4

Overview of Epidemiologic Studies

In seeking evidence of associations between health outcomes and exposure to herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), many kinds of epidemiologic studies must be considered. Each study type has different strengths and weaknesses (see Chapter 2), and each contributes evidence of an association with the health outcomes considered in Chapters 69 of this report. This chapter provides an overview of the design of new epidemiologic studies and reports reviewed by the committee. They include studies published since Veterans and Agent Orange: Update 2000 (hereafter, Update 2000) (IOM, 2001), studies that had been published but were not reviewed by the committees that wrote the prior reports, and studies that have been updated since publication of Update 2000. Tables 4-1, 4-2, and 4-3 provide a brief overview of the study design of epidemiologic studies reviewed in both the prior reports and this document. The summaries include the study method used and, if it is known, how the study subjects were selected; how the data were collected; and the inclusion criteria. The tables also list the numbers of subjects in the study and comparison populations and provide brief descriptions of the studies. The purpose of this chapter is to provide a methodologic framework for the health-outcome chapters that follow; no studies are evaluated and results are not discussed in this chapter. The committee's evaluations are presented in the health-outcome chapters. Qualitative critique— of study design, population size, methods of data collection, case and control ascertainment, and exposure assessment —has been reserved for the individual health-outcome chapters.

The text and tables in this chapter are organized into three basic sections— occupational studies, environmental studies, and studies of Vietnam veterans.



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Veterans and Agent Orange: Update 2002 4 Overview of Epidemiologic Studies In seeking evidence of associations between health outcomes and exposure to herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), many kinds of epidemiologic studies must be considered. Each study type has different strengths and weaknesses (see Chapter 2), and each contributes evidence of an association with the health outcomes considered in Chapters 6–9 of this report. This chapter provides an overview of the design of new epidemiologic studies and reports reviewed by the committee. They include studies published since Veterans and Agent Orange: Update 2000 (hereafter, Update 2000) (IOM, 2001), studies that had been published but were not reviewed by the committees that wrote the prior reports, and studies that have been updated since publication of Update 2000. Tables 4-1, 4-2, and 4-3 provide a brief overview of the study design of epidemiologic studies reviewed in both the prior reports and this document. The summaries include the study method used and, if it is known, how the study subjects were selected; how the data were collected; and the inclusion criteria. The tables also list the numbers of subjects in the study and comparison populations and provide brief descriptions of the studies. The purpose of this chapter is to provide a methodologic framework for the health-outcome chapters that follow; no studies are evaluated and results are not discussed in this chapter. The committee's evaluations are presented in the health-outcome chapters. Qualitative critique— of study design, population size, methods of data collection, case and control ascertainment, and exposure assessment —has been reserved for the individual health-outcome chapters. The text and tables in this chapter are organized into three basic sections— occupational studies, environmental studies, and studies of Vietnam veterans.

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Veterans and Agent Orange: Update 2002 Detailed descriptions of many of the study populations are in Chapter 2 of Veterans and Agent Orange (hereafter referred to as VAO) (IOM, 1994), and the criteria for inclusion in the review are discussed in Appendix A of that report. The studies reviewed addressed exposures to 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant TCDD, cacodylic acid, and picloram. The committee also examined some studies that addressed 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 the specific herbicides to which study participants were exposed or the magnitude of exposure; these complicating factors were considered when the committee weighed the relevance of a study to its findings. If they were available, details of exposure assessment and use of exposure in the analysis are discussed in Chapter 5. The occupational section covers studies of production workers, agricultural and forestry workers (including herbicide and pesticide appliers), and paper and pulp workers. The environmental section covers studies of populations accidentally exposed to unusual concentrations of herbicides or dioxins as a result of where they live, such as Seveso, Italy; Times Beach, Missouri; and the southern portion of Vietnam. The section on Vietnam veterans covers studies conducted in the United States by the Air Force, the Centers for Disease Control and Prevention (CDC), the Department of Veterans Affairs (VA), the American Legion, and the state of Michigan; it also notes studies of Australian Vietnam veterans. Many cohorts potentially exposed to dioxins and the herbicides used in Vietnam are monitored periodically, typically every 3–5 years (such as the cohorts of the National Institute for Occupational Safety and Health (NIOSH), the International Agency for Research on Cancer (IARC), the National Cancer Institute (NCI), Seveso, and Ranch Hand). For the sake of thoroughness, the discussions of specific health outcomes in Chapters 6–9 include references to studies discussed in previous Agent Orange reports and new studies, but in making its conclusions, the committee focuses on the most recent update when multiple reports on the same cohorts and end points are available. Individual researchers who are a part of research consortia evaluating cohorts in large multicenter studies (such as the IARC and NCI cohort studies) sometimes publish reports based solely on the subset of subjects they themselves are monitoring. All the studies are discussed in this report, but when making its conclusions, the committee focuses on the studies of 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 to TCDD. Occupational

