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Veterans and Agent Orange: Update 2002 (2003)

Chapter: 4. Overview of Epidemiologic Studies

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Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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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.

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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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 69 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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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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-

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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.

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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-

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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-

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

other cancers, including NHL (Cantor, 1982; Cantor et al., 1992; Zahm et al., 1993; Tatham et al., 1997); multiple myeloma (Morris et al., 1986; Boffetta et al., 1989; Brown et al., 1993); cancers of the stomach and prostate, NHL, and multiple myeloma (Burmeister et al., 1983); STS, HD, and NHL (Hoar et al., 1986); NHL and HD (Dubrow et al., 1988); and STS and NHL (Woods et al., 1987; Woods and Polissar, 1989).

Other studies outside the United States have looked at cancer end points: ovarian cancer in the Piedmont region of Italy (Donna et al., 1984); brain gliomas in two hospitals in Milan, Italy (Musicco et al., 1988); STS and other cancers in the 15 regional cancer registries that constitute the National Cancer Register in England (Balarajan and Acheson, 1984); STS and malignant lymphomas in the Victorian Cancer Registry of Australia (Smith and Christophers, 1992); lymphoid cancer in Milan, Italy (LaVecchia et al., 1989); STS among rice weeders in northern Italy (Vineis et al., 1986); primary lung cancer among pesticide users in Saskatchewan (McDuffie et al., 1990); and renal-cell carcinoma in the Denmark Cancer Registry (Mellemgaard et al., 1994). In addition, Nanni et al. (1996) conducted a population-based case –control study, based on the work of Amadori et al. (1995), of occupational and chemical risk factors for lymphocytic leukemia and NHL in northeastern Italy.

Noncancer end points have also been investigated in case–control studies. End points studied were spontaneous abortion (Carmelli et al., 1981); congenital malformations (García et al., 1998); immunosuppression and subsequently decreased host resistance to infection among AIDS patients with Kaposi's sarcoma (Hardell et al., 1987); mortality in US Department of Agriculture extension agents (Alavanja et al., 1988, 1989); spina bifida in offspring associated with paternal occupation (Blatter et al., 1997); mortality from neurodegenerative diseases associated with occupational risk factors (Schulte et al., 1996); Parkinson's disease (PD) associated with occupational and environmental risk factors (Liou et al., 1997); PD associated with various rural factors, including exposure to herbicides and wood preservatives (Seidler et al., 1996); PD associated with occupational risk factors (Semchuk et al., 1993); and birth defects in offspring of agricultural workers (Nurminen et al., 1994). Those studies are discussed in detail in VAO, Update 1996, or Update 1998. No new case–control studies of agricultural and forest workers have been published since Update 2000.

Paper and Pulp Workers

Workers in the paper and pulp industry can be exposed to TCDD and other dioxins that are generated during the bleaching process in the production and treatment of some paper and paper products. VAO describes studies of workers potentially exposed to TCDD in paper and pulp mills and various health outcomes, including general mortality in workers at five mills in Washington, Oregon, and California (Robinson et al., 1986); cancer incidence among male Finn-

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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ish paper-mill workers (Jappinen and Pukkala, 1991); respiratory health in a New Hampshire mill (Henneberger et al., 1989); and cause-specific mortality among white men employed in plants identified by the United Paperworkers International Union (Solet et al., 1989). Update 2000 describes studies of cancer risks among Danish workers in the paper industry (Rix et al., 1998) and oral-cancer risks among occupationally exposed workers in Sweden (Schildt et al., 1999). No new studies of paper and pulp workers have been published since Update 2000.

ENVIRONMENTAL STUDIES

The occurrence of accidents and industrial disasters has offered opportunities to evaluate the long-term health effects of exposure to TCDD and other potentially hazardous chemicals.

Seveso, Italy

One of the largest industrial accidents involving environmental exposures to TCDD occurred in Seveso, Italy, in July 1976 as a result of an uncontrolled reaction during trichlorophenol production. Of the various indicators used to estimate individual exposure, soil contamination with TCDD has been the most extensively used. On the basis of soil sampling, three areas were defined about the release point: zone A, the most heavily contaminated, from which all residents were evacuated within 20 days; zone B, an area of less contamination that children and pregnant women in their first trimester were urged to avoid during daytime; and zone R, a region with some contamination in which consumption of local crops was prohibited (Bertazzi et al., 1989a,b). Several cohort studies were conducted on the basis of those exposure categories. The studies are reviewed extensively in VAO, Update 1996, Update 1998, and Update 2000 and are summarized here.

Caramaschi et al. (1981) presented the distribution of chloracne among Seveso children, and Mocarelli et al. (1986) measured several chemicals in the blood and urine of children who had had chloracne. In a follow-up, dermatologic and laboratory tests were conducted among a group of the children with chloracne and controls (Assennato et al., 1989a).

Other studies looked at specific health effects associated with TCDD exposure among Seveso residents, including chloracne, birth defects, spontaneous abortion, and crude birth and death rates (Bisanti et al., 1980); chloracne and peripheral nervous system conditions (Barbieri et al., 1988); hepatic enzyme-associated conditions (Ideo et al., 1982, 1985); abnormal birth outcomes (Mastroiacovo et al., 1988); cytogenetic abnormalities in maternal and fetal tissues (Tenchini et al., 1983); neurologic disorders (Boeri et al., 1978; Filippini et al., 1981); cancer incidence (Pesatori et al., 1992, 1993; Bertazzi et al., 1993); and the sex ratio of offspring who were born in zone A (Mocarelli et al., 1996). A

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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2-year prospective controlled study was conducted of workers potentially exposed to TCDD during cleanup of the most highly contaminated areas after the accident (Assennato et al., 1989b).

Seveso residents have had long-term follow-up of their health outcomes, especially cancer. Bertazzi and colleagues conducted 10-year mortality follow-up studies among adults and children who were 1–19 years old at the time of the accident (Bertazzi et al., 1989a,b, 1992), 15-year follow-up studies (Bertazzi et al., 1997, 1998), and a 20-year follow-up study (Bertazzi et al., 2001). Pesatori et al. (1998) also conducted a 15-year follow-up study to update noncancer mortality.

A recent study by Warner et al. (2002) used data from the Seveso Women's Health Study to evaluate the association between individual serum TCDD and breast-cancer risk in women who resided in Seveso at the time of the accident in 1976. The study included 981 women who were infants to 40 years old at the time of the accident, had resided in the most contaminated areas (A and B), and had adequate stored serum collected shortly after the explosion for TCDD measurements. In addition to giving informed consent, study participants donated blood and were interviewed. In some cases medical records were obtained, and gynecologic examinations and transvaginal ultrasonography were conducted. Serum TCDD was measured, and Cox proportional hazards modeling was used for the primary analysis.

Times Beach and Quail Run Cohorts

During early 1971, byproducts of a hexachlorophene and 2,4,5-T production facility in Verona, Missouri, were mixed with waste oils and sprayed on various sites around the state for dust control, including around Times Beach and Quail Run areas. TCDD was a contaminant of the mixtures sprayed, and the contamination was reported by the Environmental Protection Agency. A number of studies were conducted to evaluate health effects of the potential exposure (Evans et al., 1988; Hoffman et al., 1986; Stehr et al., 1986; Stehr-Green et al., 1987; Stockbauer et al., 1988; Webb et al., 1987). VAO discusses those studies, and no more recent studies have been published.

Vietnam

Vietnamese researchers have conducted studies of the native population exposed to the spraying that occurred during the Vietnam conflict. In a review paper, Constable and Hatch (1985) summarized the unpublished results of those studies. The review article included nine reports that focus primarily on reproductive outcomes (Can et al., 1983a,b; Huong and Phuong, 1983; Khoa, 1983; Lang et al., 1983a,b; Nguyen, 1983; Phuong and Huong, 1983; Trung and Chien, 1983). Vietnamese researchers later published results of four additional studies

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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conducted in Vietnam—two focusing on reproductive abnormalities (Phuong et al., 1989a,b), one on mortality (Dai et al., 1990), and one on hepatocellular carcinoma (Cordier et al., 1993). VAO and Update 1996 discuss those studies. No studies have been published since Update 1996.

Other Environmental Studies

VAO, Update 1996, and Update 1998 report on numerous studies focusing on reproductive outcomes of potential environmental exposure in Oregon (US EPA, 1979); Arkansas (Nelson et al., 1979); Iowa and Michigan (Gordon and Shy, 1981); New Brunswick, Canada (White et al., 1988); Skaraborg, Sweden (Jansson and Voog, 1989); and Northland, New Zealand (Hanify et al., 1981).

Numerous other studies have focused on different outcomes of environmental exposure. They include examinations of STS and connective-tissue cancers in Midland County, Michigan (Michigan Department of Public Health, 1983); NHL in Yorkshire, England (Cartwright et al., 1988); cancer in Finland (Lampi et al., 1992); lymphomas and STS in Italy (Vineis et al., 1991); neuropsychologic effects in Germany (Peper et al., 1993); early-onset Parkinson's disease in Oregon and Washington (Butterfield et al., 1993); adverse health effects after an electric transformer fire in Binghamton, New York (Fitzgerald et al., 1989); skin cancer in Alberta, Canada (Gallagher et al., 1996); NHL, HD, and chronic lymphocytic leukemia in a rural Michigan community (Waterhouse et al., 1996); cancer mortality in four northern wheat-producing states (Schreinemachers, 2000); HD, NHL, multiple myeloma, and acute myeloid leukemia in various regions of Italy (Masala et al., 1996); effects of inhalation exposure to TCDD and related compounds in wood preservatives on cell-mediated immunity in German day-care center employees (Wolf and Karmaus, 1995); mortality and cancer incidence in two cohorts of Swedish fishermen whose primary exposure route was assumed to be diet (Svensson et al., 1995); immune effects in hobby fishermen in the Frierfjord in southeastern Norway (Lovik et al., 1996); and immunologic effects of prenatal and postnatal PCB or TCDD exposure in Dutch infants from birth to the age of 18 months (Weisglas-Kuperus et al., 1995).

Since Update 2000, Revich et al. (2001) have reported on TCDD exposure and public health in Chapaevsk, Russia, where a chemical plant produced hexachlorocyclohexane and its derivatives from 1967 to 1987. The plant now produces crop-protection materials. TCDD exposure was assessed by sampling the air, drinking water and soil in the town, human milk from 40 women (pooled to seven samples), blood from 14 people, and cow's milk from privately owned cattle. Official statistics, including demographic and medical statistics, were used to assess cancer risk and reproductive health. Congenital and morphogenetic effects were assessed by examining the medical records of 369 children born in Chapaevsk in 1990–1995 to those for the Samara region and for all of Russia. A study by Revazova et al. (2001) investigated cytogenetic effects among the

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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women residents of Chapaevsk. Three groups of women were examined: 15 women working in the fertilizer plant, 16 women with no known occupational TCDD exposures but living 1–3 km from the plant, and 14 women with no known occupational TCDD exposure who lived 5–8 km from the plant. All women were 20–40 years old. The women's plasma TCDD was measured, chromosomal aberrations were assessed in peripheral blood lymphocytes, and micronuclei and other nuclear anomalies were assessed in buccal epithelium.

VIETNAM-VETERAN STUDIES

Studies of Vietnam veterans who were potentially exposed to herbicides, including Agent Orange, have been conducted in the United States at the national and state levels and in Australia and Vietnam. Exposures in those studies have been measured on various levels, and health outcomes have been evaluated with various comparison or control groups. This section is organized primarily by research sponsor because it is more conducive to methodologic presentation of the articles. In the studies, exposure measures range from individual exposures of Ranch Hands, as reflected in serum TCDD measurements, to service in Vietnam as a surrogate of TCDD exposure in some state studies.

It should also be noted that a variety of comparison groups have been used for the veteran cohort studies: (a) Vietnam veterans who were stationed in areas essentially not exposed to active herbicide missions and were unlikely to have been in areas sprayed with herbicides; (b) Vietnam era veterans who were in the military at the time of the conflict but did not serve in Vietnam; (c) non-Vietnam veterans who served in other wars or conflicts such as the Korean War or World War II; and (d) various US male populations (either state or national). This is also discussed in Chapter 5 of this report.

