with 15 controls. Controls were identified

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LONG-TERM ADVERSE HEALTH EFFECTS 117 from the same registry but had no clinical diagnosis on record. In the absence of specific information about exposure levels, surrogate measures of Agent Orange exposure were used, including service branch, type of duty, corps area, and location of ground troops. The analysis did not adjust for confounding, because there were no effects of race and age after stratification. The only veteran exposure group with a higher incidence of testicular cancer was the Navy group (crude odds ratio [OR] 2.60, 95% CI 1.08–6.24). None of the Navy veterans who had testicular cancer served in the Brown Water Navy, and only one of the 15 Navy controls did so. The authors assumed that the Navy exposure group had lower Agent Orange exposure than ground troops and concluded that “the study results are not consistent with the hypothesis that Agent Orange may be a risk factor for testicular cancer among Vietnam veterans.” Bullman and colleagues note several limitations and biases potentially affecting their results. Interpretation of those results should consider the lack of adjustment for confounders and other exposures (race, exposure to fuels, etc.) and the potentially poor ability of surrogate exposure measures to represent actual exposure. Exposure misclassification is an important limitation in that “unexposed” troops may have been exposed by being in areas after Agent Orange spraying even if they did not work directly with the chemicals. Thus service branch may be a poor proxy for exposure. Likewise, military records are reportedly a poor source of information for estimating Agent Orange exposure. Centers for Disease Control and Prevention Selected Cancers Study For evaluating cancer risks in Blue Water Navy Vietnam veterans, the most informative study was the Selected Cancers Study conducted by the Centers for Disease Control and Prevention (CDC) (1990a,b,c). Population-based case–control studies of American men born in 1929– 1953 were designed to determine the incidence of rare cancers—such as NHL, Hodgkin’s disease, soft-tissue and other sarcomas, nasal cancer, nasopharyngeal cancer, and primary hepatic cancer—in Vietnam veterans. Hepatic, nasal-cavity, and nasopharyngeal cancers and Hodgkin’s disease were of a priori interest because they had been associated with exposure to phenoxy herbicides, such as Agent Orange, in some animal studies and a few human studies. The 1,157 study

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118 BLUE WATER NAVY VIETNAM VETERANS AND AGENT ORANGE EXPOSURE participants received a first diagnosis of cancer in 1984–1988 and were listed in any of eight city or state cancer registries—those in Atlanta, Detroit, San Francisco, Seattle, Miami, Connecticut, Iowa, and Kansas. The 1,776 controls were selected by random-digit telephone dialing in the relevant locations and frequency matched by age to the men with cancer. Analyses were adjusted for many demographic, exposure, and medical covariates. Exposure was determined on the basis of characteristics of service in Vietnam, including duration of service and calendar years, age at first tour, rank, unit type, corps (area), and land or sea duty. During the Vietnam War, the military divided South Vietnam into four administrative zones, I–IV Corps; I Corps was the farthest north, and IV Corps was in the southernmost part of the country. Blue Water Navy veterans had substantially higher risks (OR 2.17, 95% CI 1.22–3.86), including the second-highest risk of NHL in personnel in the various corps (Table 6-2). Only ground troops that served in I Corps had a higher risk of NHL. The authors concluded that the roughly 50% increase in NHL risk in all Vietnam veterans was due to service in Vietnam in general rather than to specific characteristics of service and Agent Orange exposure. Similarly, for Hodgkin’s disease, the highest risk was in I Corps, followed by the Blue Water Navy (OR 1.39, 95% CI 0.56–3.46). There were no cases of Hodgkin’s disease in shore-based or Brown Water Navy personnel in this study (Table 6-3). For soft-tissue and other sarcomas, a decreased risk among Blue Water Navy personnel was observed on the basis of only three cases (OR 0.64, 95% CI 0.18–2.21). For the other cancers tracked in this study, no results were presented for the Blue Water Navy, because there were only two cases of nasal carcinoma, three cases of nasopharyngeal carcinoma, and eight cases of primary hepatic cancer identified for all military service in Vietnam in this study combined.

