5
Exposure Assessment

Assessment of human exposure to herbicides and the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a key element in determining whether specific health outcomes are linked to them. This chapter reviews information on occupational and environmental exposures to herbicides and TCDD, including exposure of Vietnam veterans. It discusses exposure assessments from selected epidemiologic studies introduced in Chapter 4 and provides background information for the health-outcome chapters that follow; health outcomes are not discussed here. Further discussion of exposure assessment, and a detailed review of the US military’s wartime use of herbicides in Vietnam can be found in Chapters 3 and 6 of Veterans and Agent Orange (VAO; IOM, 1994); additional information is in Chapter 5 of Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), and Update 2002 (IOM, 2003a). Reviews of the most recent studies of the absorption, distribution, metabolism, and excretion of herbicides and TCDD can be found in the discussion of toxicokinetics in Chapter 3 of this report.

EXPOSURE ASSESSMENT FOR EPIDEMIOLOGY

Exposure to contaminants can be defined as the amount of the contaminant that contacts a body barrier and is available for absorption over a defined period. Ideally, exposure assessment would quantify the amount of a compound at the site of toxic action in the tissue of an organism. In studies of human populations, however, it generally is not possible to measure those concentrations. Instead, exposure assessments are based on measurements in environmental media or in



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Veterans and Agent Orange: Update 2004 5 Exposure Assessment Assessment of human exposure to herbicides and the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a key element in determining whether specific health outcomes are linked to them. This chapter reviews information on occupational and environmental exposures to herbicides and TCDD, including exposure of Vietnam veterans. It discusses exposure assessments from selected epidemiologic studies introduced in Chapter 4 and provides background information for the health-outcome chapters that follow; health outcomes are not discussed here. Further discussion of exposure assessment, and a detailed review of the US military’s wartime use of herbicides in Vietnam can be found in Chapters 3 and 6 of Veterans and Agent Orange (VAO; IOM, 1994); additional information is in Chapter 5 of Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), and Update 2002 (IOM, 2003a). Reviews of the most recent studies of the absorption, distribution, metabolism, and excretion of herbicides and TCDD can be found in the discussion of toxicokinetics in Chapter 3 of this report. EXPOSURE ASSESSMENT FOR EPIDEMIOLOGY Exposure to contaminants can be defined as the amount of the contaminant that contacts a body barrier and is available for absorption over a defined period. Ideally, exposure assessment would quantify the amount of a compound at the site of toxic action in the tissue of an organism. In studies of human populations, however, it generally is not possible to measure those concentrations. Instead, exposure assessments are based on measurements in environmental media or in

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Veterans and Agent Orange: Update 2004 biologic specimens. In either case, exposure serves as a surrogate for dose. Exposure assessments based on measurements of environmental contaminants attempt to quantify the amount of the contaminant that contacts a body barrier over a defined period. Exposure can occur through inhalation, skin contact, and ingestion. Exposure also can be assessed by measuring the compounds of interest—or their metabolites—in human tissues. Such biologic markers of exposure integrate absorption from all routes. The evaluation of those markers can be complex, because most are not stable for long periods. Knowledge of pharmacokinetics is essential to the linkage of measurements at the time of sampling with past exposures. Similarly, the assessment of markers that could be markers of effect—such as DNA adducts—shows promise, but does not necessarily provide accurate measurements of past exposure; that is, there is little evidence that currently measured DNA adducts are related to occupational or environmental exposures experienced years before. Because quantitative assessments based on environmental or biologic samples are not always available for epidemiologic studies, investigators rely on a mixture of qualitative and quantitative information to derive estimates. There are a few basic approaches to exposure assessment for epidemiology (Armstrong et al., 1994; Checkoway et al., 1989). The simplest compares the members of a presumably exposed group with the general population or with a non-exposed group. That approach offers simplicity and ease of interpretation. If, however, only a small fraction of the group is exposed to the agent, the increased risk posed by exposure might not be detectable when the risk of the entire group is assessed. A more refined method assigns each study subject to an exposure category, typically high, medium, low, or no exposure. Disease risk for each group is calculated separately and compared with a reference or non-exposed group. That method can identify the presence or absence of a dose–response trend. In some cases, more-detailed information is available for use in quantitative exposure estimates, which are sometimes called exposure metrics. They integrate quantitative estimates of exposure intensity (such as air concentration or extent of skin contact) with exposure duration to produce an estimate of cumulative exposure. Ideally, these refined estimates reduce errors associated with misclassification and thereby increase the power of statistical analysis to identify true associations between exposure and disease. The temporal relationship between exposure and disease is complex and often difficult to define in epidemiologic investigations. Many diseases do not appear immediately following exposure. In the case of cancer, for example, the disease may not appear for many years after the exposure. The time between an exposure and the occurrence of disease is often referred to as a latency period (IOM, 2004). Exposures can be brief (sometimes referred to as acute exposures) or protracted (sometimes referred to as chronic exposures). At one extreme the exposure can be the result of a single insult, as in an accidental poisoning. At the other, an individual exposed to a chemical that is stored in the body may continue