United States
Operation Ranch Hand

The men responsible for most of the aerial spraying of herbicides in Vietnam were Air Force volunteers who participated in Operation Ranch Hand. To determine whether exposure to herbicides, including Agent Orange, had adverse human health effects, the Air Force made a commitment to Congress and the White House in 1979 to conduct an epidemiologic study of Ranch Hands (AFHS, 1982). VAO, Update 1996, Update 1998, Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (hereafter referred to as Type 2 Diabetes) (IOM, 2000), and Update 2000 discuss reports and papers addressing this cohort in more detail.

A retrospective matched-cohort study design was implemented to examine morbidity and mortality; follow-up was scheduled to continue until 2002. Na-

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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tional Personnel Records Center and US Air Force Human Resources Laboratory records were searched and cross-referenced to identify all Ranch Hand personnel (AFHS, 1982; Michalek et al., 1990). A total of 1,269 participants were originally identified (AFHS, 1983). A control population of 24,971 C-130 crew members and support personnel assigned to duty in Southeast Asia but not occupationally exposed to herbicides (AFHS, 1983) was selected from the same data sources used to identify the Ranch Hand population. Controls were individually matched on age, type of job (based on Air Force specialty code), and race (white or not white). The rationale for matching on those variables was to control for age-related effects, educational and socioeconomic status, and potential race-related differences in development of chronic disease. Ranch Hands and controls performed similar combat or combat-related jobs, so many potential confounders related to the physical and psychophysiologic effects of combat stress and the Southeast Asia environment were potentially controlled for (AFHS, 1982). Rank was also used as a surrogate of exposure. Alcohol use and smoking were controlled for when they were known risk factors for the end point of interest.

Ten matches formed a control set for each exposed subject. For the mortality study, each subject classified as exposed and a random sample of half of each subject's control set are being followed for 20 years in a 1:5 matched design. The morbidity component of follow-up consists of a 1:1 matched design, with the first control randomized to the mortality ascertainment component of the study. If a control is noncompliant, another control from the matched “pool” is selected; controls who die are not replaced.

The baseline examination occurred in 1982; the final examination was scheduled for 2002. Morbidity is ascertained through questionnaire and physical examination, which emphasize dermatologic, neuropsychiatric, hepatic, immunologic, reproductive, and neoplastic conditions. Some 1,208 Ranch Hands and 1,668 comparison subjects were eligible for baseline examination. Initial questionnaire response rates were 97% for the exposed cohort and 93% for the nonexposed; baseline physical examination responses were 87% and 76%, respectively (Wolfe et al., 1990). For the 1987 examination and questionnaire (Wolfe et al., 1990), 84% of Ranch Hands (N = 955) and 75% of comparison subjects (N = 1,299) were fully compliant. Mortality outcome was obtained and reviewed by using US Air Force Military Personnel Center records, the VA's Death Beneficiary Identification and Record Location System (BIRLS), and the Internal Revenue Service database of active social security numbers. Death certificates were obtained from the appropriate health departments (Michalek et al., 1990). For this study, 84% of the 1,148 eligible Ranch Hands (N = 952), 76% of the original comparison group (N = 912), and 65% of the 567 replacement comparisons (N = 369) invited to the 1992 follow-up chose to participate in the examination and questionnaire (AFHS, 1995). The methods used to assess mortality and morbidity were identical with those described previously for the 1982 and 1987 examinations.

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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Ranch Hands were divided into three categories on the basis of their potential exposure:

  • Low potential. This group included pilots, copilots, and navigators. Exposure was primarily through preflight checks and spraying.

  • Moderate potential. This group included crew chiefs, aircraft mechanics, and support personnel. Exposure could occur by contact during dedrumming and aircraft loading operations, on-site repair of aircraft, and repair of spray equipment.

  • High potential. This group included spray-console operators and flight engineers.

Results have been published for the baseline morbidity (AFHS, 1984a) and baseline mortality studies (AFHS, 1983); the first (1984), second (1987), third (1992), and fourth (1997) follow-up examinations (AFHS, 1987, 1990, 1995, 2000); and the reproductive-outcomes study (AFHS, 1992; Wolfe et al., 1995; Michalek et al., 1998d). Mortality updates have been published for 1984–1986, 1989, and 1991 (AFHS, 1984b, 1985, 1986, 1989, 1991a). An interim technical report updated the cause-specific mortality among Ranch Hands through 1993 (AFHS, 1996), and Michalek et al. (1998b) reported on a 15-year follow-up of postservice mortality in veterans of Operation Ranch Hand, updating their cause-specific mortality study (1990). Serum TCDD was measured in 1982 (36 Ranch Hands; Pirkle et al., 1989), 1987 (866 Ranch Hands; AFHS, 1991b), and 1992 (455 Ranch Hands; AFHS, 1995). Serum TCDD analysis of the 1987 follow-up examinations was published in 1991 (AFHS, 1991b).

Other Ranch Hand publications have addressed the relationship between serum TCDD and reproductive hormones (Henriksen et al., 1996); sex ratios (Michalek et al., 1998c); TCDD and diabetes mellitus, glucose, and insulin (Henriksen et al., 1997); serum TCDD and diabetes mellitus (Longnecker and Michalek, 2000); insulin, fasting glucose, and sex hormone-binding globulin (Michalek et al., 1999a); immunologic responses (Michalek et al., 1999b); skin disorders (Burton et al., 1998); skin cancer (Ketchum et al., 1999); and TCDD and infant death (Michalek et al., 1998a).

Since Update 2000, Michalek et al. (2001a) have studied the relationship between serum TCDD and hepatic abnormalities in the cohort of veterans of Operation Ranch Hand previously described in Wolfe et al. (1990). Study participants were examined and medical records retrieved in 1982, 1985, 1987, and 1992. During the 1992 examination, 1,109 Ranch Hands and 1,493 comparisons subjects volunteered for additional testing for hepatic disease. Subjects whose TCDD measurements were missing, subjects who had detectable TCDD below the limit of quantification, comparison veterans with TCDD greater than 10 ppt, subjects who received no result, and subjects with a history of liver disease before service in Southeast Asia were excluded. According to TCDD concentrations, the Ranch Hands and comparison subjects were categorized as having “background,”

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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“low,” or “high” exposure. After those exclusions, data on 987 Ranch Hands (background, 402; low, 284; high 283) and 1,266 comparison subjects were analyzed. Liver conditions were grouped into hepatomegaly, nonalcoholic chronic liver disease and cirrhosis, and other liver disorders; and nonspecific increases in transaminase or lactic acid dehydrogenase, other nonspecific abnormal serum enzyme values, and nonspecific abnormal results on liver-function studies were also recorded. Liver-function tests included measurement of alanine aminotransferase, aspartate aminotransferase, γ-glutamyltransferase, lactic dehydrogenase, alkaline phosphatase, and total bilirubin. At the time of the examination, participants were asked about their history of liver problems, and liver abnormalities were verified by personal physicians or laboratory analysis completed during the examination. Medical records were used to determine whether identified liver conditions had occurred in the period between service in Southeast Asia and April 1993. All liver conditions were classified according to International Classification of Disease coding. Confounders —including lifetime smoking history, lifetime drinking history, lifetime industrial chemical exposure, race, and birth year—were adjusted for.

Michalek et al. (2001b) studied the relationship between serum TCDD and peripheral neuropathy in the cohort of veterans of Operation Ranch Hand previously described in Wolfe et al. (1990). Study participants underwent TCDD body-burden analysis and neurologic examinations at the 1982, 1985, 1987, 1992, and 1997 physical examinations. TCDD was measured in 2,101 veterans at the 1997 examination. Subjects with TCDD below the limit of detection were assigned a value equal to the limit of detection divided by the square root of 2. Ranch Hand veterans with TCDD not exceeding 10 ppt were assigned to the background category. Those with TCDD greater than 10 ppt and a 1982 TCDD measurement not exceeding the median (94 ppt) were assigned to the low category. Ranch Hands with TCDD concentrations greater than 10 ppt and a 1982 TCDD measurement greater than the median were assigned to the high category. Neurologic status of participants was evaluated through a standardized neurologic examination conducted by a board-certified neurologist. Nerve-conduction velocities were measured during the 1992 examination, and vibrotactile thresholds in 1992 and 1997. Study participants were identified as having possible, probable, or diagnosed peripheral neuropathy if one, two, or all three, respectively, of the following outcomes occurred bilaterally: absence of the Achilles reflex, abnormal vibration at the ankle, and abnormal pin-prick reaction. Veterans who had a history of neurologic disorders before service in Southeast Asia, whose TCDD measurements were missing, who had conditions that would interfere with an assessment of the peripheral nerves, or who had specific neurologic disorders of known causes unrelated to TCDD exposure were excluded. Sample sizes in the 1997 primary analysis after exclusions were 761 Ranch Hands (background, 338; low, 213; high, 210) and 1,086 comparison subjects. Adjustments

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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were made in the primary analysis for age, height, alcohol consumption, occupation, diabetes, and body-mass index (BMI).

Michalek et al. (2001c) also studied the relationship of serum TCDD to hematologic results in the cohort of Ranch Hand veterans previously described in Wolfe et al. (1990). Hematologic function and TCDD body burden were analyzed for veterans who participated in the 1982, 1985, 1987, and 1992 physical examinations. According to TCDD concentrations, the Ranch Hands and comparison subjects were categorized as having “background,” “low,” or “high” exposures. Veterans whose TCDD measurements were missing or nonquantifiable, and comparison subjects with TCDD greater than 10 ppt were excluded. Subjects with TCDD below the limit of detection were assigned a value of 0 ppt. Veterans who had a fever at the time of examination or who tested positive for human immunodeficiency virus were also excluded from the analysis. After exclusions, data on 953 Ranch Hands and 1,280 comparison subjects were analyzed. At each examination, red-cell count, hemoglobin, hematocrit, mean corpuscular volume, white-cell count, platelet count, and erythrocyte sedimentation rate were measured. BMI, smoking patterns, and alcohol consumption were estimated for study participants at each examination.

Barrett et al. (2001) studied the relationship between serum TCDD and cognitive function among the cohort of Ranch Hand veterans previously described in Wolfe et al. (1990). At the 1987 physical examination, or the 1992 examination if the testing was not completed at the earlier examination, blood was drawn from each veteran and assayed for TCDD. After exclusion of veterans with no TCDD measurement or a nonquantifiable TCDD result and comparison veterans with TCDD greater than 10 ppt —and one veteran who had epilepsy before the 1982 physical examination —data on 937 Ranch Hands (background, 388; low, 274; high, 275) and 1,052 comparison subjects were analyzed. An alternative analysis was conducted that included all veterans with a TCDD measurement stratified by quintile of the TCDD distribution. Nonquantifiable TCDD results were assigned the value of half the limit of quantitation. Cognitive function was tested at the 1982 examination with the Halstead-Reitan neuropsychologic test battery, the revised Wechsler adult intelligence scale, the Wechsler memory scale Form 1, and the reading subset of the wide-range achievement test. In the primary analysis, adjustments were made for military occupation, age, race, drinking history, marital status, combat-exposure quartile, psychiatric-diagnosis indicators, and psychotropic-medication indicators.

As noted earlier, Steenland et al. (2001) published a paper that reanalyzed data from two previously published studies on TCDD and diabetes mellitus: one in US workers (NIOSH study; Calvert et al., 1999) and one in Ranch Hands (Henriksen et al., 1997). In that paper, the data from the NIOSH cohort are reanalyzed with a cohort selection closer to that used in the Ranch Hand study. The combined data from the NIOSH study and the Ranch Hand study are also

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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analyzed. Further details on those reanalyses can be found in the “Occupational Studies” section of this chapter.

Centers for Disease Control and Prevention

CDC has undertaken a series of studies to examine various health outcomes of Vietnam veterans, as directed by Congress (Veterans Health Programs Extension and Improvement Act of 1979, Public Law 96-151; and Veterans' Health Care, Training, and Small Business Loan Act of 1981, Public Law 97-72). VAO and Update 1996 describe those studies in detail. The first was a case–control interview study of birth defects among offspring of men who served in Vietnam (Erickson et al., 1984a,b).

