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Veterans and Agent Orange: Update 2000 (2001)

Chapter: 6 Epidemiologic Studies

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Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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6
Epidemiologic Studies

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

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

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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the data were collected; the inclusion criteria; and how exposure was determined. The tables also list the numbers of subjects in the study and comparison populations, and provide a brief description of the study. No studies are evaluated in this chapter; rather, a methodologic framework is provided for the health outcome chapters that follow. Qualitative critique of the study design, population size, methods of data collection, case and control ascertainment, or quality of exposure assessment has been reserved for the individual health outcome chapters in which the results of these studies are discussed.

The text and tables in this chapter are organized into three basic sections— occupational studies, environmental studies, and studies of Vietnam veterans— with subsections included under each heading. The studies address exposures to 2,4-D (2,4-dichlorophenoxyacetic acid); 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) and its contaminant TCDD; cacodylic acid; and picloram. In some cases, the committee examined studies addressing compounds chemically related to the herbicides used in Vietnam, such as 2-methyl-4-chlorophenoxyacetic acid (MCPA), hexachlorophene, and chlorophenols, including trichlorophenol. In other instances, investigators did not indicate specific herbicides to which study participants were exposed or the level of exposure. These complicating factors were considered when the committee weighed the relevance of a study to its findings. Where available, details are given with regard to exposure assessment and how exposure was subsequently used in the analysis.

The occupational section includes studies of production workers, agricultural and forestry workers (including herbicide and pesticide appliers), and paper and pulp workers, as well as case-control studies of specific cancers and the association with exposures to herbicides or related compounds. The environmental section includes studies of populations accidentally exposed to unusual levels of herbicides or dioxins as a result of the location in which they live, for example, the residents of Seveso, Italy; Times Beach, Missouri; and the southern portion of Vietnam. The section on Vietnam veterans includes studies conducted in the United States by the Air Force; the Centers for Disease Control and Prevention (CDC), the Department of Veterans Affairs (DVA, formerly the Veterans Administration [VA]); the American Legion; and the State of Michigan, as well as other groups. Studies of Australian Vietnam veterans are also presented there.

Many cohorts potentially exposed to dioxin and the herbicides used in Vietnam are monitored on an ongoing basis. Studies of the groups that are assessed regularly include the National Institute for Occupational Safety and Health (NIOSH), International Agency for Research on Cancer (IARC), National Cancer Institute (NCI), Seveso, and Ranch Hand cohorts. Typically, the risks between exposure to herbicides and specific health outcomes are updated every 3 to 5 years. For example, the health of the Ranch Hand cohort was assessed in 1982, 1987, 1992, and 1997. For such studies, the committee has chosen to focus on the most recent update, when multiple reports on the same cohort are available. For the sake of thoroughness, the discussion of specific

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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health outcomes in Chapters 710 includes reference to all studies, including those subsumed by the most recent update.

Similarly, researchers investigating the constituent cohorts used in some large multicenter studies may publish reports based solely on the individuals they monitor. Examples include the I ARC and NCI cohort studies. The committee has chosen to focus on the studies of the larger multicenter cohorts. However, for the sake of thoroughness, Chapters 710 reference all of these studies, including those subsumed by the larger multicenter cohorts.

OCCUPATIONAL STUDIES

Several occupational groups in the United States and elsewhere have been exposed to the types of herbicides used in Vietnam and, more specifically, to TCDD, a contaminant of some herbicides and other products. Occupational groups exposed to these chemicals include farmers, agricultural and forestry workers, herbicide sprayers, workers in chemical production plants, and workers involved in paper and pulp manufacturing. In addition, studies that use job titles as broad surrogates of exposure and studies that rely on disease registry data have been conducted. Exposure characterization varies widely in these studies in terms of measurement, quantification, level of detail, confounding by other exposures, and individual versus surrogate or group (ecological) measures.

Production Workers

National Institute for Occupational Safety and Health

In 1978, NIOSH began a study to identify all U.S. workers potentially exposed to TCDD between 1942 and 1984 (Fingerhut et al., 1991). In a total of 12 chemical companies, 5,132 workers were identified from personnel and payroll records as having been involved in production or maintenance processes associated with TCDD contamination. Their possible exposure resulted from working with certain chemicals in which TCDD was a contaminant, including 2,4,5-trichlorophenol (TCP) and 2,4,5-T, Silvex, Erbon, Ronnel, and hexachlorophene. An additional 172 workers identified previously by their employers as being exposed to TCDD were also included in the study cohort. The 12 plants involved were large manufacturing sites of major chemical companies. Thus, many of the study subjects were potentially exposed to many other chemicals, some of which could be carcinogenic.

Prior to the publication of the cohort study, NIOSH conducted a cross-sectional study that included a comprehensive medical history, medical examination, and measurement of pulmonary function of workers employed in the manufacture of chemicals with TCDD contamination at two of the plants in the full cohort. These included workers at two chemical plants in Newark, New Jersey,

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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from 1951 to 1969, and in Verona, Missouri, from 1968 to 1969 and from 1970 to 1972 (Sweeney et al., 1989, 1993; Calvert et al., 1991, 1992; Alderfer et al., 1992). The plant in New Jersey manufactured TCP and 2,4,5-T; the Missouri plant manufactured TCP, 2,4,5-T, and hexachlorophene. A number of studies were later conducted that looked at specific health outcomes among the cohort, including pulmonary function (Calvert et al., 1991), liver and gastrointestinal function (Calvert et al., 1992), mood (Alderfer et al., 1992), the peripheral nervous system (Sweeney et al., 1993), porphyria cutanea tarda (Calvert et al., 1994), and reproductive hormones (Egeland et al., 1994). Sweeney et al. (1996, 1997/1998) also evaluated noncancer end points including liver function, gastrointestinal disorders, chloracne, serum glucose, hormone and lipid levels, and diabetes in a subgroup of the original Calvert et al. (1991) cohort. A cross-sectional medical survey reported blood serum TCDD concentrations and surrogates of cytochrome P450 induction in that cohort (Halperin et al., 1995). VAO, Veterans and Agent Orange: Update 1996 (hereafter, Update 1996) and Update 1998 describe the details of each of those studies.

Since Update 1998, Calvert et al. (1998, 1999) and Halperin et al. (1998) have published follow-up results on the cohort of workers employed more than 15 years earlier at the chemical plants in New Jersey and Missouri. Occupationally exposed individuals were compared to a referent group composed of age-, neighborhood-, race-, and sex-matched individuals with no self-reported occupational exposure to TCDD. The relationship between serum TCDD concentrations (measured as picograms per gram of lipid) and various end points were assessed in those follow-up reports. In Calvert et al. (1998) the association between exposure to TCDD and cardiovascular effects (increased risk of myocardial infarction, angina, cardiac arrhythmias, hypertension, and abnormal peripheral arterial flow) was examined in the cohort. Blood samples were analyzed for total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, and glucose. A general physical examination was conducted, which included measurement of blood pressure, as well as a Doppler examination of the peripheral pulses, a chest X-ray, and electrocardiograms (ECG). Calvert et al. (1999) examined the relationship among TCDD exposure and diabetes mellitus, thyroid function, and indicators of endocrine function in the same cohort. Serum glucose, thyroid-stimulating hormone, total thyroxine (T4), and thyroid hormone binding resin levels were measured. Halperin et al. (1998) evaluated immune parameters in this cohort; lymphocyte subsets, natural killer cell cytotoxic activity, and lymphocyte proliferative responses to stimulation were studied.

Steenland et al. (1999) studied the association between TCDD exposure and cause of death in the cohort from the 12 U.S. chemical plants described by Fingerhut et al. (1991). Those researchers investigated any association between exposure and cancer (all and site specific), respiratory disease, cardiovascular disease, and diabetes. In addition, a similar analysis was conducted in a subgroup

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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of workers who had previously been diagnosed with chloracne, indicating a higher exposure to TCDD on average.

Monsanto

Included in the NIOSH study cohort (Fingerhut et al., 1991) are a number of individual cohort members from Monsanto’s production facilities on whom studies have been conducted. One set of Monsanto studies is based on an accidental exposure that occurred on March 8, 1949, in the trichlorophenol production process at the Nitro, West Virginia, plant of Monsanto (Zack and Suskind, 1980; Moses et al., 1984; Collins et al., 1993). Other studies focused on exposure of Monsanto workers involved in numerous aspects of 2,4,5-T production (Zack and Gaffey, 1983; Moses et al., 1984; Suskind and Hertzberg, 1984). These studies are discussed in more detail in VAO. No new studies have been published on these cohorts.

Dow

Several studies have been conducted on Dow Chemical Company production workers and are summarized in VAO, Update 1996, and Update 1998. The populations in these studies, except for one report by Bond et al. (1988), are included in the NIOSH cohort (Fingerhut et al., 1991). Originally, Dow Chemical Company conducted a study on the work force engaged in the production of 2,4,5-T (Ott et al., 1980) and a study on TCP manufacturing workers exhibiting chloracne (Cook et al., 1980). Extension and follow-up studies compared potential exposure to TCDD and medical examination frequency and morbidity (Bond et al., 1983), as well as reproductive outcomes after potential paternal TCDD exposure (Townsend et al., 1982). A prospective mortality study was also conducted of Dow employees diagnosed with chloracne or classified as having chloracne on the basis of clinical description (Bond et al., 1987).

In addition, Dow Chemical Company assembled a large cohort at the Midland, Michigan, plant (Cook et al., 1986, 1997; Bond et al., 1989b). Exposure to TCDD was characterized in this cohort based on chloracne diagnosis (Bond et al., 1989a). Within this large Midland cohort, a cohort study of women (Ott et al., 1987) and a case-control study of soft-tissue sarcoma (STS) (Sobel et al., 1987) were conducted. Dow Chemical Company has also undertaken a large-scale cohort mortality study of workers exposed to herbicides in several Dow plants (Bond et al., 1988; Bloemen et al., 1993; Ramlow et al., 1996). No new studies have been published on the Dow cohort since Update 1998.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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BASF

In Germany, an accident on November 17, 1953, during the manufacture of trichlorophenol at BASF Aktiengesellschaft, resulted in the exposure of some workers in the plant to predominantly TCDD. VAO, Update 1996, and Update 1998 summarize studies of these workers. The studies include a mortality study of persons initially exposed or later involved in cleanup operations (Thiess et al., 1982), an update and expansion of that study (Zober et al., 1990), and a morbidity follow-up (Zober et al., 1994). In addition, Ott and Zober (1996) examined cancer incidence and mortality in another cohort of workers exposed to TCDD after the accident during reactor cleanup, maintenance, or demolition.