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LONG-TERM ADVERSE HEALTH EFFECTS 119 TABLE 6-2 Association of Selected Characteristics of Military Service in Vietnam with NHL in the Selected Cancers Study, 1984–1988 Controls NHL Cases Characteristic (n = 1,776) (n = 1,157) OR (95% CI) Corps in Vietnam I 18.9% (23) 25.3% (23) 2.25 (1.21–4.18) II 24.6% (30) 20.9% (19) 1.22 (0.66–2.26) III 32.8% (40) 20.9% (19) 0.89 (0.50–1.58) IV 3.3% (4) 2.2% (2) 0.90 (0.15–5.41) Navy, Blue Water 20.5% (25) 30.8% (28) 2.17 (1.22–3.86) Unknown — (11) — (8) — Land v. sea duty in Vietnam All land-based men 81.2% (108) 71.7% (71) 1.30 (0.93–1.82) All branches other than Navy 76.7% (102) 67.7% (67) 1.29 (0.92–1.82) Navy, shore 3.0% (4) 4.0% (4) 2.26 (0.52–9.78) Navy, Brown Water 1.5% (2) — (0) — Navy, Blue Water 18.8% (25) 28.3% (28) 2.18 (1.23–3.87) SOURCE: CDC, 1990a. Dalager et al. A hospital-based case–control study examined risks of NHL and Hodgkin’s disease in Vietnam veterans or era veterans seen in VA hospitals in 1969–1985 (Dalager et al., 1991, 1995). Study participants were born in 1937–1954. The number of veterans who had NHL was compared with the number of veterans who had diagnoses other than NHL. Exposure was determined on the basis of having served or not having served in Vietnam or on the basis of surrogates of Agent Orange exposure, including branch of service, combat-duty occupation, or corps. For the investigation of NHL risk, 201 cases and 358 controls were ascertained. Service in Vietnam was not associated with an increased risk of NHL (OR 1.03, 95% CI 0.70–1.50). In Navy veterans ever in Vietnam, the OR was 0.70 (95% CI 0.31–1.60) for NHL. The 283 Hodgkin’s disease cases were compared with 404 controls; the result was an OR of 1.28 (95% CI 0.94–1.76) for any service in Vietnam. For the

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120 BLUE WATER NAVY VIETNAM VETERANS AND AGENT ORANGE EXPOSURE TABLE 6-3 Association of Selected Characteristics of Military Service in Vietnam with Hodgkin’s Disease in the Selected Cancers Study, 1984–1988 Hodgkin’s Controls Disease Cases Characteristic (n = 1,776) (n = 1,157) OR (95% CI) Corps in Vietnam I 18.9% (23) 25.9% (7) 1.67 (0.67–4.18) II 24.6% (30) 11.1% (3) 0.52 (0.15–1.81) III 32.8% (40) 33.3% (9) 1.25 (0.57–2.75) IV 3.3% (4) 3.7% (1) 0.93 (0.09–9.82) Navy, Blue Water 20.5% (25) 25.9% (7) 1.39 (0.56–3.48) Unknown — (11) — (1) — Land v. sea duty in Vietnam All land-based men 81.2% (108) 75.0% (21) 1.08 (0.64–1.82) All branches other than Navy 76.7% (102) 75.0% (21) 1.18 (0.70–2.00) Navy, shore 3.0% (4) — — Navy, Brown Water 1.5% (2) — — Navy, Blue Water 18.8% (25) 25.0% (7) 1.41 (0.57–3.50) SOURCE: CDC, 1990c. Navy, the OR was 1.09 (95% CI 0.93–1.28). For both outcomes, neither service in Vietnam in general nor service in the Navy in Vietnam conferred a higher risk. Results were not confounded by age, year of hospitalization, race, or education. Results do not support any association between NHL or Hodgkin’s disease and surrogates of Agent Orange exposure in Vietnam veterans. The use of hospital-ascertained cases and controls may limit the generalizability of results to all Vietnam veterans (those hospitalized are different from other veterans) and introduce bias (exposed cases are more likely to be hospitalized than controls). It was also not possible to determine whether controls were hospitalized for diseases related to service in Vietnam.

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LONG-TERM ADVERSE HEALTH EFFECTS 121 OTHER NAVY VETERAN STUDIES Two studies by Garland et al. (1987, 1988) examined Navy veterans who served during the decade after the end of the Vietnam War. The committee considered this population to be potentially relevant even though they were not Vietnam veterans. The results of the two studies are valuable because they provide background on the potential effects of occupational exposures in Navy personnel who were not in the Vietnam environment; that is, they examined potential occupational exposures other than herbicides. In a prospective study of cancer incidence, Garland et al. (1987, 1988) examined white male Navy veterans by occupation while they were in service from 1974 to 1979 and compared them with the general US population. It was not a study of Vietnam veterans. Data collected by the Naval Health Research Center included occupational and hospitalization information. Cases of NHL and Hodgkin’s disease were identified from hospitalization records and corroborated with medical records or pathologic confirmation. To assess the risk of Hodgkin’s disease, the authors included 2.275 million person-years at risk and 88 cases. The age-adjusted incidence in Navy veterans was 2.9 per 100,000 person-years, lower than the 3.7 per 100,000 person-years reported in the general population (SIR 0.8, 95% CI 0.6–1.0). The average annual age-adjusted incidence in Navy personnel increased with duration of service from 2.3 per 100,000 person-years in those serving less than 2 years to 4.0 per 100,000 person- years for those serving 11 years or more (not statistically significant). After stratification by occupation, a significantly increased risk of Hodgkin’s disease was found only in the machinist's-mate occupational category (SIR 2.3, 95% CI 1.2–4.0) compared with a Navy control population. No occupations differed significantly from the US population. Following the same cohort through 1983, the study included 3.7 million person-years at risk and found 68 cases of NHL. No increased risk of NHL was found; rather, the incidence of NHL in Navy personnel was significantly lower than that in the US population (6.9 versus 9.9 per 100,000 person-years) with an overall SIR of 0.7 (95% CI 0.5–0.9). After stratification by occupation, there were no significant findings, mainly because there were few cases.