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Veterans and Agent Orange: Update 2004 to experience “internal exposure” for years, even if exposure from the environment has ceased. The definition of the proper time frame for exposure duration represents a challenging aspect of exposure assessment and epidemiology. Occupational–exposure studies use work histories, job titles, and workplace measurements of contaminant concentration; those data are combined to create a job–exposure matrix that assigns a quantitative exposure estimate to each job or task, and the time spent on each job or task is calculated. Those metrics incorporate exposure mitigation factors, such as process changes, engineering controls, or the use of protective clothing. The production worker cohort analysis conducted by the US National Institute for Occupational Safety and Health (NIOSH) used those methods. Many environmental-exposure studies use proximity to the source of a contaminant to classify exposure. If an industrial facility emits a contaminant, investigators might identify geographic zones around the facility and assign exposure categories to people on the basis of residence. That approach was used to analyze data from the industrial accident in Seveso, Italy, that contaminated nearby areas with TCDD. Assessments often are refined to include exposure pathways (how chemicals move from the source through the environment) and personal behavior; they sometimes include measurements of contaminants in environmental samples, such as soil. Biologic markers of exposure can provide important information for use in occupational and environmental studies; a quantitative exposure estimates can be assigned to each person in the study group. The most important marker in the context of Vietnam veterans’ exposure to Agent Orange is the measurement of TCDD in serum. Studies of the absorption, distribution, and metabolism of TCDD have been conducted over the past 20 years. In the late 1980s, the Centers for Disease Control and Prevention (CDC) developed a highly sensitive assay to detect TCDD in serum and demonstrated a high correlation between serum TCDD and TCDD in adipose tissue (Patterson et al., 1986, 1987). The serum TCDD assay is now used extensively to evaluate exposure in Vietnam veterans and other people. Exposure to Dioxin-like Compounds A major focus of the work of the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fifth Biennial Update) has been the analysis of studies involving exposure to a single compound: 2,3,7,8-tetrachlorodibenzo-p-dioxin, or TCDD. The committee recognizes that there are hundreds of similar compounds to which humans might be exposed, among them the polychlorinated biphenyls (PCBs), other polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polycyclic aromatic hydrocarbons. The literature on those compounds was often not considered in this evaluation, for several reasons. The exposure of Vietnam veterans to significant amounts (relative to TCDD) was considered unlikely or had not been docu-