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Veterans and Agent Orange: Update 2002 groups that have been studied include workers in chemical production plants; agricultural and forestry workers, including farmers and herbicide sprayers; and workers in paper and pulp manufacturing. In addition, some studies use job titles as broad surrogates of exposure or rely on disease-registry data. Exposure characterization varies widely among studies in the exposure metric used, extent of detail, confounding by other exposures, and whether individual or surrogate or group (ecologic) measures are used. Production Workers National Institute for Occupational Safety and Health Starting in 1978, NIOSH began a study to identify all US workers potentially exposed to TCDD in 1942–1984 (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 chemicals in which TCDD was a contaminant, including 2,4,5-trichlorophenol (TCP), 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, so many of the subjects were potentially exposed to many other chemicals, some of which could be carcinogenic. Before the publication of the first study of the main cohort, 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. The cross-sectional study included comparison of workers at one plant in Newark, New Jersey, in 1951–1969 and at one plant in Verona, Missouri, in 1968–1969 and 1970–1972 with neighborhood controls (Sweeney et al., 1989, 1993; Calvert et al., 1991, 1992; Alderfer et al., 1992). The New Jersey plant manufactured TCP and 2,4,5-T, and the Missouri plant manufactured TCP, 2,4,5-T, and hexachlorophene. A number of later studies 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), effects on the peripheral nervous system (Sweeney et al., 1993), porphyria cutanea tarda (Calvert et al., 1994), and effects on reproductive hormones (Egeland et al., 1994). Sweeney et al. (1996, 1997/1998) evaluated noncancer end points, including liver function, gastrointestinal disorders, chloracne, serum glucose concentration, hormone and lipid concentrations, and diabetes in a subgroup of the original Calvert et al. (1991) cohort. Recent studies of the main cohort looked at cardiovascular effects (Calvert et al., 1998); diabetes mellitus, thyroid function, and

