6
Epidemiologic Studies

In seeking evidence for associations between health outcomes and exposure to herbicides and TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), many different kinds of epidemiologic studies must be considered. Each study type has varying degrees of strengths and weaknesses and contributes evidence to an association with the health outcomes considered in Chapters 710. The three main groups of individuals studied with respect to herbicide exposure are those with occupational, environmental, and military exposures. The committee highly values studies of Vietnam veterans, but does not consider either the presence or absence of a particular health effect in a study of veterans to be definitive. The committee believes that a broad based evaluation meets its charge under P.L.102–4 to “determine, to the extent that available data permitted meaningful determinations... whether a statistical association with herbicide exposure exists.”

A detailed description of the groups studied was examined in Chapter 2 of Veterans and Agent Orange (hereafter referred to as VAO) (IOM, 1994). A discussion of the criteria for inclusion in the review is detailed in Appendix A of VAO.

This chapter summarizes the epidemiologic studies and reports reviewed by the committee. Included are new studies published after Veterans and Agent Orange: Update 1998 (hereafter, Update 1998) (IOM, 1999), studies that were not reviewed by the committees that wrote the prior reports, and studies that have been updated since publication of Update 1998. Tables 6–1, 6–2, and 6–3 (which begin on page 182) provide a brief overview of the epidemiologic studies reviewed in both the prior reports and this document. The summaries include the study method used and, if available, how the study subjects were selected; how



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Veterans and Agent Orange: Update 2000 6 Epidemiologic Studies In seeking evidence for associations between health outcomes and exposure to herbicides and TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), many different kinds of epidemiologic studies must be considered. Each study type has varying degrees of strengths and weaknesses and contributes evidence to an association with the health outcomes considered in Chapters 7–10. The three main groups of individuals studied with respect to herbicide exposure are those with occupational, environmental, and military exposures. The committee highly values studies of Vietnam veterans, but does not consider either the presence or absence of a particular health effect in a study of veterans to be definitive. The committee believes that a broad based evaluation meets its charge under P.L.102–4 to “determine, to the extent that available data permitted meaningful determinations... whether a statistical association with herbicide exposure exists.” A detailed description of the groups studied was examined in Chapter 2 of Veterans and Agent Orange (hereafter referred to as VAO) (IOM, 1994). A discussion of the criteria for inclusion in the review is detailed in Appendix A of VAO. This chapter summarizes the epidemiologic studies and reports reviewed by the committee. Included are new studies published after Veterans and Agent Orange: Update 1998 (hereafter, Update 1998) (IOM, 1999), studies that were not reviewed by the committees that wrote the prior reports, and studies that have been updated since publication of Update 1998. Tables 6–1, 6–2, and 6–3 (which begin on page 182) provide a brief overview of the epidemiologic studies reviewed in both the prior reports and this document. The summaries include the study method used and, if available, how the study subjects were selected; how

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Veterans and Agent Orange: Update 2000 the data were collected; the inclusion criteria; and how exposure was determined. The tables also list the numbers of subjects in the study and comparison populations, and provide a brief description of the study. No studies are evaluated in this chapter; rather, a methodologic framework is provided for the health outcome chapters that follow. Qualitative critique of the study design, population size, methods of data collection, case and control ascertainment, or quality of exposure assessment has been reserved for the individual health outcome chapters in which the results of these studies are discussed. The text and tables in this chapter are organized into three basic sections— occupational studies, environmental studies, and studies of Vietnam veterans— with subsections included under each heading. The studies address exposures to 2,4-D (2,4-dichlorophenoxyacetic acid); 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) and its contaminant TCDD; cacodylic acid; and picloram. In some cases, the committee examined studies addressing compounds chemically related to the herbicides used in Vietnam, such as 2-methyl-4-chlorophenoxyacetic acid (MCPA), hexachlorophene, and chlorophenols, including trichlorophenol. In other instances, investigators did not indicate specific herbicides to which study participants were exposed or the level of exposure. These complicating factors were considered when the committee weighed the relevance of a study to its findings. Where available, details are given with regard to exposure assessment and how exposure was subsequently used in the analysis. The occupational section includes studies of production workers, agricultural and forestry workers (including herbicide and pesticide appliers), and paper and pulp workers, as well as case-control studies of specific cancers and the association with exposures to herbicides or related compounds. The environmental section includes studies of populations accidentally exposed to unusual levels of herbicides or dioxins as a result of the location in which they live, for example, the residents of Seveso, Italy; Times Beach, Missouri; and the southern portion of Vietnam. The section on Vietnam veterans includes studies conducted in the United States by the Air Force; the Centers for Disease Control and Prevention (CDC), the Department of Veterans Affairs (DVA, formerly the Veterans Administration [VA]); the American Legion; and the State of Michigan, as well as other groups. Studies of Australian Vietnam veterans are also presented there. Many cohorts potentially exposed to dioxin and the herbicides used in Vietnam are monitored on an ongoing basis. Studies of the groups that are assessed regularly include the National Institute for Occupational Safety and Health (NIOSH), International Agency for Research on Cancer (IARC), National Cancer Institute (NCI), Seveso, and Ranch Hand cohorts. Typically, the risks between exposure to herbicides and specific health outcomes are updated every 3 to 5 years. For example, the health of the Ranch Hand cohort was assessed in 1982, 1987, 1992, and 1997. For such studies, the committee has chosen to focus on the most recent update, when multiple reports on the same cohort are available. For the sake of thoroughness, the discussion of specific

