Veterans and Agent Orange: Update 2006 (2007)

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9 Other Health Effects This chapter discusses data on the possible association between exposure to the herbicides used in Vietnam—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid—and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a contaminant of 2,4,5-T, and the following non-cancer health outcomes: chloracne, porphyria cutanea tarda (PCT), respiratory disorders, immune-system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), circula- tory disorders, endometriosis, and adverse effects on thyroid homeostasis. For each type of health outcome, background information is followed by a brief summary of the findings described in earlier reports by the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Ex- posure to Herbicides. In the discussion of the most recent scientific literature, studies are grouped by exposure type (occupational, environmental, or Vietnam veteran). For articles that report on only a single health outcome and that are not revisiting a previously studied population, design information is summarized with the results; design information on other studies can be found in Chapter 4 and in Appendix B. A synopsis of toxicologic and clinical information related to the biologic plausibility of the chemicals of interest influencing the occurrence of the health effect is presented next, followed by a synthesis of all the material reviewed. Each health outcome section ends with the present committee’s conclu- sions regarding the strength of the evidence for support of an association with the chemicals of interest. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2. 599 

600 VETERANS AND AGENT ORANGE: UPDATE 2006 CHLORACNE Chloracne is a skin disease that is characteristic of exposure to TCDD and other diaromatic organochlorine compounds. It shares some pathologic pro- cesses (such as the occlusion of the orifice of the sebaceous follicle) with more common forms of acne (such as acne vulgaris), but it can be differentiated by the presence of epidermoid inclusion cysts, which are caused by proliferation and hyperkeratinization (horn-like cornification) of the epidermis and sebaceous gland epithelium. Although chloracne is typically distributed over the eyes, ears, and neck, among chemical-industry workers exposed to TCDD it can also occur on the trunk, genitalia, and buttocks (Neuberger et al., 1998). Chloracne has been exploited as a marker of exposure in epidemiologic studies of populations exposed to TCDD and related chemicals. It is one of the few findings in humans that are consistently associated with such exposure, and it is a well-validated indicator of high-dose exposure to TCDD and related com- pounds (Sweeney et al., 1997/1998). If chloracne occurs, it appears shortly after the chemical exposure, not after a long latent period. Although it is resistant to acne treatments, it usually regresses over time. Therefore, new cases of chloracne in Vietnam veterans would not be the result of exposure during Vietnam and are not of concern for this report. It should be noted that absence of chloracne does not necessarily indicate absence of substantial exposure to TCDD, as is apparent from studies of people with documented exposure to TCDD after the Seveso acci- dent (Baccarelli et al., 2005a). And there is not necessarily a correlation between serum TCDD concentrations and the occurrence or severity of chloracne. Conclusions from VAO and Updates The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam, hereafter referred to as VAO (IOM, 1994), deter- mined that there was sufficient evidence of an association between exposure to at least one compound of interest and chloracne. Additional information available to the committees responsible for Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), Update 2002 (IOM, 2003), and Update 2004 (IOM, 2005) did not change that conclusion. Reviews of the studies that underlie the conclusion can be found in the earlier reports. Update of the Epidemiologic Literature Environmental Studies Since Update 2004, there has been a single environmental study concerning chloracne and a publication of case reports, one of which involved a high-profile news story. 

OTHER HEALTH EFFECTS 601 Baccarelli et al. (2005b) conducted a case–control study of chloracne in the population of Seveso, Italy. They studied 101 cases of chloracne diagnosed after the accident and 211 controls in two subsets: 101 controls matched to the individual cases by sex, age, and zone of residence at the time of the accident and 110 drawn as a random sample of noncases recruited previously by Landi et al. (1997, 1998) from residents of contaminated and noncontaminated areas. The second control group was much older (median age, 31 years compared with 8 years for the cases and the matched control group). Serum TCDD had been measured in the middle 1990s. People with high plasma TCDD (over 10 ppt) had an increased risk of chloracne, which remained significant after adjustment for age, sex, and place of residence (odds ratio [OR] 3.7, 95% confidence interval [CI] 1.6–8.8). Higher risks of having developed chloracne were observed among subjects who were younger than 9 years old at the time of the accident (OR 7.4, 95% CI 1.8–30.3) and among those with relatively light hair color (OR 9.2, 95% CI 2.6–32.5). The results were described as being similar with and without inclusion of the second set of controls. Sterling and Hanke (2005) described several individual case reports involv- ing acute dioxin exposures. The first concerns Viktor Yushchenko, president of Ukraine, who may have been poisoned at a dinner party. An extremely high concentration of dioxin in blood samples was documented—the second highest concentration recorded in humans. Severe chloracne symptoms were also de- scribed. The second case report concerns a 30-year-old secretary who may have ingested TCDD in the chemical laboratory where she worked. During the first year after exposure, facial inflammation and acne were observed; they gradually progressed to dense cysts on the entire face and a few lesions on the body. Various other symptoms were described. The patient has had several surgical interven- tions for the deep inflammation and cysts. An exposed colleague of the patient also had high serum TCDD but had only mild symptoms, which resolved after treatment. The Sterling and Hanke (2005) paper appears to be a second-hand re- port of these cases, and it is not clear that the authors had direct clinical contact with the patients. No new occupational or Vietnam veteran studies concerning exposure to the compounds of interest and chloracne were published since Update 2004. Biologic Plausibility As noted in previous reports, chloracne-like skin lesions have been reported in several animal species in response to exposure to TCDD but not to purified phenoxy herbicides. Most data that have accrued in the last two decades have demonstrated that TCDD alters differentiation of human keratinocytes. The most recent studies (Geusau et al., 2005) support the idea that TCDD accelerates the events associated with early differentiation but also obstructs completion of dif- 

602 VETERANS AND AGENT ORANGE: UPDATE 2006 ferentiation. In fact, it has recently been proposed (Panteleyev and Bickers, 2006) that the major mechanism that underlies TCDD-induced chloracne is activation of the stem cells in the basal layer of the skin to differentiate and inhibition of their ability to commit fully to a differentiated status. Recent work using a constitutively activated form of the aryl hydrocarbon receptor (AhR) implicates additional inflammation-related mechanisms by which TCDD exposure may lead to chloracne (Tauchi et al., 2005). The data provide a biologically plausible mechanism for the induction of chloracne by TCDD. Synthesis The new information supports the conclusion of previous committees that there is sufficient evidence of an association between exposure to at least one compound of interest and chloracne. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an as- sociation between exposure to at least one compound of interest and chloracne. PORPHYRIA CUTANEA TARDA Porphyrias are uncommon disorders caused by deficiencies of enzymes in- volved in the pathway of biosynthesis of heme, the iron-containing, nonprotein portion of the hemoglobin molecule. PCT is a heterogeneous group of disorders caused by a deficiency of a specific enzyme, uroporphyrinogen decarboxylase. PCT, the most common of the porphyrias, can be inherited but usually is acquired. Type I PCT, which accounts for 80–90 percent of all cases, is an acquired disease that typically becomes evident in adulthood. Type I PCT can occur spontaneously but usually occurs in conjunction with environmental factors, such as alcohol consumption, exposure to estrogens, or use of some medications. The most important clinical finding is cutaneous photosensitivity. Sensitivity to sunlight is thought to result from the excitation of excess porphyrins in the skin by long-wave ultraviolet radiation, which leads to cell damage. Fluid-filled vesicles and bullae develop on sun-exposed areas of the face and on the dorsa of the hands, feet, forearms, and legs. Other features include hypertrichosis (excess hair) and hyperpigmentation (increased pigment), especially on the face. People with PCT have increased porphyrins in the liver, plasma, urine, and stools. Iron, estrogens, alcohol, viral hepatitis, and chlorinated hydrocarbons can aggravate the disorder. Iron overload is almost always present in people who have PCT. 

OTHER HEALTH EFFECTS 603 Conclusions from VAO and Updates On the basis of strong animal studies and case reports demonstrating induc- tion of PCT with exposure and resolution following removal of exposure, the committee responsible for VAO determined that there was sufficient evidence of an association between exposure to TCDD and PCT in genetically susceptible people. Because PCT is manifested shortly after exposure to TCDD, new cases of PCT attributable to exposure during the Vietnam War are not expected to occur. The committee responsible for Update 1996 reviewed studies of three cohort populations with substantial exposures to TCDD, which all had non-positive re- sults even for those changes in urinary porphyrin levels that usually occur at lower exposure levels than clinical signs of PCT. These new data led it to conclude that there was only limited or suggestive evidence of an association. Update 1998, Update 2000, Update 2002, and Update 2004 did not further change the revised conclusion. Reviews of the relevant studies are found in the earlier reports. Update of the Epidemiologic Literature No new occupational, environmental, or Vietnam-veteran studies concerning exposure to the compounds of interest and PCT were published since Update 2004. Biologic Plausibility PCT has not been replicated in animal studies with TCDD, although other porphyrin abnormalities have been reported. However, administration of TCDD to mice results in an accumulation of uroporphyrin that occurs in a manner that requires the AhR, CYP1A1, and CYP1A2 (Robinson et al., 2002; Smith et al., 2001; Uno et al., 2004). Synthesis No new studies provide evidence of a direct risk of PCT in adults since those reviewed in Update 2004. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evi- dence of an association between exposure to at least one compound of interest and PCT. 

604 VETERANS AND AGENT ORANGE: UPDATE 2006 RESPIRATORY DISORDERS For the purposes of this report, nonmalignant respiratory disorders are acute and chronic lung diseases other than cancer. Acute nonmalignant respiratory dis- orders include pneumonia and other respiratory infections; they can be increased in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Chronic nonmalignant respiratory disorders generally take one of two forms: Airways disease encompasses disorders charac- terized by obstruction of the flow of air out of the lungs, among them asthma and chronic obstructive pulmonary disease (COPD); COPD is also known as chronic obstructive airways disease and includes emphysema and chronic bronchitis. Pa- renchymal disease, or interstitial disease, generally includes disorders that cause inflammation and scarring of the deep lung tissue, including the air sacs and sup- porting structures; parenchymal disease is less common than airways disease, and its disorders are characterized by reductions in lung capacity, although they can include a component of airway obstruction. Some severe chronic lung disorders, such as cystic fibrosis, are hereditary. Because Vietnam veterans received health screenings before entering military service, few severe hereditary chronic lung disorders are expected in that population. The major risk factor for many nonmalignant respiratory disorders is cigarette- smoking. Although cigarette-smoking is not associated with all diseases of the lungs, it is the major cause of many airways disorders, especially COPD; it contributes to some interstitial disease; and it compromises host defenses in such a way that people who smoke are generally more susceptible to some types of pneumonia. Cigarette-smoking also makes almost every respiratory disorder more severe and symptomatic than it would be in its absence. The frequency of habitual cigarette-smoking varies with occupation, socioeconomic status, and generation. For those reasons, cigarette-smoking can be a major confounding factor in in- terpreting the literature on risk factors for respiratory disease. Vietnam veterans are reported to smoke more heavily than are non-Vietnam veterans (McKinney et al., 1997). It is well known that causes of death from respiratory diseases, especially chronic ones, are highly misclassified on death certificates. Grouping various respiratory diseases for analysis, unless they all are associated with a given exposure, will lead to attenuations of the estimates of relative risk as well as a diminution of statistical power. Moreover, deaths from respiratory and cardiovas- cular diseases are often confused. In particular, when persons have both condi- tions concurrently and both contributed to death, there may be some uncertainty about which cause should be selected as the primary underlying cause. In other instances, errors may arise in selecting one underlying cause in a complex chain of health events (for example, if COPD leads to congestive heart failure and then to respiratory failure). Many study populations were rather small, so investiga- 

OTHER HEALTH EFFECTS 605 tors grouped deaths from all nonmalignant respiratory diseases into one category, combining pneumonia, influenza, and other diseases with COPD and asthma. Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to the compounds of interest and the respiratory disorders specified above. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that finding. Update 2000 drew attention to findings from the Seveso cohort that suggested a higher mortality from nonmalignant respira- tory disorders among study subjects, particularly men, who were more heavily exposed to TCDD. Those findings were not replicated in several other relevant studies, although one showed an increase (which did not attain statistical signifi- cance). The committee for Update 2000 concluded that although new evidence suggested an increased risk of nonmalignant respiratory disorders, particularly COPD, among people exposed to TCDD, the observation was tentative and the information insufficient to determine an association between the exposures of interest and respiratory disorders. Additional information available to the com- mittee responsible for Update 2002 did not change that finding. Update 2004 included a new cross-sectional study among residents near a wood-treatment plant (Dahlgren et al., 2003). Soil and sediment samples from a ditch in the neighborhood contained dioxins and furans. Although exposed residents reported greater frequency of chronic bronchitis by history (17.8 percent vs 5.7 percent, p 0.0001) and asthma by history (40.5 percent vs 11.0 percent, p 0.0001) compared with a “non-exposed” control group, the committee concluded that selection bias and recall bias limited the utility of the results and that there was a possibility of confounding because history of tobacco use was not accounted for adequately. Table 9-1 summarizes the results of the relevant studies. Update of the Epidemiologic Literature Occupational Studies In a mortality analysis of the Agricultural Health Study (AHS), Blair et al. (2005) found a decrease in deaths from COPD among private applicators and their spouses (standardized mortality ratio [SMR] 0.2, 95% CI 0.2–0.3) based on 50 deaths. There were no differences based on the number of years of handling pesticides. The deficit may have arisen because of the healthy-worker effect, lower consumption of tobacco in this cohort, increased exercise, or the protective effect of endotoxin exposure that many agricultural workers experience (Lange, 2000). 

606 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-1 Selected Epidemiologic Studies—Non-Malignant Respiratory Disease Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a OCCUPATIONAL New Studies Cohort studies Hoppin et al., US Agriculture Health Study, commercial 2006 applicators exposed to 2,4-D—cross-sectional study of wheeze 225 1.3 (1.0–1.7) Blair et al., US Agriculture Health Study—COPD mortality 2005 Private applicators 50 0.2 (0.2–0.3) Spouses 15 0.3 (0.2–0.7) ’t Mannetje New Zealand phenoxy herbicide producers, et al., 2005 nonmalignant respiratory mortality (ICD-9 480–519) 9 0.9 (0.4–1.8) New Zealand phenoxy herbicide sprayers, nonmalignant respiratory mortality (ICD-9 480–519) 6 0.65 (0.2–1.2) Studies Reviewed in Update 2002 Burns et al., Males employees of the Dow Chemical 2001 Company—manufacture exposed to 2,4-D between 1945–1994, nonmalignant respiratory mortality (ICD-8 460–519) All nonmalignant respiratory 8 0.4 (0.2–0.7) Pneumonia 4 0.6 (0.2–1.4) Studies Reviewed in Update 2000 Steenland et al., NIOSH mortality study of chemical workers 1999 at 12 plants in US exposed to TCDD, non- malignant respiratory mortality (ICD-9 460–519) 86 0.9 (0.7–1.1) Sweeney et al., NIOSH follow-up study of production workers 1997/98** of sodium trichlorophenol and of 2,4,5-T ester contaminated with TCDD, chronic bronchitis and COPD 2 — Studies Reviewed in Update 1998 Kogevinas Mortality of male and female international et al., 1997 workers producing or applying phenoxy herbicides, nonmalignant respiratory mortality (ICD-9 460–519), 1939–1992 Men 252 0.8 (0.7–0.9) Women 7 1.1 (0.4–2.2) Becher et al., Four German production facilities of phenoxy 1996 herbicides and chlorophenols, nonmalignant respiratory mortality (ICD-9 460–519) Boehringer Ingelheim 10 0.52(0.3–1.0) Bayer Uerdingen 2 0.9 (0.1–3.1) Bayer Dormagen 0 0.00 BASF Ludwigshafen 4 0.6 (0.2–1.6) 

OTHER HEALTH EFFECTS 607 TABLE 9-1 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Ott and Zober, German workers exposed to trichlorophenol 1996* contaminated with TCDD from an accident at a BASF plant, 1953–1993, nonmalignant respiratory mortality 1 0.1 (0.0–0.8) Ramlow et al., Mortality of workers at a Dow Chemical 1996 plant, Michigan, producing pentachlorophenol contaminated with polychlorophenol dibenzodioxins (PCDD), 1940–1989 Nonmalignant respiratory mortality (ICD-8 460–519) Cumulative PCP exposure 14 0.9 (0.5–1.5) 1 Unit 3 0.6 (0.2–1.9) 1 Unit 11 1.4 (0.8–2.5) Pneumonia (ICD-8 480–486) 6 1.1 (0.4–2.4) Emphysema (ICD-8 492) 4 1.3 (0.4–3.3) Svensson et al., Swedish fisherman exposed to TCDD, 1995 mortality from bronchitis or emphysema (ICD- 7 490–493) East coast 4 0.5 (0.2–1.2) West coast 43 0.8 (0.6–1.1) Studies Reviewed in Update 1996 Zober et al., German workers exposed to trichlorophenol 1994* contaminated with TCDD from an accident at a BASF plant, 1953–1989; 175 of 247 cohort members compared to unexposed workers for prevalence of nonmalignant respiratory conditions Illness episodes per 100 person-years (cohort/reference): All nonmalignant respiratory diseases (ICD- 9 460–51) — 33.7/31.0 (p 0.22) Upper respiratory tract infections (460–478) — 12.0/9.0 (p 0.00) Pneumonia or influenza (480–487) 17.4/18.8 (p 0.08) COPD (490–496) 8.0/7.5 (p 0.31) Senthilselvan Cross-sectional study of self-reported et al., 1992 prevalence of asthma among male farmers in Saskatchewan (1982–1983) Chlorinated hydrocarbons 31 0.8 (0.5–1.3) continued 

608 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-1 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Studies Reviewed in VAO Calvert et al., NIOSH cross-sectional study of production 1991** workers of sodium trichlorophenol and of 2,4,5,-trichlorophenoxyacetic ester (2,4,5-T ester) contaminated with TCDD comparing exposed to unexposed workers Odds ratios for an increase in 1 ppt of serum TCDD Chronic bronchitis — 0.5 (0.1–2.6) COPD — 1.2 (0.5–2.8) Coggon et al., Production of phenoxy herbicides and 1991 chlorophenols in four British plants, mortality from nonmalignant respiratory diseases, 1963–1985 8 0.7 (0.3–1.3) Alavanja et al., PMR study of USDA soil and forest 1989 conservationists, mortality from nonmalignant respiratory diseases (ICD-9 460-519), 1970–1979 80 0.8 (0.6–1.0) Coggon et al., British plant manufacturing MCPA, mortality 1986 from nonmalignant respiratory diseases (ICD-9 460–519), 1947–1983 93 0.6 (0.5–0.8) Suskind and Cross-sectional study of the Nitro, West Hertzberg, Virginia, plant that manufactured 2,4,5-T, 1984 comparing exposed to unexposed workers, 1979 Odds ratios comparing exposed to unexposed for the outcome of “abnormal” pulmonary functions tests: FEV1 203 2.82 (p 0.0159) FVC 203 2.25 (p 0.319) FEV1/FVC 203 2.97 (p 0.0099) FEF25-75 203 1.86 (p 0.0517) Blair et al., Licensed pesticide applicators, Florida, 1983 nonmalignant respiratory diseases (ICD-8 460–519) Analyses by length of licensure 20 0.9 10 years 8 0.6 10–19 years 8 1.5 20 years 4 1.7 

OTHER HEALTH EFFECTS 609 TABLE 9-1 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a ENVIRONMENTAL Studies Reviewed in Update 2004 Dahlgren et al., Cross-sectional study among residents 2003 living near a wood treatment plant (creosote and pentachlorophenol), Mississippi, who were plaintiffs in a lawsuit against the plant compared to subjects living in another comparable area with no known chemical exposures Adjusted scores comparing exposed to unexposed ( 0 means exposed subjects had more symptoms): Shortness of breath Adults — –2.5 (p 0.05) Children — –3.8 (p 0.05) Studies Reviewed in Update 2000 Bertazzi et al., Follow-up of 1976 accident in Seveso, Italy, 2001 who were exposed to pure TCDD in an industrial accident, 1976–1996 Nonmalignant respiratory diseases (ICD-9 460–519) 44 1.0 (0.8–1.4) Zone A 9 1.9 (1.0–3.6) Zone B 35 1.3 (0.9–2.0) COPD (ICD 9 490–493) 29 1.5 (1.1–2.2) Zone A 7 3.3 (1.6–6.9) Zone B 22 1.3 (0.9–2.0) continued 

610 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-1 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Bertazzi et al., Follow-up of residents in Seveso, Italy who 1998; Pesatori were exposed to pure TCDD in an industrial et al., 1998 accident, 1976–1991 (results from Nonmalignant respiratory diseases (ICD-9 Bertazzi) 460–519) Zone A Men 5 2.4 (1.0–5.7) Women 2 1.3 (0.3–5.3) Zone B Men 13 0.7 (0.4–1.2) Women 10 1.0 (0.5–1.9) Zone R Men 133 1.1 (0.9–1.3) Women 84 1.0 (0.8–1.2) COPD (ICD 9 490–493) Zone A Men 4 3.7 (1.4–9.8) Women 1 2.1 (0.3–14.9) Zone B Men 9 1.0 (0.5–1.9) Women 8 2.5 (1.2–5.0) Zone R Men 74 1.2 (0.9–1.5) Women 37 1.3 (0.9–1.9) Studies Reviewed in VAO Bertazzi et al., Follow-up of residents in Seveso, Italy who 1989a,b (results were exposed to pure TCDD in an industrial from Bertazzi accident, 1976–1986 et al., 1989a) Men Nonmalignant respiratory diseases (ICD-9 460–519) 55 1.0 (0.7–1.3) Pneumonia (ICD-9 480–486) 14 0.9 (0.5–1.5) COPD (ICD-9 490–493) 31 1.1 (0.8–1.7) Women Nonmalignant respiratory diseases (ICD-9 460–519) 24 1.0 (0.7–1.6) Pneumonia (ICD-9 480–486) 9 0.8 (0.4–1.6) COPD (ICD-9 490–493) 8 1.0 (0.5–2.2) VIETNAM VETERANS New Studies Kang et al., US Army Chemical Corps personnel 2006 Self-reported, nonmalignant respiratory problems diagnosed by a doctor Deployed vs non-deployed 129 1.4 (1.1–1.8) Sprayed herbicides in Vietnam vs never * 1.6 (1.3–2.1) 

OTHER HEALTH EFFECTS 611 TABLE 9-1 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a ADVA, 2005b Third Australian Vietnam Veterans Mortality Study. Deployed veterans vs Australian population All branches Respiratory system diseases 239 0.8 (0.7–0.9) Chronic obstructive pulmonary disease 128 0.8 (0.7–1.0) Navy Respiratory system diseases 50 0.8 (0.6–1.0) Chronic obstructive pulmonary disease 28 0.9 (0.6–1.3) Army Respiratory system diseases 162 0.8 (0.7–0.9) Chronic obstructive pulmonary disease 0.8 (0.7–1.0) Air Force Respiratory system diseases 28 0.6 (0.4–0.9) Chronic obstructive pulmonary disease 18 0.8 (0.4–1.2) ADVA, 2005c Australian National Service Vietnam Veterans: Mortality and Cancer Incidence study National Serviceman (SMR) Respiratory diseases 38 0.5 (0.3–0.6) Chronic obstructive pulmonary disease 18 0.9 (0.5–1.4) National Serviceman, deployed (SMR) Respiratory diseases 18 0.5 (0.3–0.8) Chronic obstructive pulmonary disease 8 0.9 (0.4–1.8) National Serviceman, non-deployed (SMR) Respiratory diseases 20 0.4 (0.2–0.6) Chronic obstructive pulmonary disease 10 0.9 (0.4–1.7) Ketchum and US Air Force Health Study Michalek, 2005 Nonmalignant respiratory mortality (ICD-9 460–519) 8 1.2 (0.6–2.5) Boehmer et al., Vietnam Experience Cohort 2004 Nonmalignant respiratory mortality (ICD-9 460–519) 20 0.8 (0.5–1.5) Studies Reviewed in Update 1998 Crane et al., Mortality of male Australian Vietnam veterans 1997a compared to the general Australian population Nonmalignant respiratory mortality (ICD-9 460–519) 1964–1979 3 0.1 (0.0–0.3) 1980–1994 92 0.9 (0.7–1.1) Chronic obstructive airways disease (ICD-9 490–496) 1980–1994 47 0.9 (0.7–1.2) continued 