Since Update 1998, Zober et al. (1997) have summarized their studies on the BASF cohort, but no new analyses of the cohort have been reported.

IARC

To avoid problems of small studies with insufficient power to detect increased cancer risks, IARC created a multinational registry of workers exposed to phenoxy herbicides, chlorophenols, and their contaminants (Saracci et al., 1991). The IARC registry includes information on mortality and exposures of 18,390 workers—16,863 men and 1,527 women. Update 1996 describes the individual national cohorts included in this multinational registry.

In a study including cohorts from 10 countries, cancer mortality from soft-tissue sarcoma (STS) and malignant lymphoma was evaluated (Kogevinas et al., 1992). Two nested case-control studies were also undertaken within this cohort to evaluate the relationship between STS and non-Hodgkin’ s lymphoma (Kogevinas et al., 1995). In an update and expansion, Kogevinas et al. (1997) assembled national studies from 12 countries that used the same protocol, jointly developed by study participants and coordinated by IARC, and studied cancer mortality. A cohort study of cancer incidence and mortality was conducted among 701 women occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins from seven countries (Kogevinas et al., 1993). VAO, Update 1996, and Update 1998 highlight these studies.

In addition, a number of the individual cohorts have been evaluated apart from the IARC-coordinated efforts. These cohorts include Danish production workers studied by Lynge (1985, 1993); British production workers studied by Coggon et al. (1986, 1991); Dutch production workers studied by Bueno de Mesquita et al. (1993); and German production workers studied by Manz et al. (1991), Becher et al. (1996), and Flesch-Janys et al. (1995). VAO, Update 1996, and Update 1998 discuss these studies in more detail.

Since Update 1998, Vena et al. (1998) published a study on nonneoplastic mortality in the cohort in which Kogevinas et al. (1997) studied cancer mortality. The cohort is composed of 21,863 workers who were employed in the production

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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or spraying of phenoxyacetic herbicides. In the study by Vena et al. (1998), data on workers from all 36 cohorts from 12 countries were studied; data for workers from cohorts for which minimum employment periods were specified were not included. Exposures were estimated by job records, company exposure questionnaires, and in some cohorts, serum, adipose, or workplace TCDD measurements. Workers were divided into three exposure categories: exposed to TCDD or higher-chlorinated dioxins, not exposed, and unknown exposure status. Standard mortality ratios (SMRs) were calculated for all major noncancer causes of death.

Hooiveld et al. (1998) analyzed data from one study at a factory in the Netherlands that followed the protocol of, and was included in, the IARC study. Exposure status was based on departmental occupational history, as well as exposure to the accident. Serum concentrations of poly chlorinated dibenzodioxins (PCDDs), poly chlorinated dibenzofurans (PCDFs), and poly chlorinated biphenyls (PCBs) were measured in a subset of survivors who were employed prior to the end of the last TCDD-contaminated process. Maximum TCDD concentrations were estimated from the measured TCDD concentrations using a one-compartment, first-order kinetic model and a half-life of 7.1 years. SMRs and relative risks were calculated by cause of death in two cohorts: 549 male workers exposed to phenoxy herbicides, chlorophenols, and contaminants; and 140 male workers exposed as a result of an accident at the plant.

Flesch-Janys (1997) summarized exposure and mortality data on employees of the Hamburg Boehringer Company plant that produced 2,4,5-T, 2,4,5-TCP, and hexachlorocyclohexane (HCH) until 1984. The cohort, which had been studied previously by Flesch-Janys et al. (1995), consisted of all regular employees of a chemical plant (N=1,189 males). Flesch-Janys (1997) used half-life data previously determined in a subgroup of the cohort (Flesch-Janys et al., 1996) to estimate blood TCDD levels in 190 workers. From that they determined department-specific exposures and, from that, estimated exposures (TCDD and toxic equivalents) for the entire cohort (Flesch-Janys et al., 1995). Using these estimates, dose-response analyses were conducted for SMRs from different causes of death.

Neuberger et al. (1999) studied the health effects of TCDD in an Austrian cohort that is part of the IARC study. Preliminary results are presented in Neuberger et al. (1998) and in an article with an English abstract (Jäger et al., 1998). Individuals in the Austrian cohort had been diagnosed with chloracne and were exposed to poly chlorinated dibenzodioxin or dibenzofuran (PCDD/F) (mainly TCDD) in a 2,4,5-T production facility in Linz, Austria. At the time of the study, of 159 individuals identified as having chloracne, 124 remained in Austria and were invited to participate in a health examination survey: 56 individuals participated in the survey and 50 individuals donated blood and urine and answered all questions. Age- and sex-matched controls who had recently participated in health checkups similar to those of the cases were employed. Two such control groups were used, one drawn from the same occupational health center in Linz and one

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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from another prospective study on workers from a chemical plant located 66 km from the 2,4,5-T plant. Occupational and medical histories, including smoking and alcohol consumption, were obtained from cases and controls. PCDF, PCDD, and PCB concentrations were measured in plasma. Chloracne, general health status (e.g., neurological symptoms, liver disease, stomach problems, arthritis), and clinical chemistry parameters (e.g., blood sugar, cholesterol, enzyme levels, leukocyte levels) were assessed in the three groups.

Other Chemical Plants

Previous studies have reviewed health outcomes among chemical workers in the United Kingdom exposed to TCDD as a result of an industrial accident in 1968 (May, 1982, 1983; Jennings et al., 1988); production workers in the former USSR involved in the production of 2,4-D (Bashirov, 1969); factory workers in Prague, Czechoslovakia, who exhibited symptoms of TCDD toxicity 10 years after occupational exposure to 2,4,5-T (Pazderova-Vejlupkova et al., 1981); 2,4-D and 2,4,5-T production workers in the United States (Poland et al., 1971); white male workers employed at a chemical plant in the United States manufacturing flavors and fragrances (Thomas, 1987); and the long-term immune system effects of TCDD in 11 industrial workers involved in production and maintenance operations at a German chemical factory producing 2,4,5-T (Tonn et al., 1996). VAO and Update 1998 detail these studies.

Since Update 1998, Hryhorczuk et al. (1998) has examined employees in a chemical plant in southwestern Illinois who were engaged in the production of PCP, lower-chlorinated phenols, and esters of chlorophenoxy acids. The study population was defined based on company personnel records. The unexposed comparison population consisted of workers from the same plant who, according to company records, had never worked in areas where they would have been exposed to PCP. Of the 743 eligible exposed workers, 473 participated in the medical examination, of whom 366 were engaged in the production of PCP. Of the 559 eligible unexposed workers, 303 participated in the medical examination. The exposed and unexposed groups were examined for general health status, chloracne, and porphyria.

Jung et al. (1998) evaluated immune effects in a cohort of workers formerly employed at a German pesticide-producing plant. Of 450 former workers, 192 (8 women) chose to participate in comprehensive health status checks that were offered following the closing of the plant and were used in the study. PCDD/F concentrations were measured in blood lipids and expressed as toxicity equivalents (TEQs). Study participants were observed clinically and were asked about medical and work history. Measurements of immunological parameters, including erythrocyte sedimentation rate, full blood count, serum electrophoresis, presence of specific antibodies, immunoglobulin (Ig) levels, and lymphocyte surface marker measurements, were conducted. The results of specific tests, however,

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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were not presented for the full cohort (e.g., tetanus antibodies before and 3 weeks after vaccination, N=53; IgA, IgG, and IgM levels, N=53). No explanation is provided for the variable number of participants in the different immunological assays. In addition, a subgroup of the 29 most highly exposed individuals was compared to 28 unexposed individuals for proliferation of lymphocytes and chromate resistance.

Agricultural and Forest Products Workers

Cohort Studies

Agricultural Workers VAO, Update 1996, and Update 1998 detail a number of cohort studies examining health effects in individuals involved in agricultural activity. These include studies of proportionate mortality among Iowa farmers (Burmeister, 1981) and among male and female farmers from 23 states (Blair et al., 1993); cancer mortality among Danish and Italian farmers (Ronco et al., 1992) and among a cohort of rice growers in the Novara Province of northern Italy (Gambini et al., 1997); cancer incidence among farmers licensed to spray pesticides in the southern Piedmont area of Italy (Corrao et al., 1989) and among female Danish gardeners (Hansen et al., 1992); sperm abnormalities among Argentinean farmers (Lerda and Rizzi, 1991); cancer birth defects among the offspring of Norwegian farmers (Kristensen et al., 1997); and immunological changes in 10 farmers who mixed and applied commercial formulations containing the chlorophenoxy herbicides (Faustini et al., 1996). In addition, a set of Canadian studies, called the Mortality Study of Canadian Male Farm Operators, evaluated the risk to farmers of general mortality and specific health outcomes including non-Hodgkin’s lymphoma (NHL) (Wigle et al., 1990; Morrison et al., 1994), prostate cancer (Morrison et al., 1992), brain cancer (Morrison et al., 1993), multiple myeloma (Semenciw et al., 1993), leukemia (Semenciw et al., 1994), and asthma (Senthilselvan et al., 1992). Based on data from the Swedish Cancer Environment Register (which links population census data, including occupation, with the Swedish Cancer Registry), cohort studies evaluated cancer mortality and farm work (Wiklund, 1983); STS and malignant lymphoma among agricultural and forestry workers (Wiklund and Holm, 1986; Wiklund et al., 1988a); and the risk of NHL, Hodgkin’s disease (HD), and multiple myeloma in relation to numerous occupational activities (Eriksson et al., 1992). Brain, lymphatic, and hematopoietic cancers in Irish agricultural workers have also been studied (Dean, 1994).