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Veterans and Agent Orange: Update 2000 health outcomes in Chapters 7–10 includes reference to all studies, including those subsumed by the most recent update. Similarly, researchers investigating the constituent cohorts used in some large multicenter studies may publish reports based solely on the individuals they monitor. Examples include the I ARC and NCI cohort studies. The committee has chosen to focus on the studies of the larger multicenter cohorts. However, for the sake of thoroughness, Chapters 7–10 reference all of these studies, including those subsumed by the larger multicenter cohorts. OCCUPATIONAL STUDIES Several occupational groups in the United States and elsewhere have been exposed to the types of herbicides used in Vietnam and, more specifically, to TCDD, a contaminant of some herbicides and other products. Occupational groups exposed to these chemicals include farmers, agricultural and forestry workers, herbicide sprayers, workers in chemical production plants, and workers involved in paper and pulp manufacturing. In addition, studies that use job titles as broad surrogates of exposure and studies that rely on disease registry data have been conducted. Exposure characterization varies widely in these studies in terms of measurement, quantification, level of detail, confounding by other exposures, and individual versus surrogate or group (ecological) measures. Production Workers National Institute for Occupational Safety and Health In 1978, NIOSH began a study to identify all U.S. workers potentially exposed to TCDD between 1942 and 1984 (Fingerhut et al., 1991). In a total of 12 chemical companies, 5,132 workers were identified from personnel and payroll records as having been involved in production or maintenance processes associated with TCDD contamination. Their possible exposure resulted from working with certain chemicals in which TCDD was a contaminant, including 2,4,5-trichlorophenol (TCP) and 2,4,5-T, Silvex, Erbon, Ronnel, and hexachlorophene. An additional 172 workers identified previously by their employers as being exposed to TCDD were also included in the study cohort. The 12 plants involved were large manufacturing sites of major chemical companies. Thus, many of the study subjects were potentially exposed to many other chemicals, some of which could be carcinogenic. Prior to the publication of the cohort study, NIOSH conducted a cross-sectional study that included a comprehensive medical history, medical examination, and measurement of pulmonary function of workers employed in the manufacture of chemicals with TCDD contamination at two of the plants in the full cohort. These included workers at two chemical plants in Newark, New Jersey,

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Veterans and Agent Orange: Update 2000 from 1951 to 1969, and in Verona, Missouri, from 1968 to 1969 and from 1970 to 1972 (Sweeney et al., 1989, 1993; Calvert et al., 1991, 1992; Alderfer et al., 1992). The plant in New Jersey manufactured TCP and 2,4,5-T; the Missouri plant manufactured TCP, 2,4,5-T, and hexachlorophene. A number of studies were later conducted that looked at specific health outcomes among the cohort, including pulmonary function (Calvert et al., 1991), liver and gastrointestinal function (Calvert et al., 1992), mood (Alderfer et al., 1992), the peripheral nervous system (Sweeney et al., 1993), porphyria cutanea tarda (Calvert et al., 1994), and reproductive hormones (Egeland et al., 1994). Sweeney et al. (1996, 1997/1998) also evaluated noncancer end points including liver function, gastrointestinal disorders, chloracne, serum glucose, hormone and lipid levels, and diabetes in a subgroup of the original Calvert et al. (1991) cohort. A cross-sectional medical survey reported blood serum TCDD concentrations and surrogates of cytochrome P450 induction in that cohort (Halperin et al., 1995). VAO, Veterans and Agent Orange: Update 1996 (hereafter, Update 1996) and Update 1998 describe the details of each of those studies. Since Update 1998, Calvert et al. (1998, 1999) and Halperin et al. (1998) have published follow-up results on the cohort of workers employed more than 15 years earlier at the chemical plants in New Jersey and Missouri. Occupationally exposed individuals were compared to a referent group composed of age-, neighborhood-, race-, and sex-matched individuals with no self-reported occupational exposure to TCDD. The relationship between serum TCDD concentrations (measured as picograms per gram of lipid) and various end points were assessed in those follow-up reports. In Calvert et al. (1998) the association between exposure to TCDD and cardiovascular effects (increased risk of myocardial infarction, angina, cardiac arrhythmias, hypertension, and abnormal peripheral arterial flow) was examined in the cohort. Blood samples were analyzed for total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, and glucose. A general physical examination was conducted, which included measurement of blood pressure, as well as a Doppler examination of the peripheral pulses, a chest X-ray, and electrocardiograms (ECG). Calvert et al. (1999) examined the relationship among TCDD exposure and diabetes mellitus, thyroid function, and indicators of endocrine function in the same cohort. Serum glucose, thyroid-stimulating hormone, total thyroxine (T4), and thyroid hormone binding resin levels were measured. Halperin et al. (1998) evaluated immune parameters in this cohort; lymphocyte subsets, natural killer cell cytotoxic activity, and lymphocyte proliferative responses to stimulation were studied. Steenland et al. (1999) studied the association between TCDD exposure and cause of death in the cohort from the 12 U.S. chemical plants described by Fingerhut et al. (1991). Those researchers investigated any association between exposure and cancer (all and site specific), respiratory disease, cardiovascular disease, and diabetes. In addition, a similar analysis was conducted in a subgroup

