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Veterans and Agent Orange: Update 2004 (2005)

Chapter: 4 Epidemiology

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Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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4
Epidemiology

In the tradition of previous Veterans and Agent Orange (VAO) reports, this chapter summarizes certain epidemiology studies considered in the ongoing effort to evaluate and integrate all study results on human subjects pertinent to health effects that might result from exposure to any of the chemicals of interest (2,4-dichlorophenoxyacetic acid [2,4-D]; 2,4,5-trichlorophenoxyacetic acid [2,4,5-T] and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]; 4-amino-3,5,6-trichloropicolinic acid [picloram]; and cacodylic acid [dimenthylarsenic acid]). Primary emphasis is put on describing work new to this review contained in publications appearing since Veterans and Agent Orange: Update 2002 (hereafter, Update 2002) (IOM, 2003).

The framework adopted in this chapter provides a means of organizing the thousands of citations considered over the successive updates. The organization into occupational studies, environmental studies, and studies of Vietnam veterans, which is carried over into the discussions and results tables in the health outcomes chapters, is not intended to imply that any of these populations is intrinsically more valuable for the committee’s purpose. Each study design has strengths and weaknesses (see Chapter 2) influencing its potential to contribute evidence of an association with the health outcomes considered in Chapters 69 of this report. Critical commentary has been reserved for the individual health outcome chapters and is not included in this chapter. The associated cumulative tables in Appendix A include the basic type of study design; criteria for sample selection; the numbers of subjects and comparison populations; how data were collected; and how exposure was determined.

The major purpose of Chapter 4 is to reduce repetition of design information

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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in the health outcomes chapters from endpoint to endpoint, and also from update to update. Of particular importance to the VAO project are a number of continuing studies of populations that have been exposed to the herbicides sprayed in Vietnam or to their components. It is essential that laboriously amassed information on a single population be recognized as such. Placing each new publication in historical context helps the committee avoid factoring what is actually a single observation into their deliberations repeatedly. Such studies are extremely important in describing the time course of a population’s response to an exposure. Furthermore, joint consideration of an entire body of research on a population may permit more insightful evaluation of relationships with potential confounding factors. This chapter augments the existing information on these study populations with descriptions of any new publications investigating any of their members, explaining how the new work meshes with earlier efforts.

Many studies, particularly cancer cohort studies, report on multiple health endpoints. The weight appropriately attributed to a study’s findings is determined in the context of its design and execution. Because repetition of this information in the health outcomes chapters for every specific endpoint report would be cumbersome and tedious, discussions of design and evaluation comments for these studies are presented in this chapter and distilled in the design tables in Appendix A. Of course, a multi-endpoint study might also qualify for inclusion in this chapter because it addresses a previously studied population.

Studies new to this update that report on a single endpoint and were conducted on a population that has not been studied by others are not included in this chapter. Their designs characteristics are present in the one place where their results are reported in one of the chapters on health outcomes.

The chapter is organized into three major sections—occupational studies, environmental studies, and studies of Vietnam veterans. Detailed descriptions of many of the study populations can be found in Chapter 2 of the original report of this committee, Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO; IOM, 1994), and the criteria for inclusion in the review are discussed in Appendix A of that report. In addition to a review of studies that involved exposures to the chemicals of interest (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram), the committee also examined some studies that addressed compounds chemically related to the herbicides used in Vietnam, such as 2-methyl-4-chlorophenoxyacetic acid, hexachlorophene, and chlorophenols, including trichlorophenol. In some published reports, the study investigators did not indicate the specific herbicides to which study participants were exposed or the magnitude of exposure; those complicating factors were considered when the committee weighed the relevance of a study. Available details of exposure assessment and use of exposure in analyses are discussed in Chapter 5.

The occupational section covers studies of production workers, agriculture and forestry workers (including herbicide and pesticide appliers), and paper and

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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pulp workers. The environmental section covers studies of populations unintentionally exposed to unusually high concentrations of herbicides or dioxins as a result of where they live, such as Seveso, Italy; Times Beach, Missouri; and the southern portion of Vietnam. The section on Vietnam veterans covers studies conducted in the United States by the Air Force, the Centers for Disease Control and Prevention (CDC), the Department of Veterans Affairs (VA), the American Legion, and the state of Michigan; it also discusses studies of Australian and Korean Vietnam veterans.

Many cohorts potentially exposed to any of the chemicals of interest are monitored periodically, typically every 3–5 years. Those groups include the cohorts of the National Institute for Occupational Safety and Health (NIOSH), the International Agency for Research on Cancer (IARC), the National Cancer Institute (NCI), residents of Seveso, and Ranch Hand personnel. For the sake of thoroughness, the discussions of specific health outcomes in Chapters 69 include references to studies discussed in previous Agent Orange reports and to new studies. However, in making its conclusions, the committee focused on the most recent update when multiple reports on the same cohorts and endpoints were available.

Individual researchers who are a part of research consortia evaluating cohorts in large multicenter studies (such as the IARC and NCI cohort studies) sometimes publish reports based solely on the subset of subjects they themselves are monitoring. All of the studies are discussed in this report, but when making its conclusions, the committee focused on the studies of the larger, multicenter cohorts.

OCCUPATIONAL STUDIES

Several occupational groups in the United States and elsewhere have been exposed to the compounds of interest. Exposure characterization varies widely in the exposure metric used; the extent of detail; confounding by other exposures; and whether individual, surrogate, or group (ecologic) measures are used. Some studies use job titles as broad surrogates of exposure, others rely on disease registry data. Occupational groups include workers in chemical production plants; agriculture and forestry workers, including farmers and herbicide appliers; and workers in paper and pulp manufacturing.

Production Workers

National Institute for Occupational Safety and Health

Starting in 1978, NIOSH began a study to identify all US workers who might have been exposed to TCDD between 1942 and 1984 (Fingerhut et al., 1991).

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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From a total of 12 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 substances for which TCDD was a contaminant: 2,4,5-trichlorophenol (TCP); 2,4,5-T, Silvex®; Erbon®; Ronnel®; and hexachlorophene. Another 172 workers identified previously by their employers as being exposed to TCDD also were included in the study cohort. The 12 plants involved were large manufacturing sites of major chemical companies, so many of the subjects were potentially exposed to many other compounds, some of which could be toxic and carcinogenic.

Before the publication of the first study of the main cohort, NIOSH conducted a cross-sectional study that included a comprehensive medical history, medical examination, and measurement of pulmonary function of workers employed in chemical manufacturing at a plant in Newark, New Jersey, between 1951 and 1969, and at a plant in Verona, Missouri, between 1968 and 1969 and 1970 and 1972. Control subjects were recruited from surrounding neighborhoods (Alderfer et al., 1992; Calvert et al., 1991, 1992; Sweeney et al., 1989, 1993). The New Jersey plant manufactured TCP and 2,4,5-T; the Missouri plant manufactured TCP, 2,4,5-T, and hexachlorophene.