Since Update 1998, Arbuckle et al. (1999) examined the incidence of spontaneous abortion in couples living on family farms in Ontario, Canada, selected from the 1986 Canadian Census of Agriculture. Farming families were contacted by telephone and were considered eligible if they were married or “living as married,” if they lived year-round on the farm, and if the wife was not older than

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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44. Eligible families were sent three questionnaires. One questionnaire, addressed to the farm operator, collected data on pesticide use (current and historical use). Another questionnaire, addressed to the husband, collected demographic, socioeconomic, and life-style information, medical history, and information on his activities on the farm, date of moving to the farm, and pesticide exposures both at home and on the farm. Another questionnaire, addressed to the wife, collected information similar to that of the husbands, but also collected a complete reproductive history. Pesticide use was recorded by specific pesticide by month and year. Spontaneous abortion occurrence was self-reported at <20 weeks of gestation and was categorized by occurrence at <12 weeks and occurrence between 12 and 19 weeks of gestation. This subgrouping provided an indirect estimate of the frequency of chromosomal anomalies because these anomalies are a much more common cause of early abortions than later abortions. Pregnancy outcome data were merged with pesticide use at the corresponding time. Potential confounders were also recorded (e.g., parental age, smoking, alcohol consumption), along with the time period during which they were present. Telephone screening identified 2,946 eligible couples (36.5 percent of all operating farms). Pregnancies were excluded if there was missing information (e.g., outcome, delivery date, gestational age at delivery), if it occurred when the woman was not living on the farm, if the study husband might not have been the father, or in the case of multiple gestations, ectopic pregnancies, or hydatidiform mole pregnancies. A total of 2,110 women were enrolled in the study with a total of 5,853 pregnancies, of which 3,396 were included in the analysis.

Forestry Workers Studies have been conducted among forestry workers potentially exposed to the types of herbicides used in Vietnam. These studies include a cohort mortality study among men employed at a Canadian public utility (Green, 1987, 1991) and a briefly outlined Dutch study of forestry workers exposed to 2,4,5-T that investigated the prevalence of acne and liver dysfunction (van Houdt et al., 1983). VAO describes these studies in greater detail.

Since Update 1998, Thörn et al. (2000) have reported on mortality and cancer incidence in a cohort of Swedish lumberjacks. The cohort analyzed consisted of males and females who were Swedish residents and employed by one Swedish forestry company at some time between 1954 and 1967. Approximate volume and concentration of phenoxy acids used daily in a particular work task or job category were obtained from former employees. Pay slips were used to determine time spent at particular work tasks, and exposure to phenoxy acids was estimated by the time spent at particular job categories. Employees who were exposed to phenoxy acids for more than 5 working days were considered to have been exposed; employees not exposed to any types of pesticides were used as the unexposed or control group; individuals who were exposed to other pesticides (including DDT) were excluded from the study. Mortality was determined from the National Register of Causes of Death, new cancer cases were determined

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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from the Swedish Cancer Register, and death certificates with underlying cause of death were provided by Statistics Sweden. Data were available for 261 exposed and 243 unexposed members of the cohort. SMRs and cancer incidence (all and site specific) ratios were calculated for each group using ratios expected from the death and cancer registries.

Herbicide and Pesticide Sprayers A number of cohort studies have assessed health outcomes among herbicide and pesticide appliers including cancer mortality among Swedish railroad workers (Axelson and Sundell, 1974; Axelson et al., 1980), mortality among pesticide appliers in Florida (Blair et al., 1983), general and cancer mortality and morbidity measured prospectively among Finnish male 2,4-D and 2,4,5-T appliers (Riihimaki et al., 1982, 1983; Asp et al., 1994), and reproductive outcomes among male chemical appliers in New Zealand (Smith et al., 1981, 1982). Other studies examined the risk of cancer including STS, HD, and NHL among pesticide and herbicide appliers in Sweden (Wiklund et al., 1987, 1988b, 1989a, b), general and cancer mortality among Dutch male herbicide appliers (Swaen et al., 1992), cancer mortality among Minnesota highway maintenance workers (Bender et al., 1989) and Minnesota pesticide appliers (Carry et al., 1994, 1996a, b), lung cancer morbidity in male agricultural plant protection workers in the former German Democratic Republic (Barthel, 1981), British Columbia sawmill workers potentially exposed to chlorophenate wood preservatives (Dimich-Ward et al., 1996; Hertzman et al., 1997; Heacock et al. 1998), and cancer risk among pesticide users in Iceland (Zhong and Rafnsson, 1996). Some of these studies include agricultural and forestry worker cohorts; the details are included in VAO, Update 1996, and Update 1998.

More recently, data from the first 2 years of a 10-year Agricultural Health Study in Iowa and North Carolina have been published (Alavanja et al., 1998). In that study, pesticide appliers completed a self-administered questionnaire that asked about hospital or doctor visits resulting from pesticide exposures. Questionnaires were administered at testing and training sessions, which are required every 3 years for certification or recertification of pesticide appliers in these states. Out of 51,256 appliers who attended the sessions, 35,879 (3 percent of those enrolled in the study were women and 3.1 percent were minorities) completed the questionnaire, which asked about general information on pesticide use, as well as specific information on the use of 50 individual pesticides. In addition, for 22 pesticides, information on the number of years and the average number of days of application per year was gathered. Questions on the use of protective clothing, application procedures, crops and livestock raised in the past year, farm size, smoking and alcohol consumption history, diet, and basic demographics were included. Cumulative lifetime application days for herbicides, insecticides, fumigants, and fungicides were calculated based on the responses, and relative risks for health care visits were determined.

Dich and Wiklund (1998) studied a cohort of 20,025 males who were li-

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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censed for pesticide application in Sweden between 1965 and 1976. This cohort had been studied previously by Wiklund et al. (1987, 1988b, 1989a, b). The use of pesticides in a random sample of 268 of these applicators has been described (Wiklund et al., 1989a). Information gathered included types of pesticides used, frequency of application, years used, application methods, use of protective clothing, smoking, and occupational history. Prostate cancer occurrence in the cohort was determined from the Swedish Cancer Registry, with all registered cases of malignant prostatic tumors included. The expected rate of tumors was based on the annual incidence of prostate tumors in the male Swedish population in 5-year age groups.

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 further investigate the possible association (Hardell and Sandstrom, 1979; Eriksson et al., 1979, 1981, 1990; Hardell and Eriksson, 1988; Wingren et al., 1990). Following 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); nasal and nasopharyngeal carcinomas (Hardell et al., 1982); and primary or unspecified liver cancer (Hardell et al., 1984). To address criticism regarding potential observer bias in some of these 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 parameters related to NHL, including histopathology, stage, and anatomical location, on the basis of the NHL cases from a previous study (Hardell et al., 1981).

Prompted by the Swedish studies (Hardell, 1977, 1979), a set of case-control studies was undertaken in New Zealand to evaluate the risks of 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).

Elevated leukemia mortality in geographic patterns for white males in the central part of the United States prompted a study of the leukemia mortality of 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) based on the cohort study of Burmeister (1981); and in

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Iowa and Minnesota (Brown et al., 1990); as well as on leukemia associated with NHL in eastern Nebraska (Zahm et al., 1990).

Case-control studies have been conducted on other cancers in various U.S. populations, 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, 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 have been conducted outside the United States looking 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 from 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 from 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 include spontaneous abortions (Carmelli et al., 1981); immunosuppression and subsequently decreased host resistance to infection among AIDS patients with Kaposi’s sarcoma (Hardell et al., 1987); mortality of U.S. Department of Agriculture (USDA) extension agents (Alavanja et al., 1988, 1989); risk of spina bifida in offspring by investigating paternal occupation (Blatter et al., 1997); mortality from neurodegenerative diseases by looking at occupational risk factors (Schulte et al., 1996); Parkinson’s disease (PD) in terms of occupational and environmental risk factors (Liou et al., 1997); PD by looking at various rural factors, including exposure to herbicides and wood preservatives (Seidler et al., 1996); PD by examining occupational risk factors (Semchuk et al., 1993); and birth defects among agricultural workers (Nurminen et al., 1994). Those earlier studies are discussed in detail in VAO, Update 1996, or Update 1998.

More recently, García et al. (1998) conducted a case-control study in an agricultural region of Spain assessing the association between paternal occupational exposure to pesticides and congenital malformations. The base population for the study was selected from couples who gave birth at selected hospitals in the study area in 1993 and 1994. From this base, study cases were chosen when they exhibited the presence of malformations or groups of defects with a relatively high prevalence at birth which were also conditions identified in earlier epide-

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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miologic research as being related to pesticide exposure. One matched control was included for each case. From a total of 336 cases and 355 controls originally identified, 261 cases and 261 controls participated in the study. Interviews were conducted by telephone when possible and in person otherwise. A questionnaire asked about possible exposures to pesticides (e.g., involvement in agricultural work and pesticide application) for 3 months preceding conception and during the first trimester for the father, and for 1 month prior to conception and during the first trimester for the mother. Individuals involved in pesticide application were then interviewed in person to collect detailed information on the characteristics of the agricultural work; exposure to pesticides, including details of the crops sprayed, duration, and types of pesticide treatments; and other sources of pesticide exposure. One individual involved in training pesticide appliers and one individual working at the local agricultural department independently assessed the exposure of individuals based on the questionnaires; a consensus rating of exposure was obtained from the two assessments. Risk estimates were calculated jointly for all congenital malformations in association with exposure to major classes of pesticides and specific active ingredients.

Ekstrom et al. (1999) published a case-control study on different geographic regions of Sweden that have different rates of gastric cancer. Three counties have gastric cancer incidences close to the national average; two other counties have Sweden’s highest incidences of gastric cancer. Individuals born in Sweden who were between 40 and 79 years of age and lived in one of five counties in Sweden during the study period were eligible for the study. New cases of histologically confirmed gastric adenocarcinoma were identified by clinicians working in hospitals in the study area, by surveillance of definite or suspected cases evaluated at county pathology departments, by checking regional cancer registries, and by a final check with the national Cancer Register 20 months after the end of the study period. Identified cases were asked by their clinicians to participate in an interview for the study, with a total of 567 cases interviewed (out of 908 identified individuals). Two age- and gender-matched controls were randomly identified and interviewed for each case. A total of 1,165 individuals were interviewed out of 1,534 control subjects who were contacted. Interviews were conducted in person by professional interviewers at Statistics Sweden. Occupation was coded by title for any position held for at least 1 year and was stratified both as “ever” and also by duration (1–10 years, >10 years). Inquiries were also made as to exposure to particular occupations and chemicals, including mining and paper mills, and asbestos, organic solvents, and specific pesticide groups. Based on job histories and the interview data, individuals were assigned an exposure status, and cumulative duration of exposure was estimated. Socioeconomic status, education level, area of residence, smoking habits, and diets were assessed as covariates. Because gastric cancer is the end point of interest, a subset of the cases and controls was assessed for antibodies to Helicobacter pylori as a potential confounder.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Hardell and Eriksson (1999) investigated the relationship between exposure to pesticides and NHL in Sweden. Males greater than 25 years of age diagnosed with NHL between 1987 and 1990 in five counties of Sweden were identified through regional cancer registries. Cases had to have been diagnosed histopathologically and the pathological diagnosis was confirmed for the study. A total of 442 cases were included. Two male controls were matched to each case. Controls for deceased cases were matched for age and year of death. A questionnaire was mailed to subjects or next of kin to collect information on work history and exposure to different chemicals, including information on years of exposure and cumulative exposure in days. Information on smoking, dietary habits, and previous diseases was also collected. Most individuals were also interviewed over the phone to clarify confusing answers or complete unanswered questions; 404 cases and 741 controls answered the questionnaire.