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Veterans and Agent Orange: Update 2000 of workers who had previously been diagnosed with chloracne, indicating a higher exposure to TCDD on average. Monsanto Included in the NIOSH study cohort (Fingerhut et al., 1991) are a number of individual cohort members from Monsanto’s production facilities on whom studies have been conducted. One set of Monsanto studies is based on an accidental exposure that occurred on March 8, 1949, in the trichlorophenol production process at the Nitro, West Virginia, plant of Monsanto (Zack and Suskind, 1980; Moses et al., 1984; Collins et al., 1993). Other studies focused on exposure of Monsanto workers involved in numerous aspects of 2,4,5-T production (Zack and Gaffey, 1983; Moses et al., 1984; Suskind and Hertzberg, 1984). These studies are discussed in more detail in VAO. No new studies have been published on these cohorts. Dow Several studies have been conducted on Dow Chemical Company production workers and are summarized in VAO, Update 1996, and Update 1998. The populations in these studies, except for one report by Bond et al. (1988), are included in the NIOSH cohort (Fingerhut et al., 1991). Originally, Dow Chemical Company conducted a study on the work force engaged in the production of 2,4,5-T (Ott et al., 1980) and a study on TCP manufacturing workers exhibiting chloracne (Cook et al., 1980). Extension and follow-up studies compared potential exposure to TCDD and medical examination frequency and morbidity (Bond et al., 1983), as well as reproductive outcomes after potential paternal TCDD exposure (Townsend et al., 1982). A prospective mortality study was also conducted of Dow employees diagnosed with chloracne or classified as having chloracne on the basis of clinical description (Bond et al., 1987). In addition, Dow Chemical Company assembled a large cohort at the Midland, Michigan, plant (Cook et al., 1986, 1997; Bond et al., 1989b). Exposure to TCDD was characterized in this cohort based on chloracne diagnosis (Bond et al., 1989a). Within this large Midland cohort, a cohort study of women (Ott et al., 1987) and a case-control study of soft-tissue sarcoma (STS) (Sobel et al., 1987) were conducted. Dow Chemical Company has also undertaken a large-scale cohort mortality study of workers exposed to herbicides in several Dow plants (Bond et al., 1988; Bloemen et al., 1993; Ramlow et al., 1996). No new studies have been published on the Dow cohort since Update 1998.

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Veterans and Agent Orange: Update 2000 BASF In Germany, an accident on November 17, 1953, during the manufacture of trichlorophenol at BASF Aktiengesellschaft, resulted in the exposure of some workers in the plant to predominantly TCDD. VAO, Update 1996, and Update 1998 summarize studies of these workers. The studies include a mortality study of persons initially exposed or later involved in cleanup operations (Thiess et al., 1982), an update and expansion of that study (Zober et al., 1990), and a morbidity follow-up (Zober et al., 1994). In addition, Ott and Zober (1996) examined cancer incidence and mortality in another cohort of workers exposed to TCDD after the accident during reactor cleanup, maintenance, or demolition. Since Update 1998, Zober et al. (1997) have summarized their studies on the BASF cohort, but no new analyses of the cohort have been reported. IARC To avoid problems of small studies with insufficient power to detect increased cancer risks, IARC created a multinational registry of workers exposed to phenoxy herbicides, chlorophenols, and their contaminants (Saracci et al., 1991). The IARC registry includes information on mortality and exposures of 18,390 workers—16,863 men and 1,527 women. Update 1996 describes the individual national cohorts included in this multinational registry. In a study including cohorts from 10 countries, cancer mortality from soft-tissue sarcoma (STS) and malignant lymphoma was evaluated (Kogevinas et al., 1992). Two nested case-control studies were also undertaken within this cohort to evaluate the relationship between STS and non-Hodgkin’ s lymphoma (Kogevinas et al., 1995). In an update and expansion, Kogevinas et al. (1997) assembled national studies from 12 countries that used the same protocol, jointly developed by study participants and coordinated by IARC, and studied cancer mortality. A cohort study of cancer incidence and mortality was conducted among 701 women occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins from seven countries (Kogevinas et al., 1993). VAO, Update 1996, and Update 1998 highlight these studies. In addition, a number of the individual cohorts have been evaluated apart from the IARC-coordinated efforts. These cohorts include Danish production workers studied by Lynge (1985, 1993); British production workers studied by Coggon et al. (1986, 1991); Dutch production workers studied by Bueno de Mesquita et al. (1993); and German production workers studied by Manz et al. (1991), Becher et al. (1996), and Flesch-Janys et al. (1995). VAO, Update 1996, and Update 1998 discuss these studies in more detail. Since Update 1998, Vena et al. (1998) published a study on nonneoplastic mortality in the cohort in which Kogevinas et al. (1997) studied cancer mortality. The cohort is composed of 21,863 workers who were employed in the production