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Veterans and Agent Orange: Update 2004 mented. Several of them might act by different mechanisms in addition to their ability to bind to and activate the aryl hydrocarbon receptor (AhR). Those mechanisms are sometimes related to the ability of the compounds to be metabolized to chemicals that might induce greater biologic activity. In addition, the exposure of human populations, for example occupationally, to those compounds occurs most often along with exposures to other compounds. It is difficult to determine whether the toxic effects should be attributed to the dioxin-like compound or to some other compound that has a different mechanism of action. The toxic equivalency factor (TEF) method of comparing the relative toxicity of dioxin-like compounds has come into common use by agencies of governments around the world. Although it is considered among the best of the approaches for assessing the relative risk posed by exposure to complex mixtures of the contaminants, it presents several uncertainties. TEFs are determined through inspection of the available congener-specific biologic and biochemical data on a compound and then assignment of a relative toxicity for that compound in comparison with TCDD. TEF values are by no means precise; they are the result of scientific judgment and expert opinion considering all available data. The quantity and quality of those data might vary considerably, and the values might differ by several orders of magnitude, depending on the different biologic endpoints chosen for a particular compound. Thus, there is considerable unquantifiable, uncertainty about their use. Although the World Health Organization values (Van den Berg et al., 1998) are most often cited and generally accepted, the values used can differ slightly among states, countries, and health organizations. Nevertheless, most agencies in the United States, including the Environmental Protection Agency, support the basic approach as providing a “reasonable estimate” of relative toxicity. Many countries and international organizations have adopted it although, again, the accepted values might differ. The TEF concept is based on the premise that the toxic and biologic responses of a particular group of compounds are mediated through the AhR. Although all the available data support that idea, the set of data on individual compounds within the group considered to be dioxin-like is incomplete. One limitation is that use of TEF values does not consider synergistic or antagonistic interactions among the compounds. It also does not consider possible actions or interactions of compounds that are not mediated by the AhR. Indeed, little research has been done on this. For some mixtures, another limitation is that the risk posed by non-dioxin-like chemicals (non-coplanar PCBs) is not assessed, and some non-coplanar PCBs can act as AhR antagonists (Safe, 1997–1998). The kinetics and metabolism of each dioxin-like compound might differ considerably from the others, and complete data on tissue concentrations often are unavailable. Extrapolation to a meaningful dose might add considerable uncertainty to calculation of the TCDD toxicity equivalent (TEQ) to which a person was exposed. There also is exposure to dietary flavonoids and other phytochemicals that bind the AhR that is not considered by the TEQ method (Ashida et al., 2000; Ciolino

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Veterans and Agent Orange: Update 2004 et al., 1999; Quadri et al., 2000). Considering the many difficulties of interpretation relative to the exposure of veterans to Agent Orange and other herbicides in Vietnam, some published literature on humans exposed either occupationally or environmentally to several other dioxin-like compounds was not evaluated. However, when such exposures were considered relevant to Vietnam veterans, the data were critically evaluated. OCCUPATIONAL EXPOSURE TO HERBICIDES AND TCDD The committee reviewed many epidemiologic studies of occupationally exposed groups for evidence of an association between health risks and exposure to TCDD and the herbicides used in Vietnam, primarily the phenoxy herbicides 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and chlorophenols. In reviewing the studies, the committee explicitly considered two types of exposure: exposure to TCDD itself and exposure to the various herbicides, particularly 2,4-D and 2,4,5-T. Separate consideration was necessary because of the possibility that, for example, some health effects could be associated with exposure to 2,4-D in agriculture and forestry. TCDD is an unwanted byproduct of 2,4,5-T production, but not of 2,4-D, although small quantities of other dioxins can be found in 2,4-D. Studies of occupational exposure to dioxins focus primarily on workers in chemical plants that produce phenoxy herbicides or chlorophenols. Other occupationally exposed groups include workers in agriculture and forestry who spray herbicides, sawmill workers exposed to chlorinated dioxins from contaminated wood preservatives, and pulp-and-paper workers exposed to dioxins through the pulp-bleaching process. Production Work US National Institute for Occupational Safety and Health Cohort Study One extensive set of data on chemical production workers potentially contaminated with TCDD has been compiled by NIOSH. More than 5,000 TCDD-exposed workers in 12 companies were identified from personnel and payroll records. Exposure status was determined initially through a review of process operating conditions; employee duties; and analytical records of TCDD in industrial-hygiene samples, process streams, products, and waste (Fingerhut et al., 1991). Occupational exposure to TCDD-contaminated processes was confirmed by measuring serum TCDD in 253 cohort members. Duration of exposure was defined as the number of years worked in processes contaminated with TCDD and was used as the primary exposure metric in the study. The use of duration of exposure as a surrogate for cumulative exposure was based on the high correlation (Pearson correlation efficient = 0.72) between log-transformed