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Veterans and Agent Orange: Update 2002 endocrine function (Calvert et al., 1999); and immune characteristics (Halperin et al., 1998). Cross-sectional medical surveys reported serum TCDD concentrations and surrogates of cytochrome P450 induction (Halperin et al., 1995) in that cohort. In addition, a follow-up study by Steenland et al. (1999) examined the association between TCDD exposure and cause of death; it looked at specific health outcomes, including cancer (all and site-specific), respiratory disease, cardiovascular disease, and diabetes. VAO, Veterans and Agent Orange: Update 1996 (hereafter, Update 1996), Update 1998, and Update 2000 describe the details of those studies. Since Update 2000, Steenland et al. (2001), acting on a research recommendation in Update 1998, published a paper that reanalyzed data from two published studies on TCDD and diabetes mellitus: one in US workers (the NIOSH cohort; Calvert et al., 1999) and one in veterans of operation Ranch Hand in which the herbicides were sprayed from planes in Vietnam (Henriksen et al., 1997). Female subjects and nonexposed subjects with serum TCDD greater than 10 ppt were excluded from the NIOSH cohort to make its study design closer to that of the Ranch Hand study. For the analysis by TCDD concentration, NIOSH exposed subjects whose TCDD concentrations were unknown were excluded (N = 8). Exposure-response analysis by back-extrapolated TCDD was conducted for exposed subjects (those with TCDD over 10 ppt). Those with TCDD of 10 ppt or lower were considered part of the nonexposed group. The combined study population consisted of 2,759 men: 494 from the NIOSH cohort (267 exposed and 227 nonexposed) and 2,265 from the Ranch Hands (990 exposed and 1,275 nonexposed). A subject was considered to have diabetes on the basis of having been diagnosed by a physician, an oral glucose tolerance test of over 200 mg/dL (as was used in the Ranch Hands study), or a fasting glucose of 126 mg/dL or more (as was used in the NIOSH study). Covariates considered included smoking history, alcohol history, family history of diabetes, body-mass index, year of birth, race, current use of medications that might contribute to diabetes or increased serum glucose, and education. Data were analyzed for prevalence of diabetes, fasting glucose, and time from last exposure to diagnosis of diabetes. A separate analysis of data from each cohort and an analysis of the combined data were conducted for each outcome. A reanalysis of an earlier published chemical plant study conducted by the National Institute for Occupational Safety and Health (NIOSH) suggested that although cancer incidence may increase at high dioxin exposures, this increase is preceded by a significant reduction in tumor incidence at lower exposures (Kayajanian, 2002). Monsanto Included in the NIOSH study cohort (Fingerhut et al., 1991) were a number of people at Monsanto's production facilities on whom studies have been con-

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Veterans and Agent Orange: Update 2002 ducted. One set of Monsanto studies was based on an accidental exposure that occurred on March 8, 1949, in the TCP production process at the Nitro, West Virginia, plant (Zack and Suskind, 1980; Moses et al., 1984; Collins et al., 1993). Others 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). The Monsanto studies are discussed in more detail in VAO. No new studies have been published on these subjects. Dow Chemical Company Several studies have been conducted on Dow Chemical Company production workers and are summarized in VAO, Update 1996, Update 1998, and Update 2000. The populations in these studies, except for one report by Bond et al. (1988), were included in the NIOSH cohort (Fingerhut et al., 1991). Originally, Dow conducted a study on workers 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 with medical-examination frequency and morbidity (Bond et al., 1983), and reproductive outcomes after potential paternal TCDD exposure (Townsend et al., 1982). A prospective mortality study of Dow employees diagnosed with chloracne or classified as having chloracne on the basis of clinical description (Bond et al., 1987) was also conducted. In addition, Dow assembled a large cohort at the Midland, Michigan, plant (Cook et al., 1986, 1987; Bond et al., 1989b). Exposure to TCDD was characterized in this cohort on the basis of 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 has also undertaken a large-scale cohort mortality study of workers exposed to herbicides in several of its plants (Bond et al., 1988; Bloemen et al., 1993; Ramlow et al., 1996). Since Update 2000, an update on mortality in a cohort of 1,517 Dow employees was published (Burns et al., 2001), extending the follow-up to 1994. A job–exposure matrix assessing potential phenoxy herbicide exposure for 1945– 1982 had been created by an industrial hygienist with categories for time-weighted average 2,4-D concentrations of greater than 1.0 mg/m3, 0.1–1.0 mg/m3, and less than 0.1 mg/m3. For follow-up from 1983 to 1994, a new category of “very low” was added for jobs that had nondetectable exposure-monitoring concentrations or in which less than 50% of time was spent in a low-exposure area and no time was spent in a high-exposure area. The limit of detection of the monitoring was not specified by the authors. A total of 495 workers worked for any length of time in either high- or moderate-exposure jobs. Standardized mortality ratios were calculated to compare the total male cohort of 1,517 workers with the US population.