To examine concerns about Agent Orange more directly, CDC conducted the Agent Orange Validation Study to evaluate TCDD in US Army veterans compared with exposure estimates based on military records and TCDD in veterans who did not serve in Vietnam (CDC, 1989a). Using those exposure estimates, CDC conducted the Vietnam Experience Study (VES), a historical cohort study of the health experience of Vietnam veterans (CDC, 1989b). The study was divided into three parts: physical health, reproductive outcomes and child health, and psychosocial characteristics (CDC, 1987, 1988a,b,c, 1989b).

Using data from the VES, CDC examined the postservice mortality (through 1983) in a cohort of 9,324 US Army veterans who served in Vietnam compared with 8,989 Vietnam-era Army veterans who served in Korea, Germany, or the United States (Boyle et al., 1987; CDC, 1987). An additional study (O'Brien et al., 1991) combined the mortality and interview data to identify all veterans with NHL. To evaluate whether self-reported assessment of exposure to herbicides influences the reporting of adverse health outcomes, CDC designed a study using VES subjects (Decoufle et al., 1992).

Finally, CDC undertook the Selected Cancers Study (CDC, 1990a) to investigate the effects of military service in Vietnam and exposure to herbicides on the health of American veterans. Outcomes studied were NHL (CDC, 1990b), STS and other sarcomas (CDC, 1990c), and HD and nasal, nasopharyngeal, and primary liver cancers (CDC, 1990d).

No CDC studies have been published since 1990.

Department of Veterans Affairs

DVA has conducted numerous cohort and case–control studies, which VAO, Update 1996, Update 1998, and Update 2000 discuss in detail. One of the first was a proportionate-mortality study conducted by Breslin et al. (1988). Study subjects were ground troops who served in the US Army or Marine Corps at any time from July 4, 1965, through March 1, 1973. A list of 186,000 Vietnam-era veterans who served in the Army or Marine Corps and were reported deceased as

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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of July 1, 1982, was assembled from DVA's BIRLS. A random sample of 75,617 names was selected from the list. Cause of death was ascertained for 51,421 men, including 24,235 who served in Vietnam. On the basis of the proportionate-mortality study (Breslin et al., 1988), Burt et al. (1987) conducted a nested case – control study of NHL with controls selected from among the cardiovascular-disease deaths. Later, Bullman et al. (1990) examined whether Army I Corps Vietnam veterans had cancer mortality similar to that of other Army Vietnam-era veterans, using the study design of Breslin et al. (1988). Watanabe et al. (1991) conducted an additional study comparing the Vietnam-veteran mortality experience of Breslin et al. (1988) with three referent groups and with additional follow-up through 1984. A third follow-up proportionate-mortality study using the veterans from Breslin et al. (1988) and Watanabe et al. (1991) was also conducted (Watanabe and Kang, 1996).

DVA also examined the morbidity and mortality experience of a subgroup of Vietnam veterans potentially exposed to high concentrations of herbicides from some US Army Chemical Corps units (Thomas and Kang, 1990). In an extension of Thomas and Kang (1990), Dalager and Kang (1997) compared mortality among veterans of the Chemical Corps specialties, including Vietnam veterans and non-Vietnam veterans. Watanabe and Kang (1995) also examined postservice mortality among Marine Vietnam veterans compared with Vietnam era marines who did not serve in Vietnam. Mortality among female Vietnam veterans was assessed by Thomas et al. (1991) and updated in Dalager et al. (1995a).

DVA has evaluated specific disease and health outcomes—including case– control studies of STS (Kang et al., 1986, 1987), NHL (Dalager et al., 1991), testicular cancer (Bullman et al., 1994), HD (Dalager et al., 1995b), and lung cancer (Mahan et al., 1997)—and has conducted a co-twin study of self-reported physical health in a series of Vietnam-era monozygotic twins (Eisen et al., 1991).

DVA has also examined other outcomes—including posttraumatic stress disorder (PTSD) (True et al., 1988; Bullman et al., 1991), suicide, motor-vehicle accidents (Farberow et al., 1990), and smoking behavior (McKinney et al., 1997)—among Vietnam veterans and has studied cause-specific mortality among veterans with nonlethal (combat and noncombat) wounds sustained during the Vietnam War (Bullman and Kang, 1996). VAO and Update 1998 discuss those studies in detail. In many of the studies, exposure to Agent Orange is not discussed; exposure to “combat” is evaluated as the risk factor of interest.

Since Update 1998, DVA has published a study on pregnancy outcomes among US female Vietnam veterans (Kang et al., 2000a). Of 5,230 women, 4,390 whose permanent tour of duty included service in Vietnam were alive as of January 1, 1992. From a pool of 6,657 potential control subjects whose military unit did not include service in Vietnam, 4,390 who were alive as of January 1, 1992, were randomly selected as controls. A questionnaire was administered on demographic background, general health, lifestyle, menstrual history, pregnancy history, pregnancy outcomes, and military experience, including nursing occupa-

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
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tion and combat exposure. Information on pregnancy complications—including smoking, infections, medications, exposure to x-rays, occupational history, and exposure to anesthetic gases, ethylene oxide, herbicides, and pesticides was collected for each pregnancy. The first pregnancy after the beginning of Vietnam service was designated as the index pregnancy for each woman. For the comparison group, the first pregnancy after July 4, 1965, was used as the index pregnancy. Odds ratios were calculated for reproductive history and pregnancy outcomes. The study analyzed data on 3,392 Vietnam and 3,038 non-Vietnam veterans and on 1,665 Vietnam and 1,912 non-Vietnam veteran indexed pregnancies.

DVA has also published a study on gynecologic cancers among US Vietnam veterans (Kang et al., 2000b). Of 5,230 potential study participants, 4,390 women veterans who served in Vietnam in July 1965–March 1973 were located and alive as of January 1, 1992. From a pool of 6,657 potential control female Vietnam-era veterans whose tour of duty did not include service in Vietnam, 4,390 who were alive as of January 1, 1992, were randomly selected as controls. A 45-min health questionnaire was administered that included questions on demographic background, general health, smoking and drinking history, menstrual history, pregnancy history, pregnancy outcomes, and military experience, including nursing occupation and combat exposure. Medical and hospital records were reviewed to document self-reported cancers of the breast, ovary, uterus, and cervix. Additional information was obtained from military records regarding effect modifiers and confounders. Of the total of 8,780 women, 500 (250 Vietnam veterans and 250 controls) were used in a feasibility pilot study and therefore were not included in the final analysis. A total of 6,430 women completed the full telephone interview.

In response to a study recommendation in VAO, Kang et al. (2001) conducted a preliminary long-term health study of US Army Chemical Corps Vietnam veterans. A review of morning reports, military personnel records, and class rosters from the Army Chemical School resulted in a pool of 2,872 Vietnam veterans and 2,737 non-Vietnam veterans who were eligible for the study. Army Chemical Corps veterans were considered eligible if they had served in the US Army on active duty for a minimum of 18 months and whose military record reflected service in Vietnam with chemical operations duties in July 1965– March 1973. Non-Vietnam veteran controls had similar military histories with respect to branch, length, and period of service and military occupation but did not have active duty in Vietnam. A random sample of 284 Vietnam and 281 non-Vietnam veterans were selected from the larger pool (Vietnam veterans, 2,872; eligible non-Vietnam veterans, 2,737) for the study. A computer-assisted telephone interview was administered to collect information on veterans' exposures, health problems, and offspring. Military records supplemented and validated self-reported interview data to the extent possible. Blood samples were collected, and

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

serum TCDD concentrations were collected from 50 Vietnam veterans and controls.

American Legion

The American Legion conducted a cohort study of the health and well-being of Vietnam veterans who belonged to the American Legion, a voluntary veterans service organization. A series of studies examining physical health and reproductive outcomes, social–behavioral consequences, and PTSD were conducted on veterans who had served in Southeast Asia and veterans who served elsewhere (Snow et al., 1988; Stellman et al., 1988a,b,c). No new studies have been published on this cohort.

State Studies

Several states have conducted studies of Vietnam veterans. Most of the studies remain unpublished in the scientific literature. VAO and Update 1996 review studies from Hawaii (Rellahan, 1985), Iowa (Wendt, 1985), Maine (Deprez et al., 1991), Massachusetts (Kogan and Clapp, 1985, 1988; Levy, 1988; Clapp et al., 1991; Clapp, 1997), Michigan (Visintainer et al., 1995), New Jersey (Kahn et al., 1988; Fiedler and Gochfeld, 1992, Kahn et al., 1992a,b,c), New Mexico (Pollei et al., 1986), New York (Greenwald et al., 1984; Lawrence et al., 1985), Pennsylvania (Goun and Kuller, 1986), Texas (Newell, 1984), West Virginia (Holmes et al., 1986), and Wisconsin (Anderson et al., 1986a,b).

Other US Vietnam Veteran Studies

Additional studies have been conducted to examine a number of health outcomes, including spontaneous abortion (Aschengrau and Monson, 1989) and late adverse pregnancy outcomes in spouses of Vietnam veterans (Aschengrau and Monson, 1990) and PTSD among monozygotic twins who served during the Vietnam era (Goldberg et al., 1990). After a published study indicated a potential association with testicular cancer in dogs that served in Vietnam (Hayes et al., 1990), Tarone et al. (1991) conducted a case–control study of testicular cancer in male veterans. VAO summarizes those studies, and no new studies have been published.

Australia

The Australian government has commissioned studies to investigate health risks to Australian veterans. Studies of birth anomalies (Donovan et al., 1983, 1984; Evatt, 1985), mortality (Commonwealth Institute of Health, 1984a,b,c; Evatt, 1985; Fett et al., 1987a,b; Forcier et al., 1987; Crane et al., 1997a,b), deaths

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

from all causes (Fett et al., 1987b), cause-specific mortality (Fett et al., 1987a), and morbidity (AIHW, 1999, 2000; CDVA 1998a,b) have been conducted. A revised morbidity study has also been published (AIHW, 2001). An independent study in Tasmania evaluated numerous reproductive and childhood health problems for association with paternal Vietnam service (Field and Kerr, 1988). In addition, O'Toole et al. (1996a,b,c) described self-reported health status in a random sample of Australian Army Vietnam veterans. VAO, Update 1998, and Update 2000 describe the studies. No new studies or data have been published since the acute myelogenous leukemia report (IOM, 2001).

Other Vietnam-Veteran Studies

A team of Vietnamese scientists examined Vietnamese veterans who served in a “dioxin-sprayed zone,” looking at antinuclear and sperm autoantibodies (Chinh et al., 1996). Available details of this study are presented in Update 1998. No other studies in similar cohorts have been published.