612 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-1 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Crane et al., Australian mortality veterans study of national 1997b servicemen that compared those who served in Vietnam to those who did not, 1982–1994 1965–1982 2 2.6 (0.2–30.0) 1982–1994 6 0.9 (0.3–2.7) AFHS, 1996 Cause-specific mortality among Ranch Hand personnel compared to Air Force veterans 2 0.5 (0.1–1.6) Bullman and Post-service study among male Vietnam Kang, 1996 veterans who were wounded in combat. Nonmalignant respiratory mortality (ICD 9 460–519) compared to the US population 43 0.9 (0.7–1.2) O’Toole et al., Australian Army Vietnam veterans self- 1996 reported health status that between 1989 and 1990 compared to a random sample from the general Australian population. Prevalence ratios, adjusted for differences in response Acute conditions that required recent medical intervention Asthma — 1.4 (0.6–2.1) Bronchitis, emphysema — 2.1 (0.2–4.0) Other — 2.1 (1.6–2.8) Chronic conditions Asthma — 0.9 (0.5–1.4) Bronchitis, emphysema — 4.1 (2.8–5.5) Other — 4.0 (2.2–5.9) Watanabe Mortality of US Vietnam veterans who and Kang, died during 1965–1988, PMR analysis of 1996; Watanabe nonmalignant respiratory mortality (ICD-8 et al., 1991 460–519) (results from Army 648 0.81 (p 0.05) 1996 paper) Marine Corps 111 0.68 (p 0.05) Studies Reviewed in VAO Eisen et al., Study of monozygotic twins who served in US 1991 military during Vietnam era Respiratory conditions Present at time of survey — 1.4 (0.8–2.4) At any time since service — 1.4 (0.9–2.0) Required hospitalization — 1.8 (0.7–4.2) 

OTHER HEALTH EFFECTS 613 TABLE 9-1 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a CDC, 1988 Cross-sectional study, with medical examinations, of US Army veterans who served in Vietnam compared to US Army veterans who had not served Odds ratios from pulmonary function tests (case definition: 80% predicted value) FEV1 254 0.9 (0.7–1.1) FVC 177 1.0 (0.8–1.3) FEV1/FVC 152 1.0 (0.8–1.3) Anderson et al., Mortality study comparing Wisconsin Vietnam 1986 veterans with Wisconsin Vietnam-era veterans SMR analysis of nonmalignant respiratory mortality (ICD-8 460–519) Vietnam veterans compared to Wisconsin 32 0.3 (0.2–0.5) Vietnam veterans compared to other veterans 32 0.5 (0.4–0.7) ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; 2,4-D, 2,4-dichlorophenoxyacetic acid; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDVA, Commonwealth Department of Veterans’ Affairs; CI, confidence interval; COPD, chronic obstruc- tive pulmonary disease; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; FEF25-75, forced mid-expiratory flow; USDA, US Department of Agriculture. a Given when available. * Information not provided by study authors. — Denoted by a dash in the original study. * Ott and Zober (1996) and Zober et al. (1994) refer to the same study population. ** Calvert et al. (1991) and Sweeney et al. (1997/98) refer to the same study population. In a new report from the AHS, Hoppin et al. (2006) used a cross-sectional design to investigate the prevalence of wheeze among 2,375 commercial pesticide applicators. The authors defined wheeze as a positive response to the question, “How many episodes of wheezing or whistling in your chest have you had in the past 12 months?” Exposure to pesticides was defined as having occurred in the year before administration of the baseline questionnaire. After adjusting for age, smoking status, physician diagnosis of asthma or atopy (allergy-proneness), and body-mass index (BMI), they found an association with the prevalence of wheeze and “current” exposure to 2,4-D (prevalence OR 1.27, 95% CI 0.96–1.68). (An association was not found for “former” use [unadjusted OR 0.89, 95% CI 0.68–1.17, computed by the present committee from Table 2 of the paper.]) The interpretation of such findings may be controversial, inasmuch as self-reported health conditions may not be reported accurately and there may be overreporting 

614 VETERANS AND AGENT ORANGE: UPDATE 2006 if people believe that their exposures were hazardous. The study showed posi- tive associations with all of 16 herbicides (including 2,4-D), 8 of 14 insecticides, and one of seven fungicides. At first glance, that seems to be a large proportion of positive findings, perhaps greater than what would be expected if some of the compounds were causal agents. Because many of the exposures were correlated, it is difficult to judge whether the number of positive associations was greater than what would be expected by chance. The authors indicated in the paper that self-reported wheeze is reported reasonably accurately and quoted a paper from Australia on a general-population survey of asthma (Jenkins et al., 1996). Al- though the Australian study did show excellent accuracy of self-reported wheeze, important differences between the two cohorts lead to questions as to whether the results of the Australian study are applicable to the AHS. Mortality from diseases of the respiratory system were reported in a cohort study of 813 chemical producers (who worked during about 1950–1980) and 699 sprayers of phenoxy herbicides in New Zealand (who worked during 1973–1984) who were followed during the period 1970–2000 (’t Mannetje et al., 2005). The researchers found no associations with mortality from diseases of the respiratory system (International Classification of Diseases-9 [ICD-9] 480–519). The SMR for production workers was 0.93 (95% CI 0.42–1.76, nine deaths) and for spray- ers 0.55 (95% CI 0.20–1.21, nine deaths). Environmental Studies No new environmental studies concerning the compounds of interest and nonmalignant respiratory diseases were published since those reviewed in Update 2004. Vietnam-Veteran Studies In the Centers for Disease Control and Prevention (CDC) Vietnam Experi- ence Study (VES), Boehmer et al. (2004) compared cause-specific mortality among Vietnam veterans with that among service personnel who did not par- ticipate in the war. They found that among Vietnam veterans the rate ratio for mortality from diseases of the respiratory system (ICD-9 460–519) was 0.82 (95% CI 0.45–1.49). Ketchum and Michalek (2005) published findings from 20 years of fol- low-up for mortality in the US Air Force Health Study (AFHS) that compared Ranch Hands with referent subjects. Respiratory diseases were identified from physical and other clinical examinations conducted during the periodic visits. The estimated relative risk for all nonmalignant respiratory causes of death (ICD-9 460–519) was 1.2 (95% CI 0.6–2.5). In the cohort study of US Army Chemical Corps (ACC) personnel, Kang et al. (2006) conducted a cross-sectional survey among 2,247 Vietnam veterans and 2,242 non-Vietnam veterans. The Vietnam veterans served at least one tour 

OTHER HEALTH EFFECTS 615 of duty during 1965–1973 and were likely to have been involved in chemical operations. The survey was conducted by the Veterans Health Administration in 1999–2000; 1,499 Vietnam veterans (66.7 percent response rate) and 1,428 com- parison subjects (63.7 percent) participated. The prevalence of self-reported non- malignant respiratory problems diagnosed by a doctor was significantly higher in the Vietnam veterans (adjusted OR 1.41, 95% CI 1.13–1.76). When those who reported spraying herbicides in Vietnam were compared with those who did not, the adjusted OR was 1.57 (95% CI 1.20–2.07); and the OR for spray- ing herbicides in both cohorts was 1.62 (95% CI 1.28–2.05). However, among a subset of workers whose serum TCDD was measured, there was no difference in the prevalence of respiratory problems between those whose serum TCDD was above and below 2.5 ppt. In the Third Australian Vietnam Veterans Mortality Study 2005 (ADVA, 2005b), Army (n 41,084), Navy (n 13,538), and Air Force (n 4,570), no associations were found comparing military personnel serving in Vietnam to the general population of Australia (nonmalignant respiratory diseases SMR = 0.77, and 95% CI 0.67–0.87; COPD SMR 0.85, and 95% CI 0.70–1.00). In Australian National Service Vietnam Veterans: Mortality and Cancer Incidence 2005 (ADVA, 2005c), which involved 19,240 Vietnam veterans and 24,729 non- deployed veterans, there was no excess risk of death from nonmalignant respira- tory diseases among those deployed to Vietnam compared with non-deployed veterans (RR 1.12, 95% CI 0.56–2.23) and no excess risk of death from COPD (RR 1.00, 95% CI 0.34–2.80). Biologic Plausibility As discussed in Chapter 3, new animal studies have shown that TCDD ex- posure increases mortality of mice infected with influenza virus. That effect was shown to depend on expression of the AhR; the mechanism underlying increased mortality was not related to the suppression of the immune response to influenza by TCDD but appeared to involve an increase in the inflammatory response in the lung. On the basis of those findings, it is biologically plausible that exposure to TCDD results in exacerbation of acute or chronic lung diseases associated with inflammatory responses. In addition, cigarette-smoking is a major risk factor for respiratory disease. TCDD is known to induce cytochrome P450 enzymes that are responsible for the activation of several chemicals found in tobacco smoke to more toxic intermediates. Thus, it is also biologically plausible that exposure to TCDD synergizes the toxic effects of a variety of compounds present in tobacco smoke and increases respiratory disease. Synthesis Results of the new studies of mortality from nonmalignant respiratory diseases (ADVA, 2005b,c; Blair et al., 2005; Ketchum and Michalek, 2005; 

616 VETERANS AND AGENT ORANGE: UPDATE 2006 ’t Mannetje et al., 2005) do not support the hypothesis that herbicides increase mortality from them. The results of the Seveso accident showed a positive as- sociation (Bertazzi et al., 2001), although it is based on only nine deaths in the high-exposure area (Zone A), and this finding could have been due to chance or misclassification of causes of death. More important, although it recognizes that mortality studies are limited by small numbers of events and misclassification of causes of death, especially respiratory conditions, the committee does not be- lieve that scientific conclusions can be based on health outcomes that are defined vaguely, for example, by combining a wide array of disparate respiratory health outcomes into one large category. Two new cross-sectional studies have reported positive associations between exposure and the prevalence of various chest conditions. To summarize (see Table 9-1 and the report of findings above), Hoppin et al. (2006) found in the AHS an association between “current” exposure to 2,4-D and the prevalence of self-reported wheeze (adjusted OR 1.27) and Kang et al. (2006) found in a study of ACC personnel an association between exposure and the prevalence of self-reported physician-confirmed respiratory problems (OR 1.41). Other cross- sectional prevalence studies considered in previous updates that bear on this mat- ter include the study of an accident at a BASF plant (Zober et al., 1994) that found no association of exposure with episodes of COPD, the NIOSH cross-sectional study of production workers exposed to 2,4,5-T ester contaminated with TCDD (Calvert et al., 1991) that found no increase in COPD associated with serum TCDD concentration, a cross-sectional study in Saskatchewan (Senthilselvan et al., 1992) that found no association between exposure to chlorinated hydro- carbons and the prevalence of self-reported asthma, and the study of residents exposed environmentally to emissions from a plant that produced creosote and pentachlorophenol (Dahlgren et al., 2003) that found positive associations with chronic bronchitis. This latter study was judged in Update 2004 to have been biased. The nonspecificity of the types of respiratory conditions reported in Kang et al. (2006) make it exceedingly difficult to draw any conclusions regarding specific respiratory conditions, and the lack of observed association with serum TCDD concentrations also argues against the existence of an association. The is- sue of nonspecificity is key to interpreting this study. The study by Hoppin et al. (2006) is also unclear about what wheeze represents: the definition of wheeze was very broad and included any episode in the year before administration of the questionnaire, and the authors reported that only 28 percent of subjects with wheeze reported having asthma or atopic conditions. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient 

OTHER HEALTH EFFECTS 617 evidence of an association between exposure to the compounds of interest and the prevalence of wheeze and asthma. IMMUNE-SYSTEM DISORDERS The immune system defends the body against infection by viruses, bacteria, and other disease-producing microorganisms, known as pathogens. The immune system also plays a role in cancer surveillance, destroying mutated cells that might otherwise develop into tumors. To recognize the wide array of pathogens in the environment, the immune system relies on many cell types that operate together to generate immune responses. Those cells arise from stem cells in the bone marrow; they are found throughout the body’s lymphoid tissues, and they circulate in the blood as white blood cells (WBCs). The main types of WBCs are granulocytes, monocytes, and lymphocytes. Immune Suppression Suppression of immune responses can result in reduced resistance to infec- tious disease and increased risk of cancer. Infection with HIV is a well-recognized example of an acquired immune deficiency in which a specific type of lympho- cyte (CD4 T cells) is the target of the virus. The decline in the number of CD4 T cells after HIV infection correlates with an increased incidence of infectious diseases, including fatal opportunistic infections, and with an increased incidence of several types of cancer. Treatment of cancer patients with toxic chemothera- peutic drugs also suppresses the immune system by inhibiting the generation of new WBCs from the bone marrow and by blocking proliferation of lymphocytes during an immune response. Immune suppression can result from exposure to chemicals in the workplace or in the environment, including dioxin (see Chapter 3). However, unless the immune suppression is severe, it is often difficult to obtain clinical evidence that directly links chemical-induced changes in immune function to increased infectious disease or cancer, because many confounding factors can influence a person’s ability to combat infection. Such confounders in- clude age, vaccination status, the virulence of the pathogen, the presence of other diseases (such as diabetes), stress, smoking, and the use of drugs or alcohol. Allergy Sometimes the immune system responds to a foreign substance that is not pathogenic. Such immunogenic substances are called allergens. The response to some allergens, like pollen or bee venom, results in the production of immuno- globulin E (IgE) antibodies. Once produced, IgE antibodies bind to specialized cells—mast cells—that occur in tissues throughout the body, including lung airways, the gut wall, and blood-vessel walls. When a person is exposed again to 

618 VETERANS AND AGENT ORANGE: UPDATE 2006 the allergen, the allergen binds to the antibodies on the mast cells, causing them to release histamine and leukotrienes, which cause the symptoms associated with an allergic response. Other allergens, such as poison ivy and nickel, activate allergen-specific lymphocytes at the site of contact (usually the skin) that release substances that cause inflammation and tissue damage. Autoimmune Disease Autoimmune disease is another example of the immune system’s causing rather than preventing disease. The immune system attacks the body’s own cells and tissues as though they are foreign. For example, the autoimmune reaction in multiple sclerosis is directed against the myelin sheath of the nervous system; in Crohn’s disease, the gut is the target of attack; in type 1 diabetes mellitus, the insulin-producing cells of the pancreas are destroyed by the immune response. Rheumatoid arthritis (RA) is an autoimmune disease that arises from immune attack on the joints. Genetic predisposition and such environmental factors as infectious diseases and stress are thought to facilitate the development of autoim- mune diseases. Systemic lupus erythematosus (SLE) is an autoimmune disease that has no specific target organ of immune attack. Instead, patients have a variety of symp- toms that often occur in other diseases, and diagnosis is difficult. A characteristic rash across the cheeks and nose and sensitivity to sunlight are common symp- toms; oral ulcers, arthritis, pleurisy, proteinuria, and neurologic disorders may be present. Almost all people with SLE test positive for antinuclear antibodies in the absence of drugs known to induce them. The causes of SLE are unknown, but environmental and genetic factors have been implicated. Some of the envi- ronmental factors that may trigger it are infections, antibiotics (especially those in the sulfa and penicillin groups), ultraviolet radiation, extreme stress, drugs, and hormones. Occupational exposures to such chemicals as crystalline silica, solvents, and pesticides have also been associated with risk of SLE (Cooper and Parks, 2004; Parks and Cooper, 2005). Conclusions from VAO and Updates The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 concluded that there was inadequate or insufficient information to determine whether an association exists between ex- posure to the chemicals of concern and immune-system disorders. Reviews of the studies that underlie that conclusion are presented in the previous reports (IOM, 1994, 1996, 1999, 2001, 2003, 2005). 

OTHER HEALTH EFFECTS 619 Update of the Epidemiologic Literature Occupational Studies De Roos et al. (2005b) studied risk factors for RA in 57,000 licensed pesti- cide applicators and their spouses in association with the AHS. Pesticide applica- tion itself did not increase risk of RA, nor did the use of herbicides. However, the broad grouping of chlorophenoxy herbicides was associated with a significantly decreased risk of RA (OR 0.05); the risk was attributable specifically to 2,4-D. In a subanalysis restricted to incident cases, an inverse association between risk of RA and use of 2,4-D was again observed (OR 0.02). Oh et al. (2005) evaluated aspects of the immune response in waste- incineration workers that were exposed to increased aerial concentrations of di- oxin and in control subjects. There was no difference in the frequency of types of lymphocytes or in concentrations of circulating lymphocytes between the workers and the controls. T cells that expressed a marker of activation were significantly more highly concentrated in the incineration workers, but the relevance of this observation is unknown. Environmental Studies Baccarelli et al. (2005b) carried out a 20-year follow-up study of the long- term health effects of TCDD exposure in Seveso residents. The incidences of various health conditions associated with the immune system were the same in exposed and control subjects, including allergic diseases, infectious diseases, respiratory diseases, anemia, and psoriasis (an autoimmune disorder). The 101 exposed subjects all had chloracne, and their mean plasma TCDD concentrations were higher than those of the 211 nonchloracne control subjects. Vietnam-Veteran Studies Boehmer et al. (2004) compared post-service mortality in male US Army Vietnam veterans with that in non-Vietnam veterans and found no significant difference in death due to “endocrine, nutritional and metabolic diseases, and immunity disorders” (ICD-9 240–279) (crude RR 1.32, 95% CI 0.50–3.47). Biologic Plausibility Exposure of laboratory animals to phenoxy herbicides has not been associ- ated with immunotoxicity. In contrast, TCDD is a known immunosuppressive chemical in laboratory animals, and exposure to TCDD has been shown to in- crease the incidence and severity of various infectious diseases. TCDD exposure also suppresses the allergic immune response of rats and decreases allergen- 

620 VETERANS AND AGENT ORANGE: UPDATE 2006 associated lung pathology. Feeding juvenile and adult mice various quantities of TCDD for 5 weeks or more produced no evidence of increased IgE synthesis, and it suppressed skin sensitization to dinitrofluorobenzene. No animal studies have specifically addressed the effects of TCDD or other compounds of interest on auto- immune disease. Chapter 3 updates recent toxicologic studies that demonstrate the effects of the compounds of interest on the immune system. Synthesis TCDD is a well-known immunosuppressive agent in laboratory animals. Therefore, one would expect that exposure of humans to sufficiently high doses would result in immune suppression. However, several studies of various mea- sures of human immune function have failed to reveal consistent correlations with TCDD exposure, and no detectable pattern of increased infectious disease has been documented in veterans exposed to TCDD or other herbicides used in Vietnam. Although suppression of the immune response by TCDD could increase the risk of some cancers in Vietnam veterans, there is no evidence to support that connection. Epidemiologic studies have been inconsistent with regard to TCDD’s influ- ence on IgE production in humans (Update 2004). No animal or human studies have specifically addressed the influence of the TCDD on autoimmune disease. The Boehmer et al. (2004) study of post-service mortality associated with various causes showed no increase in deaths of Vietnam veterans that could be attributed to immune-system disorders. Few effects of phenoxy herbicide exposure on the immune system have been reported in animals or humans, and clear association between phenoxy herbicide exposure and autoimmune or allergic disease has not been found. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evi- dence to determine whether there is an association between exposure to the com- pounds of interest and immune suppression, allergy, or autoimmune disease. DIABETES Diabetes mellitus is a group of heterogeneous metabolic disorders character- ized by hyperglycemia and quantitative or qualitative deficiency of insulin action (Orchard et al., 1992). Although all forms share hyperglycemia, the pathogenic processes involved in its development differ. Most cases of diabetes mellitus are in one of two categories: type 1 diabetes is characterized by a lack of insulin caused by the destruction of insulin-producing cells in the pancreas ( cells), and 

OTHER HEALTH EFFECTS 621 type 2 diabetes is characterized by a combination of resistance to the actions of insulin and inadequate secretion of insulin (called relative insulin deficiency). In old classification systems, type 1 diabetes was called insulin-dependent diabetes mellitus or juvenile-onset diabetes mellitus, and type 2 diabetes was called non- insulin-dependent diabetes mellitus or adult-onset diabetes mellitus. The modern classification system recognizes that type 2 diabetes can occur in children and also can require insulin treatments. Long-term complications of both types can in- clude cardiovascular disease, nephropathy, retinopathy, neuropathy, and increased vulnerability to infections. Maintaining blood sugar concentrations within the normal range is crucial for preventing complications. About 90 percent of all cases of diabetes mellitus are of type 2. Onset can occur before the age of 30 years, and incidence increases steadily with age thereafter. The main risk factors are age, obesity, central fat deposition, a his- tory of gestational diabetes (in women), physical inactivity, ethnicity (preva- lence is greater in blacks and Hispanics than in whites), and—perhaps most important—family history. The relative contributions of those features are not known. Prevalence and mortality statistics in the US population for 2004 are presented in Table 9-2. The etiology of type 2 diabetes is unknown, but three major components have been identified: peripheral insulin resistance (thought by many to be pri- mary) in target tissues (muscle, adipose tissue, and liver), a defect in -cell se- cretion of insulin, and overproduction of glucose by the liver. In states of insulin resistance, insulin secretion is initially higher for each concentration of glucose than in people without diabetes. That hyperinsulinemic state is a compensation for peripheral resistance and often can maintain normal glucose concentrations for years. Eventually, -cell compensation becomes inadequate, and there is progression to overt diabetes with concomitant hyperglycemia. Why the cells cease to produce sufficient insulin is not known. Type 1 diabetes occurs as a result of immunologically mediated destruction of cells in the pancreas, which often occurs during childhood but can occur at any age. As in many autoimmune diseases, genetic and environmental fac- tors influence pathogenesis. Some viral infections are believed to be important environmental factors that can trigger the autoimmunity associated with type 1 diabetes. Pathogenetic diversity and diagnostic uncertainty are among the important problems associated with epidemiologic study of diabetes mellitus. Given the multiple likely pathogenetic mechanisms that lead to diabetes mellitus—which include diverse genetic susceptibilities (as varied as autoimmunity and obe- sity) and the all sorts of potential environmental and behavioral factors (such as viruses, nutrition, and activity)—many agents or behaviors can contribute to risk, especially in genetically susceptible people. The multiple mechanisms also can lead to heterogeneous responses to various exposures. Because up to half the cases of diabetes are undiagnosed, the potential for ascertainment bias 

622 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-2 Prevalence and Mortality in US for 2004 from Diabetes, Lipid Disorders, and Circulatory Disorders Prevalence (% of Americans Mortality 20 years of age (number of deaths, and older) all ages) ICD-9 Range Diseases of the Circulatory System Men Women Men Women 250 Diabetes — — 35,000 37,800 Physician diagnosed 7.4a 7.9a — — Undiagnosed 2.9a 2.1a — — Prediabetes 33.8a 22.2a — — Lipid disorders Total cholesterol 200 mg/dL 47.8 55.2 — — Total cholesterol 240 mg/dL 16.2 17.1 — — LDL cholesterol 130 mg/dL 32.2 32.4 — — HDL cholesterol 40 mg/dL 25.1 9.1 — — 390–459 All circulatory disorders 37.5 36.6 410,400 461,200 390–398 Rheumatic fever and rheumatic heart — — 1,022 2,226 disease 401–404b Hypertensive disease 22,800 31,400 401 Essential hypertension — — — — 402 Hypertensive heart disease — — — — 403 Hypertensive renal disease — — — — 404 Hypertensive heart and renal disease — — — — 410–414, 429.2 Ischemic or coronary heart disease 8.9 6.1 233,300 219,100 410, 412 Acute or old myocardial infarction 5.1 2.5 83,100 74,500 411 Other acute and subacute forms of — — — — ischemic heart disease 413 Angina pectoris 4.4 3.9 — — 414 Other forms of chronic ischemic — — — — heart disease 429.2 Cardiovascular disease, unspecified 8.9 6.1 233,300 219,100 415–417b Diseases of pulmonary circulation — — — — 420-429 Other forms of heart disease (e.g., — — — — pericarditis, endocarditis, myocarditis, cardiomyopathy) 426–427 Arrhythmias — — — — 428 Heart failure 2.8 2.2 22,500 35,200 430–438b Cerebrovascular disease (e.g., 2.6 2.8 58,700 91,500 hemorrhage, occlusion, transient cerebral ischemia; includes mention of hypertension in 401) 440–448b Diseases of arteries, arterioles, and — — — — capillaries 451–459 Diseases of veins and lymphatics, and — — — — other diseases of circulatory system — Specific information not available. a For ages 18 years and above. b Gap in ICD-9 sequence follows. SOURCE: AHA, 2007. 