Paper and Pulp Workers

Workers in the paper and pulp industry may be exposed to TCDD and other dioxins that are generated during the bleaching process used in the production and treatment of some paper and paper products. VAO describes studies of workers potentially exposed to TCDD at paper and pulp mills and various health outcomes, including general mortality of workers at five mills in Washington, Oregon, and California (Robinson et al., 1986); cancer incidence among male Finnish paper mill workers (Jappinen and Pukkala, 1991); respiratory health in a New Hampshire mill (Henneberger et al., 1989); and cause-specific mortality among white males employed in plants identified by the United Paperworkers International Union (Solet et al., 1989).

More recently, Rix et al. (1998) investigated the relationship between working in the paper industry and cancer risk. A historical cohort was made up of workers in three paper mills in Denmark owned by the same company, with 1890 as the earliest year of employment. None of the mills ever produced pulp. Work history was determined from company records, and individuals were located by either personal identification numbers or the National Mortality Register. A total of 14,362 people were identified out of 14,789 in the overall cohort. Cancer cases occurring from 1943 to 1993 were identified from the Danish Cancer Register, which started in 1943. Expected cancer incidences were calculated from Danish population incidences. Overall cancer risk and site-specific cancer risks were calculated.

Schildt et al. (1999) conducted a case-control study in Sweden investigating the risk of oral cancer from occupational exposures and particular occupations. The cases consisted of all histopathologically verified squamous cell oral cancer cases in the Cancer Register for four counties in Sweden. A total of 410 cases out of 419 identified individuals were used. One control was matched for each case on the basis of age, sex, county of residence, and age at death if the case was deceased. Questionnaires were sent to all living subjects and next of kin for

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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deceased subjects to assess exposure. Information on lifetime occupational history, smoking, other exposure factors of interest, and socioeconomic status was collected. Follow-up telephone interviews were used to clarify answers or complete unanswered questions and with any individuals who were employed in farming or forestry to ensure uniform assessment of exposures of these individuals to pesticides. A total of 354 matched pairs participated in the study (354 cases and 354 controls).

ENVIRONMENTAL STUDIES

The occurrence of accidents and industrial disasters has offered opportunities to evaluate the long-term health effects of exposure to dioxin 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. A variety of indicators were used to estimate individual exposure; soil contamination by 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 lesser 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 based on these exposure categories have been conducted. These studies are reviewed extensively in VAO, Update 1996, and Update 1998 and are summarized here. Caramaschi et al. (1981) presented the distribution of chloracne among Seveso children, while Mocarelli et al. (1986) tested the children for laboratory levels of several chemicals in blood and urine based on previous chloracne. In a follow-up to these studies, dermatologic findings and laboratory tests were conducted among a group of the children with chloracne compared to controls (Assennato et al., 1989a).

Other studies looked at specific health effects associated with TCDD exposure among Seveso residents, including chloracne, birth defects, spontaneous abortions, 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); neurological disorders (Boeri et al., 1978; Filippini et al., 1981); cancer incidence (Pesatori et al., 1992, 1993; Bertazzi et al., 1993); and the sex ratio among offspring who were born in zone A (Mocarelli et al., 1996). A 2-year

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prospective controlled study was conducted of workers potentially exposed to TCDD during cleanup of the most highly contaminated areas following 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 followup studies among adults and children age 1 to 19 at the time of the accident (Bertazzi et al., 1989a, b, 1992) and 15-year follow-up studies (Bertazzi et al., 1997, 1998).

Since Update 1998, Pesatori et al. (1998) have updated the noncancer mortality causes for the 15 years from July 1976 to June 1991 for individuals living in zone A, B, or R at the time of the accident. Data were obtained from vital statistics registries. Vital status was obtained for more than 99 percent of the cohort, with information on 805 individuals from zone A; 5,943 individuals from zone B; 38,625 individuals from zone R; and 232,747 reference individuals.

Bertazzi et al. (2001) conducted a 20.5-year mortality study (1976–1996) of individuals living in zone A, B, or R at the time of the accident or who moved to the area in the 10 years after the accident. Vital statistics and cause of death for deceased subjects were determined through local vital statistics offices. Tracing was high with only 2.3 percent of the original cohort not traced; information was obtained on 804 individuals from zone A; 5,941 individuals from zone B; 38,624 individuals from zone R; and 232,745 reference individuals. In addition to analysis of the full cohort, data for zones A and B were analyzed by years since first exposure to assess latency effects and by gender, age category, calendar time, duration of residence, and residence at the time of exposure.

Times Beach and Quail Run

During early 1971, by-products 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. TCDD was a contaminant of the mixtures sprayed, and the contamination was reported by the Environmental Protection Agency (EPA). A number of studies were conducted to evaluate health effects from 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 these studies in greater detail, 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 these studies. The review article included nine reports that focus primarily on repro-

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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ductive 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 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 these studies in more detail. No studies have been published since Update 1996.

Other Environmental Studies

VAO, Update 1996, and Update 1998 reported on numerous studies focusing on reproductive outcomes of potential environmental exposure in Oregon (U.S. 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 resulting from environmental exposure. These studies 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); neuropsychological effects in Germany (Peper et al., 1993); young-onset Parkinson’s disease in Oregon and Washington (Butterfield et al., 1993); adverse health effects following an electrical 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 (CLL) in a rural Michigan community (Waterhouse et al., 1996); HD, NHL, multiple myelomas, and acute myeloid leukemias in various regions of Italy (Masala et al., 1996); inhalation exposure to TCDD and the effects of 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 for whom it is assumed that diet constitutes the primary exposure route (Svensson et al., 1995); immune effects in hobby fishermen in the Frierfjord in southeastern Norway (Lovik et al., 1996); and immunological effects of pre- and postnatal PCB or TCDD exposure in Dutch infants from birth to 18 months of age (Weisglas-Kuperus et al., 1995).

Since Update 1998, Schreinemachers (2000) has examined cancer mortality from 1980–1989 in four northern wheat-producing states. Information on total land area, total crop land, and individual harvested crop acreage by county was obtained for Minnesota, North Dakota, South Dakota, and Montana from the 1982 USD A Agricultural Census data base. Wheat acreage per county was used as a surrogate for exposure to chlorophenoxy herbicides (including 2,4-D). Counties with less than 20 percent crop land or more than 50 percent urban population were excluded. Remaining counties were divided into tertiles based on wheat

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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acreage. Cancer mortality data for 1980–1989, collected by the National Center for Health Statistics, were summarized for 34 cancers. Data were grouped by 5-year age intervals, sex, race, and county and state of residence. Age-standardized mortality rate ratios (SRRs) were calculated by comparing the top two tertiles to the first tertile for white subjects. SRRs for rare cancers were calculated by dividing counties into two groups based on the median of wheat per county. Frequently occurring cancers were investigated using individual counties as the unit of observation; analysis focussed on counties that reported five or more cancers.

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, as well as in Australia and Vietnam. Exposure measures in these studies have been done on a variety of levels, and evaluations of health outcomes have been made using a variety of different comparison or control groups. This section is organized primarily by the sponsors of the research, because this format is more conducive to methodologic presentation of the articles. In these studies, exposure measures fall along a crude scale from individual levels for Ranch Hands, as reflected in serum dioxin measurements, to use of service in Vietnam as a surrogate for 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 U.S. male populations (either state or national). This is also discussed in Chapter 5 of this report.

United States

Ranch Hands

The men responsible for the majority of aerial spraying of herbicides in Vietnam were volunteers from the Air Force who participated in Operation Ranch Hand. To determine whether there are adverse health effects associated with exposure to herbicides, including Agent Orange, 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, and Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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(hereafter referred to as Type 2 Diabetes) (IOM, 2000) discuss reports and papers addressing this cohort in more detail.

A retrospective matched cohort study design was implemented to examine morbidity and mortality, with follow-up scheduled to continue until 2002. National Personnel Records Center and U.S. Air Force Human Resources Laboratory records were searched and cross-referenced to ascertain completely 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 (using Air Force specialty code), and race (white or not white). The rationale for matching on these variables was to control for age-related effects, educational and socioeconomic status, and potential differences by race in development of chronic disease. Since Ranch Hands and controls performed similar combat or combat-related jobs, many potential confounders related to the physical and psychophysiologic effects of combat stress and the Southeast Asia environment were potentially controlled (AFHS, 1982). Rank was also used as a surrogate of exposure. Alcohol and smoking were controlled for when they are known risk factors for the endpoint of interest.

Ten matches for each exposed subject formed a control set. 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, using 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 exam occurred in 1982, and future exams are scheduled until 2002. Morbidity is ascertained through questionnaire and physical examination, which emphasize dermatologic, neuropsychiatric, hepatic, immunologic, reproductive, and neoplastic conditions. There were 1,208 Ranch Hands and 1,668 comparison subjects eligible for baseline examination. Initial questionnaire response rates were 97 percent for the exposed cohort and 93 percent for the unexposed; baseline physical exam responses were 87 and 76 percent, respectively (Wolfe et al., 1990). For the 1987 examination and questionnaire (Wolfe et al., 1990), 84 percent of Ranch Hands (N=955) and 75 percent of comparison subjects (N=1,299) were fully compliant. Mortality outcome was obtained and reviewed by using U.S. Air Force Military Personnel Center records, the DVA’s Death Beneficiary Identification and Record Location System (BIRLS), and the Internal Revenue Service’s data base of active social security numbers. Death certificates were obtained from the appropriate health departments (Michalek et al., 1990). For this study, 84 percent of the 1,148 eligible Ranch Hands (N=952), 76 percent of the original comparison group (N=912), and 65 percent of the 567

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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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 to the methods described previously for the 1982 and 1987 examinations.

Ranch Hands were divided into three categories on the basis of their potential exposures:

  1. Low potential: This group included pilots, copilots, and navigators. Exposure was primarily through preflight checks and during actual spraying.

  2. 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.