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Veterans and Agent Orange: Update 2000 or spraying of phenoxyacetic herbicides. In the study by Vena et al. (1998), data on workers from all 36 cohorts from 12 countries were studied; data for workers from cohorts for which minimum employment periods were specified were not included. Exposures were estimated by job records, company exposure questionnaires, and in some cohorts, serum, adipose, or workplace TCDD measurements. Workers were divided into three exposure categories: exposed to TCDD or higher-chlorinated dioxins, not exposed, and unknown exposure status. Standard mortality ratios (SMRs) were calculated for all major noncancer causes of death. Hooiveld et al. (1998) analyzed data from one study at a factory in the Netherlands that followed the protocol of, and was included in, the IARC study. Exposure status was based on departmental occupational history, as well as exposure to the accident. Serum concentrations of poly chlorinated dibenzodioxins (PCDDs), poly chlorinated dibenzofurans (PCDFs), and poly chlorinated biphenyls (PCBs) were measured in a subset of survivors who were employed prior to the end of the last TCDD-contaminated process. Maximum TCDD concentrations were estimated from the measured TCDD concentrations using a one-compartment, first-order kinetic model and a half-life of 7.1 years. SMRs and relative risks were calculated by cause of death in two cohorts: 549 male workers exposed to phenoxy herbicides, chlorophenols, and contaminants; and 140 male workers exposed as a result of an accident at the plant. Flesch-Janys (1997) summarized exposure and mortality data on employees of the Hamburg Boehringer Company plant that produced 2,4,5-T, 2,4,5-TCP, and hexachlorocyclohexane (HCH) until 1984. The cohort, which had been studied previously by Flesch-Janys et al. (1995), consisted of all regular employees of a chemical plant (N=1,189 males). Flesch-Janys (1997) used half-life data previously determined in a subgroup of the cohort (Flesch-Janys et al., 1996) to estimate blood TCDD levels in 190 workers. From that they determined department-specific exposures and, from that, estimated exposures (TCDD and toxic equivalents) for the entire cohort (Flesch-Janys et al., 1995). Using these estimates, dose-response analyses were conducted for SMRs from different causes of death. Neuberger et al. (1999) studied the health effects of TCDD in an Austrian cohort that is part of the IARC study. Preliminary results are presented in Neuberger et al. (1998) and in an article with an English abstract (Jäger et al., 1998). Individuals in the Austrian cohort had been diagnosed with chloracne and were exposed to poly chlorinated dibenzodioxin or dibenzofuran (PCDD/F) (mainly TCDD) in a 2,4,5-T production facility in Linz, Austria. At the time of the study, of 159 individuals identified as having chloracne, 124 remained in Austria and were invited to participate in a health examination survey: 56 individuals participated in the survey and 50 individuals donated blood and urine and answered all questions. Age- and sex-matched controls who had recently participated in health checkups similar to those of the cases were employed. Two such control groups were used, one drawn from the same occupational health center in Linz and one

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Veterans and Agent Orange: Update 2000 from another prospective study on workers from a chemical plant located 66 km from the 2,4,5-T plant. Occupational and medical histories, including smoking and alcohol consumption, were obtained from cases and controls. PCDF, PCDD, and PCB concentrations were measured in plasma. Chloracne, general health status (e.g., neurological symptoms, liver disease, stomach problems, arthritis), and clinical chemistry parameters (e.g., blood sugar, cholesterol, enzyme levels, leukocyte levels) were assessed in the three groups. Other Chemical Plants Previous studies have reviewed health outcomes among chemical workers in the United Kingdom exposed to TCDD as a result of an industrial accident in 1968 (May, 1982, 1983; Jennings et al., 1988); production workers in the former USSR involved in the production of 2,4-D (Bashirov, 1969); factory workers in Prague, Czechoslovakia, who exhibited symptoms of TCDD toxicity 10 years after occupational exposure to 2,4,5-T (Pazderova-Vejlupkova et al., 1981); 2,4-D and 2,4,5-T production workers in the United States (Poland et al., 1971); white male workers employed at a chemical plant in the United States manufacturing flavors and fragrances (Thomas, 1987); and the long-term immune system effects of TCDD in 11 industrial workers involved in production and maintenance operations at a German chemical factory producing 2,4,5-T (Tonn et al., 1996). VAO and Update 1998 detail these studies. Since Update 1998, Hryhorczuk et al. (1998) has examined employees in a chemical plant in southwestern Illinois who were engaged in the production of PCP, lower-chlorinated phenols, and esters of chlorophenoxy acids. The study population was defined based on company personnel records. The unexposed comparison population consisted of workers from the same plant who, according to company records, had never worked in areas where they would have been exposed to PCP. Of the 743 eligible exposed workers, 473 participated in the medical examination, of whom 366 were engaged in the production of PCP. Of the 559 eligible unexposed workers, 303 participated in the medical examination. The exposed and unexposed groups were examined for general health status, chloracne, and porphyria. Jung et al. (1998) evaluated immune effects in a cohort of workers formerly employed at a German pesticide-producing plant. Of 450 former workers, 192 (8 women) chose to participate in comprehensive health status checks that were offered following the closing of the plant and were used in the study. PCDD/F concentrations were measured in blood lipids and expressed as toxicity equivalents (TEQs). Study participants were observed clinically and were asked about medical and work history. Measurements of immunological parameters, including erythrocyte sedimentation rate, full blood count, serum electrophoresis, presence of specific antibodies, immunoglobulin (Ig) levels, and lymphocyte surface marker measurements, were conducted. The results of specific tests, however,