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Veterans and Agent Orange: Update 2002 To control for the healthy-worker effect, comparisons were made with an internal reference cohort of all other Dow employees at the Midland plant. For the exposed cohort, the total number of person-years of follow-up was 39,799, for an average of 26.2 years. BASF In Germany, an accident on November 17, 1953 during the manufacture of TCP at BASF Aktiengesellschaft resulted in the exposure of some workers in the plant predominantly to TCDD. VAO, Update 1996, and Update 1998 summarize studies on those workers. The studies include a mortality study of persons initially exposed or later involved in cleanup (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. No new studies have been published on those cohorts since Update 1998. International Agency for Research on Cancer 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 exposure of 18,390 workers—16,863 men and 1,527 women. Update 1996 describes the individual national cohorts included in the registry. In a study including individuals from 10 countries, cancer mortality from STS and malignant lymphoma was evaluated (Kogevinas et al., 1992). Two nested case–control studies were also undertaken using the IARC 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. Vena et al. (1998) studied nonneoplastic mortality in the IARC cohorts. A cohort study of cancer incidence and mortality was conducted among 701 women from seven countries who were occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins (Kogevinas et al., 1993). VAO, Update 1996, Update 1998, and Update 2000 highlight those studies. In addition, a number of the smaller cohorts that comprise the IARC cohort have been evaluated apart from the IARC-coordinated efforts. They 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); German production workers studied by Manz et

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Veterans and Agent Orange: Update 2002 al. (1991), Becher et al. (1996), Flesch-Janys et al. (1995), and Flesch-Janys (1997); factory workers from the Netherlands studied by Hooiveld et al. (1998); and Austrian production workers studied by Neuberger et al. (1998, 1999) and Jäger et al. (1998). VAO, Update 1996, Update 1998, and Update 2000 discuss those studies in more detail. No new studies have been published on the IARC cohort or the smaller cohorts that comprise the IARC cohort. Other Chemical Plants Studies have reviewed health outcomes among chemical workers in the UK exposed to TCDD as a result of an industrial accident in 1968 (May, 1982, 1983; Jennings et al., 1988), production workers in the former Soviet Union involved in the production of 2,4-D (Bashirov, 1969), factory workers in Prague 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 men employed at a US chemical plant manufacturing flavors and fragrances (Thomas, 1987), and US chemical workers engaged in the production of PCP, lower-chlorinated phenols, and esters of chlorophenoxy acids (Hryhorczuk et al. 1998); 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); and immune effects in a cohort of workers formerly employed at a German pesticide-producing plant (Jung et al. 1998). VAO, Update 1998, and Update 2000 detail those studies. No studies at other chemical plants have been published since Update 2000. Agricultural and Forestry Workers Cohort Studies Agricultural Workers VAO, Update 1996, Update 1998, and Update 2000 detail a number of cohort studies examining health effects in people involved in agricultural activity. They include studies of proportionate mortality among Iowa farmers (Burmeister, 1981) and among male and female farmers in 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 Argentine farmers (Lerda and Rizzi, 1991), cancer birth defects among the offspring of Norwegian farmers (Kristensen et al., 1997), the incidence of spontaneous abortion in couples living on family farms in Ontario, Canada (Arbuckle et al. 1999), and immunologic changes in 10 farmers who mixed and applied commer-