OTHER HEALTH EFFECTS 623 in population-based surveys is high (more intensively followed groups or those with more frequent health-care contact are more likely to get the diagnosis); this emphasizes the need for formal standardized testing (to detect undiagnosed cases) in epidemiologic studies. Conclusions from VAO and Updates The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether an association between exposure to the compounds of interest and diabetes mellitus exists. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that conclusion. In 1999, in response to a request from the Department of Veterans Affairs, IOM called together a committee to conduct an interim review of the scientific evidence regarding type 2 diabetes. That review focused on information published after the deliberations of the Update 1998 committee and resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes, hereafter referred to as Type 2 Diabetes (IOM, 2000). The committee responsible for that report determined that there was limited or suggestive evidence of an association between type 2 diabetes and exposure to at least one compound of interest. The committees responsible for Update 2000, Update 2002, and Update 2004 upheld that finding. Reviews of the pertinent studies are found in the earlier reports; Table 9-3 presents a summary. Update of the Epidemiologic Literature Occupational Studies Blair et al. (2005a) reported mortality results from a prospective study of 57,309 licensed private and commercial pesticide applicators and 32,345 spouses of private applicators who lived in Iowa and North Carolina and were enrolled in the AFS in 1994–1997 through 2000. The mortality experience of that cohort was compared with that of the general population in the two states. Among the 52,393 private applicators, who were mostly male, 1,558 deaths were observed, for an overall SMR of 0.5 (95% CI 0.4–0.5); 26 of the deaths were due to diabe- tes, for an SMR of 0.3 (95% CI 0.2–0.5). Among the spouses, 497 deaths were observed, for an overall SMR of 0.6 (95% CI 0.5–0.6); 18 of the deaths were due to diabetes, for an SMR of 0.6 (95% CI 0.4–1.0). The publication further reports that the low relative mortality generally varied little with such factors as years of handling pesticides and length of follow-up. 

624 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-3 Selected Epidemiologic Studies—Diabetes and Health Outcomes Related to Diabetes Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a OCCUPATIONAL New Studies Blair et al., 2005a US Agriculture Health Study—mortality Private applicators (men and women) 26 0.3 (0.2–0.5) Spouses of private applicators ( 99% women) 18 0.6 (0.4–1.0) Studies Reviewed in Update 2002 Steenland et al., Ranch Hand veterans and workers exposed to 2001 TCDD-contaminated products compared to unexposed comparison cohorts Ranch Hands 147 1.2 (0.9–1.5) Workers 28 1.2 (0.7–2.3) Kitamura et al., Workers exposed to PCDD at a municipal-waste 2000 incinerator 8 *(NS) Studies Reviewed in Update 2000 Calvert et al., Workers exposed to 2,4,5-T and derivatives 26 1.5 (0.8–2.9) 1999b Serum TCDD pg/g of lipid 20 7 2.1 (0.8–5.8) 20–75 6 1.5 (0.5–4.3) 75–238 3 0.7 (0.2–2.6) 238–3,400 10 2.0 (0.8–4.9) Steenland et al., Highly exposed industrial cohorts (n 5,132) 1999b Diabetes as underlying cause 26 1.2 (0.8–1.7) Diabetes among multiple causes 89 1.1 (0.9–1.3) Chloracne subcohort (n 608) 4 1.1 (0.3–2.7) Vena et al., 1998b Production workers and sprayers in 12 countriesb 33 2.3 (0.5–9.5) Steenland et al., Dioxin-exposed workers—mortality rates 1992b,c Diabetes as underlying cause 16 1.1 (0.6–1.8) Diabetes among multiple causes 58 1.1 (0.8–1.4) Studies Reviewed in Update 1998 Sweeney et al., Dioxin-exposed workers from 2 chemical plants 1.1 , p 0.003 1997/1998 Ramlow et al., Pentachlorophenol production 1996 workers—mortality 4 1.2 (0.3–3.0) Studies Reviewed in Update 1996 Ott et al., 1994 Trichlorophenol production workers p .06 Von Benner West German chemical production workers N/A N/A et al., 1994 Zober et al., 1994 BASF production workers 10 0.5 (0.2–1.0) Studies Reviewed in VAO Sweeney et al., NIOSH production workers 26 1.6 (0.9–3.0) 1992 Henneberger Paper and pulp workers 9 1.4 (0.7–2.7) et al., 1989 Cook et al., 1987 Production workers—mortality 4 0.7 (0.2–1.9) 

OTHER HEALTH EFFECTS 625 TABLE 9-3 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Moses et al., 2,4,5-T and TCP production workers with 1984 chloracne 22 2.3 (1.1–4.8) May, 1982 TCP production workers 2 * Pazderova- 2,4,5-T and TCP production workers 11 * Vejlupkova et al., 1981 ENVIRONMENTAL New Studies Chen HL et al., Residents around 12 municipal-waste 2006 incinerators in Taiwan—prevalence of physician diagnosed diabetes Serum TCDD/TCDF (international TEQs) in logistic model adjusted for age, sex, smoking, BMI 29 2.4 (0.2–31.9) Baccarelli et al., Children residing in Seveso at time of 2005 accident—development of diabetes 101 with chloracne 1 * 211 without chloracne 2 * Studies Reviewed in Update 2004 Fierens et al., Belgium residents (142 women; 115 men) 2003 exposed to dioxins and PCBs Subjects in the top decile for dioxins 5.1 (1.2–21.7) Studies Reviewed in Update 2002 Masley et al., Population-based survey in Saskatchewan 28 * 2000 Studies Reviewed in Update 2000 Bertazzi et al., Seveso residents—20-year follow-up 2001 Zone A and B—men 6 0.8 (0.3–1.7) —women 20 1.7 (0.1–2.7) Cranmer et al., Vertac/Hercules Superfund site residents (n 2000b 62)—OR for high insulin among non-diabetic subjects at varying times and levels for TCDD 15 ppt compared to persons with TCDD 15 ppt Fasting (insulin level, 4.5 IU/ml) 3 8.5 (1.5–49.4) 30-min (insulin level, 177 IU/ml) 3 7 (1.3–39.0) 60-min (insulin level, 228 IU/ml) 4 12 (2.2–70.1) 120-min (insulin level, 97.7 IU/ml) 6 56 (5.7–556) Bertazzi et al., Seveso residents—15-year follow-up 1998b Zone A—women 2 1.8 (0.4–7.0) Zone B—men 6 1.2 (0.5–2.7) —women 13 1.8 (1.0–3.0) continued 

626 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-3 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Pesatori et al., Zone R—men 37 1.1 (0.8–1.6) 1998b —women 74 1.2 (1.0–1.6) VIETNAM VETERANS New Studies Kang et al., 2006 US Army Chemical Corps personnel Deployed vs non-deployed 226 1.2 (0.9–1.5) Sprayed herbicides in Vietnam vs never 123 1.5 (1.1–2.0) ADVA, 2005b Australian Vietnam veterans vs Australian population—mortality 55 0.5 (0.4–0.7) Navy 12 0.5 (0.3–0.9) Army 37 0.5 (0.4–0.7) Air Force 6 0.5 (0.2–1.0) ADVA, 2005c Australian men conscripted into Army National Service—deployed vs non-deployed—mortality 6 0.3 (0.1–0.7) AFHS, 2005 Air Force Health Study—2002 exam cycle Ranch Hand veterans—relative risk with 2-fold increase in 1987 TCDD level 1.3 (1.1–1.5) Boehmer et al., Follow-up of CDC Vietnam Experience Cohort * * 2004 Kern et al., 2004 Air Force Health Study—Ranch Hand– Comparison subject pairs—within-pair differences: lower Ranch Hand insulin sensitivity with greater TCDD levels 1997 exam (29 pairs) (p 0.01) 2002 exam (71 pairs) (p 0.02) CDC, 1988b Vietnam Experience Study—deployed vs non-deployed Interviewed—self-reported diabetes 155 1.2 (p 0.05) Subset with physical exam —self-reported diabetes 42 1.1 (p 0.05) —fasting serum glucose (geometric mean) 93.4 vs 92.4 mg/dL (p 0.05) Studies Reviewed in Update 2004 Kim et al., 2003 Korean veterans of Vietnam—Vietnam veterans 154 2.7 (1.1–6.7) Michalek et al., Air Force Ranch Hand Veterans (n 343) 92 NS 2003 Studies Reviewed in Update 2000 AFHS, 2000b Air Force Heath Study—1997 exam cycle (Numerous analyses Ranch Hand veterans and comparisons discussed in the text of Herbicide/Dioxin Exposure and Type 2 Diabetes) 

OTHER HEALTH EFFECTS 627 TABLE 9-3 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Longnecker and Air Force Heath Study—comparison veterans Michalek, 2000b only, OR by quartiles of serum dioxin concentration Quartile 1: 2.8 ng/kg 26 1.00—referent Quartile 2: 2.8– 4.0 ng/kg 25 0.9 (0.5–1.7)d Quartile 3: 4.0– 5.2 ng/kg 57 1.8 (1.0–3.0)d Quartile 4: 5.2 ng/kg 61 1.6 (0.9–2.7)d CDVA, 1998ab Australian Vietnam veterans—men 2,391 1,780 reportede expected (6% of (1,558–2,003) respon- dents) CDVA, 1998bb Australian Vietnam veterans—women 5 reportede 10 expected (2% of (9–11) respon- dents) Studies reviewed in Update 1998 Henriksen et al., Air Force Health Study—through 1992 exam 1997b cycle Ranch Hand veterans—high-exposure group Glucose abnormalities 60 1.4 (1.1–1.8) Diabetes prevalence 57 1.5 (1.2–2.0) Use of oral medications for diabetes 19 2.3 (1.3–3.9) Serum insulin abnormalities 18 3.4 (1.9–6.1) O’Toole et al., Australian Vietnam veterans 12 1.6 (0.4–2.7)e 1996 Studies Reviewed in VAO AFHS, 1991a Air Force Heath Study—1987 exam cycle p 0.001, Ranch Hand veterans and comparisons 85 p 0.028 AFHS, 1984 Air Force Heath Study—1982 exam cycle Ranch Hand veterans and comparisons 158 p 0.234 ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; ADVA, Australian Department of Veterans Affairs; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDC, Centers for Disease Control and Prevention; CI, confidence interval; EOI, exposure opportunity index; HDL, high-density lipoprotein; N/A, not applicable; NIOSH, National Institute for Occupa- tional Safety and Health; NS, not significant; SS, statistically significant; TCP, trichlorophenol. a Given when available. b Study is discussed in greater detail in Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000). c May include some of the same subjects covered in the NIOSH cohorts addressed in the other refer- ences cited in the Occupational cohorts category. d Adjusted for age, race, body mass index, waist size, family history of diabetes, body mass index at the time dioxin was measured, serum triglycerides, and military occupation. e Self-reported medical history; answer to question, Since your first day of service in Vietnam, have you been told by a doctor that you have diabetes? * Information not provided by study authors. 

628 VETERANS AND AGENT ORANGE: UPDATE 2006 Environmental Studies Chen et al. (2006) investigated the prevalence of diabetes in Taiwanese who lived near municipal-waste incinerators for at least 5 years. Health information was obtained from an interviewer-administered questionnaire on which people were asked about their medical histories, including physician-diagnosed diabetes, and serum samples were collected for analysis of polychlorinated dibenzo-p- dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). A logistic regres- sion analysis found the prevalence of diabetes to be non-significantly associated with serum PCDD and PCDF concentrations, on the basis of international toxic equivalents (TEQs) (OR 8.64, 95% CI 0.87–93.3). Any relationship was even less apparent after adjustment for age, sex, smoking status, and BMI (OR 2.44, 95% CI 0.21–31.90). Baccarelli et al. (2005b) reported the results of a case–control study of resi- dents of Seveso, Italy, who experienced dioxin exposure during the accident of 1976. The accident resulted in a large outbreak of chloracne, primarily among the resident children (of the 193 cases, 88% were in people less than 14 years old). From 1993 to 1998, the study recruited 101 people with chloracne and 211 controls, 101 of whom were pair-matched on age, sex, and zone of residence and 110 of whom had lived in the Seveso area at the time of the accident. The object was to investigate the association between dioxin and chloracne occurrence. Plasma TCDD was measured with high-resolution gas chromatography–mass spectrometry. Of the 211 control subjects, 104 were characterized as having been exposed to dioxin as a result of the accident and 107 as unexposed. As a part of subject follow-up, enrollees were interviewed with respect to the occurrence of various diseases since the accident. Only one of the cases and two of the controls (one characterized as exposed and the other as unexposed) reported a diabetes diagnosis since the accident. Vietnam-Veteran Studies Kang et al. (2006) reported results of a study of Vietnam-era veterans of the US ACC and compared data on 1,499 who had been deployed to Vietnam with data on 1,428 who had not. Self-reported data were collected from the participants by telephone interview. Medical and hospital records were sought to document reported cases of diabetes; such support was obtained for 79.2% of the 362 reported cases; available records for 39 lacked confirmatory information, and no records could be obtained for the remaining 36. Serum dioxin concentrations measured in a subgroup of 897 of the participants confirmed the reliability of self- reports of herbicide spraying as a surrogate for TCDD exposure. With respect to diabetes risk, the OR for Vietnam veterans relative to non-Vietnam veterans was 1.16 (95% CI 0.91–1.49) adjusted for age, race, BMI, rank, and smoking. Among the Vietnam veterans, comparison of those who reported a history of spraying 

OTHER HEALTH EFFECTS 629 herbicides with those who did not yielded an OR of 1.49 (95% CI 1.10–2.02) adjusted for the same factors. Similarly, when Vietnam service and herbicide spraying were both included with the previous risk factors in a logistic model for diabetes applied to all the ACC subjects, the risk associated with deployment to Vietnam was not significant (OR 1.04, 95% CI 0.80–1.37), whereas the risk associated with herbicide spraying was increased (OR 1.50, 95% CI 1.15–1.95). The study concludes that Vietnam veterans employed as sprayers carried a sig- nificantly higher risk of diabetes than non-Vietnam veterans. The final examination cycle of the AFHS was conducted in 2002–2003 and used questionnaires, physical examinations, and clinical assessments to ascertain diabetes prevalence. The official report (AFHS, 2005) presents findings cumu- lated from the study’s beginning in 1982 but only on subjects who participated in the final examination cycle. Significant associations were reported between dioxin concentrations and diabetes risk and severity. In particular, among the Ranch Hand participants with dioxin measurements, there was a significantly increased risk of being diabetic (RR 1.29, 95% CI 1.10–1.51) for a doubling in 1987 dioxin concentrations after adjustment for age, race, military occupation, BMI, waist-to-hip ratio, smoking, and family history. Similarly, time to diabetes onset was significantly shorter among the Ranch Hand subjects with higher 1987 dioxin concentrations. Those results underscore and strengthen previous AFHS findings with respect to diabetes. Kern et al. (2004) report results from a substudy of the AFHS. Two subsets of AFHS participants were formed: one subset of those who participated in the 1997 AFHS physical examination and the other of those who participated in the 2002 AFHS physical examination. The subsets consisted of pairs of subjects without prior indications of diabetes that were matched one for one (on age, BMI, black vs nonblack race, and first-order family history of diabetes) and consisted of a Ranch Hand veteran with serum TCDD over 10 ppt and a com- parison veteran with serum TCDD under 10 ppt. A total of 29 matched pairs from the 1997 examination and 71 matched pairs from the 2002 examination were studied. Insulin sensitivity was measured in serum samples with two methods: a frequent-sampling intravenous-glucose tolerance test in 1997 and a quantita- tive insulin-sensitivity check index based on fasting glucose and insulin in 2002. There were no significant group differences in any of the measures of insulin sensitivity between the Ranch Hands and their matched comparisons. Regres- sions of within-pair differences for insulin sensitivity on within-pair differences in TCDD concentrations found the greater depression in the Ranch Hands’ insulin sensitivity to be significantly related to higher TCDD concentrations. The authors suggested that high blood TCDD may modestly promote insulin resistance. The Australian Department of Veterans’ Affairs (DVA) Third Vietnam Veter- ans Mortality Study (ADVA, 2005b) assessed mortality among Australian Viet- nam veterans from all branches of service. The mortality experience (through 2001) of the veterans was compared with that of the general population of 

630 VETERANS AND AGENT ORANGE: UPDATE 2006 Australia. The investigators report an SMR of 0.52 (95% CI 0.38–0.66) with respect to diabetes, which suggests a significant decrease in the rate of death from diabetes among the veterans. Similarly, in the study comparing deployed and non-deployed Australian National Service veterans (ADVA, 2005c), the risk of death from diabetes was reduced among those sent to Vietnam (SMR 0.3, 95% CI 0.1–0.7). However, the investigators noted that in Australia people with type 1 diabetes were not allowed to be sent to Vietnam, so there was considerable selection bias in the study cohort. It was brought to the present committee’s attention that the original VAO report had overlooked data related to diabetes in the report on the CDC VES (CDC, 1988). The incidence of self-reported diabetes did not differ (p 0.05) be- tween the deployed and non-deployed among the 15,288 subjects who completed telephone interviews (1.9% vs 1.4%; OR, 1.2) or the subset of 4,362 subjects who had physical examinations (1.7% vs 1.5%; OR, 1.1). Among the examined veterans, however, although there was no difference in the risk of exceeding the reference limit of 140 mg/dL, the modest difference in the geometric means of fasting glucose between the deployed (93.4 mg/dL) and the non-deployed (92.4 mg/dL) was significant (p 0.05). The recent 30-year follow-up on mortality in the cohort (Boehmer et al., 2004) did not report findings with respect to deaths associated with diabetes, and there has not been any follow-up on the morbidity profile. Biologic Plausibility The toxicity of TCDD in laboratory animals has been historically linked with body weight loss through inhibition of gluconeogenesis and enhanced lipid metabolism. Despite alterations in these key metabolic processes, diabetes (de- fined as significant and prolonged elevation of blood glucose levels) has not been reported in TCDD-exposed rodents. Chronic active inflammation, acinar cytoplasmic vacuolization, and acinar atropy were found in the pancreata of rats exposed to TCDD for two years without lesions in the insulin-secreting islet beta cells. Nonetheless, several recent in vitro studies provide evidence that TCDD exposure could contribute to the development of type 2 diabetes. Three different laboratories reported that key regulators of insulin action are altered by TCDD. Marchand et al. (2005) showed that IGFBP-1 is transcriptionally activated by TCDD in hepatocyes; Liu and Matsumura (2006) showed that TCDD suppresses insulin responsive glucose transporter (GLUT-4) gene expression in adipocytes; and Hokanson et al. (2004) showed insulin receptor substrate-1 (IRS-1) was downregulated in MCF-7 cells co-treated with TCDD and estrogen. In addition, pancreatic islets from rats treated with a single 1 ug/kg dose of TCDD showed impaired insulin secretion in response to glucose and reduced glucose uptake without an effect on GLUT2 protein level (Novelli et al., 2005). These changes could contribute to insulin resistance of cells and elevated blood sugar. Results 

OTHER HEALTH EFFECTS 631 reported by Yang and Bleich (2004) also contribute to plausibility by showing that the COX2 promoter in a pancreatic beta cell line is responsive to TCDD via direct transcriptional activation of a DRE. Induction of COX2 in beta cells is suspected to contribute to beta cell dysfunction as a part of diabetes development. Synthesis The study by Blair et al. (2005) has several acknowledged weaknesses. The AHS cohort is a working cohort being compared with the general population of two states. The possibility of bias due to the healthy-worker effect cannot be dis- missed. In addition, most of the pesticide workers and their spouses in the AHS cohort were farmers. Adults in farm families are known to have significantly lower cause-specific mortality than the general population, and this limits the generalizability of results. Furthermore, although the subjects have considerable potential for exposure to phenoxy herbicides, in the period under consideration exposure to 2,4,5-T and its contaminant TCDD was unlikely. Baccarelli et al. (2005b) studied a relatively small sample consisting almost entirely of people who were children at the time of dioxin exposure. Their ages at the time of exposure do not correspond to those of soldiers in Vietnam, and at the time of the study they had not yet reached the age at which diabetes becomes prevalent. This study comparing morbidity in those with and without chloracne has limited utility for studying an association between dioxin exposure and spe- cific diseases, such as diabetes. The finding of an association between herbicide exposure and diabetes risk among Vietnam-era US ACC veterans (Kang et al., 2006) is consistent with the results of several previous studies. Moreover, the study investigated a group of Vietnam veterans with documented herbicide exposure, and individual self- reports of herbicide spraying were effectively validated by measurements of se- rum TCDD in a subsample. The study’s reliance on self-reported data for disease classification was mitigated by fairly complete verification with medical records only for diabetes. Results of substudies implied that recall bias was unlikely to have affected the comparison appreciably. There was a potential for selection bias, but the authors strongly argued that the study group was reasonably repre- sentative of non-Vietnam veterans, as well as exposed Vietnam veterans. The Australian Vietnam-veteran study did not find a positive association between exposure and diabetes risk, but it had limitations that suggest bias in the risk estimates. Other Vietnam-veteran studies, particularly those based on the AFHS cohort, continue to provide the strongest support for a positive association between dioxin exposure and diabetes risk. The AFHS report (2005) on the 2002 examination reinforced earlier findings of a significant increase in risk, severity, and speed of disease onset associated with higher serum dioxin concentrations. Increased blood dioxin levels resulting from recommended weight loss subse- quent to diagnosis of diabetes are a possible source of bias in analyses of associa- 

632 VETERANS AND AGENT ORANGE: UPDATE 2006 tion between serum TCDD levels and the development of diabetes. Mobilization from fat stores during dieting is known to increase blood levels of dioxin, but the degree or persistence of such elevations is not well characterized. The cross- sectional analyses of Ranch Hand and comparison subjects took account of BMI, but not changes in weight (AFHS, 2005). The serum TCDD levels used in those exam cycle analyses, however, were based upon samples drawn primarily in 1989 or later that may have pre- or post-dated an individual’s diabetes diagnosis. The questionnaire for the study by Kang et al. (2006) included questions regarding weight loss as well as the year in which diabetes developed, but the analysis de- termining risk of developing diabetes with respect to degree of herbicide exposure (qualitatively and indirectly derived for all subjects from self-reports of spraying and serum levels in sprayers) also adjusted for BMI, but not for change in BMI over time. All blood samples from ACC subjects were drawn after administration of the questionnaire ascertaining diabetes status, but at various intervals after diagnosis, so a perceptible trend of diet-induced TCDD elevation in the subjects with diabetes would not be anticipated. The committee found it implausible that a bias related to post-diagnosis weight loss could be responsible for repeated findings of association between diabetes and herbicide exposure. All together, the newly added studies do not counter previous findings with respect to the association between exposure and diabetes risk. In some cases, they lend additional support to previous findings. The new studies are not, however, sufficient to merit a stronger conclusion with respect to the association. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evi- dence of an association between exposure to at least one compound of interest and diabetes. LIPID AND LIPOPROTEIN DISORDERS Plasma lipid (notably cholesterol) concentrations have been shown to predict cardiovascular disease and are considered fundamental to the underlying ath- erosclerotic process (Kuller and Orchard, 1988). Cholesterol and triglycerides, the two major types of lipids, are carried in the blood attached to proteins to form lipoproteins, which are classified by density. Very-low-density lipoprotein (VLDL, the major “triglyceride” particle) is produced in the liver and is pro- gressively catabolized (hydrolyzed), mainly by an insulin-stimulated enzyme (lipoprotein lipase), to form intermediate-density lipoprotein (IDL), or VLDL remnants. Most of the VLDL remnants are rapidly cleared by low-density lipo- protein (LDL) receptors (types B and E) in the liver, and the rest form LDL, the 

OTHER HEALTH EFFECTS 633 major “bad cholesterol.” LDL is cleared by LDL receptors in the liver and other tissues. High-density lipoprotein (HDL), the “good cholesterol,” is produced in the small intestine and liver. It also results from the catabolism of VLDL. LDL is involved in the delivery of cholesterol to the tissues, and HDL is involved in “reverse” transport and facilitates the return of cholesterol to the liver for biliary excretion (LaRosa, 1990). Disorders of lipoprotein metabolism usually result from overproduction or decreased clearance of lipoproteins or both. Common examples are hypercho- lesterolemia, which can be familial (because of an LDL-receptor genetic defect) or polygenic (because of multiple minor genetic susceptibilities); familial hy- pertriglyceridemia (sometimes linked to susceptibility to diabetes); and mixed hyperlipidemias, in which both cholesterol and triglycerides are elevated. The mixed hyperlipidemias include familial combined hyperlipidemia, which could result from hepatic overproduction of VLDL and apoprotein B, and type III dyslipidemia, which involves defective clearance of IDL and VLDL remnants and a buildup of these atherogenic particles. Although the bulk of blood lipid concentration is genetically determined, diet, activity, and other factors (such as concurrent illness, use of drugs, age, sex, and hormones) have major effects. In particular, the saturated-fat content of the diet might raise LDL concentrations through decreased LDL-receptor activity; obesity and a high-carbohydrate diet can increase VLDL and possibly are linked to insulin resistance and reduced lipoprotein lipase activity. Diabetes mellitus and metabolic syndrome are associ- ated with increased triglycerides and decreased HDL. Other diseases (thyroid and renal disorders) often result in hypercholesterolemia. It is evident that multiple host and environmental factors influence lipid and lipoprotein concentrations and that those influences must be considered before the effect of a new factor can be assessed (LaRosa, 1990). Any analysis should control for obesity as a primary determinant of triglyceride and TCDD concentrations. Finally, the ability of chronic diseases to raise triglycerides, glucose, and LDL and/or to lower HDL must be recognized. Statistics on the prevalence in the US population for 2004 of reading in the ranges defining various lipid disorders are presented in Table 9-2. Conclusions from VAO and 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 compounds of concern and lipid and lipoprotein disorders. Ad- ditional information available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. Table 9-4 provides a summary of relevant studies that have been reviewed. 