Later studies examined specific health outcomes among the cohort, including pulmonary function (Calvert et al., 1991), liver and gastrointestinal function (Calvert et al., 1992), mood (Alderfer et al., 1992), effects on the peripheral nervous system (Sweeney et al., 1993), porphyria cutanea tarda (Calvert et al., 1994), and effects on reproductive hormones (Egeland et al., 1994). Sweeney et al. (1996, 1997/1998) evaluated non-cancer endpoints, including liver function, gastrointestinal disorders, chloracne, serum glucose concentration, hormone and lipid concentrations, and diabetes in a subgroup of the original cohort studied by Calvert et al. (1991). More recent studies of the main cohort examined cardiovascular effects (Calvert et al., 1998); diabetes mellitus, thyroid function, and endocrine function (Calvert et al., 1999); immune characteristics (Halperin et al., 1998); and cancer incidence (Kayajanian, 2002). Cross-sectional medical surveys reported serum TCDD concentrations and surrogates of cytochrome P450 induction (Halperin et al., 1995) in that cohort. A follow-up study (Steenland et al., 1999) examined the association between TCDD exposure and cause of death; it examined specific health outcomes, including cancer (all and site-specific), respiratory disease, cardiovascular disease, and diabetes. Steenland et al. (2001) published a paper that reanalyzed data from two studies on TCDD and diabetes mellitus: one in US workers (the NIOSH cohort; Calvert et al., 1999) and one in veterans of Operation Ranch Hand in which the herbicides were sprayed from planes in Vietnam (Henriksen et al., 1997). VAO, Veterans and Agent Orange: Update 1996 (hereafter, Update 1996 [IOM, 1996]), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), and Update 2002 (IOM, 2003), describe the details of those studies.

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Bodner et al. (2003) compared the mortality in Dow Chemical Company workers with mortality among the NIOSH and IARC cohorts. Study details are in the Dow Chemical Company section of this chapter.

Monsanto

The NIOSH study cohort (Fingerhut et al., 1991) included employees of Monsanto’s production facilities. One set of studies was based on an unintentional release that occurred on March 8, 1949, in the TCP production process at the Monsanto plant in Nitro, West Virginia (Collins et al., 1993; Moses et al., 1984; Zack and Suskind, 1980). Others focused on exposure of workers involved in numerous aspects of 2,4,5-T production (Moses et al., 1984; Suskind and Hertzberg, 1984; Zack and Gaffey, 1983). The Monsanto studies are discussed in more detail in VAO. No new studies have been published on those subjects.

Dow Chemical Company

Several studies of Dow Chemical Company production workers are summarized in VAO, Update 1996, Update 1998, and Update 2002. The populations of many of those studies were included in the NIOSH cohort (Fingerhut et al., 1991). Originally, Dow conducted a study of workers engaged in the production of 2,4,5-T (Ott et al., 1980) and one on TCP-manufacturing workers with chloracne (Cook et al., 1980). Extension and follow-up studies compared potential exposure to TCDD with medical examination frequency and morbidity (Bond et al., 1983) and with reproductive outcomes after potential paternal TCDD exposure (Townsend et al., 1982). A prospective mortality study of Dow employees diagnosed with chloracne or classified as having chloracne on the basis of clinical description (Bond et al., 1987) and a large-scale cohort mortality study of workers exposed to herbicides in several of its plants (Bloemen et al., 1993; Bond et al., 1988; Burns et al., 2001; Ramlow et al., 1996) also were conducted.

Dow assembled a large cohort at the Midland, Michigan, plant (Bond et al., 1989a; Cook et al., 1986, 1987). Exposure to TCDD was characterized in that cohort on the basis of chloracne diagnosis (Bond et al., 1989b). Within that 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.

Since Update 2002, Bodner et al. (2003) have published a 10-year follow-up of the work of Cook et al. (1986), comparing the mortality experience of 2,187 male Dow Chemical Company workers potentially exposed to large amounts of dioxin before 1983 with that of the NIOSH and IARC cohorts. Worker exposures were determined by combining detailed work histories with an analysis of historical plant operations and industrial hygiene monitoring. All of the workers in the analysis are male; 5 female workers were excluded from the analysis. Diagnosis of chloracne resulting from high exposure incidence corroborated many of the

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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exposures. The IARC international study and the NIOSH Dioxin Registry include most of the Dow workers; Dow workers make up the largest component of those two cohorts. A modified life table program was used to calculate standardized mortality ratio and 95% confidence intervals relative to the US male population. A pool of local workers with no previous work history in the targeted departments and no known dioxin exposures served as the reference population. Internal analyses were stratified by age, calendar year, and hourly salary status.

BASF

In Germany, an accident on November 17, 1953, during the manufacture of TCP at BASF Aktiengesellschaft resulted in the exposure of some workers in the plant predominantly to TCDD. VAO, Update 1996, Update 1998, and Update 2000 summarized studies on those workers, including a mortality study of persons initially exposed or later involved in cleanup (Thiess et al., 1982), an update and expansion of that study (Zober et al., 1990), and a morbidity follow-up (Zober et al., 1994). In addition, Ott and Zober (1996) examined cancer incidence and mortality in another cohort of workers exposed to TCDD after the accident during reactor cleanup, maintenance, or demolition. No new studies have been published on those cohorts since Update 2000.

International Agency for Research on Cancer

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

One study of people from 10 countries evaluated cancer mortality from STS and malignant lymphoma (Kogevinas et al., 1992). Two nested case–control studies were undertaken using the IARC cohort to evaluate the relationship between STS and non-Hodgkin’s lymphoma (NHL) (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) to study cancer mortality. Vena et al. (1998) studied non-neoplastic mortality in the IARC cohorts. A cohort study of cancer incidence and mortality was conducted among 701 women from 7 countries who were occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins (Kogevinas et al., 1993). VAO, Update 1996, Update 1998, and Update 2000 highlight those studies.

Several of the smaller cohorts that make up the IARC cohort have been evaluated apart from the IARC-coordinated efforts. They include Danish produc-

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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tion workers (Lynge, 1985, 1993); British production workers (Coggon et al., 1986, 1991); Dutch production workers (Bueno de Mesquita et al., 1993); German production workers (Becher et al., 1996; Flesch-Janys, 1997; Flesch-Janys et al., 1995; Manz et al., 1991); factory workers from the Netherlands (Hooiveld et al., 1998); and Austrian production workers (Jäger et al., 1998; Neuberger et al., 1998, 1999). VAO, Update 1996, Update 1998, and Update 2000 discuss those studies in more detail. No new studies have been published on the IARC cohort or on the smaller constituent cohorts.

Since Update 2002, Bodner et al. (2003) published a study comparing the mortality experience of Dow Chemical Company workers with that of the NIOSH and IARC cohorts. Study details can be found in this chapter under the heading Dow Chemical Company.