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Veterans and Agent Orange: Update 2002 cial 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 death 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). On the basis of 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 2000, Masley et al. (2000) have conducted a cross-sectional survey of households in an agriculture-based rural area of Saskatchewan, Canada, to understand the short-term effects of environmental pesticide exposure on immune, neurobehavioral, and lung function. Some 3,327 people living in 1,185 private households in three towns or three rural municipalities were targeted in the survey; 875 households (74%) accepted the canvassing package, and 549 (46%) returned a completed questionnaire. Designed to be answered by an adult household representative, the questionnaire included sections about physical environmental factors (occupational and home or garden pesticide or fertilizer use, and so on), demographic characteristics of people living in the household, and general health problems, health concerns, or respiratory symptoms of each person in the household. The proportion of households using pesticide and fertilizer was determined by dividing the total number of “yes” responses by the number of “yes” and “no” responses (missing responses were not included). In addition, a number of studies have been published on the basis of data from the Ontario Family Farm Health Study, a Canadian research effort investigating male pesticide exposures and pregnancy outcomes. Update 2000 discusses a study in which Arbuckle et al. (1999) examined the incidence of spontaneous abortion in couples selected from the 1986 Canadian Census of Agriculture and living on family farms in Ontario. 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 44 years. Eligible families were sent three questionnaires. One questionnaire, addressed to the farm operator, collected data on current and historical pesticide use. A second, addressed to the husband, collected demographic, socioeconomic, and lifestyle information; medical history; and information on his activities on the farm, date of moving to the farm, and pesticide exposure both at home and on the farm. A third, addressed to the wife, collected information similar to that on the husbands but

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Veterans and Agent Orange: Update 2002 also collected a complete reproductive history. Pesticide use was recorded for specific pesticides by month and year. Pregnancy-outcome data were merged with pesticide use at the corresponding times. Potential confounders were recorded (such as parental age, smoking, and alcohol consumption), as was the period during which they were present. Telephone screening identified 2,946 eligible couples (36.5% of all operating farms), among whom 1,898 (64%) completed all three questionnaires. Pregnancies were excluded if there was missing information (such as outcome, delivery date, or gestational age at delivery), if they 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. The 2,110 women enrolled in the study had a total of 5,853 pregnancies. Since Update 2000, three other studies have been identified that report reproductive outcomes from that questionnaire and that cohort. Savitz et al. (1997) investigated the effects of male pesticide exposure on a number of pregnancy outcomes, including number of live births, number of preterm births, number of small-for-gestational-age births, number of miscarriages, and sex ratios. Of the 5,853 pregnancies of the 2,110 women enrolled in the study, 3,984 were included in the analysis. Curtis et al. (1999) examined the effect of pesticide exposure on time to pregnancy in the same cohort. For all “planned” pregnancies (pregnancies that occurred when the women reported not using any form of birth control) they recorded any method of birth control that the couple had discontinued to try to conceive and the number of months or cycles it took to conceive. They analyzed 1,048 couples and 2,012 planned pregnancies. Arbuckle et al. (2001) conducted further analyses of the data from that cohort to explore the critical windows of exposure (the point during gestation at which the fetus is sensitive to pesticide exposure), the target sites of interactions among the pesticides, and other risk factors for spontaneous abortion. Spontaneous-abortion data were correlated with exposure information to determine pesticide-exposure opportunities in the months leading up to conception, during the first trimester, and in early term (less than 12 weeks) or late term (12–19 weeks). In this study, 2,010 women participated and provided information on 3,936 pregnancies. Forestry Workers Studies have been conducted among forestry workers potentially exposed to the types of herbicides used in Vietnam. The 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 con-

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Veterans and Agent Orange: Update 2002 sisted of men and women who were Swedish residents and were employed by one Swedish forestry company at some time in the period 1954– 1967. The 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 the time spent in particular work tasks, and exposure to phenoxy acids was estimated from the time spent in 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 nonexposed or control group; people 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 from the Swedish Cancer Register, and death certificates with cause of death were provided by Statistics Sweden. Data were available on 261 exposed and 243 unexposed members of the cohort. Standardized mortality ratios and cancer incidence (all and site-specific) ratios were calculated for each group by 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), reproductive outcomes among male chemical appliers in New Zealand (Smith et al., 1981, 1982), and doctor visits resulting from pesticide exposure in Iowa and North Carolina (Alavanja et al., 1998). Other studies examined the risk of cancer—including STS, HD, NHL, and prostate cancer—among pesticide and herbicide appliers in Sweden (Dich and Wiklund, 1998; 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 (Garry 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 those studies included agricultural- and forestry-worker cohorts; details of the study design and results are included in VAO, Update 1996, Update 1998, and Update 2000. Since Update 2000, Hoppin et al. (2002) have conducted a study that examined chemical predictors of wheeze among pesticide appliers in Iowa and North Carolina in the Agricultural Health Study. Of 52,000 farmers certified for pesticide application, 20,468 farmer applicators completed both an enrollment and a