634 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-4 Selected Epidemiologic Studies—Lipid and Lipoprotein Disorders Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a OCCUPATIONAL Studies Reviewed in Update 2004 Hu et al., Workers exposed to PCDDs/PCDFs in Taipei 2003 City Comparison between high and low 67 high; exposure groups using the low exposures 66 low group as controls Total cholesterol 2.8 (1.0–7.9) Triglycerides 1.5 (0.5–4.3) Pelclová Workers exposed to 2,3,7,8-TCDD in 12 et al., 2002 Spolana, Czech Republic Correlation between the year (1968 to 2001) in which the highest level of the parameter was measured and serum 2,3,7,8-TCDD level in 1966 Cholesterol r 0.78; p 0.01 Triglycerides r 0.66; p 0.02 Studies Reviewed in Update 2002 Kitamura Workers exposed to PCDDs—hyperlipidemia 8 6.1, p 0.02 et al., 2000 Studies Reviewed in Update 1998 Calvert Workers exposed to 2,4,5-T derivatives vs et al., 1996 matched referents OR Abnormal total cholesterol Overall 95 1.1 (0.8–1.6) High TCDD 18 1.0 (0.5–1.7) Abnormal HDL cholesterol Overall 46 1.2 (0.7–2.1) High TCDD 16 2.2 (1.1–4.7) Abnormal mean total/HDL cholesterol ratio Overall 131 1.1 (0.8–1.6) High TCDD 36 1.5 (0.8–2.7) Abnormal mean triglyceride Overall 20 1.0 (0.5–2.0) High TCDD 7 1.7 (0.6–4.6) Ott and Production workers exposed to 42 Zober, 1996 2,3,7,8-TCDD Cholesterol [no significant effect]b Triglycerides [no significant effect]b HDL cholesterol Increased; p 0.05b 

OTHER HEALTH EFFECTS 635 TABLE 9-4 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Studies Reviewed in VAO Martin, Production workers exposed to TCDD 1984 No chloracne 53 Cholesterol Increased; p 0.005b Triglycerides Increased; p 0.005b HDL cholesterol [no significant effect]b With chloracne 39 Cholesterol Increased; p 0.05b Triglycerides Increased; p 0.01b HDL cholesterol [no significant effect]b Moses TCP and 2,4,5-T production workers 118 et al., 1984 Cholesterol [no significant effect]c Triglycerides [no significant effect]c Suskind and TCP production workers 204 [no significant effect]b Hertzberg, Cholesterol 1984 Triglycerides [no significant effect]b HDL cholesterol [no significant effect]b May, 1982 TCP production workers 94 Cholesterol [no significant effect]b Triglycerides [no significant effect]b Pazderova- TCP and 2,4,5-T production workers 55 Vejlupkova Cholesterol [no significant effect]b et al., 1981 Triglycerides Increased VLDL; p .01b ENVIRONMENTAL Studies Reviewed in VAO Assennato Seveso Zone A adult subjects chloracne 193 et al., 1989 Cholesterol [no significant effect]b Triglycerides [no significant effect]b Mocarelli Children exposed near Seveso 63 et al., 1986 Cholesterol [no significant effect]b Triglycerides [no significant effect]b VIETNAM VETERANS New Studies AFHS, Air Force Ranch Hand veterans (2002 exam 762 2005 data) Model 3 Low High TCDD Exp vs comparisons Cholesterol reduced, p 0.039 Model 1 Ranch Hand vs comparisons Triglycerides increased for enlisted groundcrew, p 0.034 Model 3 Low High TCDD exp vs comparisons Triglycerides increased, p 0.001 continued 

636 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-4 Continued Estimated Exposed Relative Risk Reference Study Population Casesa (95% CI)a Model 4 ORH 1987 Serum TCDD Levels Triglycerides increased, p 0.02 Studies Reviewed in Update 2000 AFHS, Air Force Ranch Hand veterans 858 2000 Cholesterol [no significant effect] Triglycerides [no significant effect] Studies Reviewed in Update 1998 AFHS, Air Force Ranch Hand veterans (1992 exam 884 1996 data) Cholesterol 884 [no significant effect]d (cholesterol:HDL ratio) Triglycerides [no significant effect]d HDL cholesterol [no significant effect]d (cholesterol:HDL ratio) O’Toole Australian Vietnam veterans, compared with 20 et al., 1996 the Australian population Cholesterol 3.0 (1.3–4.7) Studies Reviewed in VAO AFHS, Air Force Ranch Hand veterans—serum 283–304f 1991a dioxin analysis (1987 exam data) Cholesterol p 0.175e Triglycerides p 0.001e,g HDL cholesterol p 0.001e AFHS, Air Force Ranch Hand veterans—Original 8–142f 1990h exposure group analysis (1987 exam data) Model 1, Ranch Hand vs comparisons Cholesterol 1.2 (0.9–1.5) Triglycerides 1.3 (0.9–1.8) HDL cholesterol 1.0 (0.4–2.4) AFHS, Air Force Ranch Hand veterans exposed to 1,027 1984; Wolfe herbicide spraying (1982 data) et al., 1990 Cholesterol [no significant effect]h Triglycerides [no significant effect]h HDL cholesterol [no significant effect]h ABBREVIATIONS: AFHS, Air Force Health Study; HDL, high-density lipoprotein; PCDD, poly- chlorinated dibenzodioxins; TCP, trichlorophenol; VLDL, very-low-density lipoprotein. a Given when available. b p-values comparing means of subjects and controls in univariate analysis. c p-values comparing means in production workers with subsequent chloracne to those without. d Comparing change over time between exposed and comparison groups. e Comparing mean dioxin across lipid groups. f Number of exposed Ranch Hand with “high” lipid values. g Continuous analysis. h Comparing means. NOTE: Estimated risk and 95% CI reported unless p-values are specified. 

OTHER HEALTH EFFECTS 637 Update of the Epidemiologic Literature No new occupational or environmental studies concerning exposure to the compounds of interest and lipid and lipoprotein disorders were published since Update 2004. Vietnam-Veteran Studies In the study of Ranch Hand veterans by the US Air Force (AFHS, 2005), assessment of lipid and lipoprotein disorders was conducted on the basis of physical examinations in 2002. Analysis included total serum cholesterol, HDL, the ratio of total cholesterol to HDL, and triglycerides. Covariates used in the adjusted analyses of the lipid and lipoprotein values included age, race, military occupation, smoking history, alcohol-consumption history, BMI, and degreasing and industrial chemical exposure. No significant associations between dioxin exposure and total serum cho- lesterol, HDL, or the ratio of total cholesterol to HDL in Ranch Hand veterans were found. However, significantly fewer Ranch Hand veterans with 1987 serum TCDD over 10 ppt (43 of 416, or 10.3 percent) than other veterans who served in Southeast Asia (153 of 1,149, or 13.3 percent) exhibited abnormally high serum total cholesterol (over 240 mg/dL), for an adjusted RR of 0.68 (95% CI 0.47– 0.98, p 0.039). In contrast, the concentration of serum triglycerides showed a trend for a positive association when Ranch Hand veterans were categorized into low, medium, or high serum TCDD (p 0.077). However, the mean serum triglyceride in the three exposure categories ranged from 114 to 130 mg/dL—all within the normal physiologic range. In a second set of analyses, the percentage of veterans with abnormally high serum triglycerides (over 250 mg/dL) was compared between Ranch Hand veterans and other veterans who served in Southeast Asia. The percentage with abnormally high serum triglycerides was significantly higher in Ranch Hand enlisted ground-crew personnel (17.9 percent with abnormally high serum tri- glycerides vs 11.9 percent in the comparison group; adjusted RR 1.54, 95% CI 1.03–2.29, p 0.034), Ranch Hand veterans categorized as having low TCDD exposure (15.4 percent vs 9.8 percent; adjusted RR 1.72, 95% CI 1.11–2.66, p 0.015), and Ranch Hand veterans with high TCDD exposure (20.4 percent vs 9.8 percent; adjusted RR 1.70, 95% CI 1.12–2.57, p 0.012). Finally, a weak but significant positive association between the percentage of Ranch Hand veterans with abnormally high serum triglycerides and their 1987 serum TCDD (adjusted RR 1.20, 95% CI 1.03–1.40, p 0.02) was found. Biologic Plausibility The induction of lipid mobilization and alterations in lipid metabolism are well-known effects of high-dose exposure to TCDD in laboratory animals that 

638 VETERANS AND AGENT ORANGE: UPDATE 2006 results in hyperlipidemia and loss of body fat. Increases in serum triglycerides were also seen in TCDD-exposed rhesus monkeys (Rier et al., 1993) and mice. For example, Boverhof et al. (2005) found that exposure of mice to a single high dose of TCDD (30 g/kg of body weight) increased serum triglycerides 1–7 days after exposure, and the increase was associated with changes in hepatic gene expression that were consistent with mobilization of peripheral fat. Similarly, Dalton et al. (2001) found that exposure of mice to a cumulative TCDD dose of 15 g/kg over 3 days increased serum triglycerides and LDL when measured 4 weeks after exposure. The mechanism underlying altered lipid metabolism has not been elucidated, but the high-dose studies in animal models provide some evidence of biologic plausibility that TCDD exposure can directly alter serum lipid and lipoprotein concentrations. Synthesis Previously reviewed literature showed inconsistent changes in serum lipids or lipoproteins after exposure to the compounds of interest, and in most cases the sample sizes were insufficient to support any conclusions. The recent report on Ranch Hand veterans (AFHS, 2005) shows that serum TCDD concentrations are positively associated with serum triglycerides; however, even in Ranch Hand veterans with the highest TCDD exposure, the mean serum triglyceride concen- tration (130 mg/dL) is well below that considered to be abnormal (250 mg/dL). It is notable that the Ranch Hand veterans with abnormally high serum triglycerides tend to be those with the highest TCDD exposure. Hypertriglyceridemia is considered to be a major risk factor for acute pan- creatitis when serum triglyceride concentrations exceed 1,000 mg/dL, and there is some evidence that it is an independent but weak risk factor for ischemic heart disease at concentrations over 150 mg/dL (Austin et al., 1998; Jeppesen et al., 1998; Miller et al., 1998). More commonly, however, high serum triglyceride concentrations (150–500 mg/dL) are considered to be a consequence of other underlying diseases, particularly diabetes mellitus and metabolic syndrome, and hypertriglyceridemia is a well recognized marker of these diseases, especially when associated with low HDL concentrations (NCEP, 2002). The VAO committee responsible for Type 2 Diabetes concluded that there was limited or suggestive evidence of an association between type 2 diabetes mellitus and exposure to herbicides in Vietnam (IOM, 2000). Although the lat- est Ranch Hand study (AFHS, 2000) adjusted the RR of hypertriglyceridemia for smoking and BMI, it failed to account for the presence of diabetes mellitus. Diabetes mellitus is strongly associated with hypertriglyceridemia, as discussed above, so it is plausible that the increased percentage of Ranch Hand veterans with abnormally high serum triglycerides may be a consequence of diabetes mel- litus. In that regard, the percentage of all Ranch Hand veterans with a diagnosis 

OTHER HEALTH EFFECTS 639 of diabetes mellitus (about 23%) could include the percentage with hypertriglyc- eridemia (about 13%). Hypertriglyceridemia itself was not considered a health outcome by the pres- ent committee, but it was recognized that its presence may indicate the emergence of a more significant health concern, metabolic syndrome. Metabolic syndrome is characterized by obesity, high triglycerides (over 150 mg/dL), low HDL (under 40 mg/dL), hypertension (over 130/85 mm Hg), and high fasting plasma glucose or diagnosed diabetes mellitus (Alberti et al., 2006). As noted above, the com- mittee responsible for Update 2004 concluded that there is suggestive evidence of a link between exposure to herbicides in Vietnam and type 2 diabetes mellitus, whereas the present committee has concluded that there is suggestive evidence of a link between exposure to herbicides in Vietnam and hypertension (see section on circulatory disorders). Thus, an increasing number of Vietnam veterans may be exhibiting at least three of the diagnostic criteria for metabolic syndrome: hypertriglyceridemia, diabetes mellitus, and hypertension. It will be important to analyze the incidence of those individual outcomes as potential components of a larger disease syndrome. Conclusion On the basis of its evaluation of the evidence reviewed here and in previous VAO reports, the committee concludes that there is insufficient or inadequate evidence to determine whether there is an association between exposure to the compounds of interest and lipid or lipoprotein disorders. GASTROINTESTINAL AND DIGESTIVE DISEASE, INCLUDING LIVER TOXICITY This section discusses a variety of conditions encompassed by ICD-9 520– 579: diseases of the esophagus, stomach, intestines, rectum, liver, and pancreas. Details on peptic ulcer and liver disease, the two conditions most often discussed in the literature reviewed, are provided below. The symptoms and signs of gastro- intestinal disease and liver toxicity are highly varied and often vague. The essential functions of the gastrointestinal tract are to absorb nutrients and eliminate waste. Those complex tasks involve numerous chemical and molecular interactions on the mucosal surface and complex local and distant neural and endocrine activity. One common condition of the gastrointestinal tract is motility disorder, which could be present in 15% of adults. The most convenient way to categorize diseases that affect the gastrointestinal system is according to the af- fected anatomic segment. Esophageal disorders predominantly affect swallowing; gastric disorders are related to acid secretion; and conditions that affect the small and large intestines are reflected in alterations in nutrition, mucosal integrity, 

640 VETERANS AND AGENT ORANGE: UPDATE 2006 and motility. Some systemic disorders (inflammatory, vascular, infectious, and neoplastic conditions) also affect the gastrointestinal system. Peptic Ulcer Disease Peptic ulcer disease refers to ulcerative disorders of the gastrointestinal tract that are caused by the action of acid and pepsin on the stomach or duodenal mu- cosa. Peptic ulcer disease is characterized as gastric or duodenal ulcer, depending on the site of origin. Peptic ulcer disease occurs when the corrosive action of gastric acid and pepsin overcomes the normal mucosal defense mechanisms that protect against ulceration. About 10% of the population have clinical evidence of duodenal ulcer at some period in life; a similar percentage are affected by gastric ulcer. The incidence of duodenal ulcer peaks in the fifth decade, and the incidence of gastric ulcer about 10 years later. Evidence increasingly indicates that the bacterium Helicobacter pylori is linked to peptic ulcer disease (both duodenal and gastric). H. pylori colonizes the gastric mucosa in 95–100 percent of patients with duodenal ulcer and in 75–80 percent of patients with gastric ulcer. Healthy subjects in the United States under 30 years old have gastric colonization rates of about 10 percent. Over the age of 60 years, colonization rates exceed 60 percent. Colonization alone, however, is not sufficient for the development of ulcer disease; only 15–20 percent of subjects with H. pylori colonization will develop ulcers in their lifetimes. Other risk fac- tors include genetic predisposition (for instance, certain blood and HLA types), cigarette smoking, and psychological factors (chronic anxiety and stress). Liver Disease Blood tests that reflect liver function are the mainstay of diagnosis of liver disease. Increases in serum bilirubin and in the serum concentrations of some hepatic enzymes—aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and -glutamyltransferase (GGT)—are commonly noted in liver disorders. The relative sensitivity and specificity of those enzymes for diagnos- ing liver disease vary, and several tests can be required for diagnosis. The only regularly reported abnormality in liver function associated with TCDD exposure in humans is an increase in GGT. Estimated serum activity of that enzyme con- stitutes a sensitive indicator of a variety of conditions, including alcohol and drug hepatotoxicity, infiltrative lesions of the liver, parenchymal liver disease, and biliary tract obstruction. Increases are noted after many chemical and drug exposures that are not followed by evidence of liver injury. The confounding ef- fects of alcohol use (often associated with increased GGT) make interpretation of changes in GGT in exposed people difficult (Calvert et al., 1992). An increase in GGT can be considered a normal biologic adaptation to chemical, drug, or hormone exposure. 

OTHER HEALTH EFFECTS 641 Cirrhosis is the most commonly reported liver disease in epidemiologic studies of herbicide or TCDD exposure. Cirrhosis is irreversible chronic injury of the liver with extensive scarring and resulting loss of liver function. Clinical symptoms and signs include jaundice, edema, abnormalities in blood clotting, and metabolic disturbances. Cirrhosis can lead to portal hypertension with associ- ated gastroesophageal varices, enlarged spleen, abdominal swelling attributable to ascites, and ultimately hepatic encephalopathy that can progress to coma. It generally is impossible to distinguish the various causes of cirrhosis by using clinical signs and symptoms or pathologic characteristics. The most common cause of cirrhosis in North America and many parts of Western Europe and South America is excessive alcohol consumption. Other causes are chronic viral infec- tion (hepatitis B or hepatitis C), a poorly understood condition called primary biliary cirrhosis, chronic right-sided heart failure, and a variety of less common metabolic and drug-related causes. Conclusions from VAO and Updates Studies that have been reviewed by previous committees have consisted of those focusing on liver enzymes and others that have reported specific liver dis- eases. Evaluation of the effect of herbicide and TCDD exposure on non-cancer gastrointestinal ailments is challenging in that clinical experience suggests that medical history and physical examination are undependable diagnostic tools for some ailments, so incidence data are sometimes problematic. The strong interde- pendence among the characteristics of a given person (such as weight and labora- tory indexes of hepatic function and health) and TCDD body burden complicates the already difficult task of assessing association. Most of the analyses of occupational or environmental cohorts have had insufficient numbers of cases to support confident conclusions. The one study with a relatively large number of observations (Vena et al., 1998) found lower digestive system disease and cirrhosis mortality among exposed workers than among unexposed controls. A set of studies of Australian veterans suggested a higher incidence of stomach and duodenal ulcers in men and women, but the in- formation was self-reported and the analyses were not controlled for confounding influences. A report on the Ranch Hand study (AFHS, 2000) found a significantly higher percentage of other liver disorders among veterans in the high-dioxin category than among comparisons. The excesses were primarily of transaminase and other nonspecific liver abnormalities. Data were consistent with an interpreta- tion of a dose–response relationship, but other explanations were also plausible. Although there have been sporadic reports of increased gastrointestinal disease potentially related to exposure to herbicides or TCDD, the results are inconsistent among studies. In addition, interpretation of individual studies was generally subject to a lack of information on alcohol consumption and other risk factors. In the studies that showed the strongest association between potential exposure 

642 VETERANS AND AGENT ORANGE: UPDATE 2006 and gastrointestinal disease (specifically cirrhosis), there was strong evidence that excess alcohol consumption was the etiology of the cirrhosis. The committee responsible for VAO concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the compounds of interest and gastrointestinal and digestive disease, including liver toxicity. Additional information available to the committees re- sponsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. Update of the Epidemiologic Literature Occupational Studies ’t Mannetje et al. (2005) completed a mortality study in New Zealand of 813 TCDD-exposed phenoxy herbicide producers and 699 sprayers whose vital status was followed from 1969 and 1973, respectively, to 2000. No increased mortality from diseases of the digestive system were found (ICD-9 530–579) in production workers (SMR 1.3, 95% CI 0.4–3.3) or sprayers (SMR 0.8, 95% CI 0.16–2.34). Environmental Studies Baccarelli et al. (2005b) conducted a case–control study of Seveso residents who had chloracne and were about 8 years old at the time of exposure. They were no more likely to report gastrointestinal disease during the 20-year follow-up period than controls, and no cases of liver disease were reported. Lee et al. (2006) studied the association between fatty liver and hepatic function in residents of the vicinity of a closed pentachlorophenol manufacturing factory (exposure area) and nearby areas (control area). A total of 85 subjects were studied (52 in the exposure area). All subjects were identified from prior investigations of serum PCDD and PCDF measurements. The average serum PCDD and PCDF concentration was 80.1 pg 50.9 pg WHO-TEQ/g of lipid among subjects in the exposure area and 25.5 pg 18.2 pg in subjects in the con- trol area. Statistically higher ORs for fatty liver and GGT were found in subjects with the higher PCDD concentrations and high BMI. Fatty liver was diagnosed with ultrasonographic examination by a senior radiologist blinded to subject sta- tus or PCDD concentration. Diagnostic criteria of fatty liver were “bright liver,” blaring of hepatic vessels and diaphragm, and fat attenuation. With control for a substantial age difference between the groups, the findings suggest a synergistic effect of BMI, serum PCDD, and the risk of fatty liver. 

