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Veterans and Agent Orange: Update 2006 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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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 processes (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 compounds (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 accident (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), determined 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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Veterans and Agent Orange: Update 2006 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 involving 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 described. 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 interventions 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 report 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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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 association between exposure to at least one compound of interest and chloracne. PORPHYRIA CUTANEA TARDA Porphyrias are uncommon disorders caused by deficiencies of enzymes involved 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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Veterans and Agent Orange: Update 2006 Conclusions from VAO and Updates On the basis of strong animal studies and case reports demonstrating induction 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 results 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 evidence of an association between exposure to at least one compound of interest and PCT.
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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 disorders 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 characterized 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. Parenchymal disease, or interstitial disease, generally includes disorders that cause inflammation and scarring of the deep lung tissue, including the air sacs and supporting 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 interpreting 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 cardiovascular diseases are often confused. In particular, when persons have both conditions 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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Veterans and Agent Orange: Update 2006 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 respiratory 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 significance). 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 committee 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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Veterans and Agent Orange: Update 2006 TABLE 9-1 Selected Epidemiologic Studies—Non-Malignant Respiratory Disease Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a OCCUPATIONAL New Studies Cohort studies Hoppin et al., 2006 US Agriculture Health Study, commercial applicators exposed to 2,4-D—cross-sectional study of wheeze 225 1.3 (1.0–1.7) Blair et al., 2005 US Agriculture Health Study—COPD mortality Private applicators 50 0.2 (0.2–0.3) Spouses 15 0.3 (0.2–0.7) ’t Mannetje et al., 2005 New Zealand phenoxy herbicide producers, 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., 2001 Males employees of the Dow Chemical 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., 1999 NIOSH mortality study of chemical workers 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., 1997/98** NIOSH follow-up study of production workers of sodium trichlorophenol and of 2,4,5-T ester contaminated with TCDD, chronic bronchitis and COPD 2 — Studies Reviewed in Update 1998 Kogevinas et al., 1997 Mortality of male and female international 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., 1996 Four German production facilities of phenoxy 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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Veterans and Agent Orange: Update 2006 Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a Ott and Zober, 1996* German workers exposed to trichlorophenol 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., 1996 Mortality of workers at a Dow Chemical 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., 1995 Swedish fisherman exposed to TCDD, 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., 1994* German workers exposed to trichlorophenol 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 et al., 1992 Cross-sectional study of self-reported prevalence of asthma among male farmers in Saskatchewan (1982–1983) Chlorinated hydrocarbons 31 0.8 (0.5–1.3)
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Veterans and Agent Orange: Update 2006 Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a Studies Reviewed in VAO Calvert et al., 1991** NIOSH cross-sectional study of production 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., 1991 Production of phenoxy herbicides and chlorophenols in four British plants, mortality from nonmalignant respiratory diseases, 1963–1985 8 0.7 (0.3–1.3) Alavanja et al., 1989 PMR study of USDA soil and forest conservationists, mortality from nonmalignant respiratory diseases (ICD-9 460-519), 1970–1979 80 0.8 (0.6–1.0) Coggon et al., 1986 British plant manufacturing MCPA, mortality from nonmalignant respiratory diseases (ICD-9 460–519), 1947–1983 93 0.6 (0.5–0.8) Suskind and Hertzberg, 1984 Cross-sectional study of the Nitro, West Virginia, plant that manufactured 2,4,5-T, 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., 1983 Licensed pesticide applicators, Florida, 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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Veterans and Agent Orange: Update 2006 Reference Study Population Exposed Casesa Estimated Relative Risk (95% CI)a ENVIRONMENTAL Studies Reviewed in Update 2004 Dahlgren et al., 2003 Cross-sectional study among residents 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., 2001 Follow-up of 1976 accident in Seveso, Italy, 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)
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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 evidence 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 Following 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 Application 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: Epidemiologic 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 conservationists. 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. 1 Throughout the report the same alphabetic indicator following year of publication is used consistently 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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