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Veterans and Agent Orange: Update 2000 were not presented for the full cohort (e.g., tetanus antibodies before and 3 weeks after vaccination, N=53; IgA, IgG, and IgM levels, N=53). No explanation is provided for the variable number of participants in the different immunological assays. In addition, a subgroup of the 29 most highly exposed individuals was compared to 28 unexposed individuals for proliferation of lymphocytes and chromate resistance. Agricultural and Forest Products Workers Cohort Studies Agricultural Workers VAO, Update 1996, and Update 1998 detail a number of cohort studies examining health effects in individuals involved in agricultural activity. These include studies of proportionate mortality among Iowa farmers (Burmeister, 1981) and among male and female farmers from 23 states (Blair et al., 1993); cancer mortality among Danish and Italian farmers (Ronco et al., 1992) and among a cohort of rice growers in the Novara Province of northern Italy (Gambini et al., 1997); cancer incidence among farmers licensed to spray pesticides in the southern Piedmont area of Italy (Corrao et al., 1989) and among female Danish gardeners (Hansen et al., 1992); sperm abnormalities among Argentinean farmers (Lerda and Rizzi, 1991); cancer birth defects among the offspring of Norwegian farmers (Kristensen et al., 1997); and immunological changes in 10 farmers who mixed and applied commercial formulations containing the chlorophenoxy herbicides (Faustini et al., 1996). In addition, a set of Canadian studies, called the Mortality Study of Canadian Male Farm Operators, evaluated the risk to farmers of general mortality and specific health outcomes including non-Hodgkin’s lymphoma (NHL) (Wigle et al., 1990; Morrison et al., 1994), prostate cancer (Morrison et al., 1992), brain cancer (Morrison et al., 1993), multiple myeloma (Semenciw et al., 1993), leukemia (Semenciw et al., 1994), and asthma (Senthilselvan et al., 1992). Based on data from the Swedish Cancer Environment Register (which links population census data, including occupation, with the Swedish Cancer Registry), cohort studies evaluated cancer mortality and farm work (Wiklund, 1983); STS and malignant lymphoma among agricultural and forestry workers (Wiklund and Holm, 1986; Wiklund et al., 1988a); and the risk of NHL, Hodgkin’s disease (HD), and multiple myeloma in relation to numerous occupational activities (Eriksson et al., 1992). Brain, lymphatic, and hematopoietic cancers in Irish agricultural workers have also been studied (Dean, 1994). Since Update 1998, Arbuckle et al. (1999) examined the incidence of spontaneous abortion in couples living on family farms in Ontario, Canada, selected from the 1986 Canadian Census of Agriculture. Farming families were contacted by telephone and were considered eligible if they were married or “living as married,” if they lived year-round on the farm, and if the wife was not older than

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Veterans and Agent Orange: Update 2000 44. Eligible families were sent three questionnaires. One questionnaire, addressed to the farm operator, collected data on pesticide use (current and historical use). Another questionnaire, addressed to the husband, collected demographic, socioeconomic, and life-style information, medical history, and information on his activities on the farm, date of moving to the farm, and pesticide exposures both at home and on the farm. Another questionnaire, addressed to the wife, collected information similar to that of the husbands, but also collected a complete reproductive history. Pesticide use was recorded by specific pesticide by month and year. Spontaneous abortion occurrence was self-reported at <20 weeks of gestation and was categorized by occurrence at <12 weeks and occurrence between 12 and 19 weeks of gestation. This subgrouping provided an indirect estimate of the frequency of chromosomal anomalies because these anomalies are a much more common cause of early abortions than later abortions. Pregnancy outcome data were merged with pesticide use at the corresponding time. Potential confounders were also recorded (e.g., parental age, smoking, alcohol consumption), along with the time period during which they were present. Telephone screening identified 2,946 eligible couples (36.5 percent of all operating farms). Pregnancies were excluded if there was missing information (e.g., outcome, delivery date, gestational age at delivery), if it occurred when the woman was not living on the farm, if the study husband might not have been the father, or in the case of multiple gestations, ectopic pregnancies, or hydatidiform mole pregnancies. A total of 2,110 women were enrolled in the study with a total of 5,853 pregnancies, of which 3,396 were included in the analysis. Forestry Workers Studies have been conducted among forestry workers potentially exposed to the types of herbicides used in Vietnam. These studies include a cohort mortality study among men employed at a Canadian public utility (Green, 1987, 1991) and a briefly outlined Dutch study of forestry workers exposed to 2,4,5-T that investigated the prevalence of acne and liver dysfunction (van Houdt et al., 1983). VAO describes these studies in greater detail. Since Update 1998, Thörn et al. (2000) have reported on mortality and cancer incidence in a cohort of Swedish lumberjacks. The cohort analyzed consisted of males and females who were Swedish residents and employed by one Swedish forestry company at some time between 1954 and 1967. Approximate volume and concentration of phenoxy acids used daily in a particular work task or job category were obtained from former employees. Pay slips were used to determine time spent at particular work tasks, and exposure to phenoxy acids was estimated by the time spent at particular job categories. Employees who were exposed to phenoxy acids for more than 5 working days were considered to have been exposed; employees not exposed to any types of pesticides were used as the unexposed or control group; individuals who were exposed to other pesticides (including DDT) were excluded from the study. Mortality was determined from the National Register of Causes of Death, new cancer cases were determined