Other Chemical Plants

Studies have reviewed health outcomes among UK chemical workers exposed to TCDD as a result of an industrial accident in 1968 (Jennings et al., 1988; May, 1982, 1983); 2,4-D production workers in the former Soviet Union (Bashirov, 1969); factory workers in Prague who exhibited symptoms of TCDD toxicity 10 years after occupational exposure to 2,4,5-T (Pazderova-Vejlupkova et al., 1981); 2,4-D and 2,4,5-T production workers in the United States (Poland et al., 1971); white men employed at a US chemical plant manufacturing flavors and fragrances (Thomas, 1987); and US chemical workers engaged in the production of pentachlorophenol, lower-chlorinated phenols, and esters of chlorophenoxy acids (Hryhorczuk et al., 1998). The long-term immune-system effects of TCDD were examined in 11 industrial workers involved in production and maintenance operations at a German chemical factory producing 2,4,5-T (Tonn et al., 1996), and immune effects were studied in a cohort of workers formerly employed at a German pesticide-producing plant (Jung et al., 1998). VAO, Update 1998, and Update 2000 detail those studies. No studies at other chemical plants have been published since Update 2000.

Agriculture and Forestry Workers

Cohort Studies

Agriculture VAO, Update 1996, Update 1998, Update 2000, and Update 2002 detailed cohort studies that examined health outcomes in people involved in agriculture. They include studies of proportionate mortality among Iowa farmers (Burmeister, 1981) and among male and female farmers in 23 states (Blair et al., 1993); cancer mortality among Danish and Italian farmers (Ronco et al., 1992) and among a cohort of rice growers in the Novara Province of northern Italy (Gambini et al., 1997); cancer incidence among farmers licensed to spray pesti-

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

cides in Italy’s southern Piedmont (Corrao et al., 1989) and among female gardeners in Denmark (Hansen et al., 1992); sperm abnormalities among Argentinian farmers (Lerda and Rizzi, 1991); cancer and birth defects among the offspring of Norwegian farmers (Kristensen et al., 1997); pregnancy outcomes in couples living on family farms in Ontario, Canada (Arbuckle et al., 1999, 2001; Curtis et al., 1999; Savitz et al., 1997); and immune, neurobehavioral, and lung function of residents from an agricultural area of Saskatchewan, Canada, and immunologic changes in 10 farmers who mixed and applied commercial formulations that contained the chlorophenoxy herbicides (Faustini et al., 1996). The Mortality Study of Canadian Male Farm Operators evaluated the risk to farmers of death and specific health outcomes: NHL (Morrison et al., 1994; Wigle et al., 1990), prostatic 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). Data from the Swedish Cancer Environment Register (which links population census data, including occupation, with the Swedish Cancer Registry) were used in cohort studies that 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 occupational activities (Eriksson et al., 1992). Brain, lymphatic, and hematopoietic cancers in Irish agricultural workers also have been studied (Dean, 1994). No new studies of agricultural workers have been published since Update 2002.


Forestry Studies have been conducted among forestry workers potentially exposed to the types of herbicides used in Vietnam. A cohort mortality study examined men employed at a Canadian public utility (Green, 1987, 1991), a Dutch study of forestry workers exposed to 2,4,5-T investigated the prevalence of acne and liver dysfunction (van Houdt et al., 1983), and another study examined mortality and cancer incidence in a cohort of Swedish lumberjacks (Thörn et al., 2000). No new studies of forestry workers have been published since Update 2002.


Herbicide and Pesticide Application Several cohort studies have assessed health outcomes among herbicide and pesticide appliers: 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 (Asp et al., 1994; Riihimaki et al., 1982, 1983), reproductive outcomes among male chemical appliers in New Zealand (Smith et al., 1981, 1982), and doctor visits resulting from pesticide exposure (Alavanja et al., 1998) and chemical predictors of wheeze (Hoppin et al., 2002) in Iowa and North Carolina. Other studies examined the risk of cancer—including STS, HD, NHL,

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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and prostate cancer—among pesticide and herbicide appliers in Sweden (Dich and Wiklund, 1998; Wiklund et al., 1987, 1988b, 1989a,b), general and cancer mortality among Dutch male herbicide appliers (Swaen et al., 1992), cancer mortality among Minnesota highway maintenance workers (Bender et al., 1989) and Minnesota pesticide appliers (Garry et al., 1994, 1996a,b), lung cancer morbidity in male agricultural plant protection workers in the former German Democratic Republic who spent a portion of their work year applying pesticides (Barthel, 1981), British Columbia sawmill workers potentially exposed to chlorophenate wood preservatives used as a fungicide during spraying and dipping of sawed logs and planed boards (Dimich-Ward et al., 1996; Heacock et al. 1998; Hertzman et al., 1997), and cancer risk among pesticide users in Iceland (Zhong and Rafnsson, 1996). Some of those studies included agriculture and forestry worker cohorts; details of the studies, designs, and results are included in VAO, Update 1996, Update 1998, Update 2000, and Update 2002.

Since Update 2002, Alavanja et al. (2003) examined the correlation between exposure to agricultural pesticides, including 2,4-D and 2,4,5-T and prostate cancer incidence among pesticide appliers in Iowa and North Carolina in the Agricultural Health Study. The study cohort consisted of 55,332 male commercial and private pesticide appliers who completed a self-administered enrollment questionnaire between December 1993 and 1997, and who had no history of prostate cancer. The enrollment questionnaire sought information on a variety of issues: pesticide exposures, uses, and practices; dietary and cooking practices; personal medical history; and tobacco and alcohol use. A subset of 24,034 appliers also completed a take-home questionnaire that sought more specific information on similar topics. Members of the cohort were matched to Iowa and North Carolina cancer registry files, and to state and national death registries for vital statistics. Standardized incidence for prostate cancer was computed. Researchers used multivariate and unconditional logistic regression and factor analysis to evaluate and interpret the data.

Flower et al. (2004) examined the correlation between parental pesticide exposure and cancer risk in the children of pesticide appliers in the AHS cohort. That group consisted of 20,625 appliers and spouses who completed enrollment and secondary questionnaires on female and family health. Completed questionnaires identified 21,375 children born during or after 1975. Cancer cases within the group of children were identified both retrospectively and prospectively after enrollment in the study. In Iowa, 50 cases of children diagnosed with cancer between birth and 19 years of age were identified from the questionnaires and verified through cancer registries; childhood cancer cases in North Carolina were excluded from the study because too few were identified. Parental pesticide exposure data collected through the questionnaires included information on the mixing and application of pesticides and the use of protective equipment. Logistic regression was used to compute odds ratios and 95% confidence intervals.

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Confounders were analyzed, but were excluded from the final models when the researchers deemed them insignificant.

Swaen et al. (2004) published an updated mortality study of a cohort of 1,341 licensed herbicide appliers in the Netherlands (Swaen et al., 1992), extending the follow-up by 13 years (1988–2001). They reviewed information on the types and amounts of herbicides used in all municipal spraying projects in 1980; those data could not be linked to the work of any individual appliers. Mortality, using International Classification of Disease (ICD) coding, was determined from a cause-of-death registry. SMRs were calculated based on cause-specific mortality rates from the Netherlands.