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Veterans and Agent Orange: Update 2004 serum TCDD and years worked in TCDD-contaminated processes. Duration of exposure for individual workers was calculated from work records, and exposure duration categories were created: <1 year, 1 to <5 years, 5 to <15 years, and 15+ years. In some cases, information was not available for duration of exposure, so a separate metric, called duration of employment, was defined as the total time each worker was employed at the study plant. The NIOSH cohort study was updated in 1999 (Steenland et al., 1999), and a more refined exposure assessment was conducted. Workers whose records were inadequate to determine duration of exposure were excluded. The final analysis was restricted to 8 plants because 4 plants (with 591 workers) had no records on the degree of TCDD contamination of work processes or lacked the detailed work histories required to estimate TCDD exposure by job. Another 38 workers at the remaining 8 plants were eliminated because they worked in processes in which TCDD contamination could not be estimated. Finally, 727 workers with exposure to both pentachlorophenol (PCP) and TCDD were eliminated to avoid possible confounding of any TCDD effects by PCP effects. Those restrictions led to a subcohort of 3,538 workers (69% of the overall cohort). The exposure assessment for the subcohort was based on a job–exposure matrix (Piacitelli and Marlow, 1997) that assigned each worker a quantitative exposure score for each year of work. The score was based on three factors: concentration of TCDD in micrograms per gram of process materials, fraction of the day when the worker worked in the specific process, and a qualitative contact value (0.01–1.5) based on the estimated TCDD contamination reaching exposed skin or the potential for inhalation of TCDD-contaminated dust. The scores for each year of work were combined to yield a cumulative exposure score for each worker. The new exposure analysis presumably reduced misclassification (through exclusion of non-exposed workers) and uncertainty (through exclusion of workers with incomplete information) and improved accuracy (through more detailed information on daily exposure). Steenland et al. (2001) conducted a detailed exposure–response analysis from data on workers at one of the original 12 companies in the cohort study. A group of 170 workers was identified with serum TCDD greater than 10 parts per trillion (ppt), as measured in 1988. The investigators conducted a regression by using the following information: the work history of each worker, the exposure scores for each job held by each worker over time, a simple pharmacokinetic model for the storage and excretion of TCDD, and an estimated TCDD half-life of 8.7 years. That pharmacokinetic model allowed calculation of the estimated serum TCDD concentration at the time of last exposure for each worker. Results of the analysis were used to estimate serum TCDD over time that was attributable to occupational exposure for all 3,538 workers in the subcohort defined in 1999. Crump et al. (2003) conducted a meta-analysis of dioxin–cancer, dose–response studies for three occupational cohorts: the NIOSH cohort (Fingerhut et al., 1991); the Hamburg cohort (Flesch-Janys et al., 1998); and the BASF cohort

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Veterans and Agent Orange: Update 2004 (Ott and Zober, 1996). That analysis incorporated recent exposure data for the NIOSH cohort generated by Steenland et al. (2001). No other reports on the cohort have been published since Update 2002. An update of the Dow Chemical Company worker cohort (Bodner et al., 2003), which is part of the NIOSH cohort, is discussed below. International Agency for Research on Cancer Cohort Studies A multisite study by the International Agency for Research on Cancer (IARC) involved 18,390 production workers and herbicide sprayers in 10 countries (Saracci et al., 1991). The full cohort was established by using the International Register of Workers Exposed to Phenoxy Herbicides and Their Contaminants. Twenty cohorts were combined for this analysis: one each from Canada, Finland, and Sweden; two each from Australia, Denmark, Italy, the Netherlands, and New Zealand; and seven from the United Kingdom. There were 12,492 production workers and 5,898 sprayers in the full cohort. Questionnaires were constructed for manufacturers of chlorophenoxy herbicides or chlorinated phenols and for spraying cohorts. Surveys were completed with the assistance of industrial hygienists, workers, and factory personnel. Industry and production records also were used. Job histories were examined when available. Workers were classified as exposed, probably exposed, exposure unknown, or non-exposed. The exposed-workers group (N = 13,482) consisted of all known to have sprayed chlorophenoxy herbicides and all who worked in particular aspects of chemical production. Two cohorts (N = 416) had no job titles available but were deemed probably exposed. Workers with no exposure information (N = 541) were classified as “exposure unknown.” Non-exposed workers (N = 3,951) were those who had never been employed in parts of factories that produced chlorophenoxy herbicides or chlorinated phenols and those who had never sprayed chlorophenoxy herbicides. Review of the later analysis indicated that the lack of detailed occupational exposure information prevented meaningful classification beyond exposed and non-exposed. An expanded and updated version of that cohort study was published in 1997 (Kogevinas et al., 1997). The researchers added herbicide production workers from 12 plants in the United States (the NIOSH cohort) and from 4 plants in Germany. Exposure was reconstructed from individual job records, company exposure questionnaires developed specifically for the study, and, in some cohorts, measurements of TCDD and other dioxin and furan congeners in serum and adipose tissue and in the workplace. The 21,863 workers exposed to phenoxy herbicides or chlorophenols were classified in three categories of exposure to TCDD or higher-chlorinated dioxins: those exposed (N = 13,831), those not exposed (N = 7,553), and those with unknown exposure (N = 479). Several exposure metrics were constructed for the cohort—years since first exposure, duration of exposure (in years), year of first exposure, and job title—but detailed

