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), circulatory 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 Exposure 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 conclusions 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.



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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

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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.

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601 OTHER HEALTH EFFECTS 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-

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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.

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603 OTHER HEALTH EFFECTS 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.

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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-

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605 OTHER HEALTH EFFECTS 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).

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606 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-1 Selected Epidemiologic Studies—Non-Malignant Respiratory Disease Estimated Exposed Relative Risk Casesa (95% CI)a Reference Study Population 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)

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607 OTHER HEALTH EFFECTS TABLE 9-1 Continued Estimated Exposed Relative Risk Casesa (95% CI)a Reference Study Population 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

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608 VETERANS AND AGENT ORANGE: UPDATE 2006 TABLE 9-1 Continued Estimated Exposed Relative Risk Casesa (95% CI)a Reference Study Population 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

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609 OTHER HEALTH EFFECTS TABLE 9-1 Continued Estimated Exposed Relative Risk Casesa (95% CI)a Reference Study Population 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

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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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689 OTHER HEALTH EFFECTS Anderson H, Hanrahan L, Jensen M, Laurin D, Yick W, Wiegman P. 1986. Wisconsin Vietnam Veteran Mortality Study: Proportionate Mortality Ratio Study Results. Madison: Wisconsin Division of Health. Assennato G, Cervino D, Emmett E, Longo G, Merlo F. 1989. Follow-up of subjects who developed chloracne following TCDD exposure at Seveso. American Journal of Industrial Medicine 16:119–125. Austin MA, Hokanson JE, Edwards KL. 1998. Hypertriglyceridemia as a cardiovascular risk factor. American Journal of Cardiology 81(4A):7B–12B. Baccarelli A, Pfeiffer R, Consonni D, Pesatori AC, Bonzini M, Patterson DG Jr, Bertazzi PA. Landi MT. 2005a. Handling of dioxin measurement data in the presence of non-detectable values: Overview of available methods and their application in the Seveso chloracne study. Chemo- sphere 60(7):898–906. Baccarelli A, Pesatori AC, Consonni D, Mocarelli P, Patterson DG Jr, Caporaso NE, Bertazzi PA, Landi MT. 2005b. Health status and plasma dioxin levels in chloracne cases 20 years after the Seveso, Italy accident. British Journal of Dermatology 152(3):459–465. Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindorf K, Manz A, Wahrendorf J. 1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes and Control 7(3):312–321. Bertazzi P, Zocchetti C, Pesatori A, Guercilena S, Sanarico M, Radice L. 1989a. Mortality in an area contaminated by TCDD following an industrial incident. Medicina Del Lavoro 80:316–329. Bertazzi P, Zocchetti C, Pesatori A, Guercilena S, Sanarico M, Radice L. 1989b. Ten-year mortality study of the population involved in the Seveso incident in 1976. American Journal of Epide- miology 129:1187–1200. Bertazzi PA, Bernucci I, Brambilla G, Consonni D, Pesatori AC. 1998. The Seveso studies on early and long-term effects of dioxin exposure: A review. Environmental Health Perspectives 106(Suppl 2):625–633. Bertazzi PA, Consonni D, Bachetti S, Rubagotti M, Baccarelli A, Zocchetti C, Pesatori AC. 2001. Health effects of dioxin exposure: A 20-year mortality study. American Journal of Epidemiol- ogy 153(11):1031–1044. Blair A, Grauman D, Lubin J, Fraumeni JJ. 1983. Lung cancer and other causes of death among licensed pesticide applicators. Journal of the National Cancer Institute 71:31–37. Blair A, Sandler DP, Tarone R, Lubin J, Thomas K, Hoppin JA, Samanic C, Coble J, Kamel F, Knott C, Dosemeci M, Zahm SH, Lynch CF, Rothman N, Alavanja MC. 2005. Mortality among par- ticipants in the Agricultural Health Study. Annals of Epidemiology 15(4):279–285. Bloom M, Vena J, Olson J, Moysich K. 2006. Chronic exposure to dioxin-like compounds and thyroid function among New York anglers. Environmental Toxicology and Pharmacology 21(3):260–267. Boehmer TK, Flanders WD, McGeehin MA, Boyle C, Barrett DH. 2004. Postservice mortality in Vietnam veterans: 30-Year follow-up. Archives of Internal Medicine 164(17):1908–1916. Boverhof DR, Burgoon LD, Tashiro C, Chittim B, Harkema JR, Jump DB, Zacharewski TR. 2005. Temporal and dose-dependent hepatic gene expression patterns in mice provide new insights into TCDD-mediated hepatotoxicity. Toxicological Sciences 85(2):1048–1063. Brunertran KL, Rier SE, Eisenberg E, Osteen KG. 1999. The potential role of environmental toxins in the pathophysiology of endometriosis. Gynecologic and Obstetric Investigation 48(1):45–52. Bullman T, Kang H. 1996. The risk of suicide among wounded Vietnam veterans. American Journal of Public Health 86(5):662–667. Bulun SE, Zeitoun KM, Kilic G. 2000. Expression of dioxin-related transactivating factors and target genes in human eutopic endometrial and endometriotic tissues. American Journal of Obstetrics and Gynecology 182(4):767–775.