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Veterans and Agent Orange: Update 2000 from the Swedish Cancer Register, and death certificates with underlying cause of death were provided by Statistics Sweden. Data were available for 261 exposed and 243 unexposed members of the cohort. SMRs and cancer incidence (all and site specific) ratios were calculated for each group using ratios expected from the death and cancer registries. Herbicide and Pesticide Sprayers A number of cohort studies have assessed health outcomes among herbicide and pesticide appliers including cancer mortality among Swedish railroad workers (Axelson and Sundell, 1974; Axelson et al., 1980), mortality among pesticide appliers in Florida (Blair et al., 1983), general and cancer mortality and morbidity measured prospectively among Finnish male 2,4-D and 2,4,5-T appliers (Riihimaki et al., 1982, 1983; Asp et al., 1994), and reproductive outcomes among male chemical appliers in New Zealand (Smith et al., 1981, 1982). Other studies examined the risk of cancer including STS, HD, and NHL among pesticide and herbicide appliers in Sweden (Wiklund et al., 1987, 1988b, 1989a, b), general and cancer mortality among Dutch male herbicide appliers (Swaen et al., 1992), cancer mortality among Minnesota highway maintenance workers (Bender et al., 1989) and Minnesota pesticide appliers (Carry et al., 1994, 1996a, b), lung cancer morbidity in male agricultural plant protection workers in the former German Democratic Republic (Barthel, 1981), British Columbia sawmill workers potentially exposed to chlorophenate wood preservatives (Dimich-Ward et al., 1996; Hertzman et al., 1997; Heacock et al. 1998), and cancer risk among pesticide users in Iceland (Zhong and Rafnsson, 1996). Some of these studies include agricultural and forestry worker cohorts; the details are included in VAO, Update 1996, and Update 1998. More recently, data from the first 2 years of a 10-year Agricultural Health Study in Iowa and North Carolina have been published (Alavanja et al., 1998). In that study, pesticide appliers completed a self-administered questionnaire that asked about hospital or doctor visits resulting from pesticide exposures. Questionnaires were administered at testing and training sessions, which are required every 3 years for certification or recertification of pesticide appliers in these states. Out of 51,256 appliers who attended the sessions, 35,879 (3 percent of those enrolled in the study were women and 3.1 percent were minorities) completed the questionnaire, which asked about general information on pesticide use, as well as specific information on the use of 50 individual pesticides. In addition, for 22 pesticides, information on the number of years and the average number of days of application per year was gathered. Questions on the use of protective clothing, application procedures, crops and livestock raised in the past year, farm size, smoking and alcohol consumption history, diet, and basic demographics were included. Cumulative lifetime application days for herbicides, insecticides, fumigants, and fungicides were calculated based on the responses, and relative risks for health care visits were determined. Dich and Wiklund (1998) studied a cohort of 20,025 males who were li-

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Veterans and Agent Orange: Update 2000 CDC, 1988a Cohort VES—random sample of U.S. Army enlisted men 1965–1971: psychosocial outcomes 2,490 1,972 CDC, 1988b Cohort VES: physical health outcomes 2,490 1,972 CDC, 1988c Cohort VES: reproductive outcomes 12,788 children 11,910 children CDC, 1987; Boyle et al., 1987 Cohort VES: mortality 9,324 8,989 Erickson et al., 1984a, b Case-control CDC birth defects study of children born in the Atlanta area between 1968 and 1980, comparing fathers’ Vietnam experience and potential Agent Orange exposure between birth defects cases and normal controls 7,133 4,246 New Department of Veterans Affairs (DVA) Studies Kang et al., 2000 Cohort Self-reported pregnancy outcomes for female Vietnam veterans compared to contemporary veterans not deployed to Vietnam. Odds ratios were calculated for reproductive history and various birth defects 3,392 women; 1,665 women with an indexed pregnancy 3,038 women; 1,912 women with an indexed pregnancy DVA Studies Reviewed in Update 1998 Dalager and Kang, 1997 Cohort Morbidity and mortality experience (1968– 1987) of Army Chemical Corps Vietnam veterans compared to U.S. men; extension of Thomas and Kang (1990) 2,872 2,737 Mahan et al., 1997 Case-control Study of lung cancer among Vietnam veterans (1983–1990) 329 269 men hospitalized without cancer; 111 patients with colon cancer

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Veterans and Agent Orange: Update 2000 Reference Study Design Description Study Group (N) Comparison Group (N)a McKinney et al., 1997 Cross-sectional Study of the smoking behavior of veterans and nonveterans using the 1987 National Medical Expenditure Survey (NMES) 15,000 — Bullman and Kang, 1996 Cohort Mortality study of veterans with nonlethal (combat and noncombat) wounds sustained during the Vietnam war 34,534 — Watanabe and Kang, 1996 Cohort Mortality experience (1965–1988) of Army and Marine Corps Vietnam veterans; extension of Breslin et al. (1988) and Watanabe et al. (1991) 33,833 36,797 Dalager et al., 1995b Case-control Cases of HD diagnosed 1969–1985 among Vietnam era veterans 283 404 Watanabe and Kang, 1995 Cohort Postservice mortality among Marine Vietnam veterans 10,716 9,346 DVA Studies Reviewed in Update 1996 Dalager et al., 1995a Cohort Update of Thomas et al. (1991) through December 31, 1995 4,586 5,325 Bullman et al., 1994 Case-control Study of the association between testicular cancer and surrogate measures of exposure to Agent Orange in male Vietnam veterans 97 311

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Veterans and Agent Orange: Update 2000 DVA Studies Reviewed in VAO Bullman et al., 1991 Case-control PTSD cases in Vietnam veterans compared to Vietnam veterans without PTSD for association with traumatic combat experience 374 373 Dalager et al., 1991 Case-control Cases of NHL diagnosed 1969–1985 among Vietnam era veterans compared to cases of other malignancies among Vietnam era veterans for association with Vietnam service 201 358 Eisen et al., 1991 Cohort Health effects of male monozygotic twins serving in the armed forces during Vietnam era (1965–1975) 2,260 2,260 Thomas et al., 1991 Cohort Mortality experience (1973–1987) among women Vietnam veterans compared to women non-Vietnam veterans and for each cohort compared to U.S. women 4,582 5,324 Watanabe et al., 1991 Cohort Mortality experience (1965–1984) of Army and Marine Corps Vietnam veterans compared to: (1) branch-specific (Army and Marine) Vietnam era veterans; (2) all Vietnam era veterans combined; (3) the U.S. male population 24,145 Army, 5,501 Marines (1) 27,145 Army, 4,505 Marines (2) 32,422 combined Vietnam era (3) U.S. male population Bullman et al., 1990 Cohort Mortality experience of Army I Corps Vietnam veterans compared to Army Vietnam era veterans 6,668 deaths 27,917 deaths