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Veterans and Agent Orange: Update 2004 methods were not described. No new studies of the full cohort have been reported since Update 2000. Researchers have studied various subgroups of the IARC cohort. Flesch-Janys et al. (1995) updated the cohort and added quantitative exposure assessment based on blood or adipose measurements of polychlorinated dibenzo-p-dioxin and furan (PCDD/F). Using a first-order kinetics model, half-lives from an elimination study in 48 workers from this cohort, and background concentrations for the German population, the authors estimated PCDD/F exposure of the 190 workers by mean of measurements of serum or adipose concentrations of PCDD/F. The authors regressed the estimated PCDD/F exposure of those workers at the end of their exposure against the length of time they worked in each production department in the plant. The authors estimated the contribution of the time worked in each production department to PCDD/F exposure. The working-time “weights” were then used with work histories for the remainder of the cohort to estimate PCDD/F exposure for each member at the end of that person’s exposure. The epidemiologic analysis used the estimated TCDD doses. Becher et al. (1996) reported on analysis of several German cohorts, including the Boehringer–Ingelheim cohort described above (Kogevinas et al., 1997), a cohort from the BASF Ludwigshafen plant that did not include those involved in a 1953 accident, and a cohort from a Bayer plant in Uerdingen and a Bayer plant in Dormagen. All of the plants were involved in production of phenoxy herbicides or chlorophenols. Exposure assessment involved estimation of duration of employment from the start of work in a department where exposure was possible until the end of employment at the plant; a period that could include some time without exposure. Analysis was based on time since first exposure. Hooiveld et al. (1998) reported on an update of a mortality study of workers (production workers who had known exposure to dioxins, workers in herbicide production, non-exposed production workers, and workers known to be exposed as a result of an accident that occurred in 1963) from two chemical factories in the Netherlands. Assuming first-order TCDD elimination with an estimated half-life of 7.1 years, measured TCDD levels were extrapolated to the time of maximum exposure (TCDDmax) for a group of 47 workers. A regression model then estimated the effect on estimated TCDDmax for each cohort member attributable to exposure as a result of the accident, duration of employment in the main production department, and time of first exposure before (or after) 1970. No new report for that cohort has been published since Update 2002. An update of the Dow Chemical Company worker cohort (Bodner et al., 2003), which is part of the IARC cohort, is discussed below. Dow Cohort Studies Workers at Dow Chemical Company facilities where 2,4-D was manufactured, formulated, or packaged have been the subject of a cohort analysis since