  3. 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 (1984b), second (1987), and third (1992) follow-up examinations (AFHS, 1987, 1990, 1995); and the reproductive outcomes study (AFHS, 1992; Wolfe et al., 1995). 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 the end of 1993 (AFHS, 1996; Michalek et al., 1998b). Serum dioxin levels were measured in 1982 (36 Ranch Hands; Pirkle et al., 1989); 1987 (866 Ranch Hands; AFHS, 1991b); and 1992 (455 Ranch Hands; AFHS, 1995). Serum dioxin analysis of the 1987 follow-up examinations was published in 1991 (AFHS, 1991b).

Other Ranch Hand publications have addressed the relationship between serum dioxin and reproductive hormones (Henriksen et al., 1996); TCDD and diabetes mellitus, glucose, and insulin levels (Henriksen et al., 1997); and dioxin levels and infant death (Michalek et al., 1998a).

Since Update 1998, Burton et al. (1998) have investigated the incidence of skin disorders in veterans of Operation Ranch Hand, updating the previous study by Wolfe et al. (1990). Dermatological examinations were conducted in 1982, 1985, 1987, and 1992 by dermatologists who had undertaken a review program to become familiar with the clinical features of chloracne. Statistical analyses were adjusted for age, race, and military occupation. Veterans were excluded from the statistical analyses of acne located in the eyelids, ears, or temples if they had a history of acne prior to service in Southeast Asia or if they had no history of acne. Veterans were excluded if their dioxin concentration was missing. Data from 930 Ranch Hand and 1,200 comparison veterans were analyzed in the study. The association between categorized serum dioxin levels and chloracne, the occurrence of acne relative to the tour of duty in Southeast Asia, and the anatomical location of acne after service in Southeast Asia were investigated.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Michalek et al. (1998b) reported on a 15-year follow-up of postservice mortality in veterans of Operation Ranch Hand. The report updates cause-specific mortality in the population studied by Michalek et al. (1990) and described above. Cumulative mortality through December 31, 1993, for Ranch Hand veterans and comparison veterans was analyzed. There were 31 veterans whose service dates could not be located; these veterans were excluded from the analysis. A total of 1,261 Ranch Hands and 19,080 comparison veterans were included in the analysis. Exposure was based on military occupation. SMRs were calculated for major causes of death.

Michalek et al. (1998c) report the sex ratio in offspring of veterans of Operation Ranch Hand studied previously (Wolfe et al., 1990, 1995; Henriksen et al., 1996; Michalek et al., 1990). Sex ratios in offspring born after a father’s service in Southeast Asia were evaluated in 1,208 Ranch Hand veterans and 1,549 comparison Vietnam veterans. Pregnancies were categorized as being conceived less than 1 month, 1 year, or 5 years after service or at any time during the postservice period. The percentage of female children was compared among dioxin exposure categories.

Michalek et al. (1998d) report on reproductive outcomes in the Vietnam veterans cohort of Wolfe et al. (1990). Reproductive outcomes were assessed in the health evaluations, including the 1992 health evaluation, by questions regarding the health of children. Participants were also asked to provide access to medical records documenting each pregnancy and the health of each child through 18 years of age. Histories of smoking and alcohol consumption during each pregnancy were obtained during interviews with wives and partners. Blood dioxin levels were estimated as described previously for this cohort. Attempts were made to verify pregnancies through retrieval of medical documents, birth certificates, death certificates, and autopsy reports. Attempts were made to verify the existence, lineage, birthweight, gestation, and vital status of all live births. Reproductive outcomes were assessed in singleton live births fathered by study participants with a quantifiable dioxin level, conceived during or after paternal service in Southeast Asia. Any unverifiable children, children of comparison veterans who had dioxin levels greater than 10 parts per trillion (ppt), and children without a recorded birthweight were excluded. The total number of children assessed in this study was 2,082 (1,223 children of comparison veterans, 859 children of veterans of Operation Ranch Hand). Relative risks were calculated for preterm birth, intrauterine growth retardation, and infant and neonatal death.

Ketchum et al. (1999) studied cancer and exposure to dioxin in Ranch Hand veterans, in the cohort previously described by Wolfe et al. (1990). Participants were examined, and medical records were retrieved in 1982, 1985, 1987, and 1992. Cancer was defined as a malignant neoplasm and was considered if it occurred in the postservice period. Veterans with cancer prior to service, with a missing dioxin measurement, with a dioxin measurement that could not be quantified, or with a cancer that could not be verified were excluded. All cancers and

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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site-specific cancers were analyzed. The cancer analyses (except for skin cancer) were adjusted for birth year, military occupation, race, percentage of body fat at time of dioxin blood draw, smoking, alcohol consumption, and exposure to asbestos, ionizing radiation, industrial chemicals, herbicides, insecticides, and degreasing chemicals. Only nonblack veterans were included in the analysis of skin cancer; the analyses were not adjusted for race, smoking, alcohol consumption, and exposure to asbestos but were adjusted for skin coloring (dark, medium, pale, dark peach, pale peach), hair color, eye color, reaction of skin to 2 hours of sun, and average lifetime residential latitude.

Immunological responses in the cohort described by Wolfe et al. (1990) were examined (Michalek et al., 1999b). Veterans who had no dioxin measurement, or a nonquantifiable dioxin measurement, and comparison veterans with a dioxin measurement greater than 10 ppt, were excluded from the analyses. Veterans taking non-aspirin anti-inflammatory or immunosuppressant medication at the time of the 1992 exam, veterans who had recently received radiation or chemotherapy treatment for cancer, and veterans who tested positive for human immunodeficiency virus were also excluded. Exposure dioxin levels were estimated using serum levels and back-calculating with a constant half-life of 8.7 years. Exposures were categorized as background, low, or high as described above. Skin tests, immunoglobulin studies, and autoantibody panel tests were conducted on all subjects in the study; lymphocyte counts (total and subsets) were conducted on a random sample of the veterans (approximately 40 percent). Analyses were adjusted for percentage of body fat, age, race, military occupation, alcohol use, and smoking. Odds ratios were calculated for the various immunological end points.

Michalek et al. (1999a) studied insulin, fasting glucose, and sex hormone-binding globulin (SHBG) in the Ranch Hand cohort previously described by Wolfe et al. (1990). Medical records and laboratory results were reviewed to determine diabetic status. Veterans with a verified history of diabetes or with a postchallenge glucose of ≥200 mg/dl before July 1995 were classified as diabetic. Veterans taking hormone medications; individuals with cancer of the prostate, testes, or other genital organ; and individuals with a history of diabetes prior to service in Southeast Asia were excluded from the study because these cancers could confound examination of the outcomes of interest. Individuals without a dioxin measurement and comparison veterans with dioxin measurements greater than 10 ppt were also excluded. After exclusions, 871 exposed and 1,121 comparison veterans were included in correlation analyses for the end points of interest.

Longnecker and Michalek (2000) studied the relationship between serum dioxin levels and diabetes mellitus in Vietnam veterans who had never had contact with dioxin-contaminated herbicides (i.e., among the comparison veterans) because they were interested in health effects from background levels of dioxin. Diagnosis of diabetes (all were Type 2) was based on self-reported physician

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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diagnosis and subsequent verification of medical records by June 1995 or a postchallenge glucose of ≥200 mg/dl in 1992. Any individuals with serum dioxin levels greater than 10 ng/kg lipid or with missing dioxin data, waist size, postchallenge glucose levels, or triglyceride levels were excluded. A total of 1,197 individuals were included in the cohort. Logistic regression was conducted to examine the relationship between diabetes and serum dioxin levels. Results were adjusted for race, military occupation, family history of diabetes, age, body mass index, waist size, and serum triglycerides (for odds ratios).

In February 2000, the Air Force Heath Study (AFHS) released a report based on data from the 1997 physical examination of Ranch Hand veterans and their comparison cohort (AFHS, 2000). The cohort is described above and by Wolfe et al. (1990). In this study, four different models were used to determine if there were any effects in veterans of Operation Ranch Hand.

Model 1 uses group (Ranch Hands, comparisons) and military occupation (officer, enlisted flyer, and enlisted ground crew) as proxies for exposure. As indicated above, prior AFHS analyses report that on average, enlisted ground crew had the highest dioxin exposure, followed by enlisted flyers, and then officers. This model does not include any direct dioxin measure.

Model 2 is applied only to Ranch Hands. The exposure estimate is an individual’s serum dioxin level extrapolated to a time-of-exposure value (initial) adjusted for a 1987 body fat measure. Extrapolations were calculated based on a first-order elimination assumption of an exponential decrease in dioxin body burden with time; the half-life of 8.7 years is based on a sample of Ranch Hand participants with repeat dioxin measures over time. It is further limited to Ranch Hands with serum dioxin levels greater than 10 ppt measured at the 1987, 1992, or 1997 physical exam.

Model 3 divides the Ranch Hand veterans in Model 2 into two discrete dioxin categories—“low” and “high” —based on current serum dioxin levels extrapolated to initial values. This model also includes as a third category “background” Ranch Hand veterans who had been excluded from Model 2 because current serum dioxin measures were less than 10 ppt and as a fourth category all comparison subjects with serum levels less than 10 ppt. All exposure values are adjusted for 1987 body fat. The specific category definitions follow:

  • Comparisons: comparison subjects with up to 10 ppt lipid-adjusted serum dioxin level

  • Background: Ranch Hand veterans with up to 10 ppt lipid-adjusted serum dioxin level

  • Low: Ranch Hand veterans with more than 10 ppt lipid-adjusted serum dioxin but at most 94 ppt estimated initial serum dioxin level

  • High: Ranch Hand veterans with more than 10 ppt lipid-adjusted serum dioxin and more than 94 ppt estimated initial serum dioxin level

Model 4, restricted to the Ranch Hand cohort only, uses the serum dioxin

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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level measured in 1987 (the year in which most Ranch Hand veterans were initially assayed) or a later measurement extrapolated to a 1987 value. All Ranch Hand veterans with available dioxin measurements were considered in Model 4 analyses, including those with levels less than 10 ppt who were excluded from Model 2 and treated as a separate category in Model 3.

Models 2, 3, and 4 all use the same 1987 serum dioxin measures (or later where a 1987 value was not available), and the authors note that the extrapolations in Models 2 and 3 assume that the dioxin elimination rate is constant across individuals. Models 2 and 3 use serum dioxin values adjusted for body fat at the time of dioxin measure. All four models were run both “unadjusted” and “adjusted” for a set of potential confounders: age, race, military occupation, personality type, body fat, and family history of diabetes.

The authors evaluated 266 health-related end points, including 10 clinical areas: general health, neoplasia, neurological, psychological, gastrointestinal, cardiovascular, hematologic, endocrine, immunologic, and pulmonary.