OTHER HEALTH EFFECTS 643 Vietnam-Veteran Studies Boehmer et al. (2004) in a mortality analysis of the VES reported a crude RR of 1.10 for all deaths from gastrointestinal disease (95% CI 0.73–1.66). Kang et al. (2006) reported 101 hepatitis cases among 1,499 Vietnam vet- erans (adjusted OR 1.85, 95% CI 1.30–2.64). The cases were associated with Vietnam service, being nonwhite, and regular smoking but not with a history of spraying herbicide. Ketchum and Michalek (2005) reported on mortality in Ranch Hand veter- ans. The RR of death caused by disease of the digestive system was not signifi- cantly increased on the basis of small numbers of Ranch Hand deaths (RR 1.6, 95% CI 0.8–3.0). The 2002 examination report of the Ranch Hand cohort (AFHS, 2005) included seven self-reported liver disorders verified by medical-record review, hepatomegaly noted on physical examination, and 28 laboratory measures that are commonly used to assess liver function. No significant increases were found in self-reported liver disorders or hepatomegaly on examination. Several findings were increased among Ranch Hand veterans, including increased occult stool among Ranch Hand officers and decreasing C4 complement as dioxin increased. Increased risk for abnormal alkaline phosphatase and triglyceride level concen- trations were reported in the Ranch Hand ground crew. The percentage of Ranch Hand veterans with abnormal triglyceride concentrations increased significantly as the 1987 dioxin concentration increased. The only regularly reported abnor- mality in liver function associated with TCDD exposure in humans, increased GGT, was not increased in any of the comparisons made in the report. The Australian Vietnam-veterans study (ADVA, 2005b) reported 292 cases of liver disease (SMR 1.03, 95% CI 0.91–1.15) and a subset of 161 cases of alcoholic liver disease (SMR 1.19, 95% CI 1.01–1.38) among military person- nel serving in Vietnam compared to cases of liver disease among the general population of Australia. Biologic Plausibility TCDD effect on the intestine is not well understood. Ishida et al. (2005) ex- amined the effect of dioxin on the pathology and function of the intestine in AhR- sensitive and -less-sensitive mice, after oral administration of TCDD (100 g/kg). C57BL/6J mice showed changes in villous structure and nuclear/cytoplasm ratio in the epithelial cells of the intestine. In an oral glucose tolerance test, the serum glucose level was significantly increased in the C57BL/6J mouse but not in the DBA/2J mouse. The expression of intestinal mRNAs coding sodium-glucose co-transporter 1 (SGLT1) and glucose transporter type 2 were increased only in C57BL/6J mice. The intestinal activity of sucrase and lactase also was signifi- cantly increased in C57BL/6J mice by TCDD. 

644 VETERANS AND AGENT ORANGE: UPDATE 2006 Synthesis There is no evidence that Vietnam veterans are at greatly increased risk for serious liver disease, and reports of increased risk of abnormal liver-function tests have been mixed. Although increased rates of gastrointestinal disease have not been reported, the possibility of a relationship between dioxin exposure and subtle alterations in the liver and in lipid metabolism cannot be ruled out. Conclusion On the basis of its evaluation 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 compounds of interest and gastrointestinal and digestive diseases. CIRCULATORY DISORDERS This section covers a variety of conditions encompassed by ICD-9 390–459, such as acute and chronic rheumatic fever (390–398), hypertension (401–404), ischemic heart disease (410–414), heart failure (428), cerebrovascular disease (430–438), and peripheral vascular disease (443). Coronary heart disease is a specific term related to atherosclerosis; ischemic heart disease is a broader term that typically includes atherosclerosis and its symptoms. The American Heart As- sociation reports mortality related to coronary heart disease, not to its symptoms, which include angina and myocardial infarction. Table 9-2 contains estimates of prevalence and associated mortality in the US population for 2004 for the indi- vidual disorders of the circulatory system. Various methods have been used in morbidity studies to assess the circula- tory system, including analysis of symptoms or history, physical examination of the heart and peripheral arteries, Doppler measurements of peripheral pulses, electrocardiography (ECG), and chest radiography. Doppler measurements and physical examination of pulses in the arms and legs are used to detect decreases in pulse strength, which can be caused by thickening and hardening of the arter- ies. ECG can be used to detect heart conditions and abnormalities, such as ar- rhythmias (abnormal heart rhythms), heart enlargement, and heart attacks. Chest radiography can be used to assess the consequences of ischemic heart disease and hypertension, such as the enlargement of the heart seen with heart failure. How- ever, clinical testing is often nonspecific; similar test results can be observed as a consequence of various medical conditions. A common limitation of mortality studies is that they attribute death to circulatory disorders with various degrees of diagnostic confirmation. 

OTHER HEALTH EFFECTS 645 Conclusions from VAO and 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 compounds of interest and circulatory disorders. Additional infor- mation available to the committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 did not change that conclusion. New studies since Update 2004 and a study not previously discussed with respect to cardiovascular outcomes are reviewed below. In light of the newer findings, the present committee reconsidered all studies related to ischemic heart disease and hypertension that had been discussed in previous updates. Those studies are all summarized in Table 9-5. Update of the Epidemiologic Literature Occupational Studies In a report not previously reviewed for circulatory disorders, Coggon et al. (1991) studied mortality from circulatory diseases at four British herbicide- producing factories that were part of the multinational International Agency for Research on Cancer (IARC) cohort of workers exposed to phenoxy herbicides. There was a non-significant increase in mortality from circulatory diseases over- all (SMR 1.16, 95% CI 0.91–1.46), but the increase was concentrated in Plant A, which had a higher potential for TCDD exposure. A nested case–control study of the Plant A subcohort demonstrated a significant increase in risk among a group of small departments within the plant (RR 6.2, 95% CI 2.3–16.4) with no evident defining common characteristic. In another study of a subcohort of the IARC cohort, mortality records for 1969–2000 were analyzed for New Zealand workers exposed to phenoxy herbi- cides and dioxins (’t Mannetje et al., 2005). In comparison with national rates, they found that mortality from circulatory diseases in production workers was close to the expected (SMR 0.96, 95% CI 0.72–1.27) but significantly lower in sprayers (SMR 0.52, 95% CI 0.36–0.73). There was no significant differ- ence in mortality from specific circulatory diseases, except for ischemic heart disease, which was significantly decreased in sprayers (SMR 0.49, 95% CI 0.31–0.75). McLean et al. (2006) reported on another multinational IARC cohort of 60,468 pulp and paper industry workers. A job–exposure matrix was applied to 58,162 individual work histories to estimate exposure to nonvolatile organochlo- rine compounds (which would include TCDD). Death from circulatory diseases was not more strongly associated with having ever been exposed to nonvolatile organochlorine compounds, including TCDD (SMR 0.99, 95% CI 0.95–1.04), than with having never had this exposure (SMR 0.92, 95% CI 0.89–0.96). That 

TABLE 9-5 Selected Epidemiologic Studies—Circulatory Disorders 646 Exposed Estimated Relative Reference Study Population Cases Risk (95% CI) Comments Studies of Vietnam Veterans Studies on US Army Chemical Corps Kang et al., 2006 Army Chemical Corps—Morbidity and supplemental Vietnam Vets vs Non-Vietnam Vets data Hypertension requiring Rx 496 1.06 (0.89–1.27)b Diagnoses not confirmed Heart disease diagnosed by MD 243 1.09 (0.87–1.38)b by medical record review Sprayers vs Non-sprayers All (diabetics & non-diabetics) Hypertension requiring Rx 247 1.26 (1.00–1.58)b Heart disease diagnosed by MD 129 1.41 (1.06–1.89)b All Veterans, contribution of spraying to logistic regression model All (diabetics & non-diabetics) Hypertension requiring Rx 1.32 (1.08–1.61)b Heart disease diagnosed by MD 1.52 (1.18–1.94)b Non-diabetics only Hypertension requiring Rx 1.23 (0.99–1.52)b Heart disease diagnosed by MD 1.52 (1.14–2.01)b Controlling for diabetic status Hypertension requiring Rx 1.27 (1.04–1.55)c Heart disease diagnosed by MD 1.45 (1.13–1.86)c Thomas and Kang, US Army Chemical Corps vs US male population—Mortality 6 0.55 Not adjusted for known 1990 Circulatory diseases (390–458) risk factors 

Air Force Health Study of Ranch Hand Veterans AFHS, 2005 AFHS, 2002 Exam Cycle Report—Morbidity 1,951 participants in 2002 exam Model 1: RH Subjects vs SEA Comparisons (also available Number in analysis separately for Officer, Enlisted flyer, Enlisted groundcrew) 1,885 Essential hypertension 412 of 759 0.92 (0.53–1.13)a 82% overall 1,902 Heart disease (except essential hypertension) 644 of 767 1.20 (0.94–1.54)a 308 Enlisted flyer 120 of 131 2.46 (1.19–5.11)a 1,902 Myocardial infarction 77 of 767 0.81 (0.59–1.12)a 1,902 Stroke or transient ischemic attack 29 of 767 1.39 (0.82–2.34)a Model 2: RH Subjects with extrapolated initial serum TCDD ( 10 ppt in 1987) 406 Essential hypertension 244 1.12 (0.91–1.37)a Relative risk for a 2x 411 Heart disease (except essential hypertension) 344 1.08 (0.85–1.38)a increase in serum TCDD 411 Myocardial infarction 42 1.31 (0.97–1.77)a 411 Stroke or transient ischemic attack 17 1.26 (0.78–2.03)a Model 3: All Subjects with serum TCDD readings (RH group vs Comp) 1,344 Essential hypertension Comparison 644 1.0 RH background ( 10 ppt, 1987) 168 0.88 (0.67–1.16)a RH low (10–118 ppt, initial) 109 0.74 (0.53–1.04)a RH high ( 118 ppt, initial) 135 1.32 (0.94–1.87)a 1,355 Heart disease (except essential hypertension) Comparison 937 1.0 RH background ( 10 ppt, 1987) 299 1.33 (0.94–1.89)a RH low (10–118 ppt, initial) 171 1.03 (0.68–1.54)a RH high ( 118 ppt, initial) 173 1.21 (0.81–1.82)a 647 continued 

TABLE 9-5 Continued 648 Exposed Estimated Relative Reference Study Population Cases Risk (95% CI) Comments 1,355 Myocardial infarction Comparison 132 1.0 RH background ( 10 ppt, 1987) 34 0.81 (0.53–1.25)a RH low (10–118 ppt, initial) 18 0.60 (0.34–1.04)a RH high ( 118 ppt, initial) 24 1.04 (0.63–1.74)a 1,355 Stroke or transient ischemic attack Comparison 36 1.0 RH background ( 10 ppt, 1987) 12 1.21 (0.59–2.45)a RH low (10–118 ppt, initial) 7 1.10 (0.47–2.57)a RH high ( 118 ppt, initial) 10 2.16 (0.98–4.77)a Model 4: RH Subjects with 1987 serum TCDD readings 748 Essential hypertension 1.11 (0.98–1.25)a Relative risk for a 2x 755 Heart disease (except essential hypertension) 0.90 (0.78–1.06)a increase in serum TCDD 755 Myocardial infarction 1.03 (0.85–1.24)a 755 Stroke or transient ischemic attack 1.04 (0.76–1.44)a AFHS, 2000 Operation Ranch Hand—Results of 1997 exam [largely superseded Hypertension—medical record review by AFHS, 2005] Model 3: RH high TCDD vs background 1.27 (0.93–1.74)a Relative risk for a 2x Model 4: RH Vets 1987 serum TCDD 1.18 (1.04–1.34)a increase in serum TCDD AFHS, 1995 Operation Ranch Hand—Results of 1992 exam [largely superseded Hypertension—medical record review by AFHS, 2005] Model 3: RH high TCDD vs background 1.20 (0.88–1.63)a Relative risk for a 2x Model 4: RH Vets 1987 serum TCDD 1.14 (1.02–1.28)a increase in serum TCDD 

Wolfe et al., 1992 Operation Ranch Hand—Results of 1987 exam—Morbidity [largely Essential hypertension superseded; Model 3: RH high TCDD vs background NR Increase (p 0.05) summary of results Verified heart disease (w/o HT) in AFHS, 1991b] Model 4: RH high TCDD vs background NR Decrease (p 0.05) AFHS, 1990 Operation Ranch Hand—Results of 1987 exam [largely superseded Model 1: before analyses on serum TCDD levels by AFHS, 2005] All verified by medical record review Essential hypertension 297 1.07 (0.89–1.29)a Heart disease (w/o HT) 337 1.06 (0.88–1.26)a Myocardial infarction 39 0.96 (0.63–1.47)a AFHS, 1987 Operation Ranch Hand—Results of 1985 exam [largely superseded Model 1: before analyses on serum TCDD levels by AFHS, 2005] All verified by medical record review Essential hypertension 195 1.03 (0.83–1.27)a Heart disease (w/o HT) 224 1.22 (1.00–1.50)a Myocardial infarction 9 0.88 (0.38–2.08)a AFHS, 1984 Operation Ranch Hand—Results of 1982 baseline exam [largely superseded Model 1: before analyses on serum TCDD levels by AFHS, 2005] All verified by medical record review Heart disease 147 p 0.982 Myocardial infarction 7 p 0.432 649 continued 

TABLE 9-5 Continued 650 Exposed Estimated Relative Reference Study Population Cases Risk (95% CI) Comments Ketchum and AFHS—Circulatory disease—mortality Michalek, 2005 Ranch Hand Subjects vs all SEA veterans 66 1.3 (1.0–1.6) Not adjusted for known [Supersedes Pilots and navigators 18 1.1 (0.7–1.8) risk factors Michalek et al., Administrative Officers 2 1.8 (0.4–7.8) 1990, 1998] Enlisted Flight Engineers 6 0.5 (0.2–1.1) Ground Crew 40 1.7 (1.2–2.4) Atherosclerosis 28 1.7 (1.1–2.5) Hypertensive disease 2 2.5 (0.6–10.8) Stroke 5 2.3 (0.9–6.0) AFHS Veterans with serum TCDD SEA comparison group 31 1.0 Background (0.6–10 ppt) 8 0.8 (0.4–1.8)d Low (10–29.2 ppt) 12 1.8 (0.9–3.5)d High (18–617.8 ppt) 9 1.5 (0.7–3.3)d Watanabe and US Army and Marine Corps Vietnam-era veterans—Mortality Kang, 1996 (PMR, 1965–1988) Served in Vietnam vs never deployed to SEA Circulatory diseases (390–458) Army 5,756 0.97 (p 0.05) Not adjusted for known Marine Corps 1,048 0.92 (p 0.05) risk factors Bullman and Kang, US wounded Vietnam veterans vs US men—Mortality (through 1996 1981, focus on suicide) Circulatory disease 246 0.72 (0.55–0.91) 

Boehmer et al., CDC Vietnam Experience Study—Mortality 2004 Deployed vs non-deployed Circulatory disease 185 1.01 (0.82–1.24) Year of death 1970–1984 NR 0.56 (0.28–1.15)e 1985–2000 NR 1.06 (0.85–1.32)e Discharged before 1970 NR 0.83 (0.62–1.12)e Partition at 1970 arbitrary Discharged after 1970 NR 1.43 (1.02–1.99)e Ischemic heart diseases 125 0–15 years since discharge 8 0.77 (0.31–1.55) 15 years since discharge 117 1.14 (0.87–1.50) CDC, 1988 Vietnam Experience Study—Morbidity Deployed vs non-deployed Hypertension postdischarge Interviewed 2,013 1.3 (p 0.05) Not adjusted for known Examined 623 1.2 (p 0.05) risk factors Stellman et al., American Legionnaires serving during 1988 Vietnam-era—Morbidity Service in SEA vs not, with medically diagnosed High blood pressure 592 1.12 (p 0.05) Not age adjusted Heart disease 97 1.45 (p 0.05) Age adjusted 651 continued 

TABLE 9-5 Continued 652 Exposed Estimated Relative Reference Study Population Cases Risk (95% CI) Comments Anderson et al., Wisconsin Vietnam veterans—all diseases of circulatory 1986 system—Mortality White male Vietnam veterans vs 100 National population 0.69 (p 0.05) State population 0.62 (p 0.05) Non-veterans 0.58 (p 0.05) All veterans 0.86 (p 0.05) Vietnam-era veterans 0.99 (0.80–1.20) Kogan and Clapp, Massachusetts Vietnam-era veterans (1958–1973)—Mortality 1985 (1972–1983) Deployed vs non-deployed Deaths 1972–1983 Not adjusted for age; Circulatory system (except cerebrovascular) 139 PMR 0.88 (p 0.05) Vietnam veterans thought Cerebrovascular 28 PMR 1.11 (p 0.05) to be younger Deaths 1978–1983 Circulatory system (except cerebrovascular) 85 PMR 0.80 (p 0.05) Expect less “diluted” Cerebrovascular 19 PMR 1.64 (p 0.05) effect for later time? Studies of Austrian Vietnam Veterans ADVA, 2005b Australian Vietnam Veterans vs General Male Population—Mortality Circulatory disease 1,767 0.88 (0.84–0.92) Dissipation of healthy 1963–1979 186 0.69 (0.59–0.79) worker effect perhaps 1980–1990 546 0.88 (0.80–0.95) 1991–2001 1,035 0.93 (0.87–0.99) 

Ischemic heart disease 1,297 0.94 (0.89–0.99) 1963–1979 124 0.70 (0.58–0.82) 1980–1990 421 0.95 (0.86–1.04) 1991–2001 753 0.99 (0.92–1.06) Stroke 223 0.80 (0.70–0.91) 1963–1979 35 0.81 (0.54–1.07) 1980–1990 59 0.73 (0.54–0.92) 1991–2001 129 0.83 (0.69–0.97) ADVA, 2005c Australian National Service Veterans Deployed vs Non-deployed—Mortality Circulatory disease 208 1.05 (0.87–1.27) Ischemic heart disease 159 1.18 (0.94–1.47) Stroke 15 0.61 (0.30–1.15) Crane et al., 1997a Australian Vietnam Veterans—Mortality (1980–1994) [largely superseded Circulatory disease 0.96 (0.88–1.05) Not adjusted for known by ADVA, 2005b] Ischemic heart disease 1.04 (0.94–1.14) risk factors Cerebral hemorrhage 0.80 (0.53–1.22) Crane et al., 1997b Australian National Service Vietnam-era veterans—Mortality [largely superseded (1982–1994) by ADVA, 2005c] Deployed vs non-deployed Circulatory disease 77 0.95 (0.70–1.28) Not adjusted for known Ischemic heart disease 57 0.97 (0.68–1.39) risk factors Cerebral hemorrhage 3 0.96 (0.14–5.66) Other 17 0.88 (0.44–1.69) 653 continued 

TABLE 9-5 Continued 654 Exposed Estimated Relative Reference Study Population Cases Risk (95% CI) Comments O’Toole et al., Australian male Army Vietnam veterans (random 1996 sample)—Morbidity Self-report in telephone interview 99% CIs Hypertension NR 2.08 (1.63–3.31) Not adjusted for known Heart disease NR 2.02 (0.96–4.77) risk factors Other circulatory diseases (excluding above & hemorrhoids) NR 2.07 (1.35–3.97) Self-report in telephone interview (adjusted for non-response) 99% CIs Hypertension NR 2.17 (1.71–2.62) Not adjusted for known Heart disease NR 1.98 (0.91–3.05) risk factors Other circulatory diseases (excluding above & hemorrhoids) NR 2.39 (1.61–3.17) Kim et al., 2003 Korean veterans of Vietnam—Morbidity Deployed vs Non-deployed (unadjusted) Valvular heart disease 8 p 0.0019 Concerns of selection Congestive heart failure 5 p 0.5018 bias, quality of diagnosis, Ischemic heart disease 34 p 0.0045 low participation, gross Hypertension 383 p 0.0143 pooling of blood samples Adjusted for risk factors 2.29 (1.33–3.95)g made TCDD levels useless Occupational Studies McLean et al., IARC Cohort of pulp and paper workers—Circulatory 2006 disease—Mortality Never exposed to nonvolatile organochlorines 2,727 0.92 (0.89–0.96) Not adjusted for known Ever exposed to nonvolatile organochlorines 2,157 0.99 (0.95–1.04) risk factors 

Blair et al., 2005a Agricultural Health Study—Mortality Private applicators (farmers) and spouses Circulatory disease (1994–2000) 619 0.5 (0.5–0.6)f ’t Mannetje et al., New Zealand phenoxy herbicide workers—Mortality Not adjusted for known 2005 risk factors Producers (1969–2000) [IARC subcohort] Circulatory disease 51 1.0 (0.7–1.3) All causes SMR 1.0 Hypertensive disease 0 0.0 (0.0–3.5) (0.8–1.2) Ischemic heart disease 38 1.0 (0.7–1.4) Sprayers (1973–2000) Circulatory disease 33 0.5 (0.4–0.7) All causes SMR 0.6 Hypertensive disease 1 0.8 (0.0–4.5) (0.5–0.8) Ischemic heart disease 22 0.5 (0.3–0.8) Vena et al., 1998 IARC Cohort of phenoxy herbicide workers—Mortality [same dataset as (1939–1992) Kogevinas et al., All male phenoxy herbicide workers 1997 (emphasis on All circulatory disease (390–459) 1,738 0.91 (0.87–0.95) Not adjusted for known cancer) reviewed in Ischemic heart disease (410–414) 1,179 0.92 (0.87–0.98) risk factors Update 1998] Cerebrovascular disease (430–438) 254 0.86 (0.76–0.97) Other diseases of the heart (415–429) 166 1.11 (0.95–1.29) All female phenoxy herbicide workers All circulatory disease (390–459) 48 1.00 (0.73–1.32) Not adjusted for known Ischemic heart disease (410–414) 24 1.07 (0.68–1.59) risk factors Cerebrovascular disease (430–438) 9 0.73 (0.33–1.38) Other diseases of the heart (415–429) 6 0.92 (0.34–2.00) 655 continued 

TABLE 9-5 Continued 656 Exposed Estimated Relative Reference Study Population Cases Risk (95% CI) Comments Workers with phenoxy herbicide exposure only All circulatory disease (390–459) 588 0.86 (0.79–0.93) Not adjusted for known Ischemic heart disease (410–414) 394 0.85 (0.77–0.94) risk factors Cerebrovascular disease (430–438) 96 0.86 (0.70–1.05) Other diseases of the heart (415–429) 32 0.80 (0.55–1.13) TCDD-exposed workers All circulatory disease (390–459) 1,170 0.94 (0.88–0.99) Not adjusted for known Ischemic heart disease (410–414) 789 0.97 (0.90–1.04) risk factors Cerebrovascular disease (430–438) 162 0.84 (0.71–0.98) Other diseases of the heart (415–429) 138 1.20 (1.01–1.42) Contribution of TCDD exposure to Poisson regression analysis All circulatory disease 1,151 1.51 (1.17–1.96) Only adjusted for age and Ischemic heart disease 775 1.67 (1.23–2.26) timing of exposure Cerebrovascular disease 161 1.54 (0.83–2.88) Hooiveld et al., Dutch herbicide factory workers (IARC subcohort)—Mortality 1998 (1955–1991) 549 exposed vs 482 non-exposed male workers All circulatory diseases (390–459) 45 1.4 (0.8–2.5) Only adjusted for age and 124 ng/kg TCDD NR 1.5 (0.8–2.9) timing of exposure Ischemic heart diseases (410–414) 33 1.8 (0.9–3.6) 124 ng/kg TCDD NR 2.3 (1.0–5.0) Cerebrovascular diseases (430–438) 9 1.4 (0.4–5.1) 124 ng/kg TCDD NR 0.8 (0.2–4.1) Other heart disease (415–429) 3 0.7 (0.1–4.3) 124 ng/kg TCDD NR 0.4 (0.0–4.9) 