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Veterans and Agent Orange: Update 2004 the 1980s (Bond et al., 1988). Industrial hygienists developed a job–exposure matrix that ranked employee exposures as low, moderate, or high on the basis of available air-monitoring data and professional judgment. That matrix was merged with employee work histories to assign an exposure magnitude to each job assignment. A cumulative dose was then developed for each of the 878 employees by multiplying the representative 8-h time-weighted average (TWA) exposure value for each job assignment by the number of years in the job and then adding those products for all jobs. The 2,4-D TWA of 0.05 mg/m3 was used for low, 0.5 mg/m3 for moderate, and 5 mg/m3 for high exposure. The role of dermal exposure in the facilities does not appear to have been considered in the exposure estimates. It is not clear to what extent the use of air measurements alone can provide accurate classification of workers into low-, moderate-, and high-exposure groups. Biologic monitoring of 2,4-D in a subset of workers could provide a straightforward evaluation of the validity of the job–exposure matrix but apparently it was not undertaken in this study. Follow-up reports were published in 1993 (Bloemen et al., 1993) and most recently in 2001 (Burns et al., 2001); neither of those studies modified the exposure assessment procedures of the original study. Since Update 2002, new cancer risk estimates for that cohort have been reported (Bodner et al., 2003). The exposure assessment procedures were unchanged from previous studies. Dow also has conducted a cohort study of manufacturing workers exposed to PCP (Ramlow et al., 1996). Exposure assessment for that cohort was based on consideration of the available industrial-hygiene and process data, including process and job description information obtained from employees, process and engineering controls change information, industrial-hygiene surface-wipe sample data, area exposure monitoring, and personal breathing-zone data. Jobs with higher estimated potential exposure involved primarily dermal exposure to airborne PCP in the flaking–prilling–packaging area; the industrial-hygiene data suggest about a 3-fold difference between the areas of highest to lowest potential exposure. All jobs were therefore assigned an estimated exposure intensity score on a scale of 1–3 (from lowest to highest potential exposure intensity). Reliable information concerning the use of personal protective equipment was not available for modification of estimated exposure intensity. Cumulative PCP and TCDD exposure indexes were calculated for each subject by multiplying the duration of each exposed job by its estimated exposure intensity and then adding the products across all exposed jobs. Other Production Worker Studies Several other occupational studies for chemical production plants have relied on job titles as recorded on individual work histories and company personnel records to classify exposure (Coggon et al., 1986, 1991; Cook et al., 1986; Ott et al., 1980; Zack and Gaffey, 1983; Zober et al., 1990). Similarly, exposure of chemical plant workers has been characterized by worker involvement in various

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Veterans and Agent Orange: Update 2004 production processes, such as synthesis, packaging, waste removal, shipping, and plant supervision (Bueno de Mesquita et al., 1993; Garaj-Vrhovac and Zeljezic 2002; Manz et al., 1991). Agriculture, Forestry, and Other Outdoor Work Occupational studies for agricultural workers have had various methods to estimate exposure to herbicides or TCDD. The simplest method derives occupational data from death certificates, cancer registries, or hospital records (Burmeister, 1981). Although such information is relatively easy to obtain, it cannot be used to estimate duration or intensity of exposure or to determine the specific exposure. Some studies of agricultural workers have attempted to investigate differences in occupational practices, allowing identification of subsets of workers who were likely to have had higher exposures (Hansen et al., 1992; Musicco et al., 1988; Ronco et al., 1992; Vineis et al., 1986; Wiklund and Holm, 1986; Wilklund et al., 1988a). Other studies have used county of residence as a surrogate for exposure, relying on agricultural censuses of farm production and chemical use to characterize exposure in individual countries (Blair and White, 1985; Cantor, 1982; Gordon and Shy, 1981). Still others have attempted to refine exposure estimates by categorizing exposure on the basis of the number of years employed in a specific occupation as a surrogate for exposure duration, using supplier records of pesticide sales to estimate exposure or estimating acreage sprayed to determine the amount used (Morrison et al., 1992; Wigle et al., 1990). Some studies used self-reported information on exposure that recounted direct handling of a herbicide, whether it was applied by tractor or hand-held sprayer, and what type of protective equipment or safety precautions were used (Hoar et al., 1986; Zahm et al., 1990). Other studies have validated self-reported information through written records, signed statements, or telephone interviews with co-workers or former employers (Carmelli et al., 1981; Woods and Polissar, 1989). Forestry and other outdoor workers, such as highway maintenance workers, are likely to have been exposed to herbicides and other compounds (see Table A-1 in Appendix A for a summary of studies). Exposure for those groups has been classified by approaches similar to those noted above for agricultural workers, for example, by the number of years employed, job category, and occupational title. The Ontario Farm Family Health Study has produced several reports that are relevant to phenoxyacetic acid herbicide exposures, including 2,4-D. A study of male pesticide exposure and pregnancy outcome (Savitz et al., 1997) developed an exposure metric based on self-reports of mixing or application of crop herbicides, crop insecticides, and fungicides; livestock chemicals; yard herbicides; and building pesticides. Subjects were asked whether they participated in those activities during each month, and their exposure classifications were based on activities in 3-month segments of time. The exposure classification was refined