Case–Control Studies

In 1977, case-series reports in Sweden (Hardell, 1977, 1979) of a potential connection between STS and exposure to phenoxyacetic acids prompted several case–control investigations of a possible association (Eriksson et al., 1979, 1981, 1990; Hardell and Eriksson, 1988; Hardell and Sandstrom, 1979; Wingren et al., 1990). After the initial STS reports (Hardell, 1977, 1979), case–control studies of other cancer outcomes including HD, NHL, and other lymphomas were conducted in Sweden (Hardell and Bengtsson, 1983; Hardell et al., 1980, 1981). Also studied were HD and NHL (Persson et al., 1989, 1993); NHL (Hardell and Eriksson, 1999; Olsson and Brandt, 1988); nasal and nasopharyngeal carcinomas (Hardell et al., 1982); gastric cancer (Ekström et al., 1999); and primary or unspecified liver cancer (Hardell et al., 1984). To address criticism regarding potential observer bias in some of the case–control series, Hardell (1981) conducted another case–control study on colon cancer. Hardell et al. (1994) also examined the relationship between occupational exposure to phenoxyacetic acids and chlorophenols and various characteristics related to NHL—including histopathologic measures, stage, and anatomic location—on the basis of the NHL cases from a previous study (Hardell et al., 1981).

Prompted by the Swedish studies (Hardell, 1977, 1979), a set of case–control studies in New Zealand evaluated the association between phenoxy herbicide and chlorophenol exposure and STS incidence and mortality (Smith and Pearce, 1986; Smith et al., 1983, 1984). Additional case–control studies and an expanded case series were conducted on phenoxy herbicide and chlorophenol exposure and the risks of malignant lymphoma, NHL, and multiple myeloma (Pearce et al., 1985, 1986a,b, 1987).

Geographic patterns of increased leukemia mortality in white men in the central part of the United States prompted a study of the leukemia mortality in Nebraska farmers (Blair and Thomas, 1979). Additional case–control studies were later conducted on leukemia in Nebraska (Blair and White, 1985), in Iowa (Burmeister et al., 1982) on the basis of the cohort study of Burmeister (1981), in

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Iowa and Minnesota (Brown et al., 1990), and on leukemia associated with NHL in eastern Nebraska (Zahm et al., 1990).

Case–control studies have been conducted in various US populations for other cancers, including NHL (Cantor, 1982; Cantor et al., 1992; Tatham et al., 1997; Zahm et al., 1993); multiple myeloma (Boffetta et al., 1989; Brown et al., 1993; Morris et al., 1986); 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 and Polissar, 1989; Woods et al., 1987).

Other studies outside the United States have examined ovarian cancer in the Piedmont region of Italy (Donna et al., 1984); brain gliomas in two hospitals in Milan, Italy (Musicco et al., 1988); STS and other cancers in the 15 regional cancer registries that constitute the National Cancer Register in England (Balarajan and Acheson, 1984); STS and malignant lymphomas in the Victorian Cancer Registry of Australia (Smith and Christophers, 1992); lymphoid cancer in Milan, Italy (LaVecchia et al., 1989); STS among rice weeders in northern Italy (Vineis et al., 1986); primary lung cancer among pesticide users in Saskatchewan (McDuffie et al., 1990); and renal-cell carcinoma in the Denmark Cancer Registry (Mellemgaard et al., 1994). 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.

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

Paper and Pulp Workers

Workers in the paper and pulp industry can be exposed to TCDD and other dioxins that can be generated by the bleaching process during the production and treatment of paper and paper products. VAO describes studies of pulp and paper

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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mill workers potentially exposed to TCDD and various health outcomes, including general mortality in workers at five mills in Washington, Oregon, and California (Robinson et al., 1986); cancer incidence among male paper mill workers in Finland (Jappinen and Pukkala, 1991); respiratory health in a New Hampshire mill (Henneberger et al., 1989); and cause-specific mortality among white men employed in plants identified by the United Paperworkers International Union (Solet et al., 1989). Update 2000 described studies of cancer risk among workers in the Danish paper industry (Rix et al., 1998) and oral cancer risk among occupationally exposed workers in Sweden (Schildt et al., 1999). No new studies of paper and pulp workers have been published since Update 2002.

ENVIRONMENTAL STUDIES

The occurrence of industrial accidents has led to the evaluation of the long-term health outcomes of exposure to the compounds of interest.

Seveso, Italy

Among the largest industrial accidents resulting in environmental exposures to TCDD was one in Seveso, Italy, in July 1976 that resulted from an uncontrolled reaction during trichlorophenol production. TCDD contamination of soil has been the most extensively used of the indicators for estimating individual exposure. Three areas were defined on the basis of soil sampling: zone A, the most heavily contaminated, from which all residents were evacuated within 20 days; zone B, an area of lower contamination that all children and women in the first trimester were urged to avoid during daytime; and zone R, a region with some contamination in which consumption of local crops was prohibited (Bertazzi et al., 1989a,b). Several cohort studies were conducted on the basis of those exposure categories. The studies are reviewed extensively in VAO, Update 1996, Update 1998, Update 2000, and Update 2002 and are summarized here.

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

Other studies examined specific health effects associated with TCDD exposure among Seveso residents: chloracne, birth defects, spontaneous abortion, and crude birth and death rates (Bisanti et al., 1980); chloracne and peripheral nervous system conditions (Barbieri et al., 1988); hepatic-enzyme-associated conditions (Ideo et al., 1982, 1985); abnormal birth outcomes (Mastroiacovo et al., 1988); cytogenetic abnormalities in maternal and fetal tissues (Tenchini et al., 1983); neurologic disorders (Boeri et al., 1978; Filippini et al., 1981); cancer incidence (Bertazzi et al., 1993; Pesatori et al., 1992, 1993); breast cancer (Warner et al.,

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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2002); and the sex ratio of offspring who were born in zone A (Mocarelli et al., 1996). A 2-year prospective controlled study was conducted of workers potentially exposed to TCDD during cleanup of the most highly contaminated areas after the accident (Assennato et al., 1989b).

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

Since Update 2002, Eskenazi et al. (2002a,b, 2003, 2004) have published 4 studies that used data from the Seveso Women’s Health Study (SWHS) to evaluate the association between individual serum TCDD and reproductive effects in women who resided in Seveso at the time of the accident in 1976. The study group consisted of 981 volunteers who were between infancy and age 40 at the time of the accident, who had resided in zones A or B, and for whom there was adequate stored serum collected shortly after the explosion for TCDD measurements.

Eskenazi et al. (2002a) studied the association between menstrual cycle characteristics and serum TCDD. That study group consisted of 301 women from the original SWHS cohort of 981; women who were over the age of 44, who had surgical or natural menopause, who had Turner syndrome, or who were pregnant, breastfeeding, or had used an intrauterine device or hormonal medicine such as contraceptives within the previous year were excluded from this study. Researchers who were blinded to participants’ serum TCDD and zones of residence obtained sociodemographic data, information about personal habits, work histories, and medical and reproductive histories (gynecologic, menstrual, and pregnancy related factors). Logistic regression was used to study the relationship of TCDD to irregular cycle length and heaviness of menstrual flow; multiple linear regression was used to examine TCDD and cycle length and days of flow. Confounders—age at interview, education, parity, smoking, body mass index (BMI), alcohol and coffee consumption, age at menarche, sexual activity, hours of work and physical exercise per week, chronic illness, and abdominal surgeries—were factored into the final results. The final analyses were rerun to exclude women over the age of 40 to eliminate perimenopausal women.