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Veterans and Agent Orange: Update 2000 Reference Study Design Description Study Group (N) Comparison Group (N)a Farberow et al., 1990 Case-control Psychological profiles and military factors associated with suicide and motor vehicle accident (MVA) fatalities in Los Angeles County Vietnam era veterans (1977–1982) 22 Vietnam suicides; 19 Vietnam era suicides 21 Vietnam MVA; 20 Vietnam era MVA Thomas and Kang, 1990 Cohort Morbidity and mortality experience (1968– 1987) of Army Chemical Corps Vietnam veterans compared to U.S. men 894 — True et al., 1988 Cross-sectional PTSD and Vietnam combat experience evaluated among Vietnam era veterans 775 1,012 Breslin et al., 1988 Burt et al., 1987 Cohort Mortality experience (1965–1982) of Army and Marine Corps Vietnam veterans, compared to Vietnam era veterans who did not serve in Southeast Asia standardized by age and race; nested case-control study of NHL 24,235 26,685 Kang et al., 1987 Case-control STS cases (1975–1980) diagnosed at the Armed Forces Institute of Pathology, compared to controls identified from patient logs of referring pathologists or their departments for association with Vietnam service and likelihood of Agent Orange exposure 217 599 Kang et al., 1986 Case-control STS cases (1969–1983) in Vietnam era veterans for association with branch of Vietnam service as a surrogate for Agent Orange exposure 234 13,496

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Veterans and Agent Orange: Update 2000 American Legion Studies Reviewed in VAO Snow et al., 1988 Cohort Assessment of PTSD in association with traumatic combat experience among American Legionnaires serving in Southeast Asia (1961– 1975) 2,858 Study group subdivided for internal comparison Stellman et al., 1988b Cohort Assessment of physical health and reproductive outcomes among American Legionnaires who served in Southeast Asia (1961–1975) for association with combat and herbicide exposure 2,858 3,933 Stellman et al., 1988c Cohort Assessment of social and behavioral outcomes among American Legionnaires who served in Southeast Asia (1961–1975) for association with combat and herbicide exposure 2,858 3,933 State Studies Reviewed in Update 1998 Clapp, 1997 Case-control Selected cancers identified (1988–1993) among Massachusetts Vietnam veterans, compared to Massachusetts Vietnam era veterans with cancers of other sites; update of Clapp et al. (1991) 245 999 State Studies Reviewed in Update 1996 Visintainer et al., 1995 Cohort Mortality experience (1965–1971) among male Michigan Vietnam veterans, compared to non-Vietnam veterans from Michigan 3,364 deaths 5,229 deaths State Studies Reviewed in VAO Fiedler and Gochfeld, 1992; Kahn et al., 1992a, b, c Cohort New Jersey study of outcomes in select group of herbicide-exposed Army, Marine, and Navy Vietnam veterans, compared to veterans self-reported as unexposed 10 Pointman I 55 Pointman II 17 Pointman I 15 Pointman II

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Veterans and Agent Orange: Update 2000 Reference Study Design Description Study Group (N) Comparison Group (N)a Clapp et al., 1991 Case-control Selected cancers identified (1982–1988) among Massachusetts Vietnam veterans, compared to Massachusetts Vietnam era veterans with cancers of other sites 214 727 Deprez et al., 1991 Descriptive Study of Maine Vietnam veterans compared to atomic test veterans and general population for health status and reproductive outcomes 249 113 atomic test veterans Levy, 1988 Cross-sectional Study of PTSD in chloracne as indicator of TCDD-exposed and control Vietnam veterans in Massachusetts 6 25 Anderson et al., 1986a Cohort Mortality experience of Wisconsin veterans compared to nonveterans (Phase 1); mortality experience of Wisconsin Vietnam veterans and Vietnam era veterans compared to nonveterans and other veterans (Phase 2) 110,815 white male veteran deaths; 2,494 white male Vietnam era veteran deaths; 923 white male Vietnam veteran deaths 342,654 white male nonveteran deaths 109,225 white male other veteran deaths Anderson et al., 1986b Cohort Mortality experience of Wisconsin Vietnam era veterans and Vietnam veterans compared to U.S. men, Wisconsin men, Wisconsin nonveterans, and Wisconsin other veterans 122,238 Vietnam era veterans 43,398 Vietnam veterans —