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 4-1 Epidemiologic Studies—Occupational Exposure

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

PRODUCTION WORKERS

New NIOSH Studies

Steenland et al., 2001

Cohort

A study to reexamine and compare diabetes data from the NIOSH cohort and the United States Air Force Ranch Hands in order to reconcile differences between the two study methods and protocols

267 NIOSH workers 990 Ranch Hands

227 NIOSH comparisons 1,275 Ranch Hand comparisons

NIOSH Studies Reviewed in Update 2000

Calvert et al., 1999

Cohort

Continuing follow-up of workers employed more than 15 years ago at two plants that manufactured substances contaminated with TCDD to evaluate associations between serum TCDD and serum glucose (diabetes), TSH, total T4, and T3

281

260

Steenland et al., 1999

Cohort

Mortality study of workers at 12 industrial plants that produced chemicals contaminated with TCDD, using a job-exposure matrix to estimate TCDD exposure categories. End points reported are all cancers, ischemic heart disease, and diabetes

5,132 (3,538 with exposure data divided into septiles of cumulative exposure; 608 who had chloracne)

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Calvert et al., 1998

Cohort

Continuing follow-up of workers employed more than 15 years ago at two plants that manufactured substances contaminated with TCDD to evaluate the association between TCDD exposure and cardiovascular outcomes

281

260

Halperin et al., 1998

Cohort

Continuing study of a cohort of TCDD-exposed workers at two plants that manufactured substances contaminated with TCDD to assess the association between serum TCDD and immunological outcome variables for eligible workers and matched neighborhood controls

259

243

NIOSH Studies Reviewed in Update 1998

Sweeney et al., 1996, 1997/1998

Cross-sectional

Study of numerous noncancer end points for liver function, gastrointestinal disorders, chloracne, serum glucose, hormone and lipid levels, and diabetes in same group as Calvert et al. (1991)

281

260

Halperin et al., 1995

Cross-sectional

Study of surrogates for cytochrome P450 induction in same group as Calvert et al. (1991)

281

260

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

NIOSH Studies Reviewed in Update 1996

Calvert et al., 1994

Cross-sectional

Study of porphyria cutanea tarda in same group as Calvert et al. (1991)

281

260

Egeland et al., 1994

Cohort

Study of total serum testosterone and gondadotropin levels in chemical production workers exposed to dioxin, in same group as Calvert et al. (1991)

248

231

NIOSH Studies Reviewed in VAO

Sweeney et al., 1993

Cohort

Peripheral neuropathy in same group as Calvert et al. (1991)

281

260

Alderfer et al., 1992

Cohort

Assessment of psychological variables to determine depression in same group as Calvert et al. (1991)

281

260

Calvert et al., 1992

Cohort

Assessment of liver and gastrointestinal systems in same group as Calvert et al. (1991)

281

260

Calvert et al., 1991

Cohort

Study of workers employed at one of two plants manufacturing substances contaminated with TCDD at least 15 years prior to assessment of chronic bronchitis, COPD, ventilatory function, thorax, and lung abnormalities, compared to matched neighborhood controls

281

260

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Fingerhut et al., 1991

Cohort

Cancer mortality in male workers from 12 plants producing TCDD contaminated chemicals (1942– 1984), compared to US population

5,172

Monsanto Studies Reviewed in VAO

Collins et al., 1993

Cohort

Mortality of workers (through 1987) exposed and not exposed to dioxin between March 8, 1949, and November 22, 1949, as indicated by presence of chloracne, compared to local population mortality rates

122 with chloracne; 632 without chloracne

Moses et al., 1984

Cohort

Study of health outcomes in Monsanto workers (1948–1969) with chloracne reported as a surrogate to 2,4,5-T exposure compared to health outcomes in workers without chloracne as surrogate for no exposure

117

109

Suskind and Hertzberg, 1984

Cohort

Evaluation of health outcomes (1979) at clinical examination among workers exposed to 2,4,5-T (1948–1969) compared to nonexposed workers at same Monsanto plant

204

163

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Zack and Gaffey, 1983

Cohort

Study of mortality experience of all white male workers (1955– 1977) employed at a Monsanto plant through Dec. 31, 1977, compared to mortality rates of standardized US population

884

Zack and Suskind, 1980

Cohort

Evaluation of mortality experience among employees with chloracne exposed to TCP process accident in 1949 at Monsanto, compared to US male population standard

121

New Dow Studies

Burns et al., 2001

Cohort

Study comparing mortality in a cohort of chemical workers who manufactured or formulated 2,4-D between 1945 and 1994

1,567 workers

40,600 nonexposed chemical workers; US population

Dow Studies Reviewed in Update 1998

Ramlow et al., 1996

Cohort

Study of mortality in a cohort of workers exposed to pentachlorophenol (PCP)

770

36,804 nonexposed workers; US population

Dow Studies Reviewed in Update 1996

Bloemen et al., 1993

Cohort

Additional years of follow-up of Bond et al. (1988) study cohort through 1986

878

36,804 nonexposed workers; US population

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Dow Studies Reviewed in VAO

Bond et al., 1989a

Cohort

Study of incidence of chloracne among a cohort of workers potentially exposed to TCDD, and association with other risk factors

2,072

Internal comparison

Bond et al., 1989b

Cohort

Extension of Ott et al. (1987) study through 1984

2,187

Bond et al., 1988

Cohort

Study of mortality (through 1982) among workers potentially exposed to 2,4-D (1945–1983) compared to US white males and all other male employees not exposed

878

36,804 employees not exposed; US white male population

Bond et al., 1987

Cohort

Extension of Cook et al. (1980) study, mortality through 1982

322

2,026 employees without chloracne; US white male population

Cook et al., 1987; Ott et al., 1987

Cohort

Expanded Cook et al. (1986) study an additional three years, through 1982

2,187

Sobel et al., 1987

Case-control

Study of STS among Dow chemical employees (1940– 1979) compared to employees without STS for possible association with several chemical exposures

14

126

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Cook et al., 1986

Cohort

Mortality experience (1940– 1979) of men manufacturing chlorinated phenols compared to US white men

2,189

Bond et al., 1983

Cross-sectional

Study of differences in workers potentially exposed and not exposed to TCDD during chemical production for (1) morbidity and (2) medical examination frequency between 1976 and 1978

(1) 183

(2) 114

(1) 732

(2) 456

Townsend et al., 1982

Cohort

Study of adverse reproductive outcomes among wives of Dow chemical employees potentially exposed to TCDD (1939–1975) compared to reproductive outcomes among wives whose husbands were not exposed

370

345

Cook et al., 1980

Cohort

Mortality experience (through 1978) of male workers involved in a chloracne incident (1964) from TCDD exposure, compared to mortality experience of US white men

61

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Ott et al., 1980

Cohort

Mortality experience among workers exposed to 2,4,5-T in manufacturing (1950–1971) compared to mortality experience of US white men

204

BASF Studies Reviewed in Update 2000

Zober et al., 1997

Cohort (1953 accident)

Cross-sectional (1988 cohort)

Review and summary of previous BASF studies of morbidity and mortality in workers exposed to TCDD after BASF accidents in 1953 and 1988

154 surviving (as of 1989) members of 1953 accident cohort 42 exposed (1988) extruder personnel

No comparison group

BASF Studies Reviewed in Update 1998

Ott and Zober, 1996

Cohort

Cancer incidence and mortality experience (through 1992) of workers exposed to TCDD after the BASF accident, during reactor cleanup, maintenance, or demolition (based on the cohort of Zober et al., 1990)

243

BASF Studies Reviewed in Update 1996

Zober et al., 1994

Cohort

Morbidity experience in the same group as Zober et al. (1990)

158

161

BASF Studies Reviewed in VAO

Zober et al., 1990

Cohort

Mortality experience of workers exposed to TCDD (1954–1987) at BASF plant compared to population of Federal Republic of Germany (FRG)

247

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Thiess et al., 1982

Cohort

Study of mortality experience among BASF employees potentially exposed to TCDD during Nov. 17, 1953, accident compared to population and other workers not exposed

74

180,000 (town); 1.8 million (district); 60.5 million (FRG); two groups of 74 each from other cohort studies

IARC Studies Reviewed in Update 2000

Neuberger et al., 1999

Austrian chloracne cohort

Morbidity up to 1993 of exposed chemical workers assessed by health insurance data and health examination, laboratory measures, and interviews with participating survivors and controls

159, including 50 who participated in examination

Two control groups comparable to the 50 participants— numbers not given

Hooiveld et al., 1998

Cohort

Mortality (through 1991), using SMRs, of workers at one Dutch factory assessed in relation to work and exposure history; SMR and relative risk analyses

562 (serum samples for 50); 140 males at accident

567

Jäger et al., 1998

Cohort

Preliminary data from Neuberger et al. (1999; English abstract only)

159 in original cohort; 56 screened; 49 full data

Matched nonexposed controls

Neuberger et al., 1998

Cohort of exposed cases

Preliminary data from Neuberger et al. (1999)

50

Age- and sex-matched controls; number not given

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Vena et al., 1998

Cohort

International study (36 cohorts from 12 countries) of workers producing or spraying phenoxy acid herbicides and chlorophenols, categorized into one of three TCDD or higher chlorinated dioxin categories. Noncancer mortality (1939–1992) was analyzed by standardized mortality rate comparisons and by Poisson multiple regression

21,863

No comparison group

Flesch-Janys, 1997

Cohort

Mortality (1952–1984) study of German workers exposed to TCDD and other contaminants in the production of herbicides and insecticides. SMRs and Cox regression models were calculated

1,189

IARC Studies Reviewed in Update 1998

Kogevinas et al., 1997

Cohort

Mortality study (through 1992) of workers engaged in the production or application of phenoxy herbicides and composed of (1) the Saracci et al. (1991) cohorts, (2) the German cohorts of Becher et al. (1996), and (3) the NIOSH cohorts of Fingerhut et al. (1991)

26,615 total (21,863 exposed; 4,160 probably exposed; 592 unknown exposure)

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Becher et al., 1996

Cohort

Cancer mortality (through 1989) among German workers in four chemical factories exposed to 2,4,5-T and/or trichlorophenol (subcohorts I and II) and phenoxy herbicides and chlorophenols (subcohorts III and IV)

2,479

Flesch-Janys et al., 1995

Cohort

Cancer and circulatory system mortality among workers in a chemical plant in Hamburg, Germany exposed in varying degrees to herbicides contaminated with PCDD/F

1,189

(1) population

(2) 2,528 gas workers

IARC Studies Reviewed in Update 1996

Kogevinas et al., 1995

Case-control

Two nested case-control studies of the relationship between STS and NHL and occupational exposures in members of the IARC cohort

STS: 11 cases

NHL: 32 cases

5 controls per case

Kogevinas et al., 1993

Cohort

Cancer incidence and mortality experience of female workers in seven countries, potentially exposed to chlorophenoxy herbicides, chlorophenols, and dioxin compared to national death rates and cancer incidence rates

701

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Lynge, 1993

Cohort

Cancer incidence in the same group as Lynge (1985), with follow-up extended through 1987

3,390 men

1,071 women

Kogevinas et al., 1992

Cohort

Study of mortality from STS and malignant lymphomas in an international cohort of production workers and herbicide sprayers (same group as Saracci et al., 1991)

14,439 (13,482 exposed; 416 probably exposed; 541 unknown exposure)

3,951 nonexposed employees

IARC Studies Reviewed in VAO

Bueno de Mesquita et al., 1993

Cohort

Mortality experience of production workers exposed to phenoxy herbicides and chlorophenols in the Netherlands compared to national rates

2,310

Coggon et al., 1991

Cohort

Mortality experience among four cohorts of workers potentially exposed (1963–1985) to phenoxy herbicides and chlorophenols compared to national (England and Wales) expected numbers and to the local population where factory is located

1,104 Factory A

271 Factory B

345 Factory C

519 Factory D

Manz et al., 1991

Cohort

Mortality experience of workers (1952–1984) at Hamburg plant of Boehringer exposed to TCDD compared to national mortality and workers from another company

1,184 men

399 women

(a) population

(b) 3,120 gas workers

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Saracci et al., 1991

Cohort

Study of mortality experience of 20 international cohorts of herbicide sprayers and production workers compared to mortality experience expected for the nation

16,863 men

1,527 women

Coggon et al., 1986

Cohort

Study of mortality experience (through 1983) among workers manufacturing and spraying MCPA (1947–1975) compared to expected numbers of deaths among men of England and Wales and for rural areas

5,754

Lynge, 1985

Cohort

Study of cancer incidence among Danish workers exposed to phenoxyherbicides compared to expected results from the general population

3,390 men

1,069 women

Studies from Other Chemical Plants Reviewed in Update 2000

Hryhorczuk et al., 1998

Cohort

Morbidity study of workers involved in pentachlorophenol production at one factory between 1938 and 1978 and nonexposed workers at the same factory. Assesses chloracne, prophyria, and general health status

366

303

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Jung et al., 1998

Cohort

Self-selected group of former workers at pesticide-producing factory participated in physical examination, laboratory measures, and questionnaires. Associations between serum PCDD/F, infectious disease, and immunologic measures were assessed

192

 
   

Lymphocyte proliferation and chromate resistance tests were compared between a subgroup of the mostly highly exposed workers at the study factory and an nonexposed group of workers in another industry

29 (highly exposed subgroup)

28 (external nonexposed group)