Another study by Eskenazi et al. (2002b) examined the association between endometriosis and serum TCDD concentration. The group consisted of 601 SWHS participants who had consented to participate; women who were 30 years of age or younger at the time of the accident or who were virgins, had Turner syndrome, or refused examinations or ultrasound were excluded. Study participants gave blood samples; received gynecologic and ultrasound examinations; and were interviewed about their sociodemographic information, personal habits, and work and medical history, including gynecologic and reproductive histories. Detailed information about pelvic pain, pain during intercourse, and menstrual

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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cramps was collected during interviews. Endometriosis was confirmed by laparoscopy, laparotomy, or ultrasound examination. Results were analyzed in association with serum TCDD.

Eskenazi et al. (2003) examined the association between maternal serum TCDD and birth outcome. The researchers identified 888 pregnancies that occurred in 510 women from the original SWHS cohort in the years after the Seveso accident. An analysis of spontaneous abortion identified 769 pregnancies (476 women) that did not end in voluntary abortions or ectopic or molar pregnancies. Study participants provided information about sociodemographic characteristics; personal habits; work history; and detailed medical histories that included gynecologic, menstrual, pregnancy (outcome; date pregnancy ended; length of pregnancy; birth weight, sex, and presence of congenital anomalies or developmental disorders in offspring), and other medical information. Statistical analyses tracked pregnancy outcome in relation to time elapsed since the accident, and logistic regression examined the relationship between serum TCDD and spontaneous abortion, preterm delivery, and the ratio of size to gestational age in offspring. Further analysis evaluated the relationship between serum TCDD and birth weight and gestational age. Confounders, including maternal age at pregnancy, maternal tobacco and alcohol use, and years from pregnancy to interview also were considered.

The most recent study by Eskenazi et al. (2004) examined the relationship between serum TCDD concentration and age at exposure of female Seveso residents. Of the SWHS cohort, 92%—899 of 981 women—had serum TCDD concentrations measured between 1976 and 1977, 54 (5%) serum measurements between 1978 and 1981, and 28 (3%) for whom there was inadequate stored serum had serum measured in 1996. For women whose serum TCDD measured >10 parts per trillion (ppt) after 1977, TCDD exposure was extrapolated back to 1976. Serum TCDD from women in zones A and B was pooled by age to determine concentrations of 22 polychlorinated dibenzodioxins, polychlorinated dibenzofurans, and coplanar polychlorinated biphenyls (PCBs) by high-resolution gas chromatography and mass spectrometry. Multiple linear regression was used to determine associations within zones A and B between serum log TCDD concentrations and exposure-related covariates—reports of chloracne, consuming homegrown produce, finding dead animals on their property, and being indoors versus outdoors at the time of the accident. Additional analysis calculated the mean, standard deviation, and toxic equivalents from pooled samples.

Three studies since 2002 have used 62 randomly chosen subjects from zones A and B matched with 59 control subjects from uncontaminated areas who were matched for age, sex, and tobacco use (Baccarelli et al., 2002, 2004; Landi et al., 2003). Interviewers collected detailed personal medical histories and information about medicine use in the week before the study from all study participants. Internal dose of TCDD and 21 other dioxin or dioxin-like congeners was determined from participants’ plasma by high-resolution gas chromatography–high-

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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resolution mass spectrometric analysis. Baccarelli et al. (2002) studied immunologic effects among the cohort of Seveso residents and compared the results with those in previously published studies. The plasma immunoglobulins IgA, IgG, and IgM, and complement components C3 and C4 were quantified by common nephelometric methods. Plasma protein electrophoresis was used to exclude monoclonal immunoglobulins. Non-parametric tests were used for group comparisons, and simple and multiple regression analyses were used to assess correlations between variables—age, sex, tobacco and alcohol use, BMI, diet, medical history, and medication use—for possible confounding. A comprehensive literature search was conducted to identify any work on associations between TCDD and immunologic parameters that had been published from 1966 through 2001. Baccarelli et al. (2004) examined messenger ribonucleic acid (mRNA) concentrations of the arylhydrocarbon receptor (AhR), arylhydrocarbon receptor nuclear transporter (ARNT), cytochrome P450 1A1 (CYP1A1), and cytochrome P450 1B1 (CYP1B1) genes and 7-ethoxyresorufun-O-deethylase (EROD) activity in peripheral blood lymphocytes for the cohort. The population-based study by Landi et al. (2003) evaluated the effect of TCDD-mediated alterations in the AhR-dependent pathway in residents living in zones A and B in Seveso. Peripheral blood lymphocytes, extracted from study participant’s plasma, were evaluated to measure the expression of several genes involved in the AhR pathway, specifically AhR, ARNT, and CYP1A1, CYP1B1, and CYP1A1-associated EROD activity. Those AhR pathways were further evaluated in relation to serum TCDD concentrations to determine whether associations existed between them and whether environmental or host factors affected the association.

Times Beach and Quail Run Cohorts

During early 1971, byproducts of a hexachlorophene and 2,4,5-T production facility in Verona, Missouri, were mixed with waste oils and sprayed on various sites around the state, including the Times Beach and Quail Run areas, for dust control. TCDD was a contaminant of the mixtures sprayed, and the contamination was reported by the Environmental Protection Agency. Several studies evaluated health effects attributable to 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 discussed those studies; no further work has been published.

Vietnam

Researchers in Vietnam have studied the native population exposed to the spraying that occurred during the Vietnam conflict. In a review paper, Constable and Hatch (1985) summarized the unpublished results of those studies. That article also examined nine reports that focus primarily on reproductive outcomes

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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(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, two on reproductive abnormalities (Phuong et al., 1989a,b), one on mortality (Dai et al., 1990), and one on hepatocellular carcinoma (Cordier et al., 1993). VAO and Update 1996 discuss those studies. No studies have been published since Update 1996.

Other Environmental Studies

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

Other studies have focused on different outcomes of environmental exposure: 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); early-onset PD in Oregon and Washington (Butterfield et al., 1993); adverse health effects after an electric transformer fire in Binghamton, New York (Fitzgerald et al., 1989); skin cancer in Alberta, Canada (Gallagher et al., 1996); NHL, HD, and chronic lymphocytic leukemia in a rural Michigan community (Waterhouse et al., 1996); cancer mortality in four northern wheat-producing states (Schreinemachers, 2000); HD, NHL, multiple myeloma, and acute myeloid leukemia in various regions of Italy (Masala et al., 1996); effects of inhalation exposure to TCDD and related compounds in wood preservatives on cell-mediated immunity in German day-care center employees (Wolf and Karmaus, 1995); mortality and cancer incidence in two cohorts of Swedish fishermen whose primary exposure route was assumed to be diet (Svensson et al., 1995); immune effects in hobby fishermen in the Frierfjord in southeastern Norway (Lovik et al., 1996); immunologic effects of prenatal and postnatal exposure to PCB or TCDD in Dutch infants from birth to 18 months of age (Weisglas-Kuperus et al., 1995); and public health and cytogenetic effects in residents of Chapaevsk, Russia (Revazova et al., 2001; Revich et al., 2001).