Centers for Disease Control and Prevention

The 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 these studies in more detail. The first of these was a case-control interview study of birth defects among offspring of fathers serving in Vietnam (Erickson et al., 1984a, b).

To examine concerns about Agent Orange more directly, the CDC conducted the Agent Orange Validation Study to evaluate TCDD levels in U.S. Army veterans, compared to exposure estimates based on military records and TCDD levels of veterans who did not serve in Vietnam (CDC, 1989a). Using the exposure estimates from this study, the CDC subsequently 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: (1) physical health; (2) reproductive outcomes and child health; and (3) psychosocial characteristics (CDC, 1987, 1988a, b, c, 1989b).

Using data from the VES, the CDC also examined the postservice mortality (through 1983) of a cohort of 9,324 U.S. Army veterans who served in Vietnam, compared to 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, the CDC designed a study using VES subjects (Decoufle et al., 1992).

Finally, the CDC undertook the Selected Cancers Study (CDC, 1990a) to

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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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, nasal, nasopharyngeal, and primary liver cancers (CDC, 1990d).

No new CDC studies have been published.

Department of Veterans Affairs

The DVA has conducted numerous cohort and case-control studies, which VAO, Update 1996, and Update 1998 discuss in greater detail. One of the first of these was a proportionate mortality study conducted by Breslin et al. (1988). Study subjects were ground troops who served in the U.S. 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 of July 1, 1982, was assembled from DVA’s BIRLS. A random sample of 75,617 names was selected from this group. Cause of death was ascertained for 51,421 men, including 24,235 who served in Vietnam. Based on this 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 mortality deaths. Later, Bullman et al. (1990) examined whether Army I Corps Vietnam veterans had cancer mortality experiences similar to other Army Vietnam era veterans, based on 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 different 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).

The DVA also examined the morbidity and mortality experience of a subgroup of Vietnam veterans potentially exposed to high levels of herbicides from certain U.S. 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 to Vietnam era Marines who did not actually serve in Vietnam. Mortality among women Vietnam veterans was assessed by Thomas et al. (1991) and updated in Dalager et al. (1995a).

The 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), Hodgkin’s disease (Dalager et al., 1995b), and lung cancer (Mahan et al., 1997), as well as conducting a co-twin study of self-reported physical health in a series of Vietnam era monozygotic twins (Eisen et al., 1991).

Other outcomes including posttraumatic stress disorder (PTSD) (True et al.,

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1988; Bullman et al., 1991), suicide, motor vehicle accidents (Farberow et al., 1990), and smoking behavior (McKinney et al., 1997) among Vietnam veterans, as well as cause-specific mortality among veterans with nonlethal (combat and noncombat) wounds sustained during the Vietnam War (Bullman and Kang, 1996), have also been examined by the DVA. VAO and Update 1998 discuss these studies in greater 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, the DVA has published a study on pregnancy outcomes among U.S. women Vietnam veterans (Kang et al., 2000). Of a total of 5,230 women, 4,390 women whose permanent tour of duty included service in Vietnam were found 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 women 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 occupation and combat exposure. Information on pregnancy complications, including smoking, infections, medications, exposure to X-rays, occupational history, exposure to anesthetic gases, ethylene oxide, herbicides, and pesticides was also 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. A total of 3,392 Vietnam and 3,038 non-Vietnam veterans and a total of 1,665 Vietnam and 1,912 non-Vietnam veterans indexed pregnancies were analyzed in the study.

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 compared with 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 these 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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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(Kahn et al., 1988; Fielder 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 U.S. 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 veterans (Aschengrau and Monson, 1990), and PTSD among monozygotic twins who served during the Vietnam era (Goldberg et al., 1990). After a published study indicating 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 these studies, and no new studies have been published.

Australia

The Australian government has also commissioned studies to investigate the health risks of 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 from all causes (Fett et al., 1987b); and cause-specific mortality (Fett et al., 1987a) have been conducted. 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 and Update 1998 describe the studies.

Since Update 1998, the government of Australia has published three studies of Australian Vietnam veterans to assess the health and well-being of Vietnam veterans, their spouses, and their children (CDVA, 1998a, b; AIHW, 1999). Data on male veterans (CDVA, 1998a), data on female veterans (CDVA, 1998b), and a validation of the male veterans study (AIHW, 1999) have been published. All members of the Australian Defence Force and the Citizen Military Force who landed in Vietnam or entered Vietnamese water between May 1962 and July 1973 were considered Vietnam veterans. Besides those involved in combat, this included entertainers, medical teams, war correspondents, and philanthropy workers. All of these individuals who could be located were surveyed by mail. The self-report data gathered were compared with age-matched Australian national data. Three distinct questionnaires were mailed to male veterans (49,944 mailed, 80 percent response rate); female veterans (278 mailed, 81 percent response rate); and widow(er), separated, or divorced partners (691 mailed, 45.1 percent response rate). A comparable control group was not used; comparison was drawn

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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by reference to community data for individuals of comparable age where data were available. The self-reported survey sent to male veterans inquired about their own health, both physical and mental; the physical and mental health of their partner(s) and children; and their reproductive history (CDVA, 1998a). A similar questionnaire was sent to female veterans (CDVA, 1998b). The study of female veterans, however, was limited by the small sample cohort—only 57 percent (278 of 484) of eligible veterans were located, and the authors speculated that married veterans were underrepresented in this sample since married women were more likely to have changed their name and thus less likely to have been found. The objective of the validation study was to medically confirm selected conditions, including a number of specific cancers and degenerative diseases of the nervous system in male Vietnam veterans and congenital abnormalities, cancers, and deaths in their children. The validation study population consisted of 6,842 male veterans and their children. Validation was done using medical documents (e.g., pathology results), doctor’s certification (e.g., a response to a validation study questionnaire or a standard doctor’s certificate), and records on a disease or death registry.

Other Vietnam Veteran Studies

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

OBSERVATIONS AND RESEARCH RECOMMENDATIONS

As noted above, the Air Force Health Study (AFHS) is an epidemiologic study whose purpose is to determine whether exposure to the herbicides used in Vietnam may be responsible for any adverse health conditions observed in a cohort of Air Force personnel responsible for conducting aerial spray missions (the Ranch Hands). A baseline morbidity study of the Ranch Hands and a matched comparison cohort (comprising over 2,000 individuals total) was conducted in 1982, with follow-up assessments in 1985, 1987, 1992, and 1997. In accordance with the study protocol, one additional assessment is planned for 2002, after which a final report will be issued.

Because the study represents one of the few primary sources of information on the health of Vietnam veterans and is coming close to its scheduled end, the committee believes it is timely to offer some observations and recommendations concerning it.

The AFHS cohorts represent an unusually thoroughly studied population. Some of the data generated in the course of the study are already or will soon be available to the public. However, there are also medical records and biological

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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specimens that are not amenable to such public disclosure. The committee believes that there is scientific merit in retaining and maintaining these medical records and samples, so that—with proper respect for the privacy of the study participants—they could be available for future research. It therefore recommends that the federal government examine whether and how the various forms of data and specimens collected in the course of the Air Force Health Study could be retained and maintained, and what form of oversight should be established for their future use. The committee further recommends that consideration be given to whether it is appropriate to continue the study past its planned completion date. It notes that the AFHS cohorts are only now reaching the age where several health outcomes of interest may be expected to manifest. The committee cannot draw a conclusion on whether or not a continuation of research on the AFHS cohorts will inform specific questions regarding the health effects of exposure to the herbicides used in Vietnam. However, the committee’s judgment is that continued research on the health of the Ranch Hand and Comparison veterans is likely to yield important information on the determinants of health and disease in males who served in the military during the Vietnam era and perhaps their offspring. If the records were to be retained and maintained and/or the research continued, this would have to be done with the full knowledge and consent of the AFHS population, and to be subject to controls that would respect the privacy of the participants.

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Trung CB, Chien NT. 1983. Spontaneous abortions and birth defects in area exposed to toxic chemical sprays in Giong Trom District. Summarized in: Constable JD, Hatch MC. Reproductive effects of herbicide exposure in Vietnam: recent studies by the Vietnamese and others. Teratogenesis, Carcinogenesis, and Mutagenesis 5:231–250, 1985.


U.S. EPA (Environmental Protection Agency). 1979. Report of Assessment of a Field Investigation of Six-Year Spontaneous Abortion Rates in Three Oregon Areas in Relation to Forest 2,4,5-T Spray Practices. Washington: DC. Epidemiologic Studies Program, Human Effects Monitoring Branch.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

van Houdt JJ, Fransman LG, Strik JJ. 1983. Epidemiological case-control study in personnel exposed to 2,4,5-T. Chemosphere 12:575.

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Vineis P, Faggiano F, Tedeschi M, Ciccone G. 1991. Incidence rates of lymphomas and soft-tissue sarcomas and environmental measurements of phenoxy herbicides. Journal of the National Cancer Institute 83:362–363.

Visintainer PF, Barone M, McGee H, Peterson EL. 1995. Proportionate mortality study of Vietnam-era veterans of Michigan. Journal of Occupational and Environmental Medicine 37(4):423– 428.


Watanabe KK, Kang HK. 1995. Military service in Vietnam and the risk of death from trauma and selected cancers. Annals of Epidemiology 5(5):407–412.

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Wiklund K. 1983. Swedish agricultural workers: a group with a decreased risk of cancer. Cancer 51:566–568.

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Wiklund K, Dich J, Holm LE. 1987. Risk of malignant lymphoma in Swedish pesticide appliers. British Journal of Cancer 56:505–508.

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Wiklund K, Dich J, Holm LE. 1988b. Soft tissue sarcoma risk in Swedish licensed pesticide applicators. Journal of Occupational Medicine 30:801–804.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Wiklund K, Dich J, Holm LE, Eklund G. 1989a. Risk of cancer in pesticide applicators in Swedish agriculture. British Journal of Industrial Medicine 46:809–814.

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Woods JS, Polissar L. 1989. Non-Hodgkin’s lymphoma among phenoxy herbicide-exposed farm workers in western Washington State. Chemosphere 18:401–406.

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Zack JA, Gaffey WR. 1983. A mortality study of workers employed at the Monsanto company plant in Nitro, West Virginia. Environmental Science Research 26:575–591.

Zack JA, Suskind RR. 1980. The mortality experience of workers exposed to tetrachlorodibenzo-dioxin in a trichlorophenol process accident. Journal of Occupational Medicine 22:11–14.

Zahm SH, Weisenburger DD, Babbitt PA, Saal RC, Vaught JB, Cantor KP, Blair A. 1990. A case-control study of non-Hodgkin’s lymphoma and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in eastern Nebraska . Epidemiology 1:349–356.