Studies from Other Chemical Plants Reviewed in Update 1998

Tonn et al., 1996

Cohort

Study of the long-term immune system effects of TCDD in industrial workers involved in production and maintenance operations at a German chemical factory producing 2,4,5-T between 1966 and 1976

11

10

Studies from Other Chemical Plants Reviewed in VAO

Jennings et al., 1988

Cohort

Assessment of immunological abnormalities among workers exposed to TCDD during accident manufacturing 2,4,5-T compared to matched controls

18

15

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Thomas, 1987

Cohort

Assessment of mortality experience as of Jan. 1, 1981, for white men employed in fragrance and flavors plant with possible exposure to TCDD, compared to US white men and for cancers compared to local men

1,412

May, 1982, 1983

Cohort

Health outcomes among workers exposed and probably exposed to TCDD following a 1968 accident, compared to nonexposed workers

41 exposed

54 possibly exposed

31

Pazderova-Vejlupkova et al., 1981

Descriptive

Study of development of TCDD intoxication among men in Prague (1965 –1968)

55

No comparison group

Poland et al., 1971

Cross-sectional

Assessment of porphyria cutanea tarda (PCT), chloracne, hepatotoxicity, and neuropsychiatric symptoms among 2,4-D and 2,4,5-T workers compared to other plant workers

73 total (20 administrators; 11 production supervisors; 28 production workers; 14 maintenance workers)

Internal comparison

Bashirov, 1969

Cross-sectional

Descriptive results of examination of workers involved in production of herbicides and study of workers at examination of cardiovascular and digestive systems compared to unexposed controls

292 (descriptive);

50 (examined)

20 (examined)

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

AGRICULTURAL AND FOREST PRODUCTS

New Cohort Studies of Agricultural Workers Studies

Arbuckle et al., 2001

Cohort

Spontaneous abortions in couples living on full-time family-run farms in Ontario, Canada

2,110 women;

3,936 pregnancies

none

Masley et al., 2000

Cross-sectional survey

Targeted survey of households in an agricultural-based rural area of Saskatchewan, Canada

548 households;

1,407 individuals

none

Curtis et al., 1999

Cohort

Time to pregnancy in couples living on full-time family-run farms in Ontario, Canada

2,012 pregnancies

none

Savitz et al., 1997

Cohort

Male pesticide exposure and pregnancy outcome among full-time family-run farms in Ontario, Canada

1,898 couples;

3,984 pregnancies

none

Cohort Studies of Agricultural Workers Reviewed in Update 2000

Arbuckle et al., 1999

Cohort

Spontaneous abortions in couples living on full-time family-run farms in Ontario, Canada

2,110 women (3,936 pregnancies)

none

Cohort Studies of Agricultural Workers Reviewed in Update 1998

Gambini et al., 1997

Cohort

Cancer mortality (1957–1992) among a cohort of rice growers in the Novara Province of northern Italy

958

Kristensen et al., 1997

Cohort

Birth defects among the offspring of Norwegian farmers born after 1924

192,417 births

61,351 births

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Faustini et al., 1996

Cohort

Study of immune system components and function among farmers who mixed and applied commercial formulations containing the chlorophenoxy herbicides 2,4-D and MCPA

10

Internal comparison

Cohort Studies of Agricultural Workers Reviewed in Update 1996

Dean, 1994

Cohort

Study of mortality from brain and hematopoietic cancers of agricultural workers compared to nonagricultural workers in Ireland (1971–1987)

(population size unclear)

Morrison et al., 1994

Cohort

Update of mortality experience in Wigle et al. (1990) cohort through 1987, with addition of farmers from Alberta and Manitoba

155,547

Semenciw et al., 1994

Cohort

Study of leukemia mortality in same group as Morrison et al. (1993)

155,547

Blair et al., 1993

Cohort

Study of causes of death, including cancer, among farmers in 23 states (1984–1988)

119,648 white men;

2,400 white women;

11,446 nonwhite men;

2,066 nonwhite women

Semenciw et al., 1993

Cohort

Study of multiple myeloma mortality of male farmers compared to male population of the three prairie provinces of Canada (1971–1987)

155,547

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Senthilselvan et al., 1992

Cross-sectional

Study of the association between pesticide exposure and asthma in male farmers

1,939

No comparison group

Cohort Studies of Agricultural Workers Reviewed in VAO

Morrison et al., 1993

Cohort

Mortality experience of male Canadian farmers 45 years or older in Manitoba, Saskatchewan, and Alberta, Canada, (1971–1987) compared to Canadian prairie province mortality rates

145,383

Eriksson et al., 1992

Cohort

Study of incidence of NHL, HD, and multiple myeloma (1971– 1984) among selected occupational groups in Swedish men and women, compared to expected rates of disease in general population

Number in occupational group unknown

Hansen et al., 1992

Cohort

Study of cancer incidence among male and female Danish gardeners compared to incidence expected among the general population

4,015 (859 women; 3,156 men)

Morrison et al., 1992

Cohort

Mortality experience of male farmers 35 or older (1971–1987) compared to Canadian prairie province rates

155,547

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Ronco et al., 1992

Cohort

Study of cancer incidence (1970–1980) among male and female Danish farm workers 15 to 74 years old, compared to expected numbers of cancers among persons economically active, and study of cancer mortality (November 1981– April 1982) among male and female Italian farmers 18 to 74 years old compared to persons in other occupational groups

No N given

No N given

Lerda and Rizzi, 1991

Cohort

Study of farmers exposed to 2,4-D, as measured in urine, compared to unexposed men for differences in sperm volume, death count, motility, and abnormalities between March and June 1989

32

25

Wigle et al., 1990

Cohort

Mortality experience from NHL of male farmers 35 years or older (1971 – 1985) in Saskatchewan, Canada, compared to age- and period-specific mortality rates expected for Saskatchewan males

69,513

Corrao et al., 1989

Cohort

Study of cancer incidence among male farmers licensed (1970–1974) to use pesticides, compared to number of cancers expected among licensed nonusers

642

18,839

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Wiklund et al., 1988a

Cohort

Malignant lymphoma incidence among agricultural and forestry workers in Sweden compared to the general population of men; 1960 census

354,620

1,725,845

Wiklund and Holm, 1986

Cohort

STS incidence among agricultural and forestry workers in Sweden compared to the general population of men; 1960 census

354,620

1,725,845

Wiklund, 1983

Cohort

Study of cancer incidence (diagnosed 1961–1973) among agricultural workers in Sweden compared to rates expected from the 1960 population census

19,490

Burmeister, 1981

Cohort

Study of mortality of farmers compared to nonfarmers in Iowa (1971 –1978)

6,402

13,809

New Cohort Studies of Forestry Workers

Thörn et al., 2000

Cohort

Study of mortality and cancer incidence in a cohort of Swedish lumberjacks exposed to phenoxy herbicides

261

243

Cohort Studies of Forestry Workers Reviewed in VAO

Green, 1991

Cohort

Mortality experience of male forestry workers (1950–1982) in Ontario, compared to expected mortality of the male Ontario population

1,222

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Green, 1987

Cohort

Suicide experience in a cohort of Canadian forestry workers by number of years in forestry trade as a surrogate for exposure to phenoxy herbicides compared to population

1,222

Van Houdt et al., 1983

Cross-sectional

Study of acne and liver dysfunction in a select group of Dutch forestry workers exposed to 2,4,5-T, compared to nonexposed workers

54

54

New Cohort Studies of Herbicide and Pesticide Sprayers

Hoppin et al., 2002

Cohort

Study predicting wheeze among farmers who applied pesticide in the Agricultural Health Study

3,838 appliers with wheeze

16,630 appliers without wheeze

Cohort Studies of Herbicide and Pesticide Sprayers Reviewed in Update 2000

Alavanja et al., 1998

Cohort

Analysis of self-reported health care visits having resulted from pesticide use by Iowa and North Carolina pesticide appliers

35,879

None

Dich et al., 1998

Cohort

Study of men licensed for pesticide application in Sweden. Cancer cases ascertained from cancer registry and standardized incidence ratio reported for prostate cancer

20,025

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Cohort Studies of Herbicide and Pesticide Sprayers Reviewed in Update 1998

Heacock et al., 1998

Cohort

Fertility study among British Columbia workers potentially exposed to chlorophenate wood preservatives in 14 sawmills between 1955 and 1988; includes the cohort of Hertzman et al. (1997)

18,016 births

1,668 births

Hertzman et al., 1997

Cohort

Mortality study among British Columbia workers potentially exposed to chlorophenate wood preservatives in 11 sawmills between 1950 and 1985

23,829

2,658

Dimich-Ward et al., 1996

Cohort; Nested case-control

Analysis of birth defects among offspring born between 1952 and 1988 of the Hertzman et al. (1997) cohort

19,675 births among 9,512 fathers

5 nondefect births as controls per case

Garry et al., 1996a

Cohort

Study of chromosome abnormalities based on the cohort of Garry et al. (1994)

23 fumigant appliers; 18 insecticide appliers; 20 herbicide appliers

33

Garry et al., 1996b

Cohort

Birth defects among the offspring of male pesticide appliers in Minnesota born between 1989 and 1992

4,935 births among 34,772 pesticide appliers (125 with birth anomalies)

3,666 births with anomalies in the general population

Zhong and Rafnsson, 1996

Cohort

Cancer mortality among various subgroups of pesticide users in Iceland

2,449 (1,860 males and 589 females)

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Cohort Studies of Herbicide and Pesticide Sprayers Reviewed in Update 1996

Asp et al., 1994

Cohort

Mortality and cancer morbidity experience of male chlorophenoxy herbicide appliers (same cohort as Riihimaki et al., 1982, 1983) in Finland (1955– 1971), through 1989, compared to general population rates for morbidity and mortality

1,909

Garry et al., 1994

Cross-sectional

Evaluation of health outcomes resulting from exposure to pesticides by male pesticide appliers in Minnesota

719

No comparison group

Cohort Studies of Herbicide and Pesticide Sprayers Reviewed in VAO

Swaen et al., 1992

Cohort

Cancer mortality experience (through 1987) among Dutch male herbicide appliers licensed before 1980, compared to total male Dutch population

1,341

Bender et al., 1989

Cohort

Cancer mortality of Minnesota highway maintenance workers compared to expected numbers based on white Minnesota men

4,849

Wiklund et al., 1989a

Cohort

Risk of cancer in Wiklund et al. (1987) cohort through 1982

20,245

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Wiklund et al., 1989b

Cohort

Risk of STS, HD, and NHL in Wiklund et al. (1987) cohort through 1984

20,245

Wiklund et al., 1988b

Cohort

Risk of STS in Wiklund et al. (1987) cohort through 1984

20,245

Wiklund et al., 1987

Cohort

Risk of HD and NHL among Swedish pesticide appliers from date of license through 1982, compared to expected number of cases in the total population

20,245

Blair et al., 1983

Cohort

Mortality experience of white male Florida pesticide appliers compared to US and Florida men

3,827

Riihimaki et al., 1983

Cohort

Cancer morbidity and mortality in cohort of Riihimaki et al. (1982), through 1980

1,926

Riihimaki et al., 1982

Cohort

Study of mortality among herbicide appliers exposed to 2,4-D and 2,4,5-T in Finland compared to mortality expected in the population

1,926

Smith et al., 1982

Cohort

Study of adverse reproductive outcomes among chemical appliers and agricultural contractors by category of exposure: none; chemicals not 2,4,5-T; 2,4,5-T

113 pregnancies (chemicals not 2,4,5-T); 486 pregnancies (2,4,5-T)

401 pregnancies (not exposed)

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Barthel, 1981

Cohort

Study of male agricultural production workers (1948–1972) for incidence of cancer, compared to incidence rates expected in the population

1,658

 

Smith et al., 1981

Cohort

Study of chemical appliers (1973–1979) in New Zealand compared to agricultural contractors for differences in adverse reproductive outcomes

459

422

Axelson et al., 1980

Cohort

Additional years of follow-up to cohort established in Axelson and Sundell (1974)