Flesch-Janys, Hamburg, Germany herbicide production workers vs national Potential for exposure 1997/1998 (TEQ FRG population (IARC subcohort)—Mortality (1952–1992; misclassification info); estimated of PCDD/F and TCDD blood levels from work history Flesch-Janys et al., and measures on 190 of 1,189 men, divided into 4 lowest quintiles 1998 (in German, & top 2 deciles) also TCDD info) Estimated final PCDD/F TEQs (ng/kg) Circulatory disease (390–459) 156 1.06 (0.90–1.24) Not adjusted for known 1.0–12.2 0.71 (0.44–1.17) risk factors 12.3–39.5 0.73 (0.46–1.16) 39.6–98.9 1.20 (0.82–1.76) 99.0–278.5 1.22 (0.84–1.78) 278.6–545.0 1.18 (0.73–1.92) 545.1–4361.9 1.70 (1.02–2.85) p-trend 0.04 Ischemic heart disease (410–414) 76 0.97 (0.77–1.22) 1.0–12.2 0.80 (0.42–1.56) 12.3–39.5 0.76 (0.40–1.45) 39.6–98.9 0.75 (0.40–1.42) 99.0–278.5 0.88 (0.50–1.58) 278.6–545.0 1.26 (0.67–2.39) 545.1–4361.9 2.17 (1.18–4.00) p-trend 0.03 Estimated final TCDD (ng/kg) Circulatory disease (390–459) 156 1.06 (0.90–1.24) 0–2.8 0.94 (0.62–1.43) Not adjusted for known 2.81–14.4 0.69 (0.42–1.14) risk factors 14.5–49.2 1.13 (0.75–1.68) 49.3–156.7 1.29 (0.88–1.89) 156.8–344.6 1.10 (0.69–1.78) 344.7–3890.2 1.62 (0.95–2.77) p-trend 0.04 657 continued 

TABLE 9-5 Continued 658 Exposed Estimated Relative Reference Study Population Cases Risk (95% CI) Comments Ischemic heart disease (410–414) 76 0.97 (0.77–1.22) 0–2.8 1.13 (0.65–1.95) 2.81–14.4 0.63 (0.31–1.27) 14.5–49.2 0.94 (0.51–1.73) 49.3–156.7 0.70 (0.36–1.36) 156.8–344.6 1.17 (0.61–2.23) 344.7–3890.2 1.99 (1.05–3.75) p-trend 0.10 Flesch-Janys et al., Hamburg, German herbicide production workers vs gas 1995 workers (IARC subcohort)—Mortality Estimated final PCDD/F TEQs (ng/kg) Circulatory disease (390–459) 156 Not adjusted for known 1.0–12.2 0.93 (0.57–1.50) risk factors 12.3–39.5 0.92 (0.59–1.46) 39.6–98.9 1.48 (1.01–2.17) 99.0–278.5 1.55 (1.07–2.24) 278.6–545.0 1.63 (1.01–2.64) 545.1–4361.9 2.06 (1.23–3.45) p-trend 0.01 Ischemic heart disease (410–414) 76 1.0–12.2 1.02 (0.54–1.95) 12.3–39.5 0.96 (0.51–1.82) 39.6–98.9 0.97 (0.52–1.81) 99.0–278.5 1.13 (0.64–2.00) 278.6–545.0 1.73 (0.92–3.27) 545.1–4361.9 2.72 (1.49–4.98) p-trend 0.01 

Estimated final TCDD (ng/kg) Circulatory disease (390–459) 156 1.22 (0.81–1.83) Not adjusted for known 0–2.8 0.88 (0.54–1.44) risk factors 2.81–14.4 1.35 (0.91–2.01) 14.5–49.2 1.64 (1.12–2.39) 49.3–156.7 1.53 (0.95–2.44) 156.8–344.6 1.96 (1.15–3.34) 344.7–3890.2 p-trend 0.01 Ischemic heart disease (410–414) 76 1.43 (0.83–2.44) 0–2.8 0.81 (0.41–1.61) 2.81–14.4 1.18 (0.65–2.16) 14.5–49.2 0.90 (0.47–1.75) 49.3–156.7 1.61 (0.85–3.04) 156.8–344.6 2.48 (1.32–4.66) 344.7–3890.2 p-trend 0.01 Becher et al., 1996 Phenoxy herbicide workers at 4 German plants (4 IARC [mortality subcohorts, including Hamburg)–Flesch-Janys)—Mortality through 1992 (through 1989) for I. Hamburg Circulatory diseases (390–458) reported above by Bayer Uerdingen 12 0.74 (0.38–1.30) Flesch-Janys] Bayer Dormagen 3 0.34 (0.07–0.99) BASF Ludwigshafen 32 0.78 (0.53–1.10) Coggon et al., 1991 British Chemical Manufacturers from 4 Plants (4 IARC subcohorts)—Mortality Circulatory disease 74 1.16 (0.91–1.46) Plant A (1975–1987) 1.67 (adjusted 1.39, 34 p 0.05) Plant B (1969–1987) 5 0.95 Plant C (1963–1987) 12 0.84 659 Plant D (1969–1987) 23 0.97 continued 

TABLE 9-5 Continued 660 Exposed Estimated Relative Reference Study Population Cases Risk (95% CI) Comments Coggon et al., 1986 British MCPA manufacturers (5th of 7 UK IARC cohorts)—Mortality Hypertensive & ischemic heart disease (401–414, 428–429) 337 Vs national rates 0.81 (0.73–0.90) With rural adjustment 0.86 (0.77–0.96) US Cohorts in NIOSH Cohort (and also in IARC Cohort) Burns et al., 2001 Dow 2,4-D production workers—Mortality (1945–1994) [part of IARC and Circulatory disease NIOSH cohorts] 0 years latency 158 0.95 (0.80–1.11) Not adjusted for known 20 years latency 130 1.05 (0.87–1.24) risk factors Ramlow et al., Dow PCP workers (1930–1980) (subcohort)—Mortality 1996 (1940–1989) Circulatory diseases (390–458) 115 0.95 (0.79–1.14) Arteriosclerotic heart disease (410–414) 86 1.02 (0.82–1.26) Cerebrovascular disease (430–438) 15 1.02 (0.57–1.68) Steenland et al., NIOSH Cohort (subcohorts of IARC cohort from 12 US 1999 plants)—Mortality (through 1993) 

Total Cohort (5,132) vs US population Cerebrovascular disease (430–438) 0.96 (0.74–1.21) Not adjusted for known Ischemic heart disease (410–414) 69 1.09 (1.00–1.20) risk factors Chloracne subcohort (608) vs US population 456 1.17 (0.94–1.44) Exposure subcohort (3,538) 92 19 cumulative TCDD 1.0 Adjusted for age 19–139 NR 1.23 (0.75–2.00) 139–580 NR 1.34 (0.83–2.18) 581–1,649 NR 1.30 (0.79–2.13) (no units for JEM-derived 1,650–5,739 NR 1.39 (0.86–2.24) exposure) 5,740–20,199 NR 1.57 (0.96–2.56) 20,200 NR 1.75 (1.07–2.87) NR p-trend cum expo 0.05 p-trend log[cum expo] 0.001 Calvert et al., 1998 2 US Chemical Plants (part of NIOSH and IARC cohorts)—Morbidity Verified conditions TCDD-exposed (281) vs unexposed (260) Myocardial infarction 17 1.33 (0.62–2.84) Not adjusted for known Current systolic hypertension 64 1.05 (0.70–1.58) risk factors Current diastolic hypertension 77 1.23 (0.83–1.82) TCDD effect vs unexposed in logistic model Self-reported and verified conditions combined Myocardial infarction Serum TCDD 238 pg/g lipid NR 1.14 (0.29–4.49)i Serum TCDD 238 pg/g lipid NR 1.09 (0.23–5.06)i 661 continued 

TABLE 9-5 Continued 662 Exposed Estimated Relative Reference Study Population Cases Risk (95% CI) Comments Hypertension Serum TCDD 238 pg/g lipid NR 1.34 (0.89–2.02)i Serum TCDD 238 pg/g lipid NR 1.05 (0.58–1.89)i Verified conditions Current systolic hypertension Serum TCDD 238 pg/g lipid NR 1.09 (0.65–1.83)i Serum TCDD 238 pg/g lipid NR 1.20 (0.61–2.34)i Current diastolic hypertension Serum TCDD 238 pg/g lipid NR 1.35 (0.88–2.09)i Serum TCDD 238 pg/g lipid NR 0.97 (0.51–1.87)i Suskind and Monsanto workers at Nitro, WV—Morbidity Hertzberg, 1984 Workers exposed to 2,4,5-T production (n 204) vs not exposed (n 163) (self-report) Hypertension 70 (p 0.05) Adjusted for age Coronary artery disease 22 (p 0.05) Zack and Gaffey, Monsanto workers at Nitro, WV (n 884)—Mortality 1983 (1955–1977) Circulatory diseases (390–458) 92 1.11 (p 0.05) Not adjusted for known Atherosclerosis and CHD (410–413) 79 1.33 (p 0.05) risk factors All other 13 0.56 (p 0.05) Zack and Suskind, Monsanto workers at Nitro, WV—Mortality (1955–1978) 1980 Workers with chloracne (n 121) Circulatory diseases (390–458) 17 0.68 (p 0.05) Not adjusted for known Atherosclerosis and CHD (410–413) 13 0.73 (p 0.05) risk factors 

Swaen et al., 2004 Dutch licensed herbicide applicators—Mortality (1980–2000) [supersedes Swaen Circulatory disease 70 0.68 (0.53–0.86) et al., 1992] Ott and Zober, Clean-up workers at German TCP reactor (BASF)—Mortality 1996 (1953–1992) [supersedes Zober Circulatory diseases 37 0.8 (0.6–1.2) Reliability of estimated et al., 1994 & Von 0.1 estimated TCDD g/kg bw 13 0.8 (0.4–1.4) body burden? Benner et al., 1994 0.1–0.99 11 1.0 (0.5–1.7) (translation from 1.0 German)] 13 0.8 (0.4–1.3) Ischemic heart disease 16 0.7 (0.4–1.1) 0.1 estimated TCDD g/kg bw 7 0.9 (0.3–1.8) 0.1–0.99 4 0.7 (0.2–1.7) 1.0 5 0.6 (0.2–1.3) Other Occupational Studies Kitamura K et al., Municipal waste incinerator workers—Morbidity 2000 Hypertension by PCDD/PCDF levels 14 of 94 No increases observedh Gambini et al., Italian rice growers—Mortality (1957–1992) 1997 (Phenoxy herbicide use common 1960–1980) Myocardial infarction 67 0.72 (0.56–0.92) Other ischemic heart diseases 72 0.41 (0.32–0.52) Stroke 155 0.96 (0.81–1.12) Alavanja et al., US forest and soil conservationists—Mortality PMRs Not adjusted for known 1989 risk factors Ischemic heart disease (410–414) 543 1.0 (0.9–1.1) Cerebrovascular disease (430–438) 99 0.9 (0.8–1.1) 663 continued 

TABLE 9-5 Continued 664 Exposed Estimated Relative Reference Study Population Cases Risk (95% CI) Comments Blair et al., 1983 Florida, US licensed pesticide applicators—Mortality Circulatory diseases (390–458) 159 0.88 (p 0.05) Not adjusted for known risk factors Environmental Studies Chen et al., 2006 Residents around 12 municipal waste incinerators in Taiwan—Prevalence Hypertension diagnosed by a physician 118 5.6 (1.6–19.6) Serum PCDD/PCDF levels 0.9 (0.2–3.7)j (international TEQs in logistic model) Bertazzi et al., Seveso, Italy—Mortality–20 yr (1976–1996) 2001 Zones A and B, sexes combined [supersedes All circulatory diseases (390–459) 265 1.0 (0.8–1.1) Adjusted for age and Pesatori et al., Chronic rheumatic heart diseases (393–398) 3 0.9 (0.3–3.0) gender only 1998, Bertazzi et Hypertensive vascular disease (401–405) 9 0.6 (0.3–1.2) al., 1989a,b, 1998] Ischemic heart diseases (410–414) 97 1.0 (0.8–1.2) Acute myocardial infarction (410) 50 0.8 (0.6–1.1) Chronic ischemic heart diseases (412, 414) 46 1.2 (0.9–1.6) Cerebrovascular diseases (430–438) 88 1.1 (0.9–1.3) 

a Adjusted for age, race, rank, smoking, alcohol history, cholesterol, HDL, cholesterol-HDL ratio, uric acid, diabetes, BMI or percent body fat, waist-to-hip ratio, and family history of heart disease. b Adjusted for age, race, rank, BMI, and smoking. c Adjusted for age, race, rank, BMI, smoking, and diabetes. d Adjusted for smoking and family history of heart disease. e Adjusted for age, race, and military occupation. f Adjusted for age, race, state, sex, and calendar year of death. g Adjusted for age, smoking, alcohol, BMI, education, and martial status. h Adjusted for age, BMI, and smoking. i Adjusted for age, sex, BMI, smoking, drinking, diabetes, triglycerides, total cholesterol, HDL, family history of heart disease, and which plant. j Adjusted for age, sex, BMI, and smoking. NR, Not reported. 665 

666 VETERANS AND AGENT ORANGE: UPDATE 2006 the confidence intervals scarcely overlap raises the possibility that exposure to TCDD counters the expected healthy-worker effect. Blair et al. (2005a) analyzed mortality records for 1994–2000 for participants of the AHS, which included licensed pesticide applicators and their spouses. Mortality from circulatory diseases was significantly lower (SMR 0.5, 95% CI 0.5–0.6) than in the general population. Furthermore, the reduction in SMR for circulatory diseases remained significant after control for the effects of farm size, years of handling pesticides, presence of farm animals, and whether corn was grown on the farm. That finding is consistent with the noncomparability of a rural working population with the general population (the healthy-worker effect). Environmental Studies Chen et al. (2006) investigated the prevalence of hypertension in Taiwanese residents who lived near municipal-waste incinerators for at least 5 years. Health information was obtained with an interviewer-administered questionnaire for which people were asked about their medical histories, including physician- diagnosed high blood pressure, and serum samples were collected for analysis of PCDDs and PCDFs. A logistic regression analysis showed that the incidence of hypertension was significantly associated with serum PCDD and PCDF con- centrations on the basis of international TEQs (OR 5.58, 95% CI 1.63–19.62). However, the incidence of hypertension was no longer increased when the model was adjusted for age, sex, smoking status, and BMI (OR 0.91, 95% CI 0.23– 3.73). Furthermore, the significant increases in PCDDs and PCDFs in older subjects, in women, and in passive smokers and the marginally significant (p 0.075) increase with BMI demonstrate that PCDD and PCDF concentrations co- vary with hypertension risk factors. Vietnam-Veteran Studies A 30-year follow-up study was conducted on post-service mortality from the date of discharge through 2000 for the Army Vietnam veterans in CDC’s cohort for the VES. Boehmer et al. (2004) compared mortality rates in those deployed to Vietnam with those in non-deployed Vietnam-era veterans. Mortality from circulatory diseases was lower, but not significantly, among Vietnam veterans in the first 15 years after discharge (RR 0.56, 95% CI 0.28–1.15) and was more comparable with that among the non-deployed men in the 15- to 30-year follow-up period (RR 1.06, 95% CI 0.85–1.32). Analysis of only the 15- to 30- year period after discharge revealed that mortality from circulatory diseases was increased among Veterans discharged after 1970 (RR 1.43, 95% CI 1.02–1.99) but not among those discharged before 1970 (RR 0.83, 95% CI 0.62–1.12); it is unclear how to interpret this finding. The Australian DVA (ADVA, 2005b) reported a significantly lower mortal- 

OTHER HEALTH EFFECTS 667 ity from circulatory diseases among Australian Vietnam veterans than among the male Australian population (SMR 0.88, 95% CI 0.84–0.92). More specifi- cally, the reduction associated with stroke was stronger (SMR 0.80, 95% CI 0.70–0.91), and the reduction associated with ischemic heart disease was less pronounced over the entire observation period (SMR 0.94, 95% CI 0.89–0.99) and was no longer evident after 1980 (see Table 9-5). When the data were ana- lyzed for each of the three branches of service, Army and Air Force veterans exhibited a significant reduction in mortality from all circulatory diseases, which was reflected by decreases in mortality from stroke among Army veterans and from ischemic heart disease among Air Force veterans. Navy veterans did not exhibit any differences in circulatory-disease mortality. It is also notable that the reduction in circulatory-disease mortality in Australian Vietnam veterans was most apparent from 1963 to 1979 (SMR 0.69, 95% CI 0.59–0.79), less appar- ent from 1980 to 1990 (SMR 0.88, 95% CI 0.80–0.95), and nearly equivalent to that in the general male population from 1991 to 2001 (SMR 0.93, 95% CI 0.87–0.99). As in the CDC VES (Boehmer et al., 2004), the change in mortal- ity over time could reflect the fading of a “healthy-warrior effect” as the cohort matures. As noted above, however, although the pattern was clear for ischemic heart disease, there was no such trend for mortality from stroke. In a parallel study, the Australian DVA (ADVA, 2005c) reported the RR of death from all circulatory diseases in Vietnam-era Australian National Service veterans, comparing those deployed to those not deployed to Vietnam. The rate of death from all circulatory diseases did not differ between the deployed and non- deployed (RR 1.05, 95% CI 0.87–1.27), whereas among the deployed veterans the rate of death from ischemic heart disease was non-significantly higher (RR 1.18, 95% CI 0.94–1.47) and that from stroke was non-significantly lower (RR 0.61, 95% CI 0.30–1.15). Ketchum and Michalek (2005) assessed the cumulative post-service mortal- ity from 1982 to 1999 in veterans of Operation Ranch Hand. When all Ranch Hand veterans were considered as a group, mortality from circulatory diseases was marginally higher (RR 1.3, 95% CI 1.0–1.6) than in Vietnam-era Air Force veterans who did not spray herbicides. However, in analyses that were restricted to enlisted ground crew, Ranch Hand veterans had increased mortal- ity from circulatory diseases (RR 1.7, 95% CI 1.2–2.4). When mortality from circulatory diseases in all enlisted ground crew was divided into five categories (atherosclerotic heart disease, cardiomyopathy, stroke, hypertension, and other), only mortality from atherosclerotic heart disease, which accounted for most of the deaths, was significantly higher in the Ranch Hand personnel (RR 1.7, 95% CI 1.1–2.5). Ketchum and Michalek (2005) also analyzed mortality in a subgroup of 1,016 Ranch Hand veterans and 1,436 Vietnam-era comparison veterans who had at least one physical examination during 1982–1997 and had their serum dioxin measured. Potential risk factors were also assessed, including smoking, alcohol 

668 VETERANS AND AGENT ORANGE: UPDATE 2006 consumption, and family history of heart disease. When categorized according to serum TCDD concentration, mortality from circulatory diseases was non- significantly higher in the Ranch Hand veterans in the low-TCDD group (RR 1.8, 95% CI 0.9–3.5) and the high-TCDD group (RR 1.5, 95% CI 0.7–3.3). In the final examination cycle of Ranch Hand veterans by the US Air Force (AFHS, 2005), cardiovascular diseases were identified through medical-record verification of questionnaire data and physical examination and were classified into four conditions based on ICD-9: essential hypertension (401), heart disease excluding essential hypertension (391, 392, 393–398, 402, 404, and 410–429), myocardial infarction (410 and 412), and stroke or transient ischemic attack (435.0[sic]–436). Participants who had verified heart conditions before service in Southeast Asia were excluded. Covariates used in the adjusted analyses of the cardiovascular assessment included age, race, military occupation, smoking his- tory, alcohol-consumption history, uric acid, BMI, waist-to-hip ratio, cholesterol, HDL, cholesterol-to-HDL ratio, family history of heart disease, diabetes mellitus, and use of blood-pressure medication. The analyses revealed a significant positive association between essential hypertension and 1987 serum dioxin concentration for all Ranch Hand veterans (unadjusted RR 1.18, 95% CI 1.08–1.29), which remained after adjustment for covariates (adjusted RR 1.11, 95% CI 0.98–1.25). The relative risk of heart disease excluding essential hypertension in all Ranch Hand veterans was not associated with 1987 serum dioxin concentrations (ad- justed RR 0.90, 95% CI 0.78–1.06). In a separate study, Kang et al. (2006) assessed the incidence of hypertension and heart disease in 1,499 US ACC veterans who handled or sprayed Agent Or- ange in Vietnam and 1,428 veterans from the same era who did not serve in Viet- nam. Health information was gathered through telephone interviews that asked whether a medical doctor had diagnosed any type of heart condition, including coronary arterial disease, angina pectoris, myocardial infarction, and heart attack. In addition, the veterans were asked whether a medical doctor had diagnosed hypertension, whether a doctor had recommended weight loss or prescription medicine for the hypertension, and in what year the diagnosis and/or therapy had begun. Of the individual heart conditions that were reported, 68 percent of the cases were in the category of ischemic heart disease (ICD-9 410–414), includ- ing myocardial infarction, coronary arterial disease, and surgery required for coronary arterial disease (Kang, personal communication). The accuracy of self- reports of chronic medical conditions was supported by medical-record review, which confirmed 79 percent of self-reported diabetes diagnoses. When the entire cohort was considered, the prevalence of neither hyper- tension nor heart disease was significantly associated with service in Vietnam. However, in analyses restricted to ACC veterans who served in Vietnam, men who reported having sprayed exhibited a higher incidence of hypertension (adjusted OR 1.26, 95% CI 1.00–1.58) and a significantly increased incidence of heart disease (adjusted OR 1.41, 95% CI 1.06–1.89) than veterans who did not report 

OTHER HEALTH EFFECTS 669 spraying herbicides. In an effort to evaluate the possibility of over-reporting of medical conditions among former sprayers compared with non-sprayers, the ana- lysts compared prevalence proportions in subsets of sprayers who were grouped according to a serum TCDD concentration obtained after the study interviews. Those who had serum TCDD above the median (2.5 ppt) had reported a greater prevalence of heart conditions (22.9 percent vs 15.7 percent; two-sided p 0.08) and of hypertension (43.6 percent vs 33.7 percent; two-sided p 0.05) than had those who had lower serum TCDD. In contrast no such difference in frequency of reporting of, for instance, respiratory problems, was associated with serum TCDD concentration. To evaluate whether service in Vietnam itself was responsible for the higher prevalence of hypertension and heart conditions in the ACC veterans, Kang et al. (2006) conducted a logistic regression analysis that included deployed and non-deployed veterans. In a model containing Vietnam service and herbicide spraying, service in Vietnam was not independently associated with hyperten- sion or heart disease; herbicide spraying, however, was a significant covariate with adjusted ORs of 1.32 (95% CI 1.08–1.61) for hypertension and 1.52 (95% CI 1.18–1.94) for heart disease. The analysis included adjustment for age, race, BMI, and smoking. Because there is suggestive evidence of an association between exposure to herbicides in Vietnam and type 2 diabetes (IOM, 2005) and diabetes is a major risk factor for hypertension and heart disease, additional analyses were conducted to elucidate the degree to which hypertension and heart disease may have been at- tributable to diabetes in the ACC cohort (Kang, personal correspondence). When a logistic regression analysis was conducted on only non-diabetic ACC veterans, herbicide spraying was associated with the prevalence of heart disease (OR 1.52, 95% CI 1.14–2.01) and with the prevalence of hypertension (OR 1.23, 95% CI 0.99–1.52). Analysis of all ACC veterans that controlled for diabetic sta- tus revealed that herbicide spraying was associated with the prevalence of heart disease (OR 1.45, 95% CI 1.13–1.86) and with the prevalence of hypertension (OR 1.27, 95% CI 1.04–1.55), but merely being deployed to Vietnam was not significantly associated with either. Although the prevalence of heart disease or hypertension was greater in diabetic veterans than in non-diabetic veterans, her- bicide spraying increased the prevalence equally in the two groups. Those results imply that the increases in the risk of heart disease and hypertension in Vietnam veterans who sprayed herbicides are associated with spraying herbicides, regard- less of diabetes status. Biologic Plausibility It is well established that the vasculature is a target of TCDD toxicity, which leads to significant increases in oxidative stress and induces major changes in gene expression regulating numerous signaling pathways (Puga et al., 2004). 