Zahm SH, Weisenburger DD, Saal RC, Vaught JB, Babbitt PA, Blair A. 1993. The role of agricultural pesticide use in the development of non-Hodgkin’s lymphoma in women. Archives of Environmental Health 48:353–358.

Zhong Y, Rafnsson V. 1996. Cancer incidence among Icelandic pesticide users. International Journal of Epidemiology 25(6):1117–1124.

Zober A, Messerer P, Huber P. 1990. Thirty-four-year mortality follow-up of BASF employees exposed to 2,3,7,8-TCDD after the 1953 accident. International Archives of Occupational and Environmental Health 62:139–157.

Zober A, Ott MG, Messerer P. 1994. Morbidity follow-up study of BASF employees exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after a 1953 chemical reactor incident. Occupational and Environmental Medicine 51:479–486.

Zober A, Messerer P, Ott MG. 1997. BASF studies: epidemiological and clinical investigations on dioxin-exposed chemical workers. Teratogenesis, Carcinogenesis, and Mutagenesis 17(4–5): 249–256.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 6-1 Epidemiologic Studies—Occupational Exposure

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

Production Workers

New NIOSH Studies

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)

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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

Fingerhut et al., 1991

Cohort

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

5,172

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Monsanto Studies Reviewed in VAO

Collins et al., 1993

Cohort

Mortality of workers (through 1987) exposed and unexposed 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

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 U.S. population

884

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

Zack and Suskind, 1980

Cohort

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

121

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 unexposed workers; U.S. 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

U.S. population; 36,804 unexposed workers

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Bond et al., 1988

Cohort

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

878

U.S. white male population; 36,804 employees not exposed

Bond et al., 1987

Cohort

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

322

U.S. white male population; 2,026 employees without chloracne

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

Cook et al., 1986

Cohort

Mortality experience (1940– 1979) of men manufacturing chlorinated phenols compared to U.S. white men

2,189

Bond et al., 1983

Cross-sectional

Study of differences in workers potentially exposed and unexposed 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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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 U.S. white men

61

Ott et al., 1980

Cohort

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

204

New BASF Studies

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

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

New IARC Studies

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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

Jager 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

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 (from 1939 to 1992) was analyzed by standardized mortality rate comparisons and by Poisson multiple regression

21,863

No comparison group

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Flesch-Janys, 1997

Cohort

Mortality (from 1952 to 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)

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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: I I 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

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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

New Studies from Other Chemical Plants

Hryhorczuk et al., 1998

Cohort

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

366

303

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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 unexposed group of workers in another industry

29 (highly exposed subgroup)

28 (external unexposed 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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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 U.S. 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 accidents, compared to unexposed 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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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)

Agricultural and Forest Products

New Cohort Studies of Agricultural Workers Studies

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

Faustini et al., 1996

Cohort

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

10

Internal comparison

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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 non white 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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

Morris on 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)

Morris on et al., 1992

Cohort

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

155,547

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

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

Thorn et al., 2000

Cohort

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

261

243

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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

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 and unexposed

54

54

New Cohort Studies of Herbicide and Pesticide Sprayers

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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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 U.S. 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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Case-Control Studies

New Case-Control Studies

Ekstrom et al., 1999

Case-control

All new cases of histologically confirmed gastric adenocarcinona 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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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

Hardell et al., 1987

Case-control

Study of Kaposi’s sarcoma in AIDS patients (23–53 years of age) 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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

Hardell et al., 1984

Case-control

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

98

200

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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, 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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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 or older 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 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:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Hardell et al., 1980

Hardell et al., 1981

Case-control

Cases of malignant lymphomas (HD, NHL, unknown) diagnosed in men age 25–85, 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

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) 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

New Paper and Pulp Worker Studies

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study

Design Description

Study Group (N)

Comparison Group (N)a

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)

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, N.H., paper and pulp industry, compared to expected mortality in U.S. white men

883

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Solet et al., 1989

Cohort

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

NOTE: 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; NHL=non-Hodgkin’s lymphoma; NIOSH=National Institute for Occupational Safety and Health; PCDD/F=polychlorinated dibenzodioxin or dibenzofuran; PMR=proportionate mortality ratio; SEER=surveillance, epidemiology, and end results; SES=socio-economic status; STS=soft-tissue sarcoma; T3=Triiodothyronine; T4=thyroxine; TSH=Thyroid-stimulating hormone; 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). aThe dash (—) indicates the comparison group is based on a population (e.g., U.S. white males, country rates), and details are given in the text for specifics of the actual population.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 6-2 Epidemiologic Studies—Environmental Exposure

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

New Studies from Seveso

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

Seveso Studies 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)

 

Seveso Studies 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 unexposed areas

724 zone A

4,824 zone B

31,647 zone R

181,579

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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 unexposed areas

Approximately 20,000

167,391

Seveso Studies 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 unexposed residents in neighboring towns

556 zone A

3,920 zone B

26,227 zone R

167,391

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

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 uncontaminated 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

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 unexposed areas

308

305

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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 unexposed 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 unexposed 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)

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

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

Constable and Hatch, 1985

Review

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

 

 

Other New Environmental Studies

Schreinemachers, 2000

Cross-sectional

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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, multiple myeloma (MM), and acute myeloid leukemia (AML) in Italy by region

HD: 421

NHL: 1,822

MM: 325

AML: 263

Internal comparison by region

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 pre- 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 inhalative 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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

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

Vineis et al., 1991

Ecological

Presentation of rates (1985–1988) of NHL, HD, and STS in men and women 15–74 years 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 unexposed control

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

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

U.S. 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

NOTE: HD=Hodgkin’s disease; NHL=non-Hodgkin’s lymphoma; STS=soft-tissue sarcoma; Update 1998=Veterans and Agent Orange: Update 1998 IOM, 1999); Update 1996=Veterans and Agent Orange: Update 1996 (IOM, 1996); VAO=Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994). aThe dash (—) indicates the comparison group is based on a population (e.g., U.S. white males, country rates), with details given in the text for specifics of the actual population.

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 6-3 Epidemiologic Studies—Veterans’ Exposure

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

United States Studies

New Ranch Hand Studies

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 levels 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

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

Ranch Hand Studies Reviewed in Update 1998

Michalek et al., 1998a

Cohort

Paternal serum dioxin levels 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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

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 tasked with herbicide spraying operations during the Vietnam conflict, 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)

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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 tasked with herbicide spraying operations during the Vietnam conflict, 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

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

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

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

CDC, 1990d

Case-control

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

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

1,776

CDC, 1989b

Cohort

Vietnam Experience Study—random sample of U.S. Army enlisted men 1965–1971

2,490

1,972

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

CDC, 1988a

Cohort

VES—random sample of U.S. Army enlisted men 1965–1971: psychosocial outcomes

2,490

1,972

CDC, 1988b

Cohort

VES: physical health outcomes

2,490

1,972

CDC, 1988c

Cohort

VES: reproductive outcomes

12,788 children

11,910 children

CDC, 1987; Boyle et al., 1987

Cohort

VES: mortality

9,324

8,989

Erickson et al., 1984a, b

Case-control

CDC birth defects study of children born in the Atlanta area between 1968 and 1980, comparing fathers’ Vietnam experience and potential Agent Orange exposure between birth defects cases and normal controls

7,133

4,246

New Department of Veterans Affairs (DVA) Studies

Kang et al., 2000

Cohort

Self-reported pregnancy outcomes for female Vietnam veterans compared to contemporary veterans not deployed to Vietnam. Odds ratios were calculated for reproductive history and various birth defects

3,392 women; 1,665 women with an indexed pregnancy

3,038 women; 1,912 women with an indexed pregnancy

DVA Studies Reviewed in Update 1998

Dalager and Kang, 1997

Cohort

Morbidity and mortality experience (1968– 1987) of Army Chemical Corps Vietnam veterans compared to U.S. men; extension of Thomas and Kang (1990)

2,872

2,737

Mahan et al., 1997

Case-control

Study of lung cancer among Vietnam veterans (1983–1990)

329

269 men hospitalized without cancer; 111 patients with colon cancer

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

McKinney et al., 1997

Cross-sectional

Study of the smoking behavior of veterans and nonveterans using the 1987 National Medical Expenditure Survey (NMES)

15,000

Bullman and Kang, 1996

Cohort

Mortality study of veterans with nonlethal (combat and noncombat) wounds sustained during the Vietnam war

34,534

Watanabe and Kang, 1996

Cohort

Mortality experience (1965–1988) of Army and Marine Corps Vietnam veterans; extension of Breslin et al. (1988) and Watanabe et al. (1991)

33,833

36,797

Dalager et al., 1995b

Case-control

Cases of HD diagnosed 1969–1985 among Vietnam era veterans

283

404

Watanabe and Kang, 1995

Cohort

Postservice mortality among Marine Vietnam veterans

10,716

9,346

DVA Studies Reviewed in Update 1996

Dalager et al., 1995a

Cohort

Update of Thomas et al. (1991) through December 31, 1995

4,586

5,325

Bullman et al., 1994

Case-control

Study of the association between testicular cancer and surrogate measures of exposure to Agent Orange in male Vietnam veterans

97

311

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

DVA Studies Reviewed in VAO

Bullman et al., 1991

Case-control

PTSD cases in Vietnam veterans compared to Vietnam veterans without PTSD for association with traumatic combat experience

374

373

Dalager et al., 1991

Case-control

Cases of NHL diagnosed 1969–1985 among Vietnam era veterans compared to cases of other malignancies among Vietnam era veterans for association with Vietnam service

201

358

Eisen et al., 1991

Cohort

Health effects of male monozygotic twins serving in the armed forces during Vietnam era (1965–1975)

2,260

2,260

Thomas et al., 1991

Cohort

Mortality experience (1973–1987) among women Vietnam veterans compared to women non-Vietnam veterans and for each cohort compared to U.S. women

4,582

5,324

Watanabe et al., 1991

Cohort

Mortality experience (1965–1984) of Army and Marine Corps Vietnam veterans compared to: (1) branch-specific (Army and Marine) Vietnam era veterans; (2) all Vietnam era veterans combined; (3) the U.S. male population

24,145 Army, 5,501 Marines

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

(2) 32,422 combined Vietnam era

(3) U.S. male population

Bullman et al., 1990

Cohort

Mortality experience of Army I Corps Vietnam veterans compared to Army Vietnam era veterans