348

Axelson and Sundell, 1974

Cohort

Study of mortality and cancer incidence among cohorts of Swedish railroad workers spraying herbicides (>45 days) compared to the expected number of deaths (1957–1972) from Swedish age- and sex-specific rates

348 total herbicide exposure; 207 phenoxy acids and combinations; 152 amitrole and combinations; 28 other herbicides and combinations

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

CASE-CONTROL STUDIES

Case-Control Studies Reviewed in Update 2000

Ekström et al., 1999

Case-control

All new cases of histologically confirmed gastric adenocarcinoma in two geographic areas in Sweden; age-and gender-matched control group randomly selected using computerized population register

565

1,164

Hardell and Eriksson, 1999

Case-control

Male cases 25 or older with histopathologically confirmed NHL during 1987–1990 in northern and mid-Sweden; age matched controls from National Population Registry

404

741

Garcia et al., 1998

Case-control

Matched-paired study of congenital malformations or defects in an agricultural region of Spain

261

261

Case-Control Studies Reviewed in Update 1998

Blatter et al., 1997

Case-control

Multicenter Dutch study of paternal occupation and risk of spina bifida in offspring (1980– 1992)

222

764

Liou et al., 1997

Case-control

Study of occupational and environmental risk factors and Parkinson 's disease (PD) in Taiwan (1993–1995)

120

240

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Tatham et al., 1997

Nested case-control

Population-based study of occupational risk factors for subgroups of NHL patients based on the CDC's Selected Cancers Study (CDC, 1990a,b,c,d)

1,048

1,659

Nanni et al., 1996

Case-control

Population-based study in northeastern Italy of occupational and chemical risk factors for chronic lymphocytic leukemia (CLL) and NHL (1987–1990)

187

977

Schulte et al., 1996

PMR analysis with nested case-control

Study of neurodegenerative diseases and occupational risk factors from 27 states

Based on 130,420 death certificates

 

Seidler et al., 1996

Case-control

Study of PD and various rural factors, including exposure to herbicides and wood preservatives in Germany

380

379 neighborhood controls; 376 regional controls

Case-Control Studies Reviewed in Update 1996

Hardell et al., 1994

Case-control

Study of the association between occupational exposures and parameters related to NHL in white males in Sweden

105

335

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Mellemgaard et al., 1994

Case-control

Study of cases of renal cell carcinoma (20–79 years) in Denmark, compared to population-based sample without cancer for identification of occupational risk factors

365

396

Nurminen et al., 1994

Case-control

Study of structural defects in infants born to mothers engaged in agricultural work during the first trimester of pregnancy, compared to infants with structural defects born to mothers who did not engage in agricultural work during the first trimester

1,306

1,306

Brown et al., 1993

Case-control

Population-based case-control study of multiple myeloma in Iowa men for association with pesticide exposures

173

650

Persson et al., 1993

Case-control

Study of risk factors potentially associated with HD and NHL in males identified from the Regional Cancer Registry in Sweden

NHL: 93

HD: 31

204

Semchuk et al., 1993

Case-control

Study of cases of PD (36–90 years) in Canada, compared to population-based sample for association with occupational exposure to herbicides and other exposures

75 men

55 women

150 men

110 women

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Zahm et al., 1993

Case-control

Study of NHL and exposure to pesticides in white women diagnosed with NHL between July 1, 1983, and June 30, 1986

206

824

McDuffie et al., 1990

Case-control

Study of pesticide exposure in male cases of primary lung cancer in Saskatchewan, compared to control subjects matched by age, sex, and location of residence

273

187

Case-Control Studies Reviewed in VAO

Cantor et al., 1992

Case-control

Population-based case-control study of NHL in Iowa and Minnesota men for association with farming exposures

622

1,245

Smith and Christophers, 1992

Case-control

Study of STS and malignant lymphomas in men diagnosed 1982–1988 in Australia, compared to other cancers for association with exposure to phenoxy herbicides and chlorophenols

82

82 other cancers; 82 population controls

Brown et al., 1990

Case-control

Population-based case-control study of leukemia in Iowa and Minnesota men for association with farming exposures

578

1,245

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Eriksson et al., 1990

Case-control

Study of male cases of STS (25–80 years) diagnosed 1978–1986 in central Sweden compared to population-based sample without cancer for association with occupational exposure to phenoxyacetic acids and chlorophenols

218

212

Wingren et al., 1990

Case-control

Study of male cases of STS (25–80 years) diagnosed 1975–1982 in southeast Sweden, compared to two referent groups: (1) population-based sample, (2) with other cancers, for association with phenoxyacetic acids and chlorophenols

71

315 population based; 164 other cancers

Zahm et al., 1990

Case-control

Study of white men 21 years or older diagnosed with NHL (1983–1986) in Nebraska, compared to residents of the same area without NHL, HD, multiple myeloma (MM), chronic lymphocytic leukemia for association with herbicides (2,4-D) on farms

201

725

Alavanja et al., 1989

PMR analysis with nested case-control

Mortality experience of United States Department of Agriculture (USDA) forest or soil conservationists (1970–1979) evaluated for specific cancer excess; case-control study of specific cancers identified from PMR analysis

1,411

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Boffetta et al., 1989

Nested case-control

National study of MM compared to other cancer controls for association with exposures including pesticides and herbicides

282

1,128

LaVecchia et al., 1989

Case-control

Study of Italian men and women with HD, NHL, and MM (1983– 1988), compared to population of Italy for association with occupations and herbicide use

69 HD

153 NHL

110 MM

396

Persson et al., 1989

Case-control

Study of HD and NHL among living men and women in Sweden, compared to those without these cancers for association with occupational exposures, including phenoxy herbicides

54 HD

106 NHL

275

Woods and Polissar, 1989

Case-control

Study of NHL from the Woods et al. (1987) cohort for association with phenoxy herbicides in farm workers

576

694

Alavanja et al., 1988

PMR analysis with nested case-control

Mortality experience of USDA extension agents (1970–1979) evaluated for specific cancer excess; case-control study of specific cancers identified from PMR analysis

1,495

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Dubrow et al., 1988

Case-control

Death certificate study (1958– 1983) of NHL and HD among white male residents of Hancock County, Ohio, compared to a random sample of those dying from other causes for association with farming

61 NHL

15 HD

304

Hardell and Eriksson, 1988

Case-control

Study of male cases of STS (25– 80 years) diagnosed between 1978 and 1983 in northern Sweden compared to two referent groups: (1) population based, (2) with other cancers, for association with occupational exposure to phenoxyacetic acids and chlorophenols

55

330 population based; 190 other cancers

Musicco et al., 1988

Case-control

Study of brain gliomas diagnosed 1983–1984 in men and women in Italy, compared to (1) patients with nonglioma nervous system tumors and (2) patients with other neurologic diseases, for association with chemical exposures in farming

240

(1) 465

(2) 277

Olsson and Brandt, 1988

Case-control

Study of NHL (1978–1981) in Swedish men, compared to two groups of men without NHL for association with occupational exposures including phenoxy acids

167

50 same area; 80 other parts of Sweden

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Hardell et al., 1987

Case-control

Study of Kaposi's sarcoma in AIDS patients (23–53 years old) compared to controls for association with TCDD and pesticide exposure in Sweden

50

50

Pearce et al., 1987

Case-control

Expanded study (Pearce et al., 1986b) of NHL to include ICD-9 200-diagnosed cases and additional controls for association with farming exposures

183

338

Woods et al., 1987

Case-control

Study of STS or NHL in men 20–79 years old (1983–1985) in western Washington State compared to a population sample without these cancers for association with occupational exposure to phenoxy herbicides and chlorinated phenols

128 STS

576 NHL

694

Hoar et al., 1986

Case-control

Study of STS, NHL, and HD in Kansas (1976–1982), compared to controls without cancer for association with 2,4-D, 2,4,5-T, and other herbicides in white men 21 years or older

133 STS

121 HD

170 NHL

948

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Morris et al., 1986

Case-control

Study of multiple myeloma (1977–1981) in four SEER areas compared to population controls for risk factors associated with MM, including farm use of herbicides

698

1,683

Pearce et al., 1986a

Case-control

Study of male MM cases diagnosed 1971–1981 in New Zealand, compared to controls for other cancers for potential association with phenoxy herbicides and chlorophenols

76

315

Pearce et al., 1986b

Case-control

Study of NHL cases (ICD-9 202) in men diagnosed between 1977 and 1981 in New Zealand, compared to sample with other cancers and population sample, for association with occupational exposure to phenoxy herbicides and chlorophenols

83

168 other cancers; 228 general population

Smith and Pearce, 1986

Case-control

Update of Smith et al. (1983) with diagnoses through 1982

51 in update (133 when combined with Smith et al., 1983)

315 (407)

Vineis et al., 1986

Case-control

Study of cases of STS in men and women diagnosed 1981– 1983 in northern Italy, compared to population sample of controls for association with phenoxy herbicide exposure

37 men

31 women

85 men

73 women

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Blair and White, 1985

Case-control

Study of leukemia cases by cell type in Nebraska (1957–1974) compared to nonleukemia deaths for association with agricultural practices

1,084

2,168

Pearce et al., 1985

Case-control

Study of malignant lymphoma and multiple myeloma in men diagnosed 1977–1981 in New Zealand, compared to men with other cancers for association with agricultural occupations

734

2,936

Balarajan and Acheson, 1984

Case-control

Study of STS (1968–1976) diagnosed in men in England and Wales compared to men with other cancers for association with farming, agriculture, and forestry occupations

1,961

1,961

Donna et al., 1984

Case-control

Study of ovarian cancer in women (1974–1980) for association with herbicide use, compared to women without ovarian cancer

60

127

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Hardell et al., 1984

Case-control

Study of primary liver cancer diagnosed 1974–1981 in men 25–80 years old residing in northern Sweden compared to population based controls for association with occupational exposure to phenoxyacetic acids and chlorophenols

98

200

Smith et al., 1984

Case-control

Study of STS among New Zealand residents (1976–1980) compared to those without these cancers for association with occupational exposures, including phenoxy herbicides

82

92

Burmeister et al., 1983

Case-control

Study of multiple myeloma, NHL, prostate, and stomach cancer mortality (1964–1978) in white men 30 years or older compared to mortality from other causes for association with farming practices including herbicide use in Iowa

550 MM

1,101 NHL

4,827 prostate

1,812 stomach

1,100

2,202

9,654

3,624

Hardell and Bengtsson, 1983

Case-control

Study of HD diagnosed in men 25–85 years old, between 1974 and 1978 in northern Sweden, compared to population-based sample without cancer for association with occupational exposure to phenoxyacetic acid and chlorophenols

60

335

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Smith et al., 1983

Case-control

Preliminary report of men with STS reported 1976–1980 in New Zealand, compared to controls with other cancers for association with phenoxyacetic acid exposure

80

92

Burmeister et al., 1982

Case-control

Study of leukemia deaths (1964– 1978) in white men ≥ 30 years old in Iowa, compared to nonleukemia deaths for association with farming

1,675

3,350

Cantor, 1982

Case-control

Study of NHL in Wisconsin among males (1968–1976) compared to men dying from other causes for association with farming exposures

774

1,651

Hardell et al., 1982

Case-control

Study of nasal and nasopharyngeal cancers diagnosed 1970–1979 in men 25–85 years old residing in northern Sweden, compared to controls selected from previous studies (Hardell and Sandstrom, 1979; Hardell et al., 1981) for association with occupational exposure to phenoxyacetic acids and chlorophenols

44 nasal;

27 nasopharyngeal

541

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Carmelli et al., 1981

Case-control

Cases of spontaneous abortions occurring to women (1978–1980) compared to live births for association with paternal exposure to 2,4-D

134

311

Eriksson et al., 1979, 1981

Case-control

Cases of STS diagnosed between 1974 and 1978 in southern Sweden compared to population based sample without cancer for association with occupational exposure to phenoxyacetic acids and chlorophenols

110

219

Hardell, 1981

Case-control

(1) Cases of STS (Hardell and Sandstrom, 1979) and malignant lymphomas (Hardell et al., 1981) compared to colon cancer cases (2) Colon-cancer cases compared to population-based controls for association with occupational exposure to phenoxyacetic acids and chlorophenols