670 VETERANS AND AGENT ORANGE: UPDATE 2006 There is also growing evidence from a variety of experimental models that TCDD induces or promotes cardiovascular disease in adult animals. For example, chronic exposure of the ApoE knockout mouse to TCDD increased the incidence, severity, and progression of atherosclerotic plaques (Dalton et al., 2001), and rats chronically exposed to TCDD exhibited significant arterial remodeling character- ized by endothelial cell hypertrophy, extensive smooth muscle cell proliferation, and inflammation (Jokinen et al., 2003). The rats in this study also showed a dose-related increase in cardiomyopathy. Other studies have shown that TCDD exposure increased myocardial fibrosis (Riecke et al., 2002) and led to cardiac hy- pertrophy and alteration in control of heart rhythm (Lin et al., 2001; Thackaberry et al., 2005). In one study, acute exposure of mice to a relatively high dose of TCDD significantly increased the release of vasoconstricting eicosanoids and induced hypertension (Dalton et al., 2001). Those data demonstrate that activation of the AhR by xenobiotics induces cardiovascular injury and leads to cardiovas- cular disease in animal models. Recently, the role of the AhR in normal cardiovascular function in adult ani- mals has been established with studies of AhR-null mice. The animals develop hypertension, cardiac hypertrophy, and reduction in cardiac function with age; hence, the AhR has a role in cardiovascular function (Lund et al., 2003, 2005, 2006; Thackaberry et al., 2003; Vasquez et al., 2003). That both the sustained activation of the AhR by TCDD and the genetic deletion of the AhR result in cardiovascular disease suggests that the AhR acts to maintain the physiologic balance of the cardiovascular system and that either its excessive activation or its insufficient activation disrupts this homeostasis. However, additional stud- ies are needed to confirm the relationships and to determine their relevance to humans. Specifically, future research studies are needed to establish animal models of TCDD-induced cardiovascular disease to increase understanding of the physiologic and pathologic mechanisms that mediate the increased morbid- ity and mortality from circulatory diseases, including hypertension and ischemic heart disease, that have been suggested to be associated with herbicide and TCDD exposure in epidemiologic studies. Synthesis In this section, the committee synthesizes information on circulatory dis- orders from the new studies described above and reconsiders studies that were reviewed in prior updates. Because circulatory diseases constitute a broad group of diverse conditions, hypertension is discussed separately from other circulatory diseases so that the new studies can be adequately synthesized and integrated with the earlier studies. 

OTHER HEALTH EFFECTS 671 Hypertension Hypertension, typically defined as blood pressure above 140/90 mm Hg, af- fects more than 70 million adult Americans and is a major risk factor for coronary heart disease, myocardial infarction, stroke, and heart and renal failure. The major quantifiable risk factors for hypertension are well established and include age, race, BMI or percentage body fat, and diabetes; and the strongest conclusions regarding a potential increase in the incidence of hypertension come from studies that have controlled for these risk factors. The study by Kang et al. (2006 and personal correspondence) has several strengths. In studying the ACC, one of the most highly exposured Vietnam- veteran cohorts, it addresses subjects of primary concern to the VAO committee. Exposure to TCDD was directly measured in a subset of the study population and linked to the entire sample by establishing correlations of high values with self-reported spraying. It also had the merit of controlling for established risk factors for hypertension. Although the absolute increase in prevalence among ACC-veteran sprayers (about 25 percent) is not large, it is consistent with the fact that there are several other well-established contributors to the development of hypertension. One limitation of this study is the potential for information bias, inasmuch as the data on hypertension and on herbicide spraying were self-reported. That con- cern is diminished, in part, because a patient is more likely to report accurately a chronic disorder that requires continuing management, including hypertension and diabetes; this accuracy rate typically exceeds 90 percent (Okura et al., 2004). Although self-reported hypertension was not verified by medical-record review in the Kang et al. study, self-report of diabetes was found to be quite reliable: 79 percent of the reported cases were verified, confirmatory information was not found in the medical records available for 11 percent of the reported cases, and medical records were not obtained for the remaining 10 percent. A high level of verification of a health outcome, however, does not guarantee the absence of bias due to under-reporting and the related differential misclassification among expo- sure groups. Recall bias that leads to over-reporting of herbicide spraying among men who have serious health conditions must also be considered in evaluating this study. Although there is evidence that ex-sprayers were more likely to report several health conditions besides hypertension, comparison within the ex-sprayer subgroup according to serum TCDD concentration suggests that recall bias does not fully explain the associations. Selection bias could arise from the cross-sectional nature of the study, which accounts for disease prevalence only among people in the original deployed and non-deployed ACC cohorts who were still alive and participated. Concern for that type of selection bias is tempered by the high and nearly equal rates of participa- tion by deployed veterans (72 percent) and non-deployed veterans (69 percent). Furthermore, the prevalence of hypertension among the non-deployed veterans 

672 VETERANS AND AGENT ORANGE: UPDATE 2006 (30 percent) was similar to that among US men of comparable age (32 percent) (Fields et al., 2004). Despite those data, it remains unknown whether the observed relationship of spraying to the prevalence of hypertension is equivalent to what one would have observed if the cohort had been followed longitudinally. None- theless, that the primary population of concern to VA is the current living cohort of Vietnam veterans makes findings from the study particularly relevant. The results of the Kang et al. study are not consistent with those of a previ- ously reviewed study by Calvert et al. (1998), which investigated cardiovascular outcomes in a cohort of herbicide-factory workers exposed to TCDD. The report of the earlier study failed to identify a significant association between measured serum TCDD and hypertension after controlling for hypertension risk factors. The negative findings argue against an association between TCDD exposure and hypertension although the study was limited by self-reported diagnosis of hyper- tension and possibly by selection bias due to low response rates (28 percent for neighborhood referents, 70 percent for living and located cohort members, and 48 percent for the original cohort). The study by Kang et al. (2006) is also not consistent with the new environmental study of Chen et al. (2006), which showed that serum concentrations of dioxin-like PCDDs and PCDFs are not associated with an increased incidence of hypertension when major risk factors are adjusted for; the interpretation of this study was limited by lack of information on the criteria for diagnosing hypertension and by a very narrow range of serum TEQ concentrations. Two other occupational studies were uninformative because they failed to define hypertension (Kitamura et al., 2000) or used a definition that was not com- parable with that in veteran studies (Suskind and Hertzberg, 1984). In contrast, the results of Kang et al. (2006) are consistent with those of other studies of Vietnam veterans, including the other most highly exposed cohort composed of Vietnam veterans who served in Operation Ranch Hand (AFHS, 1995, 2000, 2005). Multiple examination cycles of the AFHS have consistently reported an increase in the prevalence of hypertension with a doubling of serum dioxin concentration. The analyses controlled for the major risk factors for hyper- tension, and diagnosis was confirmed with medical-record review. Limitations of the AFHS studies include the potential for selection bias and the variation in the comparison group over examination cycles. Selection bias is reduced, in part, by the relatively high participation rates across cycles 4–6 (74–83 percent in Ranch Hand veterans and 57–73 percent in the comparison group). The study by Kang et al. (2006) is also consistent with other veteran studies, including those of Australian Vietnam veterans (O’Toole et al., 1996) and Ameri- can Legion Vietnam veterans (Stellman et al., 1988) and the VES (CDC, 1988). All those studies reported significant increases in the incidence of hypertension, but only the study by Kang et al. controlled for potential confounding variables and used an index of herbicide-related exposure. Finally, the Korean-veteran study by Kim et al. (2003) was not considered despite an increased prevalence 

OTHER HEALTH EFFECTS 673 of hypertension and control for established risk factors, because of concern re- garding selection bias when the study population was assembled, the very low participation in each group (by 28 percent and 6 percent of Vietnam and non- Vietnam veterans, respectively), the inability to assess the quality or definition of hypertension as a diagnosis, and the relatively low values and narrow range of reported serum TCDD concentrations (IOM, 2005). Circulatory Diseases Circulatory diseases constitute a group of diverse conditions—of which hypertension, coronary heart disease, and stroke are the most prevalent—that ac- count for 75 percent of mortality from circulatory diseases in the United States. The major quantifiable risk factors for circulatory diseases are similar to those for hypertension and include age, race, smoking, serum cholesterol, BMI or percent- age of body fat, and diabetes. Reported results of new morbidity and mortality studies of the most highly exposed Vietnam-veteran cohorts (ACC and Operation Ranch Hand) were not entirely consistent. ACC veterans who sprayed Agent Orange reported a sig- nificant increase in the prevalence of heart disease, with ischemic heart disease representing nearly 70 percent of the conditions reported (Kang et al., 2006). In contrast, the AFHS did not find the prevalence of heart disease, myocardial infarction, or stroke to be significantly associated with either current or back- extrapolated serum TCDD concentrations in Ranch Hand veterans (AFHS, 2005). Ketchum and Michalek (2005) found a significant increase in mortality due to atherosclerotic heart disease in Ranch Hand ground crew personnel, but the increase in mortality from circulatory disease among all Ranch Hand veterans based on back-extrapolated serum TCDD was not significant. The strengths and limitations of the cross-sectional studies of veterans are the same as discussed above for hypertension. The new evidence of an increase in the incidence of heart disease is con- sistent with results of previously reviewed studies on herbicide-factory workers occupationally exposed to TCDD. In the IARC cohort of phenoxy-herbicide workers overall (Vena et al., 1998), an internal comparison found that being in the subgroup with the highest likelihood for TCDD exposure was associated with increased mortality from ischemic heart disease (RR 1.67, 95% CI 1.23–2.26). In analyses of three IARC subcohorts, herbicide-factory workers with high serum TCDD exhibited significant increases in mortality from ischemic heart disease (RR 1.99, 95% CI 1.05–3.75 compared with national rates [Flesch-Janys et al., 1997/1988] or RR 2.48, 95% CI 1.32–4.66 compared with gas workers [Flesch- Janys et al., 1995]; RR 2.3, 95% CI 1.0–5.0 [Hooiveld et al., 1998]; RR 1.75, 95% CI 1.07–2.87 [Steenland et al., 1999]). Furthermore, in two of the studies a significant trend was observed with increasing TCDD exposure (Flesch-Janys et al., 1995; Steenland et al., 1999). Although those studies did not control for 

674 VETERANS AND AGENT ORANGE: UPDATE 2006 potential disease confounders, the effect of confounding on the studies was re- duced by the use of comparison groups of workers who probably have similar cardiovascular risk characteristics. So, for example, although BMI is a risk fac- tor for ischemic heart disease and people who have a higher BMI will eliminate TCDD more slowly, it is unlikely that BMI would influence the choice of jobs associated with higher TCDD exposure. The evidence from the cohort studies is based on the association of ischemic heart disease mortality with back-extrapolated TCDD concentrations derived by using a first-order elimination model. New physiologically based pharmaco- kinetic models that use a dose-dependent elimination rate to back-extrapolate peak blood concentrations (discussed in Chapter 3) predict a much larger range of initial exposures and probable changes in relative exposure rankings (Emond et al., 2005). Other limitations on the evidence of an association between the compounds of interest and ischemic heart disease are the lack of control for known risk factors and reporting (in many earlier studies) in terms of less specific classifications of cardiac mortality. It is also problematic that only cross-sectional analyses are available on Vietnam veterans; results derived from longitudinal analyses could be interpreted with greater confidence. Although the evidence for an association of exposure to the chemicals of interest with hypertension may appear similar to that for an association with ischemic heart disease, many of the overtly positive findings for ischemic heart disease were derived from mortality studies that did not have access to the infor- mation necessary to adjust for known risk factors, as was possible in the ACC and AFHS analyses. In the studies with data on potential confounders, however, endpoints comparable to ischemic heart disease were only defined in a relatively imprecise fashion. The primary reason approximately half the committee could not agree to a conclusion of limited or suggestive evidence for an association for ischemic heart disease was that uncontrolled confounders might be distorting the results, while the remainder was not concerned that this was likely to be a major problem in occupational cohort studies. Conclusion Following extensive deliberations regarding the strengths and weaknesses of the new evidence and evidence from studies reviewed in previous VAO re- ports, the present committee deemed that the strengths of the evidence related to hypertension outweighed the weaknesses and concluded that there is limited or suggestive evidence of an association between exposure to the compounds of interest and hypertension (ICD-9 401–405), but that issues of chance, bias, and confounding could not be ruled out entirely. In contrast, members of the commit- tee were divided on the relative weight to be given to the weaknesses of the heart disease studies and thus remained divided in their judgments as to whether the evidence related to ischemic heart disease (ICD-9 410–414) and exposure to the 

OTHER HEALTH EFFECTS 675 compounds of interest was adequately informative to advance this health outcome from the “inadequate or insufficient” category into the “limited or suggestive” category. For all other types of circulatory disease, the committee found that the evidence is inadequate or insufficient to determine whether there is an association with exposure to the compounds of interest. AL AMYLOIDOSIS VA identified AL amyloidoisis (ICD-9 277.3) as of concern after the publi- cation of Update 1998. AL amyloidosis has been considered by the committees responsible for Update 2000, Update 2002, and Update 2004. Those commit- tees concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to the compounds of interest and AL amyloidosis. The committee responsible for the current update has moved the section on AL amyloidosis to Chapter 6, on neoplastic endpoints, where it is considered with multiple myeloma and B-cell lymphoma. The available scientific literature indicates that the three conditions are closely related in that they share many biologic features, most notably a clonal hyperproliferation of B cells and underlying chromosomal damage. ENDOMETRIOSIS Endometriosis (ICD-9 617) affects 5.5 million women in the United States and Canada at any given time (NICHD, 2004). The endometrium is the tissue that lines the inside of the uterus and is built up and shed each month during menstrua- tion. In endometriosis, endometrium is found outside the uterus—usually in other parts of the reproductive system, the abdomen, or surfaces near the reproductive organs. That misplaced tissue develops into growths or lesions that continue to respond to hormonal changes in the body and break down and bleed each month in concert with the menstrual cycle. Unlike blood released from endometrium in the uterus, blood released in endometriosis has no way to leave the body, and the results are inflammation, internal bleeding, and degeneration of blood and tissue that can cause scarring, pain, infertility, adhesions, and intestinal problems. There are several theories about the etiology of endometriosis, including genetics, but the cause remains unknown. It has been proposed that endometrium is distributed through the body via blood or the lymphatic system; that menstrual tissue backs up into the fallopian tubes, implants in the abdomen, and grows; and that all women experience some form of tissue backup during menstruation but only those with immune-system or hormonal problems experience the tissue growth associated with endometriosis. Despite numerous symptoms that can indicate endometriosis, diagnosis is possible only through laparoscopy or a more invasive surgical technique. Several treatments for endometriosis are available, but there is no cure. 

676 VETERANS AND AGENT ORANGE: UPDATE 2006 The suspicion that TCDD can be involved in the etiology of endometriosis began after the observation that the incidence of endometriosis was higher in monkeys that had been treated with low doses of TCDD than in control monkeys (Rier et al., 1993). Experimental and epidemiologic studies have been conducted. Several epidemiologic studies have investigated non-dioxin-like polychlorinated biphenyls (PCBs), and some have examined a possible association with TCDD or dioxin-like compounds. Conclusions from VAO and Updates Endometriosis was first reviewed in this series of reports in Update 2002, which identified two relevant studies, and Update 2004 examined three envi- ronmental studies. The present review updates the literature review with two additional studies. Table 9-6 provides a summary of relevant studies that have been reviewed. Update of the Epidemiologic Literature Environmental Studies Heilier et al. (2005) conducted a case–control study of endometriosis in Belgium. Overnight fasting serum concentrations of PCDDs, PCDFs, and PCBs, expressed as TEQs, were compared among three groups of women: 25 with peri- toneal endometriosis and 25 with deep endometriosis—both those groups were recruited from a hospital—and 21 healthy controls recruited concurrently from the consultations of the same gynecologists who referred the deep-endometriosis cases. The controls were of similar age as the other two groups and showed no clinical signs of peritoneal or deep endometriosis or clinical evidence of another gynecologic abnormality. A significant association was found between PCDDs and PCDFs together and dioxin-like PCBs and the two endometriosis outcomes combined, with an OR of 2.6 (95% CI 1.3–5.3) for an increase of 10 pg in total TEQ/g lipids in serum PCDDs and PCDFs and dioxin-like PCBs. The analysis included consideration of and adjustment for potential confounders (including age, age at menarche, menstrual irregularities, BMI, oral-contraceptive use, breastfeeding, parity, and family history). The association with PCDD and PCDF serum concentrations was strongest when comparing those with deep endometriosis to the controls (OR 7.7 [per 10 pg/g], 95% CI 1.97–30.17). The distinction between the two types of endometriosis contributed to the strength of this study, as did the fact that the healthy controls were likely not to have either (although this was not confirmed laparoscopically). A study of endometriosis in Italy included a group of women who were undergoing laparoscopy for suspected endometriosis or other benign gyneco- 

OTHER HEALTH EFFECTS 677 TABLE 9-6 Selected Epidemiologic Studies—Endometriosis Reference Study Population Study Results ENVIRONMENTAL New Studies Porpora Italian women with Cases Mean cumulative value of 410 ng g–1 et al., endometriosis with Control value of 250 ng g–1 2006 increased levels of OR 4.0, CI 95% 1.3–13; (p 0.0003). polychlorobiphenyls Heilier Endometriosis in 50 exposed cases; OR 2.6 (95% CI 1.3–5.3) et al., Belgium women with 2005 overnight fasting serum levels of PCDD/PCDF and PCB Studies Review in Update 2004 De Felip Pilot study of Italian Mean Concentration TCDD (pg/g lipid) et al., and Belgian women Italy: 2004 of reproductive age; Controls (10 pooled samples) 1.6; compared concentrations Cases (2 sets of 6 pooled samples) 2.1, 1.3 of TCDD and total TEQ in pooled blood samples Belgium: from women diagnosed Controls (7 pooled samples) 2.5; with endometriosis to Cases (Set I, 5 pooled samples; Set II, 6 pooled samples) controls 2.3, 2.3 Mean Concentration (pg TEQ/g lipid) Italy: Controls (10 pooled samples) 8.9 1.3 (99% CI, 7.2–11); Cases (2 sets of 6 pooled samples) 10.7 1.6; 10.1 1.5 Belgium: Controls (7 pooled samples) 24.7 3.7 (99% CI, 20–29); Cases (Set I, 5 pooled samples; Set II, 6 pooled samples) 18.1 2.7; 27.1 4.0 Fierens Belgian women with Mean concentrations (pg TEQ/g lipid): et al., environmental exposure Cases (n 10) 26.2 (95% CI, 18.2–37.7) 2003 to PCDDs/PCDFs or Controls (n 132) 25.6 (95% CI, 24.3–28.9) dioxins; compared analyte No significant difference concentrationsa in cases vs controls Eskenazi Residents of Seveso Serum TCDD 20.1–100 ppt: et al., Zones A and B 30 years 8 exposed cases; OR 1.2 (90% CI, 0.3–4.5) 2002 of age in 1976; compared Serum TCDD 100 ppt: incidence of endometriosis 9 exposed cases; OR 2.1 (90% CI, 0.5–8.0) across serum TCDD concentrations continued 

678 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-6 Continued Reference Study Population Study Results Studies Reviewed in Update 2002 Pauwels Patients undergoing 6 exposed cases; OR 4.6 (95% CI, 0.5–43.6) et al., infertility treatment in 2001 Belgium; compared number of women with endometriosis and without endometriosis who had serum dioxin levels 100 pg TEQ/g serum lipid Mayani Residents of Jerusalem 8 exposed cases; OR 7.6 (95% CI, 0.9–169.7) et al., being evaluated for 1997 infertility; compared number of women with elevated TCDD concentrations in diagnosed with endometriosis (n 44) with subjects not diagnosed with endometriosis (n 35) ABBREVIATIONS: PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofuran; TCDD, tetrachlorodibenzo-p-dioxin; TEQ, toxicity equivalents. a Dioxin TEQs calculated using the WHO (1998) Toxic Equivalency Factor methodology. logic conditions during April 2000–January 2004 in a hospital in Rome (Porpora et al., 2006). The selection of study subjects allowed investigators to rule out the presence of endometriosis among controls. The final study group consisted of 40 cases and 40 controls; all provided blood specimens for analysis of dioxin- like compounds. Women with endometriosis had higher overall concentrations of PCBs than the controls (410 vs 250 ng/g of lipid base). In addition, several specific PCBs were measured, and dose–response relationships were observed across tertile groups for PCB 118 and 138 with increasing risk of endometriosis, although the confidence limits were very wide and overlapped. The analysis included proper control for confounders (with either statistical analysis or eligi- bility restrictions). However, because the study indicated higher concentrations of both doxin-like and non-dioxin-like PCBs among cases than among controls, the contribution of dioxin-like PCBs alone to the increased risk of endometriosis cannot be determined. No new occupational or Vietnam-veteran studies concerning exposure to the compounds of interest and endometriosis were published since Update 2004. 

OTHER HEALTH EFFECTS 679 Biologic Plausibility Laboratory studies that used animal models and examined gene-expression changes associated with human endometriosis and TCDD exposure provide evi- dence to support the biologic plausibility of a link between that TCDD exposure and endometriosis. The first suggestion that TCDD exposure may be linked to en- dometriosis came as a secondary finding from a study that exposed female rhesus monkeys (Macaca mulatta) chronically to low concentrations of dietary TCDD for 4 years (Rier et al., 1993). Ten years after the exposure ended, the investiga- tors documented an increased incidence of endometriosis in the monkeys that correlated with the dioxin exposure concentration. The small sample prevented a definitive conclusion that TCDD was a causal agent in the development of the endometriosis, but it led to numerous studies of the ability of TCDD to promote the growth of pre-existing endometriotic lesions. When fragments of uterine tissue were implanted in the peritoneal cavity to mimic eutopic endometrial lesions, TCDD exposure was shown to promote the survival and growth of the lesions in rhesus monkeys and in mice (Cummings et al., 1996; Johnson et al., 1997; Yang et al., 2000). In mice, direct treatment of endometrial tissue with TCDD before placement into the peritoneal cavity resulted in increased size and number of endometrial lesions (Bruner-Tran et al., 1999). A number of proposed mechanisms by which TCDD may promote en- dometrial lesions provide additional biologic plausibility of the link between TCDD and endometriosis. Human endometrial tissue expresses both the AhR and its dimerization partner, the aryl hydrocarbon nuclear translocator (Khorram et al., 2002), and three AhR target genes: CYP1A1, 1A2, and 1B1 (Bulun et al., 2000). That suggests that endometrial tissue is responsive to TCDD. Furthermore, TCDD significantly decreases the ratio of progesterone receptor B to progester- one receptor A in normal human endometrial stromal cells and blocks the ability of progesterone to suppress matrix metalloproteinase (MMP) expression; these actions may promote endometrial-tissue invasion. Both the reduced ratio and the resistance to progesterone-mediated MMP suppression are observed in endome- trial tissue from women with endometriosis (Igarashi et al., 2005; Nayyar et al., 2006). TCDD induces changes in gene expression that mirror those observed in endometrial lesions. For example, TCDD can induce expression of histamine- releasing factor, which is increased in endometrial lesions and accelerates their growth (Oikawa et al., 2002, 2003). Similarly, TCDD stimulates expression of RANTES (regulated on activation, normal T cell expressed, and secreted) in en- dometrial stromal cells, and RANTES concentration and bioactivity are increased in women with endometriosis (Zhao et al., 2002). Although those studies do not establish the degree to which TCDD may cause or promote endometriosis, they do provide evidence that supports the bio- logic plausibility of a link between TCDD exposure and endometriosis. 