Fierens et al. (2003) completed a population-based cross-sectional study in several Belgian towns to assess the association between serum dioxin concentrations and the prevalence of diabetes and endometriosis. A total of 194 adults were recruited from households near likely sources of exposure to dioxins (an iron and steel plant, a waste-dumping site, and a municipal solid-waste incinerator). Employees of the aforementioned worksites were excluded from the study, given its focus on the effects of exposure in the general community environment. In selecting the sample, Fierens and co-workers specifically sought people who had

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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lived in the neighborhoods for a long time and who regularly consumed local produce. A comparison sample of 63 adults was chosen from a separate area with no known source of exposure to dioxins. Self-administered questionnaires identified 10 cases of endometriosis among the 142 female respondents. The presence of diabetes was based on self-report of physicians’ diagnoses. Seventeen 2,3,7,8-polychlorinated dibenzodioxins or dibenzofurans were measured from fasting blood samples; the analyses were based on the sum of all dioxins in toxicity equivalents (TEQs) per gram of fat. (See the section “Exposure to Dioxin-like Compounds” in Chapter 5 for an explanation of how TEQs are used in the toxic equivalency factor method of comparing the relative toxicity of dioxin-like compounds.)

Fukuda et al. (2003) examined the correlation between incinerator dioxin emissions and mortality in 803 municipalities in Japan. Researchers used dioxin measurements, in TEQs, from incinerator emissions data collected by the Ministry of Health and Welfare to establish four dioxin-related municipal indices. Socioeconomic conditions—population and six health-related indicators—were evaluated and compared among the municipalities. Sex-specific and age-adjusted mortality rates were calculated using 1995 population data and mortality rates for all causes and five disease categories (stroke, ischemic heart disease, cancer at all sites, stomach cancer, lung cancer), according to municipality and sex and age categories in 1994–1996, data from a 1985 population model, and the average number of deaths for three consecutive years per municipality and category. Mortality rates were evaluated in relation to the dioxin emission data. Further calculations were done to evaluate the influence of socioeconomic conditions on mortality within the municipalities.

VIETNAM-VETERAN STUDIES

Studies of Vietnam veterans who might have been exposed to herbicides, including Agent Orange, have been conducted in the United States at the national and state levels and in Australia, Korea, and Vietnam. Exposures in those studies have been estimated by various means, and health outcomes have been evaluated with reference to various comparison or control groups. This section is organized primarily by research sponsor because it is more conducive to methodologic presentation of the articles. Exposure measures fall on a crude scale from individual exposures of Ranch Hand personnel, as reflected in serum TCDD measurements, to some statewide studies’ use of service in Vietnam as a surrogate for TCDD exposure.

Several comparison groups have been used for veteran cohort studies: 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; Vietnam-era veterans who were in the military at the time of the conflict but did not serve in Vietnam; non-Vietnam veterans who served in other wars or con-

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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flicts such as the Korean War or World War II; and various US male populations (either state or national).

United States

Operation Ranch Hand

The men responsible for most of the aerial spraying of herbicides in Vietnam were Air Force volunteers who participated in Operation Ranch Hand. To determine whether exposure to herbicides, including Agent Orange, had adverse human health effects, the Air Force made a commitment to Congress and the White House in 1979 to conduct an epidemiologic study of Ranch Hands (AFHS, 1982). VAO, Update 1996, Update 1998, Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (hereafter referred to as Type 2 Diabetes) (IOM, 2000), Update 2000, Update 2002, and Veterans and Agent Orange: Length of Presumptive Period for Association Between Exposure and Respiratory Cancer (IOM, 2004) discussed reports and papers addressing the cohort in more detail.

A retrospective matched-cohort study design was used to examine morbidity and mortality; follow-up was scheduled to continue until 2002. Records from the National Personnel Records Center and the US Air Force Human Resources Laboratory were searched and cross-referenced to identify all Ranch Hand personnel (AFHS, 1982; Michalek et al., 1990). A total of 1,269 participants were originally identified (AFHS, 1983). A control population of 24,971 C-130 crew members and support personnel assigned to duty in Southeast Asia but not occupationally exposed to herbicides (AFHS, 1983) was selected from the same data sources. Control subjects were individually matched for age, type of job (based on Air Force specialty code), and race (white or not white) to control for age-related effects, educational and socioeconomic status, and potential race-related differences in development of chronic disease. To control for many potential confounders related to the physical and psychophysiological effects of combat stress and the Southeast Asia environment, Ranch Hands were matched to control subjects who performed similar combat or combat-related jobs (AFHS, 1982). Rank also was used as a surrogate of exposure. Alcohol use and smoking were included in the analysis when they were known risk factors for the outcome of interest.

Ten matches formed a control set for each exposed subject. For the mortality study, the intent was to follow each exposed subject and a random sample of half of each subject’s control set for 20 years in a 1:5 matched design. The morbidity component of follow-up consisted of a 1:1 matched design, with the first control randomized to the mortality ascertainment component of the study. If a control was noncompliant, another control from the matched “pool” was selected; controls who died were not replaced.

The baseline physical examination occurred in 1982; subsequent exams took

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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place in 1985, 1987, 1992, 1997, and 2002. Morbidity was ascertained through questionnaire and physical examination, which emphasized dermatologic, neurobehavioral, hepatic, immunologic, reproductive, and neoplastic conditions. Some 1,208 Ranch Hands and 1,668 comparison subjects were eligible for baseline examination. Initial questionnaire response rates were 97% for the exposed cohort and 93% for the non-exposed; baseline physical examination responses were 87% and 76%, respectively (Wolfe et al., 1990). Mortality outcome was obtained and reviewed by using US Air Force Military Personnel Center records, the VA’s Death Beneficiary Identification and Record Location System (BIRLS), and the Internal Revenue Service database of active social security numbers. Death certificates were obtained from the appropriate health departments (Michalek et al., 1990).

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

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

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

  • High potential. This group included spray-console operators and flight engineers. Exposure could occur while operating spray equipment and through contact with herbicides in the aircraft.

Serum TCDD was measured in 1982 (36 Ranch Hands; Pirkle et al., 1989), 1987 (866 Ranch Hands; AFHS, 1991b), 1992 (455 Ranch Hands; AFHS, 1995), and 1997 (443 Ranch Hands; AFHS, 2000). Serum TCDD analysis of the 1987 follow-up examinations was published in 1991 (AFHS, 1991b).

Results have been published for baseline morbidity (AFHS, 1984a) and baseline mortality studies (AFHS, 1983); the first (1984), second (1987), third (1992), and fourth (1997) follow-up examinations (AFHS, 1987, 1990, 1995, 2000); and for the reproductive-outcomes study (AFHS, 1992; Michalek et al., 1998d; 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 1993 (AFHS, 1996), and Michalek et al. (1998b) reported on a 15-year follow-up of postservice mortality in veterans of Operation Ranch Hand, updating their cause-specific mortality study (1990).

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

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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1998c); skin cancer (Ketchum et al., 1999); insulin, fasting glucose, and sex-hormone-binding globulin (Michalek et al., 1999a); immunologic responses (Michalek et al., 1999b); diabetes mellitus (Longnecker and Michalek, 2000; Steenland et al., 2001); cognitive function (Barrett et al., 2001); hepatic abnormalities (Michalek et al., 2001a); peripheral neuropathy (Michalek et al., 2001b); and hematologic results (Michalek et al., 2001c).