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122 BLUE WATER NAVY VIETNAM VETERANS AND AGENT ORANGE EXPOSURE Those findings do not indicate an association between NHL or Hodgkin’s disease and naval service in the short term. Follow-up may not have been long enough to capture any excess cases, inasmuch as latency may be up to 35 years. Data were available only on active-duty personnel, not on those who may have left the Navy; this might lead to underestimation of disease incidence. The authors noted that the excess of Hodgkin’s disease cases in naval machinists may be due to other exposures that could not be assessed in this analysis, including exposures to solvents, cutting and lubricating oils, metal dusts or vapors, Freon, and radiation. The exposure of most concern would be exposure to benzene, which has been linked to NHL. CONCLUSIONS The committee was unable to identify published results, other than those discussed in this chapter, of cancer or noncancer health outcomes or mortality in US Blue Water Navy Vietnam veterans that would shed light on disease risks specific to this group. Several epidemiologic studies have measured TCDD concentrations in human tissues, including Vietnam veterans and people living in southern Vietnam. For example, the Air Force (AF) Health Study (AFHS), a cohort study to evaluate adverse health effects of exposure to Agent Orange, included USAF personnel who played an active part in Operation Ranch Hand and additional USAF personnel presumed not exposed. Other studies have looked for TCDD in biological samples from Vietnam veterans, such as blood and semen from Michigan veterans (Schecter et al., 1986), adipose tissue and plasma in Massachusetts veterans (Schecter et al., 1990), and serum in nonexposed Air Force veterans (Pavuk et al., 2005). To the committee’s knowledge, no studies assessing TCDD in biological samples of Blue Water Navy veterans are available. The 2008 VAO report (IOM, 2009) notes that In trying to harvest evidence from a fairly broad spectrum of populations targeted in epidemiologic studies, the VAO committees have factored in results on Vietnam veterans in general on the grounds that they are representative of all subjects who might have had increased exposure to herbicide components (as surrogates for VA’s clientele). With respect to the Blue Water Navy issue, the AFHS data document that

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LONG-TERM ADVERSE HEALTH EFFECTS 123 herbicide spraying did not occur solely in Vietnam and did not affect only those deployed to Vietnam. Serum TCDD results from the AFHS demonstrate that the Ranch Hands in general were, indeed, more highly exposed than the Southeast Asia (SEA) veterans, but the SEA veterans had serum TCDD concentrations that tended to exceed background values in the US population. For Navy veterans as a whole, the Australian cancer-incidence study indicated a significantly higher risk of lung cancer (although the study did not adjust for smoking) and prostatic cancer, both of which are currently recognized as TCDD-related malignancies. A previous IOM committee has concluded that there is limited or suggestive evidence of an association between both cancers and Agent Orange exposure (IOM, 2009). The Australian study found significant associations with melanoma and colon cancer, neither of which has been categorized as TCDD-related by the IOM or the VA. The Australian mortality study corroborated the Australian cancer-incidence findings on lung cancer and melanoma. However, both Australian reports found significantly lower risk of NHL, one of the first cancers associated with Agent Orange exposure by the IOM. One study (Dalager et al., 1991) found neither higher nor lower risk of NHL in Vietnam-era Navy veterans. In contrast, the CDC Selected Cancers Study found a significantly higher prevalence of NHL in Blue Water Navy Vietnam veterans. Finally, in a small study, testicular cancer was associated with service in the Navy (although the Blue Water Navy was not specified) in Vietnam veterans, although testicular cancer has not been found by the IOM to be associated with Agent Orange exposure (IOM, 2009). There are numerous limitations for this small number of studies. Many did not distinguish between Blue Water Navy and Brown Water Navy populations (or Navy personnel serving on the ground). None characterized exposure to Agent Orange, the committee’s primary focus. Some studies are further limited by their small numbers of cases. In addition, some of the studies are hospital-based case–control studies and thus have low generalizability for drawing inferences about risks to the entire Blue Water Navy population. Hospitalization studies typically are conducted in selected hospitals, such as those of the VA or the Department of Defense (DoD), and therefore they are not representative of the entire veteran population, including those no longer on active duty