(1) 221

(2) 154

154

541

Hardell et al., 1980;

Hardell et al., 1981

Case-control

Cases of malignant lymphomas (HD, NHL, unknown) diagnosed in men 25–85 years old, between 1974 and 1978 in northern Sweden, compared to population-based controls for association with occupational exposure to phenoxyacetic acids and chlorophenols

60 HD

109 NHL

338

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Blair and Thomas, 1979

Case-control

Cases in Nebraska (1957–1974) compared to deaths from other causes for association with agricultural practices

1,084

2,168

Hardell and Sandstrom, 1979

Case-control

Cases of STS (26–80 years old) diagnosed between 1970 and 1977 in northern Sweden, compared to population-based controls for association with occupational exposure to phenoxyacetic acids and chlorophenols

52

206

PAPER AND PULP WORKERS

Paper and Pulp Worker Studies Reviewed in Update 2000

Schildt et al., 1999

Case-control

Matched study of histopathologically verified oral cancer cases. Mailed exposure questionnaire on lifetime occupational history, oral cancer risk factors, pesticide use, smoking, SES, and place of residence

410

410

Rix et al., 1998

Cohort

Cancer incidence rates of blue-collar workers at three Danish paper mills were compared to population rates from national population and mortality registers

14,788 (14,362 were identified for follow-up)

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Paper and Pulp Worker Studies Reviewed in VAO

Jappinen and Pukkala, 1991

Cohort

Cancer incidence (through 1987) among male Finnish pulp and paper workers (1945–1961), compared to rates in the local central hospital district

152

Approximately 135,000

Henneberger et al., 1989

Cohort

Mortality experience through August 1985 of white men employed in Berlin, New Hampshire, paper and pulp industry, compared to expected mortality in US white men

883

Solet et al., 1989

Cohort

Mortality (1970–1984) among white male United Paperworkers International union members, compared to expected number of deaths in US men

201

Robinson et al., 1986

Cohort

Mortality experience through March 1977 of white male workers employed in five paper or pulp mills compared to expected number of deaths among U.S. population

3,572

aThe dash (—) indicates the comparison group is based on a population (e.g., US white males, country rates), and details are given in the text for specifics of the actual population.

ABBREVIATIONS: CDC, Centers for Disease Control and Prevention; COPD, chronic obstructive pulmonary disease; HD, Hodgkin's disease; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; MM, multiple myeloma; NIOSH, National Institute for Occupational Safety and Health; NHL, non-Hodgkin's lymphoma; PMR, proportionate mortality ratio; SEER, surveillance, epidemiology, and end results; STS, soft-tissue sarcoma; Update 2000, Veterans and Agent Orange: Update 2000 (IOM, 2001); Update 1998, Veterans and Agent Orange: Update 1998 (IOM, 1999); Update 1996, Veterans and Agent Orange: Update 1996 (IOM, 1996); and VAO, Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994).

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 4-2 Epidemiologic Studies—Environmental Exposure

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

New Studies from Seveso

Warner et al., 2002

Cohort

Study to evaluate the association between individual serum TCDD levels and breast cancer risk in women who participated in the Seveso Women 's Health Study

15

981

Studies from Seveso Reviewed in Update 2000

Bertazzi et al., 2001

Cohort

Mortality (through 1996) study of residents in industrial accident exposure-related geographic regions

804 zone A

5,941 zone B

38,624 zone R

232,745

Bertazzi et al., 1998;

Pesatori et al., 1998

Cohort

Mortality (through 1991) study of residents in industrial accident exposure-related geographic regions

805 zone A

51,943 zone B

38,625 zone R

232,747

Studies from Seveso Reviewed in Update 1998

Bertazzi et al., 1997

Cohort

Study of cancer incidence among Seveso residents in contaminated zones (A, B, R) after 15 years of follow-up through 1991

45,373 total

805 zone A

5,943 zone B

38,625 zone R

232,747

Mocarelli et al., 1996

Cohort

Study of sex ratio among the offspring of Seveso residents born in zone A from (1) 1977 to 1984 and (2) 1985 to 1994

(1) 74 births (28 male, 48 female)

(2) 124 births (60 male, 48 female)

 
Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Studies from Seveso Reviewed in Update 1996

Bertazzi et al., 1993

Cohort

Study of cancer incidence in Seveso residents (aged 20 to 74 years) in contaminated zones (A, B, R) exposed to TCDD on July 10, 1976, compared to neighboring residents in nonexposed areas

724 zone A

4,824 zone B

31,647 zone R

181,579

Pesatori et al., 1993

Cohort

Evaluation of cancer incidence in Seveso residents aged 1–19 years in the first postaccident decade compared to age-matched residents of neighboring nonexposed areas

Approximately 20,000

167,391

Studies from Seveso Reviewed in VAO

Bertazzi et al., 1992

Cohort

Comparison of mortality of children (1976– 1986) exposed during Seveso accident compared to children in uncontaminated areas

306 zone A

2,727 zone B

16,604 zone R

95,339

Pesatori et al., 1992

Cohort

Cancer incidence (1976–1986) among those in zones A, B, R around Seveso compared to residents of uncontaminated surrounding areas

Data given in person-years

Data given in person-years

Assennato et al., 1989a

Cohort

Comparison of dermatologic and laboratory findings in children during periodic exams following accident in Seveso

193 with chloracne

123

Assennato et al., 1989b

Cohort

Study of health outcomes in workers assigned to cleanup or referent group following Seveso accident

36

36

Bertazzi et al., 1989a,b

Cohort

Comparison of mortality experience (1976– 1986) of residents of contaminated zones (A, B, R) around Seveso to mortality experience of nonexposed residents in neighboring towns

556 zone A

3,920 zone B

26,227 zone R

167,391

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Barbieri et al., 1988

Cohort

Comparison of prevalence of peripheral nervous system involvement among Seveso residents with chloracne, compared to residents of unexposed areas

152

123

Mastroiacovo et al., 1988

Cohort

Comparison of birth defects occurring among zone A, B, and R mothers with live and stillbirths to birth mothers who were non-A, B, or R residents

26 zone A

435 zone B

2,439 zone R

12,391 (non-A, B, or R)

Mocarelli et al., 1986

Cross-sectional

Study of laboratory measures of serum and urine in Seveso zone A and B children measured over 6 years (1977–1982), compared to zone R children

69 zone A

528 zone B

874 zone R

241, subset of zone R

Ideo et al., 1985

Cross-sectional

Evaluation of levels of enzyme activity among residents of Seveso zone B and an noncontaminated community

117 adults

127 adults

Tenchini et al., 1983

Cross-sectional

Cytogenetic analysis of maternal and fetal tissue among Seveso exposed, compared to control sample

19

16

Ideo et al., 1982

Cross-sectional

Evaluation of hepatic enzymes in children exposed in Seveso compared to normal values

16 zone A

51 zone B

60 Bristo Assizio

26 Cannero

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Caramaschi et al., 1981

Cohort

Evaluation of chloracne among children in Seveso, compared to children with no chloracne, and association with other health outcomes between chloracne and no-chloracne groups

146

182

Filippini et al., 1981

Cohort

Comparison of prevalence of peripheral neuropathy on two screening examinations among Seveso residents, compared to residents in nonexposed areas

308

305

Bisanti et al., 1980

Descriptive

Descriptive report of selected health outcomes among residents of Seveso located in zones A, B, R

730 zone A

4,737 zone B

31,800 zone R

No comparison group

Boeri et al., 1978

Cohort

Evaluation of neurological disorders among Seveso residents exposed to TCDD on July 10, 1976, compared to residents in nonexposed areas

470 zone A

152 zone R

Times Beach/Quail Run Studies Reviewed in VAO

Evans et al., 1988

Cross-sectional

Comparison of retesting for skin delayed-type hypersensitivity among nonresponders in earlier test (Stehr et al., 1986)

28

15

Stockbauer et al., 1988

Cohort

Study of adverse reproductive outcomes (1972– 1982) among mothers potentially exposed to TCDD-contaminated areas of Missouri (1971) compared to births among nonexposed mothers

402 births

804 births

Webb et al., 1987

Cross-sectional

Pilot study of Missouri residents exposed to TCDD in the environment (1971) for health effects, comparing potentially high-exposed to low-exposed residents

68 (high exposure)

36 (low exposure)

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Stehr et al., 1986

Cross-sectional

Pilot study of Missouri residents exposed to TCDD in the environment (1971) for health effects, comparing potentially high-exposed to low-exposed residents

68 (high exposure)

36 (low exposure)

Studies of Vietnamese Reviewed in Update 1996

Cordier et al., 1993

Case-control

Study of cases of hepatocellular carcinoma (1989–1992) in males living in Vietnam, compared to other hospitalized patients for association with a range of exposures including herbicides

152

241

Studies of Vietnamese Reviewed in VAO

Dai et al., 1990

Cohort

Study of infant mortality (1966–1986) in two South Vietnam villages exposed to Agent Orange spraying compared to infant mortality in unsprayed area

5,609

3,306

Phuong et al., 1989a

Case-control

Study of deformed babies and hydatidiform mole compared to normal births (1982) in Ho Chi Minh City for association with mother's exposure to Agent Orange and TCDD in Vietnam conflict

15 birth defects

50 hydatidiform moles

104

134

Phuong et al., 1989b

Cohort

Comparison of reproductive anomalies among births to women (May 1982 –June 1982) living in areas heavily sprayed with herbicides in southern Vietnam, to women from Ho Chi Minh City

7,327 births

6,690 births

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Constable and Hatch, 1985

Review

Summaries of reproductive outcomes among Vietnamese populations, includes nine unpublished studies

   

Other New Environmental Studies

Revazova et al., 2001

Cohort

Cytogenetic effects in women exposed to different levels of dioxin while living in Chapaevsk, Russia

15 possibly exposed workers

30 nonexposed but living close to plant

Revich et al., 2001

Cohort

Study of dioxin exposures in Chapaevsk, Russia which looked at various health outcomes in children and adults

Children and adults in Chapaevsk, Russia

Samara region and all of Russia

Other Environmental Studies Reviewed in Update 2000

Schreinemachers, 2000

Cross-sectional

Study of cancer mortality rates in four northern wheat-producing states using wheat acreage per county as surrogate for exposure

Other Environmental Studies Reviewed in Update 1998

Gallagher et al., 1996

Case-control

Community-based study of primary basal cell carcinoma (BCC) and patients with primary squamous cell carcinoma (SCC) in Alberta, Canada

BCC: 226

SCC: 180

406

Lovik et al., 1996

Cohort

Study of immune system parameters in hobby fishermen in the Frierfjord in southeastern Norway

24

10

Masala et al., 1996

Case-control

Multicenter study of NHL, HD, MM, and AML in Italy by region

HD: 421

NHL: 1,822

MM: 325

AML: 263

Internal comparison by region

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Svensson et al., 1995

Cohort

Mortality and cancer incidence experience in two cohorts of Swedish fishermen

East coast: 2,896

West coast: 8,477

Weisglas-Kuperus et al., 1995

Cohort

Study of the immunological effects of prenatal and postnatal PCB or TCDD exposure in 207 Dutch infants from birth to 18 months

105 breast-fed

102 bottle-fed

Wolf and Karmaus, 1995

Cross-sectional

Study of the effects of inhalation exposure to TCDD and related compounds in wood preservatives on cell-mediated immunity in German day care center employees

221

189

Other Environmental Studies Reviewed in Update 1996

Butterfield et al., 1993

Case-control

Study of possible environmental risk factors associated with young-onset Parkinson's disease

63

68

Peper et al., 1993

Descriptive

Study of environmental exposure to dioxins and furans and potential association with adverse neuropsychological effects in Germany

19

None

Other Environmental Studies Reviewed in VAO

Lampi et al., 1992

Nested case-control/ cohort

Study of cancer incidence among a community in Finland exposed to water and food contaminated with chlorophenols (1987), compared to other communities; study of several cancers compared to population controls for association with potential risk factors including food and water consumption