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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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691 OTHER HEALTH EFFECTS Cranmer M, Louie S, Kennedy RH, Kern PA, Fonseca VA. 2000. Exposure to 2,3,7,8-tetrachloro- dibenzo-p-dioxin (TCDD) is associated with hyperinsulinemia and insulin resistance. Toxico- logical Sciences 56(2):431–436. Cummings AM, Metcalf JL, Birnbaum L. 1996. Promotion of endometriosis by 2,3,7,8-tetrachloro- dibenzo-p-dioxin in rats and mice: time-dose dependence and species comparison. Toxicology and Applied Pharmacology 138:131–139. Dahlgren J, Warshaw R, Thornton J, Anderson-Mahoney CP, Takhar H. 2003. Health effects on nearby residents of a wood treatment plant. Environmental Research 92(2):92–98. Dalton TP, Kerzee JK, Wang B, Miller M, Dieter MZ, Lorenz JN, Shertzer HG, Nerbert DW, Puga A. 2001. Dioxin exposure is an environmental risk factor for ischemic heart disease. Cardio- vascular Toxicology 1(4):285–298. De Felip E, Porpora MG, di Domenico A, Ingelido AM, Cardelli M, Cosmi EV, Donnez J. 2004. Dioxin-like compounds and endometriosis: A study on Italian and Belgian women of reproduc- tive age. Toxicology Letters 150(2):203–209. De Roos AJ, Cooper GS, Alavanja MC, Sandler DP. 2005b. Rheumatoid arthritis among women in the Agricultural Health Study: Risk associated with farming activities and exposures. Annals of Epidemiology 15(10):762–770. Eisen S, Goldberg J, True W, Henderson W. 1991. A co-twin control study of the effects of the Viet- nam War on the self-reported physical health of veterans. American Journal of Epidemiology 134:49–58. Emond C, Michalek JE, Birnbaum LS, DeVito MJ. 2005. Comparison of the use of physiologically based pharmacokinetic model and a classical pharmacokinetic model for dioxin exposure as- sessments. Environmental Health Perspectives 113(12):1666–1668. Eskenazi B, Mocarelli P, Warner M, Samuels S, Vercellini P, Olive D, Needham LL, Patterson DG Jr, Brambilla P, Gavoni N, Casalini S, Panazza S, Turner W, Gerthoux PM. 2002. Serum dioxin concentrations and endometriosis: A cohort study in Seveso, Italy. Environmental Health Per- spectives 110(7):629–634. Fett M, Nairn J, Cobbin D, Adena M. 1987. Mortality among Australian conscripts of the Vietnam conflict era. II. Causes of death. American Journal of Epidemiology 125:878–884. Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. 2004. The burden of adult hyperten- sion in the United States 1999 to 2000: A rising tide. Hypertension 44(4):398–404. Fierens S, Mairesse H, Heilier JF, De Burbure C, Focant JF, Eppe G, De Pauw E, Bernard A. 2003. Dioxin/polychlorinated biphenyl body burden, diabetes and endometriosis: Findings in a popula- tion-based study in Belgium. Biomarkers 8(6):529–534. Flesch-Janys D. 1997/1998. Analyses of exposure to polychlorinated dibenzo-p-dioxins, furans, and hexachlorocyclohexane and different health outcomes in a cohort of former herbicide- producing workers in Hamburg, Germany. Teratogenesis, Carcinogenesis and Mutagenesis 17(4-5):257–264. Flesch-Janys D, Berger J, Gurn P, Manz A, Nagel S, Waltsgott H, Dwyer JH. 1995. Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany. American Journal of Epidemiology 142:1165–1175. Flesch-Janys D, Becher H, Berger J, Dwyer JH, Gurn P, Manz A, Nagel S, Steindorf K, Waltsgott H. 1998. Aspects of dose-response relationship of mortality due to malignant regeneration and cardiovascular diseases and exposure to polychlorinated dibenzodioxins and furans (PCDD/F) in an occupational cohort study. Arbeitsmedizin Sozialmedizin Umweltmedizin 24:54–59. Foster WG, Holloway AC, Hughes CL Jr. 2005. Dioxin-like activity and maternal thyroid hormone levels in second trimester maternal serum. American Journal of Obstetrics and Gynecology 193(6):1900–1907. Gambini G, Mantovani C, Pira E, Piolatto P, Negri E. 1997. Cancer mortality among rice growers in Novara Province, Northern Italy. American Journal of Industrial Medicine 31:435–441.