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124 BLUE WATER NAVY VIETNAM VETERANS AND AGENT ORANGE EXPOSURE in the case of DoD or veterans who are eligible for but do not seek treatment from the VA. In addition, not all health outcomes require hospitalization, so such cases may not be representative of the entire veteran population. Confounding factors—such as smoking, alcohol use, and sun exposure—are major contributors to some of the cancers identified as increased in the Australian studies of naval personnel. For example, lung cancer and melanoma were found to be higher in the Australian incidence study. Naval personnel are exposed to some chemicals that have carcinogenic potential, and these were not considered in the analyses of any of the above studies. In the selection of the general male Australian population as a comparison group, the Australian studies did not account for those other exposures and therefore did not account for a healthy-veteran effect. A third report compared Australian Vietnam veterans with era veterans who were stationed in Australia to correct for any healthy-worker effect but did not present results specific to the Navy. The CDC studies, which showed an increase in NHL, are the most robust, having adjusted for smoking, socioeconomic factors, and a variety of known risk factors for NHL. However, they are the only studies that have identified this link. Overall, the committee concludes that because of the small number of studies and their limitations, there is no consistent evidence to suggest that Blue Water Navy Vietnam veterans were at higher or lower risk for cancer or other long-term health outcomes than shore-based veterans, Brown Water Navy veterans, or Vietnam veterans in other branches of service. REFERENCES Bullman, T. A., K. K. Watanabe, and H. K. Kang. 1994. Risk of testicular cancer associated with surrogate measures of Agent Orange exposure among Vietnam veterans on the Agent Orange Registry. Annals of Epidemiology 4(1):11-16. CDC (Centers for Disease Control and Prevention). 1990a. The association of selected cancer with service in the US military in Vietnam. I. Non- Hodgkin’s lymphoma. Archives of Internal Medicine 150(12):2473-2483. CDC. 1990b. The association of selected cancer with service in the US military in Vietnam. II. Soft-tissue and other sarcomas. Archives of Internal Medicine 150(12):2485-2492.

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LONG-TERM ADVERSE HEALTH EFFECTS 125 CDC. 1990c. The association of selected cancer with service in the US military in Vietnam. III. Hodgkin’s disease, nasal cancer, nasopharyngeal cancer, and primary liver cancer. Archives of Internal Medicine 150(12):2495-2505. Dalager, N. A., H. K. Kang, L. B. Burt, and L. Weatherbee. 1991. Non- Hodgkin’s lymphoma among Vietnam veterans. Journal of Occupational Medicine 33(7):774-779. Dalager, N. A., H. K. Kang, L. B. Burt, and L. Weatherbee. 1995. Hodgkin’s disease and Vietnam service. Annals of Epidemiology 5(5):400-406. Garland, F. C., E. D. Gorham, and C. F. Garland. 1987. Hodgkin’s disease in the US Navy. International Journal of Epidemiology 16(3):367-372. Garland, F. C., E. D. Gorham, C. F. Garland, and J. A. Ferns. 1988. Non- Hodgkin’s lymphomas in US Navy personnel. Archives of Environmental Health 43(2):425-429. IOM (Institute of Medicine). 2009. Veterans and Agent Orange: Update 2008. Washington, DC: The National Academies Press. Pavuk, M., J. E. Michalek, A. Schecter, N. S. Ketchum, F. Z. Akhtar, and K. A. Fox. 2005. Did TCDD exposure or service in southeast Asia increase the risk of cancer in air force Vietnam veterans who did not spray Agent Orange? Journal of Occupational and Environmental Medicine 47(4):335-342. Schecter, A. J., J. J. Ryan, and J. D. Constable. 1986. Chlorinated dibenzo-p- dioxin and dibenzo-p-furant levels in human adipose-tissue and milk samples from the north and south of Vietnam. Chemosphere 15(9-12):1613- 1620. Schecter, A., J. J. Ryan, J. D. Constable, R. Baughman, J. Bangert, P. Furst, K. Wilmers, and R. P. Oates. 1990. Partitioning of 2,3,7,8-chlorinated dibenzo- para-dioxins and dibenzofurans between adipose-tissue and plasma-lipid of 20 Massachusetts Vietnam veterans. Chemosphere 20(7-9):951-958. Wilson, E .J., K. W. Horsley, and R. van der Hoek. 2005a. Australian National Service Vietnam Veterans Mortality and Cancer Incidence Study 2005. Canberra, Australia: Department of Veterans’ Affairs. Wilson, E. J., K. W. Horsley, and R. van der Hoek. 2005b. Australian Vietnam Veterans Mortality Study 2005. Canberra, Australia: Department of Veterans’ Affairs. Wilson, E. J., K. W. Horsley, and R. van der Hoek. 2005c. Cancer Incidence in Australian Vietnam Veterans Study 2005. Canberra, Australia: Department of Veterans’ Affairs.

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