680 VETERANS AND AGENT ORANGE: UPDATE 2006 Synthesis The two studies described above were of similar design and were strength- ened by appropriate consideration of potential confounders, differentiation of cases and controls, and serum measurements of dioxin-like compounds. Both studies resulted in similar findings of a significant association between blood concentrations of dioxin-like chemicals and risk of endometriosis. Although the Porpora et al. (2005) study was limited by not being able to distinguish dioxin- like and non-dioxin-like PCBs, the two studies produced similar and consistent results. The studies reviewed previously in Updates 2002 and 2004 were limited primarily by their small study sizes, which did not produce statistically significant associations between the compounds of interest and endometriosis. However, they showed positive associations that can be considered consistent with the results of the two studies reviewed above. Conclusion On the basis of its evaluation of the evidence reviewed here and in Update 2002 and Update 2004, the committee concludes that there is inadequate or insuf- ficient evidence to support an association between exposure to the compounds of interest and endometriosis. THYROID HOMEOSTASIS Clinical disruptions of thyroid function include various disorders grouped in ICD-9 242.8 and 246.8. The thyroid gland secretes the hormones thyroxine (T4) and triiodothyronine (T3), which stimulate and help to regulate metabolism throughout the body. The thyroid also secretes calcitonin, a hormone that controls calcium concentration in the blood and storage of calcium in bones. Secretion of T4 and T3 is under the control of thyroid-stimulating hormone (TSH), which is secreted by the anterior pituitary gland. Iodine operates in thyroid physiology both as a constituent of thyroid hormones and as a regulator of glandular function. Control of circulating concentrations of those hormones is regulated primarily by a negative-feedback pathway that involves three organs: the thyroid, the pi- tuitary, and the hypothalamus. In the hypothalamus–pituitary–thyroid feedback scheme, the hypothalamus releases thyrotropin-releasing hormone (TRH), which stimulates the pituitary to produce TSH, which triggers the thyroid to produce T4 and T3. Cells in the hypothalamus and pituitary respond to concentrations of circulating T4 and T3. When T4 and T3 are low, the pituitary is stimulated to deliver more TSH to the thyroid, which increases T4 and T3 output. When cir- culating T4 and T3 are high, they signal to reduce the output of TRH and TSH. This negative-feedback loop maintains hormone homeostasis. Disruption of thyroid homeostasis can be stimulatory (hyperthyroidism) 

OTHER HEALTH EFFECTS 681 or suppressive (hypothyroidism). Both conditions are diagnosed by analysis of blood concentrations of thyroid hormones, TSH, and other proteins (anti-thyroid antibodies). The prevalence of thyroid dysfunction among adults in the general population ranges from 1 to 10%, depending on the group, the testing setting, sex, age, method of assessment, and the presence of conditions that might affect thyroid function. People with subclinical (biochemical) conditions may or may not show other evidence (signs or symptoms) of thyroid dysfunction. In hypothyroidism, the body lacks sufficient thyroid hormone. Overt hypothy- roidism is seen as a high serum concentration of TSH and a low serum concentra- tion of free T4. Subclinical hypothyroidism is defined as a high serum concentration of TSH and a normal serum concentration of free T4. People with hypothyroidism typically have symptoms of low metabolism. Studies consistently show that sub- clinical hypothyroidism is common and occurs more frequently in women than in men (Canaris et al., 2000; Hollowell et al., 2002; Sawin et al., 1985). In the Framingham study, for example, among 2,139 people 60 years old or older, 14 percent of women and 6 percent of men had subclinical hypothyroidism (Sawin et al., 1985). Subclinical hypothyroidism is a risk factor for overt hypothyroidism. Studies have reported an association of hypothyroidism with a wide variety of other conditions. The term hyperthyroidism may involve any disease that results in overabun- dance of thyroid hormone. Clinical or overt hyperthyroidism is characterized as a low serum concentration of TSH and high serum concentration of free T4. Subclinical hyperthyroidism is defined as a low serum concentration of TSH and a normal serum concentration of free T4. The prevalence of subclinical hyper- thyroidism was estimated at about 1 percent in men and 1.5 percent in women over 60 years old (Helfand and Redfern, 1998). Conditions associated with hy- perthyroidism include Graves disease and diffuse toxic goiter. Like hypothyroid- ism, hyperthyroidism is more common in women than in men, and, although it occurs at all ages, it is most likely to occur in people over 15 years old. A form of hyperthyroidism called neonatal Graves disease occurs in infants born of mothers who have Graves disease. Occult hyperthyroidism may occur in patients over 65 years old and is characterized by a distinct lack of typical symptoms. It is important to distinguish between potential effects on adults and effects that may occur during development. In adults, the thyroid gland is able, within reason, to compensate for mild or moderate disruption (such as that caused by hyperplasia or goiter). In contrast, the fetus is highly sensitive to alterations in thyroid hormones, and alterations in thyroid homeostasis can hamper the devel- opment of many organ systems, including the nervous and reproductive systems. Both adult and developmental outcomes are considered here. Summary of Updates The thyrotoxic potential of the compounds of interest was addressed first in Update 2002 and again in Update 2004 (IOM, 2003, 2005). The committee 

682 VETERANS AND AGENT ORANGE: UPDATE 2006 responsible for Update 2002 concluded that there was inadequate or insufficient information to determine whether there is an association between exposure to the compounds of interest and adverse effects on thyroid homeostasis in Vietnam veterans. Some effects on thyroid homeostasis have been observed in humans, mainly after exposure in the perinatal period. The Update 2004 committee also concluded that there was inadequate or insufficient evidence of an association between exposure to the compounds of interest and adverse effects on thyroid homeostasis. Although additional effects had been observed in human studies, the committee concluded that the functional importance of those changes remained unclear because adaptive capacity could be adequate to accommodate them. Update of the Scientific Literature Occupational Studies No new occupational studies concerning the compounds of interest and thy- roid homeostasis were published since Update 2004. Environmental Studies The one environmental study published since Update 2002 involved anglers chronically exposed to dioxin-like compounds in the diet (Bloom et al., 2006). The study group was part of the New York State Angler Cohort Study, a pro- spective study of health effects in consumers of sport fish from the Great Lakes (Vena et al., 1996). The study population was licensed anglers between 18 and 40 years old. The subset of people in the Dioxin Exposure Substudy included 23 who had reported eating sport fish and who had serum concentrations of PCB 153 (a marker of general exposure) that placed them in the 75th percentile and 15 nonconsumers. Serum concentrations of eight PCDDs, nine PCDFs, and four co- planar PCBs were measured in all 38 people by CDC, and the sum of dioxin-like compounds was compared the concentrations of T3, T4, free T4, and TSH. A sig- nificant inverse relationship was seen between the sum of dioxin-like compounds and the concentration of free T4. However, there was no association between the sum of dioxin-like compounds and TSH. The study results are based on the sum of dioxin-like compounds, not TCDD specifically. However, the results add to information that indicates that such chemicals do show association with change in some measure of thyroid function. In a study published in 2001 but not included in earlier reports, Nagayama et al. (2001) examined relationships between dioxin and dioxin-related com- pounds and thyroid hormones in patients with so-called Yusho disease. The study population was drawn from among 83 patients whose blood was examined in 1994–1995 for PCDD congeners (including TCDD), PCDFs, and PCB congeners. There were 16 in the study (3 men and 13 women), and blood drawn in 1996 and 

OTHER HEALTH EFFECTS 683 1997 was analyzed for T3, T4, free T4, and TSH. TEQ concentrations in the study population ranged from less than 100 to over 1,000 pg/g of lipid. The average TEQ concentration was 7-fold greater than average serum TEQ concentrations in the Japanese population. However, there were no significant correlations between serum TEQ and the concentrations of T3, T4, free T4, or TSH, all of which were in the normal range except for one serum T4 value that was slightly higher than the normal range. In a study by Foster et al. (2005), dioxin-like activity and thyroid hormone concentrations were examined in 150 women who were undergoing amniocen- tesis. Subjects were excluded if they had language problems, daily alcohol- consumption or drug-use history, other health conditions that required medical intervention, or a history of endocrine disease, including thyroid disease. On entrance into the study, subjects completed questionnaires that addressed other factors, such as diet and tobacco use. Serum TSH and T4 were measured with radioimmunoassay. Serum dioxin-like compounds were measured only with a cell-based bioassay to yield TEQs. There was no association between thyroid function and TEQ. The qualitative measure of TEQ precludes conclusions regard- ing specific chemicals of concern. Similar studies of adults by Nagayama et al. (2001) on 16 Yusho patients but with TEQs determined from direct measure- ments of PCDD, PCDF, and PCB congeners showed no association with thyroid function. Wang et al. (2005) examined the associations between transplacental expo- sure to various chlorinated dioxin, dibenzofuran, and PCB congeners and thyroid- hormone status in 118 newborn–mother pairs in Tiawan. The mothers were all healthy, were 25–34 years old, had a single pregnancy, and had no tobacco use or alcohol use during pregnancy. Dioxin and other congeners were measured chemi- cally in placentas; the 2,3,7,8-substituted congeners of dioxins were examined specifically. Indexes of infant thyroid function were measured in cord blood taken 1 minute after delivery. Significant (p 0.05) effects on TSH and thyroid-binding globulin were detected. In a study by Matsuura et al. (2001), thyroid function was examined in in- fants who had been breast-fed and those who had been bottle-fed. Breast milk was collected at various times over a year from 80 primaparous mothers, 25–34 years old, in four prefectures in Japan and analyzed for PCDDs, PCDFs, and PCBs. Blood was taken from infants at 1 year. Blood also was taken from 30 bottle-fed infants at 1 year. Serum T4, T3, and free T4 were not different between the groups. Serum TSH was significantly higher in the breast-fed group (p 0.027), but values in both groups were in the normal range. Vietnam-Veteran Studies No new publications examining thyroid function in the AFHS cohort or in other Vietnam veterans since Update 2004 were identified (IOM, 2005). However, 

684 VETERANS AND AGENT ORANGE: UPDATE 2006 two studies that evaluated post-service mortality in Vietnam veterans considered individual causes and all causes of death (Boehmer et al., 2004; Ketchum and Michalek, 2005). Among individual causes, both studies examined mortality from endocrine disorders, which would include thyroid disorders. In the Boehmer et al. (2004) study, deaths ascribed to “endocrine, nutritional and immunity disorders” (ICD-9 240–279) included 10 of Vietnam veterans and 7 of non-Vietnam veterans (RR 1.32, 95% CI 0.50–3.47). Ketchum and Michalek (2005) examined mortal- ity in the Ranch Hand and comparison veteran groups. There were 3 deaths from endocrine diseases in the Ranch Hand group and 31 in the comparison group (RR 1.4, 95% CI 0.4–4.7). Biologic Plausibility TCDD has been demonstrated to affect concentrations of T4, T3, and TSH in experimental animals, but the effects appear to be species-dependent, and they lack consistency in demonstrating either definite hyperthyroidism or hypothyroid- ism after exposure to TCDD. Nevertheless, long-term exposure of animals to TCDD usually results in suppressed T4 and T3 and stimulated TSH. The National Toxicology Program reported that female rats exposed chronically to TCDD showed a follicular-cell hyperplasia and hypertrophy of thyroid follicles. Chapter 3 discusses recent toxicologic studies of TCDD effects on thyroid indexes relevant to the biologic plausibility of effects of TCDD and the herbicides of interest on the thyroid gland. TCDD influences the metabolism of thyroid hormones and TSH. Notably, the study by Nishimura et al. (2005) confirmed that induction of the glucuronyl transferase UGT1A6, thought to be involved in the reduction in serum thyroid hormone in mice, depends on the AhR. Thus, some dioxin-like PCB congeners (such as PCB-77) can be metabolized to hy- droxy derivatives that more closely resemble the structure of T4 and displace it from thyroid-binding proteins, such as transthyretin—a mechanism not likely with TCDD. Not all mechanisms by which chemicals might affect thyroid ho- meostasis are understood, and dioxin may act on thyroid function via different mechanisms. Synthesis The synthesis of this review is similar to that in Update 2004. Numerous ani- mal experiments and several epidemiologic studies have shown that TCDD and dioxin-like compounds appear to exert an influence on thyroid homeostasis. Two occupational studies were considered in that 2004 report. Johnson et al. (2001) measured serum hormone and TCDD concentrations in 37 men who had sprayed 2,4,5-T in Victoria, Australia. In correlation analysis, TCDD concentrations were inversely related to T3 and TSH concentrations. The association was strongest when historical, but not current, serum TCDD concentrations were considered. 

OTHER HEALTH EFFECTS 685 In a paper reviewed in Update 1998, Zober et al. (1994) examined 138 BASF workers exposed to TCDD in a 1953 industrial incident and reported that thyroid disease was increased (p 0.05) in the exposed population. In the AFHS study considered in Update 2004, Pavuk et al. (2003) reported on thyroid-hormone status in the AFHS cohort, which was examined in 1982, 1985, 1987, 1992, and 1997. At each time, there was a trend toward an increasing concentration of TSH that was not accompanied by changes in circulating T4 or in the percentage uptake of T3 (measured only in the earlier years). In a repeated- measures linear regression adjusted for age, race, and military occupation, the low-exposure and high-exposure Ranch Hand veterans had TSH significantly higher than the comparison population, and the trend test showed a significant linear increase over the comparison and background-, low-, and high-exposure groups (p 0.002). No changes in microsomal or antithyroid antibodies were observed, nor was there any evidence of changes in clinical thyroid disease. The percentage with abnormally high TSH was higher at each examination in the high-exposure Ranch Hand group than in the comparison population, but the confidence intervals were wide and included 1 at each examination (1982: OR 1.8, 95% CI 0.7–5.9; 1985: OR 1.4, 95% CI 0.7–3.2; 1987: OR 1.9, 95% CI 0.8–4.5; 1992: OR 1.7, 95% CI 0.8–3.9; 1997: OR 1.8, 95% CI 0.9–3.4). The assessment of endocrine function in that study included a series of thyroid- function tests that showed no difference in thyroid function between exposed and control veterans. The effects on maternal or fetal thyroid status are evident in numerous stud- ies and are of concern because TCDD and dioxin-like compounds may affect the early development of neurologic and sensory organs and of motor function if exposure occurs in utero or during lactation. In animal studies, effects of TCDD on thyroid homeostasis have been observed in adults exposed in the laboratory, and there are indications of similar effects in the wild. In human studies, increases in TSH have been seen without evidence of increases in T4. In the new studies of adults reviewed here, there was lack of correlation between dioxin-like com- pounds and TSH concentrations. Likewise, in the studies in infants, there were not significant associations between magnitude of exposure to dioxin or dioxin- like compounds and measures of thyroid function. Those studies, then, suggest that people were able to adapt to changes in thyroid status that might have been induced by exposure to TCDD and other dioxin-like compounds. Conclusions There is inadequate or insufficient evidence of an association between expo- sure to the compounds of interest and clinical or overt adverse effects on thyroid homeostasis. Some effects have been observed in humans, but the functional importance of the changes reported in the studies reviewed remains unclear to the present committee, because adaptive capacity could be adequate to accom- modate them. 

686 VETERANS AND AGENT ORANGE: UPDATE 2006 SUMMARY On the basis of the occupational, environmental, and veterans studies re- viewed and in light of information concerning biologic plausibility, the commit- tee reached one of four conclusions about the strength of the evidence regarding an association between exposure to the compounds of interest and each of the health effects discussed in this chapter. In categorizing diseases according to the strength of the evidence, the committee applied the same criteria (discussed in Chapter 2) that were used in VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004. To be consistent with the charge to the commit- tee by the Secretary of Veterans Affairs in Public Law 102-4 and with accepted standards of scientific reviews, the distinctions between conclusions are based on statistical association, not on causality. Despite extensive consideration of the full evidentiary databases, the com- mittee could not reach consensus as to whether ischemic heart disease satisfied the criteria for inclusion in the category of limited or suggestive evidence of an association or should be retained in the category of inadequate or insufficient evidence. Health Outcomes with Sufficient Evidence of an Association For diseases in this category, a positive association between exposure and outcome must be observed in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. The committee regarded evidence from several small studies that were free of bias and confounding and that showed an association that was consistent in magnitude and direction as sufficient to con- clude that there is an association. The committes responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 concluded that there was sufficient evi- dence of an association between exposure to at least one compound of interest and chloracne. The scientific literature continues to support the classification of chloracne in the category of sufficient evidence. On the basis of the literature, no additional health effects discussed in this chapter satisfy the criteria necessary for inclusion in this category. Health Outcomes with Limited or Suggestive Evidence of an Association For this category, the evidence must suggest an association between exposure and outcome, although it can be limited because chance, bias, or confounding could not be ruled out with confidence. The committees responsible for Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 concluded that there was limited or suggestive evidence of an association between exposure to at least one compound of inter- 

OTHER HEALTH EFFECTS 687 est and porphyria cutanea tarda. The scientific literature continues to support the classification of this disorder in the category of limited or suggestive evidence. On the basis of its evaluation of available scientific evidence, the committee responsible for Type 2 Diabetes concluded that there was limited or suggestive evidence of an association between exposure to at least one compound of inter- est and type 2 diabetes; the committee responsible for Update 2004 reached the same conclusion. Evidence reviewed in the present report continues to support that conclusion. The present committee has added the cardiovascular condition hypertension to the list of health outcomes in the category of limited or suggestive evidence. The committee was unable to reach consensus as to whether another cardiovas- cular endpoint, ischemic heart disease, belonged in this category or in the clas- sification below, “inadequate or insufficient evidence to determine whether there is an association.” Health Outcomes with Inadequate or Insufficient Evidence to Determine Whether There Is an Association The scientific data on many of the health effects reviewed by the present com- mittee were inadequate or insufficient to determine whether there is an associa- tion between exposure to the compounds of interest and the health outcomes. For the health effects in this category, the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. Some studies failed to control for confounding or used inadequate exposure assessment. This category includes nonmalignant respiratory disorders, such as asthma in isolation, pleurisy, pneumonia, and tuberculosis; immune-system disorders (immune suppression and autoimmunity); lipid and lipoprotein disorders; gastrointestinal diseases; digestive diseases; liver toxicity; circulatory disorders (except as qualified above); endometriosis; and disorders of thyroid homeostasis. The committee was unable to reach consensus as to whether another cardio- vascular endpoint, ischemic heart disease, belonged in this category or in the classification above, “limited or suggestive evidence of an association.” Health Outcomes with Limited or Suggestive Evidence of No Association To classify outcomes in this category, several adequate studies covering the full range of known human exposure must be consistent in not showing a positive association between exposure and outcome at any magnitude of exposure. The studies also must have relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the conditions, magnitudes of exposure, and periods of observation covered by the available studies. The possibility of a very small increase in risk at the exposure studied can never be excluded. 

688 VETERANS AND AGENT ORANGE: UPDATE 2006 The committees responsible for VAO, Update 1996, Update 1998, Update 2000, Update 2002, and Update 2004 concluded that none of the health outcomes discussed in this chapter had limited or suggestive evidence of no association with the exposures to the compounds of interest. The most recent scientific evi- dence continues to support that conclusion. REFERENCES1 ADVA (Australian Department of Veterans Affairs). 2005b. The Third Australian Vietnam Veterans Mortality Study 2005. Canberra, Australia: Department of Veterans’ Affairs. ADVA. 2005c. Australian National Service Vietnam Veterans: Mortality and Cancer Incidence 2005. Canberra, Australia: Department of Veterans’ Affairs. AFHS (Air Force Health Study). 1984. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A138-340. AFHS. 1990. An Epidemiologic Investigation of Health Effects in Air Force Personnel Follow- ing Exposure to Herbicides. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-90-2. AFHS. 1991a. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. AFHS. 1991b. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update: 1991. Brooks AFB, TX: Armstrong Laboratory. AFHS. 1995. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1992 Follow-up Examination Results. Brooks AFB, TX: Epidemiologic Research Division; Armstrong Laboratory. AFHS. 1996. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update 1996. Brooks AFB, TX: Epidemiologic Research Division. Armstrong Laboratory. AL/AO-TR-1996-0068. AFHS. 2000. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Follow-up Examination and Results. Reston, VA: Science Ap- plication International Corporation. F41624-96-C1012. AFHS. 2005. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1997 Follow-up Examination and Results. Brooks AFB, TX: Epidemio- logic Research Division. Armstrong Laboratory. AFRL-HE-BR-SR-2005-0003. AHA (American Heart Association). 2007. Heart disease and stroke statistics—2007 update: a report from the American Health Association statistics committee and stroke statistics subcommittee. Circulation 115:69–171. Alavanja M, Merkle S, Teske J, Eaton B, Reed B. 1989. Mortality among forest and soil conservation- ists. Archives of Environmental Health 44:94–101. Alberti KGMM, Zimmet P, Shaw J. 2006. Metabolic syndrome—a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabetic Medicine 23(5):469–480. 1Throughout the report the same alphabetic indicator following year of publication is used con- sistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed. 

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690 VETERANS AND AGENT ORANGE: UPDATE 2006 Burns C, Beard K, Cartmill J. 2001. Mortality in chemical workers potentially exposed to 2,4-dichlo- rophenoxyacetic acid (2,4-D) 1945-94: An update. Occupational and Environmental Medicine 58:24–30. Calvert GM, Sweeney MH, Morris JA, Fingerhut MA, Hornung RW, Halperin WE. 1991. Evaluation of chronic bronchitis, chronic obstructive pulmonary disease, and ventilatory function among workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. The American Review of Respiratory Disease 144(6):1302–1306. Calvert GM, Hornung RV, Sweeney MH, Fingerhut MA, Halperin WE. 1992. Hepatic and gastro- intestinal effects in an occupational cohort exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin. Journal of the American Medical Association 267:2209–2214. Calvert GM, Willie KK, Sweeney MH, Fingerhut MA, Halperin WE. 1996. Evaluation of serum lipid concentrations among US workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Archives of Environmental Health 51(2):100–107. Calvert GM, Wall DK, Sweeney MH, Fingerhut MA. 1998. Evaluation of cardiovascular outcomes among US workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environmental Health Per- spectives 106(Suppl 2):635-643. Calvert GM, Sweeney MH, Deddens J, Wall DK. 1999. Evaluation of diabetes mellitus, serum glu- cose, and thyroid function among United States workers exposed to 2,3,7,8-tetrachlorodibenzo- p-dioxin. Occupational and Environmental Medicine 56(4):270–276. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. 2000. The Colorado thyroid disease prevalence study. Archives of Internal Medicine 160(4):526–534. CDC (Centers for Disease Control and Prevention). 1988. Centers for Disease Control Vietnam Ex- perience Study. Health status of Vietnam veterans. II: physical health. Journal of the American Medical Association 259(18):2708–2714. CDVA (Commonwealth Department of Veterans’ Affairs). 1998a. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community. Volume 1: Male Vietnam Veterans Survey and Community Comparison Outcomes. Canberra, Australia: Department of Veterans’ Affairs. CDVA. 1998b. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community. Volume 2: Female Vietnam Veterans Survey and Community Comparison Outcomes. Canberra, Australia: Department of Veterans’ Affairs. Chen H-L, Su H-J, Guo Y-L, Liao P-C, Hung C-F, Lee C-C. 2006. Biochemistry examinations and health disorder evaluation of Tiawanese living near incinerators and with low serum PCDD/Fs levels. Science of the Total Environment 366:538–548. Coggon D, Pannett B, Winter P, Acheson E, Bonsall J. 1986. Mortality of workers exposed to 2- methyl-4-chlorophenoxyacetic acid. Scandinavian Journal of Work, Environment and Health 12:448–454. Coggon D, Pannett B, Winter P. 1991. Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine 48:173–178. Cook RR, Bond GG, Olson RA, Ott MG. 1987. Update of the mortality experience of workers ex- posed to chlorinated dioxins. Chemosphere 16:2111–2116. Cooper GS, Parks CG. 2004. Occupational and environmental exposures as risk factors for systemic lupus erythematosus. Current Rheumatology Reports 6(5):367–374. Crane P, Barnard D, Horsley K, Adena M. 1997a. Mortality of Vietnam Veterans: The Veteran Cohort Study. A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans. Canberra, Australia: Department of Veterans’ Affairs. Crane P, Barnard D, Horsley K, Adena M. 1997b. Mortality of National Service Vietnam Veterans: A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans. Canberra, Australia: Department of Veterans’ Affairs. 

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