6,668 deaths

27,917 deaths

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Farberow et al., 1990

Case-control

Psychological profiles and military factors associated with suicide and motor vehicle accident (MVA) fatalities in Los Angeles County Vietnam era veterans (1977–1982)

22 Vietnam suicides; 19 Vietnam era suicides

21 Vietnam MVA; 20 Vietnam era MVA

Thomas and Kang, 1990

Cohort

Morbidity and mortality experience (1968– 1987) of Army Chemical Corps Vietnam veterans compared to U.S. men

894

True et al., 1988

Cross-sectional

PTSD and Vietnam combat experience evaluated among Vietnam era veterans

775

1,012

Breslin et al., 1988

Burt et al., 1987

Cohort

Mortality experience (1965–1982) of Army and Marine Corps Vietnam veterans, compared to Vietnam era veterans who did not serve in Southeast Asia standardized by age and race; nested case-control study of NHL

24,235

26,685

Kang et al., 1987

Case-control

STS cases (1975–1980) diagnosed at the Armed Forces Institute of Pathology, compared to controls identified from patient logs of referring pathologists or their departments for association with Vietnam service and likelihood of Agent Orange exposure

217

599

Kang et al., 1986

Case-control

STS cases (1969–1983) in Vietnam era veterans for association with branch of Vietnam service as a surrogate for Agent Orange exposure

234

13,496

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

American Legion Studies Reviewed in VAO

Snow et al., 1988

Cohort

Assessment of PTSD in association with traumatic combat experience among American Legionnaires serving in Southeast Asia (1961– 1975)

2,858

Study group subdivided for internal comparison

Stellman et al., 1988b

Cohort

Assessment of physical health and reproductive outcomes among American Legionnaires who served in Southeast Asia (1961–1975) for association with combat and herbicide exposure

2,858

3,933

Stellman et al., 1988c

Cohort

Assessment of social and behavioral outcomes among American Legionnaires who served in Southeast Asia (1961–1975) for association with combat and herbicide exposure

2,858

3,933

State Studies Reviewed in Update 1998

Clapp, 1997

Case-control

Selected cancers identified (1988–1993) among Massachusetts Vietnam veterans, compared to Massachusetts Vietnam era veterans with cancers of other sites; update of Clapp et al. (1991)

245

999

State Studies Reviewed in Update 1996

Visintainer et al., 1995

Cohort

Mortality experience (1965–1971) among male Michigan Vietnam veterans, compared to non-Vietnam veterans from Michigan

3,364 deaths

5,229 deaths

State Studies Reviewed in VAO

Fiedler and Gochfeld, 1992; Kahn et al., 1992a, b, c

Cohort

New Jersey study of outcomes in select group of herbicide-exposed Army, Marine, and Navy Vietnam veterans, compared to veterans self-reported as unexposed

10 Pointman I

55 Pointman II

17 Pointman I

15 Pointman II

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Clapp et al., 1991

Case-control

Selected cancers identified (1982–1988) among Massachusetts Vietnam veterans, compared to Massachusetts Vietnam era veterans with cancers of other sites

214

727

Deprez et al., 1991

Descriptive

Study of Maine Vietnam veterans compared to atomic test veterans and general population for health status and reproductive outcomes

249

113 atomic test veterans

Levy, 1988

Cross-sectional

Study of PTSD in chloracne as indicator of TCDD-exposed and control Vietnam veterans in Massachusetts

6

25

Anderson et al., 1986a

Cohort

Mortality experience of Wisconsin veterans compared to nonveterans (Phase 1); mortality experience of Wisconsin Vietnam veterans and Vietnam era veterans compared to nonveterans and other veterans (Phase 2)

110,815 white male veteran deaths; 2,494 white male Vietnam era veteran deaths; 923 white male Vietnam veteran deaths

342,654 white male nonveteran deaths 109,225 white male other veteran deaths

Anderson et al., 1986b

Cohort

Mortality experience of Wisconsin Vietnam era veterans and Vietnam veterans compared to U.S. men, Wisconsin men, Wisconsin nonveterans, and Wisconsin other veterans

122,238 Vietnam era veterans 43,398 Vietnam veterans

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Goun and Kuller, 1986

Case-control

Cases of STS, NHL, and selected rare cancers compared to controls without cancer for Vietnam experience in Pennsylvania men (1968–1983)

349

349 deceased

Holmes et al., 1986

Cohort

Mortality experience (1968–1983) of West Virginia veterans, Vietnam veterans, and Vietnam era veterans compared to nonveterans; Vietnam veterans compared to Vietnam era veterans

615 Vietnam veterans

610 Vietnam era veterans

Pollei et al., 1986

Cohort

Study of chest radiographs of New Mexico Agent Orange Registry Vietnam veterans compared to radiographs of control Air Force servicemen for pulmonary and cardiovascular pathology

422

105

Kogan and Clapp, 1985, 1988

Cohort

Mortality experience (1972–1983) among white male Massachusetts Vietnam veterans, compared to non-Vietnam veterans and to all other nonveteran white males in Massachusetts

840 deaths

2,515 deaths of Vietnam era veterans

Lawrence et al., 1985

Cohort

Mortality experience of New York State (1) Vietnam era veterans compared to nonveterans and (2) Vietnam veterans compared to Vietnam era veterans

(1) 4,558

(2) 555

17,936

941

Rellahan, 1985

Cohort

Study of health outcomes in Vietnam era (1962–1972) veterans residing in Hawaii associated with Vietnam experience

232

186

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Wendt, 1985

Descriptive

Descriptive findings of health effects and potential exposure to Agent Orange among Iowa veterans who served in Southeast Asia

10,846

None

Greenwald et al., 1984

Case-control

Cases of STS in New York State compared to controls without cancer for Vietnam service and herbicide exposure including Agent Orange, dioxin, or 2,4,5-T

281

281 live controls

130 deceased controls

Newell, 1984

Cross-sectional

Preliminary (1) cytogenetic, (2) sperm, and (3) immune response tests in Texas Vietnam veterans compared to controls

(1) 30

(2) 32

(3) 66

30

32

66

Other U.S. Veteran Studies Reviewed in VAO

Tarone et al., 1991

Case-control

Study of cases between January 1976 and June 1981 with testicular cancer (18–42 years old) compared to hospital controls for association with Vietnam service

137

130

Aschengrau and Monson, 1990

Case-control

Study of cases with late adverse pregnancy outcomes compared to normal control births for association with paternal Vietnam service (1977–1980)

857 congenital anomalies

61 stillbirths

48 neonatal deaths

998

Goldberg et al., 1990

Cohort

Study of male twin pairs who served in Vietnam era (1965–1975) for association between Vietnam service and PTSD

2,092

2,092

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Aschengrau and Monson, 1989

Case-control

Association between husband’s military service and women having spontaneous abortion at or by 27 weeks compared to women delivering at 37 weeks

201

1,119

Australian Studies

New Australian Studies

AIHW, 1999

Cohort

Validation of the male veterans study (CDVA, 1998a) using medical documents, doctors’ certification and records on a disease or death registry

6,842

CDVA, 1998a

Cohort

Self-reported data on male members of the Australian Defence Force and the Citizen Military Force who landed in Vietnam or entered Vietnamese water. Questions on physical (including reproductive history) and mental health, and that of their partner(s) and children

49,944 mailed; 39,955 responded

CDVA, 1998b

Cohort

Self-reported data on female members of the Australian Defence Force and the Citizen Military Force who landed in Vietnam or entered Vietnamese water. Questions on physical (including reproductive history) and mental health, and that of their partner(s) and children

278 mailed

225 responded

Australian Studies Reviewed in Update 1998

Crane et al., 1997a

Cohort

Mortality experience (through 1994) of Australian veterans who served in Vietnam

59,036 males

484 females

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Design

Description

Study Group (N)

Comparison Group (N)a

Crane et al., 1997b

Cohort

Mortality experience (through 1994) of Australian national servicemen who served in Vietnam

18,949

24,646

O’Toole et al., 1996a, b, c

Cross-sectional

Survey of self-reported health status (1989– 1990) of Australian Army Vietnam veterans

641

Australian Studies Reviewed in VAO

Field and Kerr, 1988

Cohort

Study of Tasmanian Vietnam veterans compared to neighborhood controls for adverse reproductive and childhood health outcomes

357

281

Fett et al., 1987a

Cohort

Australian study of mortality experience of Vietnam veterans compared to Vietnam era veterans through 1981

19,205

25,677

Fett et al., 1987b

Cohort

Australian study of cause-specific mortality experience of Vietnam veterans compared to Vietnam era veterans through 1981

19,205

25,677

Forcier et al., 1987

Cohort

Australian study of mortality in Vietnam veterans by job classification, location, and time of service

19,205

Internal comparison

Suggested Citation:"6 Epidemiologic Studies." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Donovan et al., 1983, 1984

Case-control

Australian study of cases of congenital anomalies in children born (1969–1979), compared to infants born without anomalies for association with paternal Vietnam service

8,517

8,517

Other Vietnam Veterans Studies Reviewed in Update 1998

Chinh et al., 1996

Cohort

Study of antinuclear antibodies and sperm autoantibodies among Vietnamese veterans who served 5–10 years in a “dioxin- sprayed zone”

25

63 age-matched controls; 36 additional male controls

NOTE: CDVA=Commonwealth Department of Veterans’ Affairs; HD=Hodgkin’s disease; NHL=non-Hodgkin’s lymphoma; PTSD=posttraumatic stress disorder; STS=soft-tissue sarcoma; Update 1998=Veterans and Agent Orange: Update 1998 (IOM, 1999); Update 1996=Veterans and Agent Orange: Update 1996 (IOM, 1996); VAO=Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994). aThe dash ( —) indicates the comparison group is based on a population (e.g., U.S. white males, country rates), with details given in the text for specifics of the actual population.

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Veterans and Agent Orange: Update 2000 examines the state of the scientific evidence regarding associations between diseases and exposure to dioxin and other chemical compounds in herbicides used in Vietnam. It is the fourth in a series of comprehensive reviews of epidemiologic and toxicologic studies of the agents used as defoliants during the Vietnam War. Over forty health outcomes in veterans and their children are addressed.

Among the report's conclusions is that there is sufficient evidence of a link between exposure and the development of soft-tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, and chloracne in veterans. Additionally, it found that scientific studies offer "limited or suggestive" evidence of an association with other diseases in veterans—including Type 2 diabetes, respiratory cancers, prostate cancer, multiple myeloma and some forms of transient peripheral neuropathy—as well as the congenital birth defect spina bifida in veterans' children.

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