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Veterans and Agent Orange: Update 2004 through answers to questions regarding use of protective equipment and specificity of pesticide use. A related study included analysis of 2,4-D residues in semen as a biologic marker of exposure (Arbuckle et al., 1999a). The study began with 773 potential participants, but only 215 eventually consented to the study. Of the 215, 97 provided semen and urine samples for 2,4-D analysis. The Ontario Farm Family Health Study also examined the effect of pesticide exposure, including 2,4-D, on time to pregnancy (Curtis et al., 1999) and the risk of spontaneous abortion (Arbuckle et al., 1999b, 2001). About 2,000 farm couples participated in the study. Exposure information was pooled from interviews with husbands and wives to construct a history of monthly agricultural and residential pesticide use. Exposure classification was based on a yes/no response for each month. Data on such variables as acreage sprayed and use of protective equipment were collected but were not available in all cases. More recent studies have used herbicide biomonitoring in a subset of the population to evaluate the validity of self-reported predictors of exposure (Arbuckle et al., 2002). Assuming that the presence of 2,4-D in urine was an accurate measure of exposure and that the results of the questionnaire indicating 2,4-D use were more likely to be subject to exposure classification error (that is, the questionnaire results were less accurate than was the urine analysis), the questionnaire’s prediction of exposure, when compared with the urine 2,4-D concentrations, had a sensitivity of 57% and a specificity of 86%. In multivariate models, the variables for pesticide formulation, protective clothing and gear, application equipment, handling practice, and personal-hygiene practice were significant as predictors of urinary herbicide concentrations in the first 24-h after application was initiated. The Agricultural Health Study in the United States enrolled approximately 58,000 commercial and private pesticide applicators in two states (Iowa and North Carolina) between 1993 and 1997 (Alavanja et al., 1994). Exposure assessment in this study is based primarily on questionnaire data collected at the time of enrollment and in periodic follow-up. Recently, Dosemeci et al. (2002) published an algorithm designed to better characterize personal exposures for that population. Weighting factors for key exposure variables were developed from the literature on pesticide exposure. That new quantitative approach is likely to improve the accuracy of exposure classification for the cohort. Herbicide Spraying Studies of herbicide applicators are relevant because they can be presumed to have had more sustained exposure to herbicides. However, because they also are likely to be exposed to a variety of compounds, assessment of individual or group exposure to specific phenoxy herbicides or TCDD is complicated. Some studies have attempted to measure applicators’ exposure on the basis of information from work records on acreage sprayed or on the number of days of spraying. Employ-

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Veterans and Agent Orange: Update 2004 Orange study (CDC, 1985) attempted to classify veterans’ service-related exposures to herbicides. That involved determining the proximity of troops to Agent Orange spraying by using military records to track troop movement and the HERBS tapes to locate herbicide-spraying patterns. The CDC Birth Defects Study developed an exposure opportunity index to score Agent Orange exposure (Erickson et al., 1984a,b). In 1987, CDC conducted the Agent Orange Validation Study to test the validity of the various indirect methods used to estimate exposure of ground troops to Agent Orange in Vietnam. The study measured serum TCDD in a non-random sample of Vietnam veterans and in Vietnam-era veterans who did not serve in Vietnam (CDC, 1988b). Vietnam veterans were selected for further study on the basis of the estimated number of Agent Orange hits, derived from the number of days on which at least one company location was within 2 km and 6 days of a recorded Agent Orange spray. The “low” exposure group consisted of 298 veterans, the “medium” exposure group had 157 veterans, and the “high” exposure group had 191 veterans. Blood samples were obtained from 66% of Vietnam veterans (N = 646) and from 49% of the eligible comparison group of veterans (N = 97). More than 94% of those whose serum was obtained had served in one of five battalions. The median serum TCDD in Vietnam veterans in 1987 was 4 ppt, with a range of <1–45 ppt; 2 veterans had concentrations above 20 ppt. The distribution of the measurements was nearly identical to that for a control group of 97 non-Vietnam veterans. The CDC validation study reported that study subjects could not be distinguished from controls on the basis of serum TCDD. In addition, none of the record-derived estimates of exposure and neither type of self-reported exposure to herbicides identified Vietnam veterans who were likely to have currently high serum TCDD (CDC, 1988b). The report concluded that it is unlikely that military records alone can be used to identify a large number of US Army veterans who might have been heavily exposed to TCDD in Vietnam. The serum TCDD measurements for Vietnam veterans also suggest that exposure to TCDD in Vietnam was substantially less, on the average, than was that of persons exposed as a result of the industrial explosion in Seveso or that of the heavily exposed occupational workers who are the focus of many of the studies evaluated by the committee. This assessment of average exposure does not deny the existence of a heavily exposed subgroup of Vietnam veterans. In 1997, a committee convened by IOM issued a request for proposals (RFP) seeking individuals and organizations to develop historical exposure reconstruction approaches suitable for epidemiologic studies of herbicide exposure among US veterans during the Vietnam War (IOM, 1997). The RFP resulted in the project “Characterizing Exposure of Veterans to Agent Orange and Other Herbicides in Vietnam”, carried out under contract by a team of researchers from Columbia University’s Mailman School of Public Health. The project, which began in 1998, created a geographic information system (GIS) for Vietnam with