Since Update 2002, Akhtar et al. (2004) conducted a follow-up study of the work by Ketchum et al. (1999) comparing cancer incidence among US Air Force Veterans to Vietnam veterans who served in Southeast Asia but did not spray herbicides and US national cancer rates. Researchers used serum dioxin measurements from the 1987, 1992, and 1997 examinations; missing TCDD measurements from either of the later exams were extrapolated back to 1987 (the first exam in which serum TCDD was measured) using a half-life of 7.6 years. Cancer incidence was determined from physicals, interviews, and reviews of medical records. Veterans were categorized by tour date and time spent in Southeast Asia. Internal comparisons were made between Ranch Hand veterans who had existing serum dioxin measurements and who served in Vietnam (N = 2,965) and veterans who served in Southeast Asia but did not spray herbicides. External comparisons were made between participants who attended one of the first five physicals and who did not have cancer either before or during their tour (N = 2,438), and national cancer incidence and mortality rates; national statistics were analyzed according to anatomical site, sex, race, and 5-year intervals of age and calendar year, covering the period 1950–2000.

Barrett et al. (2003) studied the relationship between serum dioxin measurements and psychological functioning among the cohort of Ranch Hand veterans previously described by Wolfe et al. (1990). TCDD measurements from physical examinations through 1997 were analyzed and used to categorize 1,109 Ranch Hand and 1,493 comparison subjects as “background,” “low,” or “high,” according to their current and initial dioxin concentrations. Veterans whose TCDD measurements were missing or non-quantifiable, and comparison subjects with TCDD concentrations greater than 10 ppt were excluded. As part of the physical exam, study participants completed one of two self-administered questionnaires—the Minnesota Multiphasic Personality Inventory (MMPI) (1982 and 1985 examinations) and the Million Clinical Multiaxial Inventory (MCMI) (1987 and 1992 examinations)—to evaluate personality status and emotional adjustment and basic personality characteristics and clinical disorders, respectively. Researchers analyzed T-scores and posttraumatic stress disorder (PTSD) subscales from the MMPI, and used MCMI results to evaluate personality patterns, pathological personality disorders, and clinical symptom syndromes. Adjustments were made for age, race, military rank, marital status, and combat exposure according to participants’ responses relating to their military service.

A recent study by Michalek et al. (2003) used data from a pharmacokinetic study of TCDD in Ranch Hand veterans (Michelak and Tripathi, 1999) to examine

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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the correlation between Ranch Hand veterans with diabetes and TCDD elimination. The original study analyzed TCDD measurements from 343 Ranch Hand veterans during physical examinations through 1997; some veterans’ TCDD measurements were missing because of follow-up medical deferral, broken blood bags, or death. Cases of diabetes mellitus were confirmed at the exams or through medical records, and they were included in the analysis only if diabetes was diagnosed after a veteran’s last tour of duty through December 2000. A proportional-hazards model, logistic regression models, and analyses of covariance were used to study the relationships between TCDD serum values and diagnoses of diabetes mellitus in veterans; adjustments were made for age at the 1982 physical examination, logarithm of 1982 TCDD body burden, family history of diabetes, BMI at the end of the tour of duty in Vietnam, percentage change in BMI from end of tour to the 1982 physical examination, and smoking history.

Pavuk et al. (2003) studied the relationship of serum TCDD to thyroid function in the cohort of veterans of Operation Ranch Hand previously described by Wolfe et al. (1990). TCDD measurements from physical examinations through 1997 were analyzed and used to categorize Ranch Hand and comparison subjects as “background,” “low,” or “high,” according to current and initial dioxin concentrations; missing TCDD measurements from 1987 (the first exam in which serum TCDD was measured) were extrapolated back from later exams using a half-life of 8.7 years. Cases of thyroid disease were confirmed at the physical examinations or through medical records; they were included in the analysis only if thyroid disease was diagnosed after service in Southeast Asia through December 1998. Analyses of thyroxine, thyroid-stimulating hormone, triiodothyronin percentage uptake, free thyroxine index, and thyroid diseases were completed for the 1,009 Ranch Hands and 1,429 comparison subjects participating in the study. Veterans without TCDD serum measurements who were diagnosed with thyroid disease before leaving Southeast Asia, who had thyroidectomies, or who also were receiving irradiation of the thyroid were excluded from analysis. Logistic regression was used to evaluate associations between abnormal results of thyroid biochemical parameters or the presence of thyroid disease and serum TCDD measurement. Adjustments were made for age, race, and military occupation.

Centers for Disease Control and Prevention

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

To examine concerns about Agent Orange more directly, CDC conducted the

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Agent Orange Validation Study to evaluate TCDD in US Army veterans compared with exposure estimates based on military records and TCDD in veterans who did not serve in Vietnam (CDC, 1989a). Using those exposure estimates, CDC conducted the Vietnam Experience Study (VES), a historical cohort study of the health experience of Vietnam veterans (CDC, 1989b). The study was divided into three parts: physical health, reproductive outcomes and child health, and psychosocial characteristics (CDC, 1987, 1988a,b,c, 1989b).

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

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

No CDC studies have been published since 1990.

Department of Veterans Affairs

Numerous cohort and case–control studies are discussed in detail in VAO, Update 1996, Update 1998, Update 2000, and Update 2002. Among the earliest was a proportionate-mortality study (Breslin et al., 1988). The subjects were ground troops who served in the US Army or Marine Corps at any time from July 4, 1965, through March 1, 1973. A list of 186,000 Vietnam-era veterans who served in the Army or Marine Corps and were reported deceased as of July 1, 1982, was assembled from VA’s BIRLS. A random sample of 75,617 names was selected from the list. Cause of death was ascertained for 51,421 men, including 24,235 who served in Vietnam. On the basis of the proportionate-mortality study (Breslin et al., 1988), Burt et al. (1987) conducted a nested case–control study of NHL with controls selected from among the cardiovascular-disease deaths. Later, Bullman et al. (1990) examined whether Army I Corps Vietnam veterans had cancer mortality similar to that of other Army Vietnam-era veterans, using the study design of Breslin et al. (1988). Watanabe et al. (1991) compared the Vietnam-veteran mortality experience of Breslin et al. (1988) with three referent groups and with additional follow-up through 1984. A third follow-up proportionate-mortality study using the veterans from Breslin et al. (1988) and Watanabe et al. (1991) also was conducted (Watanabe and Kang, 1996).

VA also examined the morbidity and mortality experience of a subgroup of

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Vietnam veterans from some US Army Chemical Corps units who might have been exposed to high concentrations of herbicides (Thomas and Kang, 1990). In an extension, Dalager and Kang (1997) compared mortality among veterans of the Chemical Corps specialties, including Vietnam veterans and non-Vietnam veterans. Watanabe and Kang (1995) examined postservice mortality among Marine Vietnam veterans compared with Vietnam-era marines who did not serve in Vietnam. Mortality among female Vietnam veterans was assessed by Thomas et al. (1991) and updated in Dalager et al. (1995a).