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693 OTHER HEALTH EFFECTS Jenkins MA, Clarke JR, Carlin JB, Robertson CF, Hopper JL, Dalton MF, Holst DP, Choi K, Giles GG. 1996. Validation of questionnaire and bronchial hyperresponsiveness against respira- tory physician assessment in the diagnosis of asthma. International Journal of Epidemiology 25(3):609–616. Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. 1998. Triglyceride concentration and ischemic heart disease: An eight-year follow-up in the Copenhagen Male Study. Circulation 97(11):1029–1036. Johnson KL, Cummings AM, Birnbaum LS. 1997. Promotion of endometriosis in mice by polychlo- rinated dibenzo-p-dioxins, dibenzofurans, and biphenyls. Environmental Health Perspectives 105(7):750–755. Johnson ES, Shorter C, Bestervelt LL, Patterson DG, Needham LL, Piper WN, Lucier G, Nolan CJ. 2001. Serum hormone levels in humans with low serum concentrations of 2,3,7,8-TCDD. Toxicology and Industrial Health 17(4):105–112. Jokinen MP, Walker NJ, Brix AE, Sells DM, Haseman JK, Nyska A. 2003. Increase in cardiovas- cular pathology in female Sprague-Dawley rats following chronic treatment with 2,3,7,8- tetrachlorodibenzo-p-dioxin and 3,3’,4,4’,5-pentachlorobiphenyl. Cardiovascular Toxicology 3(4):299–310. Kang HK, Dalager NA, Needham LL, Patterson DG, Lees PSJ, Yates K, Matanoski GM. 2006. Health status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam. American Journal of Industrial Medicine 49(11):875–884. Kern PA, Said S, Jackson WG Jr, Michalek JE. 2004. Insulin sensitivity following agent orange expo- sure in Vietnam veterans with high blood levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Clinical Endocrinology and Metabolism 89(9):4665–4672. Ketchum NS, Michalek JE. 2005. Postservice mortality of Air Force veterans occupationally ex- posed to herbicides during the Vietnam War: 20-Year follow-up results. Military Medicine 170(5):406–413. Khorram O, Garthwaite M, Golos T. 2002. Uterine and ovarian aryl hydrocarbon receptor (ahr) and aryl hydrocarbon receptor nuclear translocator (arnt) MRNA expression in benign and malignant gynaecological conditions. Molecular Human Reproduction 8(1):75–80. Kim J-S, Lim HS, Cho SI, Cheong HK, Lim MK. 2003. Impact of Agent Orange exposure among Korean Vietnam veterans. Industrial Health 41(3):149–157. Kitamura K, Kikuchi Y, Watanabe S, Waechter G, Sakurai H, Takada T. 2000. Health effects of chronic exposure to polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans (PCDF) and coplanar PCB (Co-PCB) of municipal waste incinerator workers. Journal of Epidemiology 10(4):262–270. Kogan M, Clapp R. 1985. Mortality Among Vietnam Veterans in Massachusetts, 1972–1983. Massa- chusetts Office of the Commissioner of Veterans Services, Agent Orange Program. Kogevinas M, Becher H, Benn T, Bertazzi P, Boffetta P, Bueno-de-Mesquita H, Coggon D, Colin D, Flesch-Janys D, Fingerhut M, Green L, Kauppinen T, Littorin M, Lynge E, Mathews J, Neuberger M, Pearce N, Saracci R. 1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study. American Journal of Epidemiology 145(12):1061–1075. Kuller LH, Orchard TJ. 1988. The epidemiology of atherosclerosis in 1987: Unraveling a common- source epidemic. Clinical Chemistry 34(8B):B40–B48. Landi MT, Needham LL, Lucier G, Mocarelli P, Bertazzi PA, Caporaso N. 1997. Concentrations of dioxin 20 years after Seveso. Lancet 349(9068):1811. Landi MT, Consonni D, Patterson DG Jr, Needham LL, Lucier G, Brambilla P, Cazzaniga MA, Mocarelli P, Pesatori AC, Bertazzi PA, Caporaso NE. 1998. 2,3,7,8-Tetrachlorodibenzo-p-dioxin plasma levels in Seveso 20 years after the accident. Environmental Health Perspectives 106(5): 273–277. Lange JH. 2000. Reduced cancer rates in agricultural workers: A benefit of environmental and oc- cupational endotoxin exposure. Medical Hypothesis 55(5):383–385.

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