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Veterans and Agent Orange: Update 2002 secondary questionnaire and were included in the study. Of the respondents, 3,838 recorded episodes of wheeze in the previous year when responding to this question: “How many episodes of wheezing in your chest have you had in the past 12 months. No wheezing or whistling, 1–2 episodes, 3–6 episodes, 7–12 episodes, more than 12 episodes.” Pesticide exposures and related activities of study participants were assessed in relation to episodes of wheeze. A base logistic-regression model controlling for age, state, smoking history (current, past, or never), and asthma-atopy status was evaluated for the exposures. Case–Control Studies In 1977, case-series reports in Sweden (Hardell, 1977, 1979) of a potential connection between soft-tissue sarcoma and exposure to phenoxyacetic acids prompted several case–control studies in Sweden to investigate the possible association (Hardell and Sandstrom, 1979; Eriksson et al., 1979, 1981, 1990; Hardell and Eriksson, 1988; Wingren et al., 1990). After the initial reports on STS (Hardell, 1977, 1979), case–control studies of other cancer outcomes were also conducted in Sweden, including studies of HD, NHL, and other lymphomas (Hardell et al., 1980, 1981; Hardell and Bengtsson, 1983); HD and NHL (Persson et al., 1989, 1993); NHL (Olsson and Brandt, 1988; Hardell and Eriksson, 1999); nasal and nasopharyngeal carcinomas (Hardell et al., 1982); gastric cancer (Ekström et al., 1999); and primary or unspecified liver cancer (Hardell et al., 1984). To address criticism regarding potential observer bias in some of the case– control series, Hardell (1981) conducted another case–control study on colon cancer. Hardell et al. (1994) also examined the relationship between occupational exposure to phenoxyacetic acids and chlorophenols and various characteristics related to NHL—including histopathologic measures, stage, and anatomic location—on the basis of the NHL cases from a previous study (Hardell et al., 1981). Prompted by the Swedish studies (Hardell, 1977, 1979), Smith and co-workers undertook a set of case–control studies in New Zealand to evaluate the association between phenoxy herbicide and chlorophenol exposure and STS incidence and mortality (Smith et al., 1983, 1984; Smith and Pearce, 1986). Additional case–control studies and an expanded case series were conducted on phenoxy herbicide and chlorophenol exposure and the risks of malignant lymphoma, NHL, and multiple myeloma (Pearce et al., 1985, 1986a,b, 1987). Geographic patterns of increased leukemia mortality in white men in the central part of the United States prompted a study of the leukemia mortality in Nebraska farmers (Blair and Thomas, 1979). Additional case–control studies were later conducted on leukemia in Nebraska (Blair and White, 1985), in Iowa (Burmeister et al., 1982) on the basis of the cohort study of Burmeister (1981), in Iowa and Minnesota (Brown et al., 1990), and on leukemia associated with NHL in eastern Nebraska (Zahm et al., 1990). Case–control studies have been conducted in various US populations on