56 colon cancer; 40 bladder cancer; 8 STS; 7 HD; 23 NHL; 43 leukemia

688

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Vineis et al., 1991

Ecological design

Presentation of rates (1985–1988) of NHL, HD, and STS in men and women 15–74 years old living in provinces in Italy where phenoxy herbicides are used in rice weeding and defined in two categories

63 HD

253 NHL

49 STS

No nonexposed controls

Fitzgerald et al., 1989

Cohort

Health outcomes in group exposed to electrical transformer fire in 1981 compared to standardized rates among upstate New York residents

377

Jansson and Voog, 1989

Cohort/ case study

Case study of facial cleft (April–August 1987) and study of facial clefts (1975–1987) compared to the rates expected in Swedish county with incinerators

20,595 births after incineration 6 case studies

71,665 births before incineration

Cartwright et al., 1988

Case-control

Study of living cases of NHL (1979–1984) in Yorkshire, England, compared to other hospitalized patients for association with a range of exposures including fertilizers or herbicides

437

724

Michigan Department of Public Health, 1983

Descriptive

Comparison of Michigan county rates of mortality for STS and connective tissue cancer (1960–1981), compared to state and national rates for potential excess in areas where dioxin may be in the environment

County rates

State and national rates

Gordon and Shy, 1981

Case-control

Study of agricultural chemical exposures and potential association with cleft palate or lip in Iowa and Michigan, compared to other live births

187

985

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Hanify et al., 1981

Ecological design

Study of adverse birth outcomes occurring 1960–1966, compared to 1972–1977 for association with 2,4,5-T spraying in the later period

9,614 births

15,000 births

Nelson et al., 1979

Ecological design

Study of prevalence of oral cleft palates in high, medium, and low 2,4,5-T sprayed areas in Arkansas (1948–1974)

US EPA, 1979

Ecological design

Study of spontaneous abortions occurring during 1972–1977 in herbicide-sprayed areas around Alsea, Oregon, compared to spontaneous abortions occurring in unsprayed areas

2,344 births

1,666 births— unsprayed area; 4,120 births— urban area

aThe dash (—) indicates the comparison group is based on a population (e.g., US white males, country rates), with details given in the text for specifics of the actual population.

ABBREVIATIONS: AML, acute myelogenous leukemia; HD, Hodgkin's disease; MM, multiple myeloma; NHL, non-Hodgkin's lymphoma; STS, soft-tissue sarcoma; Update 2000, Veterans and Agent Orange: Update 2000 (IOM, 2001); Update 1998, Veterans and Agent Orange: Update 1998 (IOM, 1999); Update 1996, Veterans and Agent Orange: Update 1996 (IOM, 1996); and VAO, Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994).

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

TABLE 4-3 Epidemiologic Studies—Veterans' Exposure

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

UNITED STATES STUDIES

New Ranch Hand Studies

Michalek et al., 2001a

Cohort

Based on physical examination through 1992 and medical records reviewed through March of 1993; analyzed association between serum dioxin levels and hepatic abnormalities

931

1,199

Michalek et al., 2001b

Cohort

Based on physical examination in 1982, 1985, 1987, 1992, and 1997 and medical records through 1997; analyzed association between serum dioxin levels and peripheral neuropathy

926

918

872

834

761

1,067

1,144

1,131

1,110

1,086

Michalek et al., 2001c

Cohort

Based on physical examination in 1982, 1985, 1987, and 1992 and medical record through 1997; analyzed association between serum dioxin levels and hematological function

1,046

1,017

996

953

1,223

1,292

1,298

1,280

Barrett et al., 2001

Cohort

Based on tests of cognitive function in 1982, and dioxin levels measured in 1987 and 1992; analyzed association between serum dioxin levels and cognitive function

937

1,052

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Steenland et al., 2001

Cohort

A study to reexamine and compare diabetes data from the NIOSH cohort and the United States Air Force Ranchs Hands in order to reconcile differences between the two study methods and protocols

267 NIOSH workers

990 Ranch Hands

227 NIOSH comparisons

1,275 Ranch Hand comparisons

Ranch Hand Studies Reviewed in Update 2000

AFHS, 2000

Cohort

Evaluation of 266 health-related end points, including assessments of 10 clinical areas: general health, neoplasia, neurological, psychological, gastrointestinal, cardiovascular, hematologic, endocrine, immunologic, and pulmonary

995

1,299

Longnecker and Michalek, 2000

Cohort

Based on physical examination and medical record review through 1992, analyzed association between serum dioxin concentrations and diabetes mellitus among the comparison group (no Ranch Hands)

1,281

1,197

Ketchum et al., 1999

Cohort

Based on physical examination and medical record review through 1992, analyzed association between serum dioxin levels and cancer, skin cancer, and other than skin cancer

1,109

980

922

980

1,493

1,275

1,202

1,275

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Michalek et al., 1999a

Cohort

To further elucidate the relationship between dioxin and diabetes mellitus, this analysis studies the effect of dioxin body burden on the relationship between sex hormone-binding globulin and insulin and fasting glucose

952

871

1,281

1,121

Michalek et al., 1999b

Cohort

Based on physical examinations in 1982, 1985, 1987, and 1992, examination of immunologic response and exposure to dioxin among Ranch Hand and comparison cohorts

952

914

372

358

1,281

1,186

491

456

Burton et al., 1998

Cohort

Based on physical examination and medical record review through 1992, analyzed association between serum dioxin levels and occurrence and timing (relative to Southeast Asia service) of chloracne and acne

952

930

476

1,281

1,200

598

Michalek et al., 1998b

Cohort

Updates all-cause and cause-specific postservice mortality (through 1993) among veterans of Operation Ranch Hand, using standardized mortality ratios

1,261

19,080

Michalek et al., 1998c

Cohort

Prospective study of exposure and long-term health, survival, or reproductive outcome

1,208 veterans

903 offspring

1,549 veterans

1,254 offspring

Michalek et al., 1998d

Cohort

Third report in a series investigating dioxin body burden and preterm birth, intrauterine growth retardation, and infant death among offspring of Ranch Hand veterans

995

932

859

1,299

1,202

1,223

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Ranch Hand Studies Reviewed in Update 1998

Michalek et al., 1998a

Cohort

Paternal serum dioxin concentrations and infant death among offspring of Ranch Hands

859 children:

323 background exposure,

267 low exposure,

269 high exposure

1,223 children

Henriksen et al., 1997

Cohort

Study of the relationship between serum dioxin and glucose levels, insulin levels, and diabetes mellitus in Ranch Hands through 1992

989

1,276

AFHS, 1996; Michalek et al., 1998b

Cohort

Mortality update of Ranch Hands through the end of 1993 in the same cohort as AFHS (1983, 1984b, 1985, 1986, 1989, 1991a, 1995)

1,261

19,080

Henriksen et al., 1996

Cohort

Study of serum dioxin and reproductive hormones in Ranch Hands in 1982, 1985, 1987, and 1992

1,045 (participants, 1982)

474 (provided semen)

1,224 (participants, 1982)

532 (provided semen)

Ranch Hand Studies Reviewed in Update 1996

AFHS, 1995

Cohort

Mortality updates of Ranch Hands compared with Air Force C-130 air and ground crew veterans in Southeast Asia who did not participate in herbicide spraying missions

1,261 (original cohort)

19,101 (original cohort)

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Wolfe et al., 1995

Cohort

Paternal serum dioxin levels and reproductive outcomes of Ranch Hand veterans compared with Air Force veterans from Southeast Asia who did not participate in herbicide spraying missions

932

1,202

Ranch Hand Studies Reviewed in VAO

AFHS, 1992

Cohort

Reproductive outcomes of participants in the Air Force Health Study (AFHS)

791

942

AFHS, 1984a, 1987, 1990, 1991b, 1995

Cohort

Baseline morbidity and follow-up exam results of the AFHS

1,208 (baseline)

1,668 (baseline)

AFHS, 1983, 1984b, 1985, 1986, 1989, 1991a

Cohort

Mortality updates of Ranch Hands compared with Air Force C-130 air and ground crew veterans in Southeast Asia who did not participate in herbicide spraying missions

1,261 (original cohort)

19,101 (original cohort)

Michalek et al., 1990

Cohort

Mortality of Ranch Hands compared with Air Force C-130 air and ground crew veterans in Southeast Asia

1,261

19,101

Wolfe et al., 1990

Cohort

Health status of Ranch Hands at second follow-up, compared with Air Force C-130 air and ground crew veterans in Southeast Asia

995

1,299

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Centers for Disease Control (CDC) Studies Reviewed in VAO

Decoufle et al., 1992

Cohort

Association between self-reported health outcomes and perception of exposure to herbicides based on Vietnam Experience Study (VES)

7,924

7,364

O'Brien et al., 1991

Cohort

Interview report and mortality for NHL based on VES

8,170

7,564

CDC, 1990a

Case-control

Selected Cancers Study—population-based case-control study of all men born between 1921 and 1953; cases diagnosed area covered by eight cancer registries and controls selected by random-digit dialing

1,157 NHL; 342 STS; 310 HD; 48 nasal carcinoma; 80 nasopharyngeal carcinoma; 130 primary liver cancer

1,776

CDC, 1990b

Case-control

Selected Cancers Study—population-based case-control study of all men born between 1921 and 1953; cases diagnosed area covered by eight cancer registries and controls selected by random-digit dialing: NHL

1,157

1,776

CDC, 1990c

Case-control

Selected Cancers Study: soft-tissue sarcoma

342

1,776

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

CDC, 1990d

Case-control

Selected Cancers Study: HD, nasal cancer, nasopharyngeal cancer, and primary liver cancer

310 HD; 48 nasal carcinoma; 80 nasopharyngeal carcinoma; 130 primary liver cancer

1,776

CDC, 1989b

Cohort

Vietnam Experience Study—random sample of US Army enlisted men 1965–1971

2,490

1,972

CDC, 1988a

Cohort

VES—random sample of US 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., 1984 a,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 (VA) Studies

Kang et al., 2000a

Cohort

Self-report pregnancy outcomes for female Vietnam veterans compared to contemporary female 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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Kang et al., 2000b

Cohort

Study of gynecologic cancers among female Vietnam veterans compared to femae veteran controls

484

5,946

Kang et al., 2001

Cohort

Study evaluating the health of Army Chemical Corps Vietnam veterans compared to Army Chemical Corps veterans who did not serve in Vietnam

2,872

2,737

Department of Veterans Affairs (VA) Studies Reviewed in Update 1998

Dalager and Kang,1997

Cohort

Morbidity and mortality experience (1968– 1987) of Army Chemical Corps Vietnam veterans compared to US 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

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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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

VA 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

VA 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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

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 US 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 US male population

24,145 Army,

5,501 Marines

(1) 27,145 Army, 4,505 Marines

(2) 32,422 combined Vietnam era

(3) US 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

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 US men

894

True et al., 1988

Cross-sectional

PTSD and Vietnam combat experience evaluated among Vietnam-era veterans

775

1,012

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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

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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

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

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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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 US men, Wisconsin men, Wisconsin nonveterans, and Wisconsin other veterans

122,238 Vietnam-era veterans

43,398 Vietnam veterans

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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

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

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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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 US 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

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

Australian Studies Reviewed in Update 2000

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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

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

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

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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

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

a The dash (—) indicates the comparison group is based on a population (e.g., US white males, country rates), with details given in the text for specifics of the actual population.

ABBREVIATIONS: HD, Hodgkin's disease; NHL, non-Hodgkin's lymphoma; PTSD, posttraumatic stress disorder; STS, soft-tissue sarcoma; CDVA, Commonwealth Department of Veterans' Affairs; Update 2000, Veterans and Agent Orange: Update 2000 (IOM, 2001); Update 1998, Veterans and Agent Orange: Update 1998 (IOM, 1999); Update 1996, Veterans and Agent Orange: Update 1996 (IOM, 1996); and VAO, Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994).

Suggested Citation:"4. Overview of Epidemiologic Studies." Institute of Medicine. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. doi: 10.17226/10603.
×

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This book updates and evaluates the available scientific evidence regarding statistical associations between diseases and exposure to dioxin and other chemical compounds in herbicides used in Vietnam, focusing on new scientific studies and literature.

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