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Veterans and Agent Orange: Update 2004 a grid resolution of 0.01° latitude and 0.01° longitude. Herbicide-spraying records were integrated into the GIS and linked with data on military unit locations to permit estimation of exposure opportunity scores for individuals. The results are the subject of reports by the contractor (Stellman and Stellman, 2003) and the committee (IOM, 2003b,c). A summary of the findings regarding the extent and pattern of herbicide spraying (Stellman et al., 2003a), a description of the GIS for characterizing exposure to Agent Orange and other herbicides in Vietnam (Stellman et al., 2003b), and an explanation of the exposure opportunity models based on that work (Stellman and Stellman, 2004) have been published in peer-reviewed journals. Those publications demonstrate the feasibility of epidemiologic investigations of veterans who served as ground troops during the Vietnam War. REFERENCES AFHS (Air Force Health Study). 1991. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. 9 vols. Akhmedkhanov A, Revich B, Adibi JJ, Zeilert V, Masten SA, Patterson DG Jr, Needham LL, Toniolo P. 2002. Characterization of dioxin exposure in residents of Chapaevsk, Russia. Journal of Exposure Analysis and Environmental Epidemiology 12(6):409–417. Akhtar FZ, Garabrant DH, Ketchum NS, Michalek JE. 2004. Cancer in US Air Force Veterans of the Vietnam War. Journal of Occupational and Environmental Medicine 46(2):123–136. Alavanja MC, Akland G, Baird D, Blair A, Bond A, Dosemeci M, Kamel F, Lewis R, Lubin J, Lynch C. 1994. Cancer and noncancer risk to women in agriculture and pest control: The Agricultural Health Study. Journal of Occupational Medicine 36(11):1247–1250. Andrews JS Jr, Garrett WA Jr, Patterson DG Jr, Needham LL, Roberts DW, Bagby JR, Anderson JE, Hoffman RE, Schramm W. 1989. 2,3,7,8-Tetrachlorodibenzo-p-dioxin levels in adipose tissue of persons with no known exposure and in exposure persons. Chemosphere 18:499–506. Arbuckle TE, Schrader SM, Cole D, Hall JC, Bancej CM, Turner LA, Claman P. 1999a. 2,4-Dichlorophenoxyacetic acid (2,4-D) residues in semen of Ontario farmers. Reproductive Toxicology 13(6):421–429. Arbuckle TE, Savitz DA, Mery LS, Curtis KM. 1999b. Exposure to phenoxy herbicides and the risk of spontaneous abortion. Epidemiology 10:752–760. Arbuckle TE, Lin Z, Mery LS. 2001. An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population. Environmental Health Perspectives 109(8):851–857. Arbuckle TE, Burnett R, Cole D, Teschke K, Dosemecci M, Bancej C, Zhang J. 2002. Predictors of herbicide exposure in farm applicators. International Archives of Occupational and Environmental Health 75:406–414. Armstrong BK, White E, Saracci R. 1994. Principles of Exposure Assessment in Epidemiology. New York: Oxford University Press. Ashida H, Fakuka I, Yamashita T, Kanazawa K. 2000. Flavones and flavonols at dietary levels inhibit a transformation of aryl hydrocarbon receptor induced by dioxin. FEBS Letters 476:213–217. Baccarelli A, Mocarelli P, Patterson DG Jr, Bonzini M, Pesatori AC, Caporaso N, Landi MT. 2002. Immunologic effects of dioxin: new results from Seveso and comparison with other studies. Environmental Health Perspectives 110(12):1169–1173.

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