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Veterans and Agent Orange: Update 2000 Goun and Kuller, 1986 Case-control Cases of STS, NHL, and selected rare cancers compared to controls without cancer for Vietnam experience in Pennsylvania men (1968–1983) 349 349 deceased Holmes et al., 1986 Cohort Mortality experience (1968–1983) of West Virginia veterans, Vietnam veterans, and Vietnam era veterans compared to nonveterans; Vietnam veterans compared to Vietnam era veterans 615 Vietnam veterans 610 Vietnam era veterans — Pollei et al., 1986 Cohort Study of chest radiographs of New Mexico Agent Orange Registry Vietnam veterans compared to radiographs of control Air Force servicemen for pulmonary and cardiovascular pathology 422 105 Kogan and Clapp, 1985, 1988 Cohort Mortality experience (1972–1983) among white male Massachusetts Vietnam veterans, compared to non-Vietnam veterans and to all other nonveteran white males in Massachusetts 840 deaths 2,515 deaths of Vietnam era veterans Lawrence et al., 1985 Cohort Mortality experience of New York State (1) Vietnam era veterans compared to nonveterans and (2) Vietnam veterans compared to Vietnam era veterans (1) 4,558 (2) 555 17,936 941 Rellahan, 1985 Cohort Study of health outcomes in Vietnam era (1962–1972) veterans residing in Hawaii associated with Vietnam experience 232 186

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Veterans and Agent Orange: Update 2000 Reference Study Design Description Study Group (N) Comparison Group (N)a Wendt, 1985 Descriptive Descriptive findings of health effects and potential exposure to Agent Orange among Iowa veterans who served in Southeast Asia 10,846 None Greenwald et al., 1984 Case-control Cases of STS in New York State compared to controls without cancer for Vietnam service and herbicide exposure including Agent Orange, dioxin, or 2,4,5-T 281 281 live controls 130 deceased controls Newell, 1984 Cross-sectional Preliminary (1) cytogenetic, (2) sperm, and (3) immune response tests in Texas Vietnam veterans compared to controls (1) 30 (2) 32 (3) 66 30 32 66 Other U.S. Veteran Studies Reviewed in VAO Tarone et al., 1991 Case-control Study of cases between January 1976 and June 1981 with testicular cancer (18–42 years old) compared to hospital controls for association with Vietnam service 137 130 Aschengrau and Monson, 1990 Case-control Study of cases with late adverse pregnancy outcomes compared to normal control births for association with paternal Vietnam service (1977–1980) 857 congenital anomalies 61 stillbirths 48 neonatal deaths 998 Goldberg et al., 1990 Cohort Study of male twin pairs who served in Vietnam era (1965–1975) for association between Vietnam service and PTSD 2,092 2,092

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Veterans and Agent Orange: Update 2000 Aschengrau and Monson, 1989 Case-control Association between husband’s military service and women having spontaneous abortion at or by 27 weeks compared to women delivering at 37 weeks 201 1,119 Australian Studies New Australian Studies AIHW, 1999 Cohort Validation of the male veterans study (CDVA, 1998a) using medical documents, doctors’ certification and records on a disease or death registry 6,842 — CDVA, 1998a Cohort Self-reported data on male members of the Australian Defence Force and the Citizen Military Force who landed in Vietnam or entered Vietnamese water. Questions on physical (including reproductive history) and mental health, and that of their partner(s) and children 49,944 mailed; 39,955 responded — CDVA, 1998b Cohort Self-reported data on female members of the Australian Defence Force and the Citizen Military Force who landed in Vietnam or entered Vietnamese water. Questions on physical (including reproductive history) and mental health, and that of their partner(s) and children 278 mailed 225 responded — Australian Studies Reviewed in Update 1998 Crane et al., 1997a Cohort Mortality experience (through 1994) of Australian veterans who served in Vietnam 59,036 males 484 females —

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Veterans and Agent Orange: Update 2000 Reference Study Design Description Study Group (N) Comparison Group (N)a Crane et al., 1997b Cohort Mortality experience (through 1994) of Australian national servicemen who served in Vietnam 18,949 24,646 O’Toole et al., 1996a, b, c Cross-sectional Survey of self-reported health status (1989– 1990) of Australian Army Vietnam veterans 641 — Australian Studies Reviewed in VAO Field and Kerr, 1988 Cohort Study of Tasmanian Vietnam veterans compared to neighborhood controls for adverse reproductive and childhood health outcomes 357 281 Fett et al., 1987a Cohort Australian study of mortality experience of Vietnam veterans compared to Vietnam era veterans through 1981 19,205 25,677 Fett et al., 1987b Cohort Australian study of cause-specific mortality experience of Vietnam veterans compared to Vietnam era veterans through 1981 19,205 25,677 Forcier et al., 1987 Cohort Australian study of mortality in Vietnam veterans by job classification, location, and time of service 19,205 Internal comparison

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Veterans and Agent Orange: Update 2000 Donovan et al., 1983, 1984 Case-control Australian study of cases of congenital anomalies in children born (1969–1979), compared to infants born without anomalies for association with paternal Vietnam service 8,517 8,517 Other Vietnam Veterans Studies Reviewed in Update 1998 Chinh et al., 1996 Cohort Study of antinuclear antibodies and sperm autoantibodies among Vietnamese veterans who served 5–10 years in a “dioxin- sprayed zone” 25 63 age-matched controls; 36 additional male controls NOTE: CDVA=Commonwealth Department of Veterans’ Affairs; HD=Hodgkin’s disease; NHL=non-Hodgkin’s lymphoma; PTSD=posttraumatic stress disorder; STS=soft-tissue sarcoma; Update 1998=Veterans and Agent Orange: Update 1998 (IOM, 1999); Update 1996=Veterans and Agent Orange: Update 1996 (IOM, 1996); VAO=Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994). aThe dash ( —) indicates the comparison group is based on a population (e.g., U.S. white males, country rates), with details given in the text for specifics of the actual population.