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Veterans and Agent Orange: Update 2002 Hoffman RE, Stehr-Green PA, Webb KB, Evans RG, Knutsen AP, Schramm WF, Staake JL, Gibson BB, Steinberg KK. 1986. Health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of the American Medical Association 255:2031–2038. Holmes AP, Bailey C, Baron RC, Bosanac E, Brough J, Conroy C, Haddy L. 1986. West Virginia Department of Health Vietnam-Era Veterans Mortality Study, Preliminary Report. Charleston: West Virginia Health Department. Hooiveld M, Heederik DJ, Kogevinas M, Boffetta P, Needham LL, Patterson DG Jr, Bueno-de-Mesquita HB. 1998. Second follow-up of a Dutch cohort occupationally exposed to phenoxy herbicides, chlorophenols, and contaminants. American Journal of Epidemiology 147(9):891– 901. Hoppin JA, Umbach DM, London SJ, Alavanja CR, Sandler DP. 2002. Chemical predictors of wheeze among farmer pesticide applicators in the Agricultural Health Study. American Journal of Critical Care Medicine 165:683–689. Hryhorczuk DO, Wallace WH, Persky V, Furner S, Webster JR Jr, Oleske D, Haselhorst B, Ellefson R, Zugerman C. 1998. A morbidity study of former pentachlorophenol-production workers. Environmental Health Perspectives 106(7):401–408. Huong LD, Phuong NTN. 1983. The state of abnormal pregnancies and congenital malformations at the Gyneco-Obstetrical Hospital of Ho Chi Minh City (formerly Tu Du Hospital). Summarized in: Constable JD, Hatch MC. Reproductive effects of herbicide exposure in Vietnam: recent studies by the Vietnamese and others. As cited in Constable and Hatch, 1985. Ideo G, Bellati G, Bellobuono A, Mocarelli P, Marocchi A, Brambilla P. 1982. Increased urinary d-glucaric acid excretion by children living in an area polluted with tetrachlorodibenzo-para-dioxin (TCDD). Clinica Chimica Acta 120:273–283. Ideo G, Bellati G, Bellobuono A, Bissanti L. 1985. Urinary d-glucaric acid excretion in the Seveso area, polluted by tetrachlorodibenzo-p-dioxin (TCDD): five years of experience. Environmental Health Perspectives 60:151–157. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2000. Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes Washington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. Jäger R, Neuberger M, Rappe C, Kundi M, Pigler B, Smith AG. 1998. Chloracne and other symptoms 23 years after dioxin-exposure. Atemwegs-Und Lungenkrankheiten 24 (Suppl 1): S101–S104. Jansson B, Voog L. 1989. Dioxin from Swedish municipal incinerators and the occurrence of cleft lip and palate malformations. International Journal of Environmental Studies 34:99–104. Jappinen P, Pukkala E. 1991. Cancer incidence among pulp and paper workers exposed to organic chlorinated compounds formed during chlorine pulp bleaching. Scandinavian Journal of Work, Environment & Health 17:356–359. Jennings AM, Wild G, Ward JD, Ward AM. 1988. Immunological abnormalities 17 years after accidental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. British Journal of Industrial Medicine 45:701–704. Jung D, Berg PA, Edler L, Ehrenthal W, Fenner D, Flesch-Janys D, Huber C, Klein R, Koitka C, Lucier G, Manz A, Muttray A, Needham L, Päpke O, Pietsch M, Portier C, Patterson D, Prellwitz W, Rose DM, Thews A, Konietzko J. 1998. Immunological findings in formerly exposed workers to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds in pesticide production. Arbeitsmedizin Sozialmedizin Umweltmedizin, Supplement 24:38–43. Kahn PC, Gochfeld M, Nygren M, Hansson M, Rappe C, Velez H, Ghent-Guenther T, Wilson WP. 1988. Dioxins and dibenzofurans in blood and adipose tissue of Agent Orange-exposed Vietnam veterans and matched controls. Journal of the American Medical Association 259:1661– 1667