VA has evaluated specific disease and health outcomes—including case–control studies of STS (Kang et al., 1986, 1987), NHL (Dalager et al., 1991), testicular cancer (Bullman et al., 1994), HD (Dalager et al., 1995b), lung cancer (Mahan et al., 1997), and pregnancy outcomes and gynecologic cancers in female veterans (Kang et al., 2000a,b). It also has conducted a co-twin study of self-reported physical health in a series of Vietnam-era monozygotic twins (Eisen et al., 1991). A preliminary long-term health study of US Army Chemical Corps Vietnam veterans began in 2001 (Kang et al., 2001).

VA has examined other outcomes—PTSD (Bullman et al., 1991; True et al., 1988), suicide and motor-vehicle crashes (Farberow et al., 1990), and tobacco use (McKinney et al., 1997)—among Vietnam veterans and has studied cause-specific mortality among veterans with non-lethal (combat and non-combat) wounds sustained during the Vietnam War (Bullman and Kang, 1996). VAO and Update 1998 discuss those studies in detail. Most of those publications do not discuss exposure to Agent Orange; exposure to “combat” is evaluated as the risk factor of interest.

No new VA studies have been published since Update 2002.

American Legion

The American Legion conducted a cohort study of the health and well-being of Vietnam veterans who were members of the American Legion, a voluntary service organization for veterans. Studies examined physical health and reproductive outcomes, social–behavioral consequences, and PTSD among veterans who had served in Southeast Asia and elsewhere (Snow et al., 1988; Stellman SD et al., 1988; Stellman JM et al., 1988). No new studies have been published on this cohort.

State Studies

Several states have conducted studies of Vietnam veterans, most of them unpublished in the scientific literature. VAO and Update 1996 reviewed studies from Hawaii (Rellahan, 1985), Iowa (Wendt, 1985), Maine (Deprez et al., 1991), Massachusetts (Clapp, 1997; Clapp et al., 1991; Kogan and Clapp, 1985, 1988; Levy, 1988), Michigan (Visintainer et al., 1995), New Jersey (Fiedler and

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Gochfeld, 1992, Kahn et al., 1992a,b,c, 1998), New Mexico (Pollei et al., 1986), New York (Greenwald et al., 1984; Lawrence et al., 1985), Pennsylvania (Goun and Kuller, 1986), Texas (Newell, 1984), West Virginia (Holmes et al., 1986), and Wisconsin (Anderson et al., 1986a,b).

Other US Vietnam-Veteran Studies

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

Australia

The Australian government has commissioned studies to investigate health risks to Australian veterans: birth anomalies (Donovan et al., 1983, 1984; Evatt, 1985), mortality (Crane et al., 1997a,b; Commonwealth Institute of Health, 1984a,b,c; Evatt, 1985; Fett et al., 1987a,b; Forcier et al., 1987), deaths from all causes (Fett et al., 1987b), cause-specific mortality (Fett et al., 1987a), and morbidity (AIHW, 1999, 2000; CDVA, 1998a,b). A revised morbidity study has been published (AIHW, 2001). An independent study in Tasmania evaluated reproductive and childhood-health problems for associations with paternal service in Vietnam (Field and Kerr, 1988). O’Toole et al. (1996a,b,c) described self-reported health status in a random sample of Australian Army Vietnam veterans. VAO, Update 1998, and Update 2000 describe the studies. No new studies or data have been published since the acute myelogenous leukemia report (IOM, 2001).

Other Vietnam-Veteran Studies

A team of Vietnamese scientists examined antinuclear and sperm autoantibodies in Vietnamese veterans who served in a “dioxin-sprayed zone” (Chinh et al., 1996). Available details of this study are presented in Update 1998.

Since Update 2002, Kim J-S et al. (2003) published a cross-sectional epidemiologic study examining the effect of Agent Orange exposure in 1,224 male Korean Vietnam veterans and in 154 Korean non-Vietnam veterans between the ages of 45 and 64. Standardized comprehensive clinical investigations were conducted to assess health outcomes of study subjects. Examination results were categorized by health outcome and were evaluated based on veteran status and exposure quartile (described below). Multiple logistic regression analysis was

Suggested Citation:"4 Epidemiology." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

used and adjustments were made for age, tobacco use, BMI, education, and marital status. An earlier report (Kim et al., 2001) described the scoring method used to categorize Agent Orange exposure for that cohort; the committee had this article translated into English from Korean. Study participants responded to questions about their age, service in Vietnam, military rank, and Agent Orange exposure; responses were checked against military records. An Agent Orange net exposure index was calculated for each study participant by calculating a service-exposure matrix that calculated data on annual Agent Orange spraying in Vietnam, troop locations and exposures, and information on individual exposure opportunities (ingestion and dermal exposures). Researchers used net exposure index scores to assign each Vietnam veteran to a quartile. The order of the quartiles was validated using TCDD concentrations from three pooled blood samples for each quartile and one pooled sample for the non-veterans’ group, but there were so few measurements that the distinction between quartiles could not actually be demonstrated.

Another study of Korean Vietnam War veterans (Kim H-A et al., 2003) examined the immunotoxicologic effects of Agent Orange exposure. Study participants were divided into three categories based on general health and TCDD exposure: veterans–patient (24 veterans with chronic disease who were exposed to TCDD while serving in Vietnam); veterans–normal (27 veterans with no chronic disease who were exposed to TCDD while serving in Vietnam); or control volunteers (36 age-matched, healthy volunteers with no Vietnam War military service). Researchers conducted a variety of immunologic tests, including blood analysis, determination of cytokine concentration, concentration of plasma IgG subclass, and evaluation of plasma IgE and autoantibody concentrations.

An English abstract described one study (Mo et al., 2002) that examined skin and general disease patterns in 332 Korean veterans who were exposed to dioxin in Vietnam. Researchers used clinical and dermatologic evaluations, physical and pathology examinations, and other medical tests to determine the prevalence of disease among the exposed veterans.

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Veterans and Agent Orange: Update 2004 Get This Book
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Sixth in a series of congressionally mandated studies, this book is an updated review and evaluation of the available evidence regarding the statistical assoication between exposure to herbicides used in Vietnam and various adverse health outcomes suspected to be linked with such exposure.

This book builds upon the information contained in the earlier books in the series:

  • Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (1994)
    • Veterans and Agent Orange: Update 1996
    • Veterans and Agent Orange: Update 1998
    • Veterans and Agent Orange: Update 2000
    • Veterans and Agent Orange: Update 2002
    • Veterans and Agent Orange: Herbicides and Dioxin Exposure and Type 2 Diabetes (2000)
    • Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans (2002)

      Veterans and Agent Orange: Update 2004 focuses primarily on scientific studies and other information developed since the release of these earlier books. The previous volumes have noted that sufficient evidence exists to link chronic lymphocytic leukemia, soft-tissue sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s disease, and chloracne with exposure. The books also noted that there is “limited or suggestive” evidence of an association between exposure and respiratory cancers, prostate cancer, multiple myeloma, the metabolic disorder porphyria cutanea tarda, early-onset transient peripheral neuropathies, Type 2 diabetes, and the congenital birth defect spinal bifida in veterans’ children. This volume will be critically important to both policymakers and physicians in the federal government, Vietnam veterans and their families, veterans’ organizations, researchers, and health professionals.

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