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Veterans and Agent Orange: Update 2002 Moses M, Lilis R, Crow KD, Thornton J, Fischbein A, Anderson HA, Selikoff IJ. 1984. Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: comparison of findings with and without chloracne. American Journal of Industrial Medicine 5:161–182. Musicco M, Sant M, Molinari S, Filippini G, Gatta G, Berrino F. 1988. A case-control study of brain gliomas and occupational exposure to chemical carcinogens: the risks to farmers. American Journal of Epidemiology 128:778–785. Nanni O, Amadori D, Lugaresi C, Falcini F, Scarpi E, Saragoni A, Buiatti E. 1996. Chronic lymphocytic leukæmias and non-Hodgkin's lymphomas by histological type in farming-animal breeding workers: a population case–control study based on a priori exposure matrices Occupational and Environmental Medicine 53(10):652–657. Nelson CJ, Holson JF, Green HG, Gaylor DW. 1979. Retrospective study of the relationship between agricultural use of 2,4,5-T and cleft palate occurrence in Arkansas. Teratology 19:377–383. Neuberger M, Kundi M, Jäger R. 1998. Chloracne and morbidity after diozin exposure (preliminary results) Toxicology Letters 96/97:347–350. Neuberger M, Rappe C, Bergek S, Cai H, Hansson M, Jager R, Kundi M, Lim CK, Wingfors H, Smith AG. 1999. Persistent health effects of dioxin contamination in herbicide production Environmental Research 81(3):206–214. Newell GR. 1984. Development and Preliminary Results of Pilot Clinical Studies. Report of the Agent Orange Advisory Committee to the Texas Department of Health. University of Texas System Cancer Center. Nguyen HD. 1983. Pregnancies at the Polyclinic of Tay Ninh Province. Summarized in: Constable JD, Hatch MC. Reproductive effects of herbicide exposure in Vietnam: recent studies by the Vietnamese and others. As cited in Constable and Hatch, 1985. Nurminen T, Rantala K, Kurppa K, Holmberg PC. 1994. Agricultural work during pregnancy and selected structural malformations in Finland. Epidemiology 1:23–30. O'Brien TR, Decoufle P, Boyle CA. 1991. Non-Hodgkin's lymphoma in a cohort of Vietnam veterans. American Journal of Public Health 81:758–760. Olsson H, Brandt L. 1988. Risk of non-Hodgkin's lymphoma among men occupationally exposed to organic solvents. Scandinavian Journal of Work, Environment & Health 14:246–251. O'Toole BI, Marshall RP, Grayson DA, Schureck RJ, Dobson M, Ffrench M, Pulvertaft B, Meldrum L, Bolton J, Vennard J. 1996a. The Australian Vietnam Veterans Health Study: I. Study design and response bias. International Journal of Epidemiology 25(2):307–318. O'Toole BI, Marshall RP, Grayson DA, Schureck RJ, Dobson M, Ffrench M, Pulvertaft B, Meldrum L, Bolton J, Vennard J. 1996b. The Australian Vietnam Veterans Health Study: II. Self-reported health of veterans compared with the Australian population. International Journal of Epidemiology 25(2):319–330. O'Toole BI, Marshall RP, Grayson DA, Schureck RJ, Dobson M, Ffrench M, Pulvertaft B, Meldrum L, Bolton J, Vennard J. 1996c. The Australian Vietnam Veterans Health Study: III. Psychological health of Australian Vietnam veterans and its relationship to combat International Journal of Epidemiology 25(2):331–340. Ott MG, Zober A. 1996. Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident. Occupational and Environmental Medicine 53(9): 606–612. Ott MG, Holder BB, Olson RD. 1980. A mortality analysis of employees engaged in the manufacture of 2,4,5-trichlorophenoxyacetic acid. Journal of Occupational Medicine 22:47–50. Ott MG, Olson RA, Cook RR, Bond GG. 1987. Cohort mortality study of chemical workers with potential exposure to the higher chlorinated dioxins. Journal of Occupational Medicine 29:422– 429. Pazderova-Vejlupkova J, Lukas E, Nemcova M, Pickova J, Jirasek L. 1981. The development and prognosis of chronic intoxication by tetrachlorodibenzo-p-dioxin in men. Archives of Environmental Health 36:5–11.

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