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. The purpose of this chapter is to discuss exposure assessment and the exposure assessment that has been conducted in some of the epidemiologic studies as background for the health-outcome chapters that follow; no studies are evaluated and results are not discussed in this chapter. The committee's evaluations are presented in the health-outcome chapters. A more complete discussion of the exposures 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 (IOM, 1994) and in Chapter 5 of Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), and Update 2000 (IOM, 2001). 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 chemical 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 chemical at the site of toxic action in the tissue of an organism. In studies of human populations, however, it is not usually possible to measure those concentrations.



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Veterans and Agent Orange: Update 2002 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. The purpose of this chapter is to discuss exposure assessment and the exposure assessment that has been conducted in some of the epidemiologic studies as background for the health-outcome chapters that follow; no studies are evaluated and results are not discussed in this chapter. The committee's evaluations are presented in the health-outcome chapters. A more complete discussion of the exposures 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 (IOM, 1994) and in Chapter 5 of Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), and Update 2000 (IOM, 2001). 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 chemical 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 chemical at the site of toxic action in the tissue of an organism. In studies of human populations, however, it is not usually possible to measure those concentrations.

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Veterans and Agent Orange: Update 2002 Instead, exposure assessments are based on chemical measurements in either environmental media or biological specimens. In either case, exposure serves as a surrogate for dose. Exposure assessments based on measurements of chemical contaminants in the environment attempt to quantify the amount of the contaminant that contacts a body barrier over a defined time period. Exposure can occur via three routes: inhalation, skin contact, and ingestion. Exposure can also be assessed by measuring chemicals or their metabolites in human tissues. Such biomarkers of exposure integrate absorption from all routes. The evaluation of biomarkers can be complex, since most markers are not stable for long periods of time. Knowledge of pharmacokinetics is essential to the linkage of measurements at the time of sampling with past exposures. Similarly, biomarkers that have the possibility of being biomarkers of effect, such as DNA adducts, show promise, but do not necessarily provide accurate measures of past exposures; that is, there is no evidence that currently measured DNA adducts have any relationship to occupational or environmental exposures experienced years before. Quantitative assessments based on environmental or biologic samples are rarely available for epidemiologic studies; instead, investigators must rely on a mixture of qualitative and quantitative information to produce exposure estimates. One can usefully distinguish a few basic approaches to exposure assessment for epidemiology (Checkoway et al., 1989; Armstrong et al., 1994). The simplest approach compares the members of a group presumably exposed to a toxic agent with the general population or with a nonexposed group. The advantages of that approach are its simplicity and the ease of interpretation of results. If, however, only a small fraction of the group is exposed to the agent, any increased risk posed by exposure of this subgroup may not be detectable when the risk of the entire group is assessed. A more refined method of exposure assessment assigns each study subject to an exposure category, such as high, medium, low, and no exposure. Disease risk in each group can then be calculated separately and compared with a reference or nonexposed group. This method, in contrast with the simple exposed–nonexposed comparison above, can evaluate the presence or absence of a dose–response trend. In some cases, more detailed information is available, and quantitative exposure estimates can be developed. Such estimates are sometimes referred to as exposure metrics. Exposure metrics 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, such refined estimates reduce errors associated with misclassification and thereby increase the power of statistical analysis to identify true associations between exposure and disease. Occupational-exposure studies tend to rely on work histories, job titles, and workplace measurements of contaminant concentration, which can be combined to create a job–exposure matrix, in which a quantitative exposure estimate is

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Veterans and Agent Orange: Update 2002 assigned to each job or work task, and time spent on each job or task is calculated. Such metrics are able to 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) is a good example of a study that has used those methods. Many environmental-exposure studies use proximity to a contaminant source as the primary means of exposure classification. If, for example, an industrial facility emits a chemical contaminant, investigators may create geographic zones around the facility and assign exposure categories to individuals on the basis of location of residence. That approach was taken in the case of a serious industrial accident in Seveso, Italy, that contaminated nearby areas with TCDD. Assessments of this kind are often refined to include knowledge of exposure pathways (how chemicals move from the source through the environment) and personal behavior, and sometimes include measurements of chemicals in environmental samples such as soil. Biomarkers of exposure can provide crucial information for both occupational and environmental studies, in that a quantitative exposure estimate can be assigned to each individual in the study. The most important biomarker 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 last 20 years. In the late 1980s, the Centers for Disease Control (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 TCDD exposure in Vietnam veterans and other populations. 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 may 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.

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Veterans and Agent Orange: Update 2002 Studies of occupational exposure to dioxins focus primarily on chemical-plant workers who 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 of the most extensive sets of data on workers engaged in the production of chemicals potentially contaminated with TCDD has been compiled by NIOSH. More than 5,000 workers in 12 companies were identified from personnel and payroll records as TCDD-exposed. Exposure status was determined initially through a review of process operating conditions, employee job duties, and analytic 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 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 coefficient = 0.72) between log-transformed 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, such as, <1 year, 1 to <5 years, 5 to <15 years, and 15+ years. In some cases, information was not available to determine duration of exposure, so a separate metric called duration of employment was defined as the total time that each worker was employed at the study plant. The NIOSH cohort study was updated recently (Steenland et al., 1999), and a more refined exposure assessment was conducted. Workers whose records lacked adequate information to determine duration of exposure were excluded. The final analysis was restricted to eight plants because four plants (with 591 workers) lacked records on the degree of TCDD contamination of their work processes or lacked the detailed work histories required to estimate TCDD exposure by job. Another 38 workers at the remaining eight plants were eliminated because they worked in a process in which TCDD contamination could not be estimated. Finally, another 727 workers with exposure to both pentachlorophenol and TCDD were eliminated to avoid possible confounding of any TCDD effects by pentachlorophenol. Those restrictions led to a subcohort of 3,538 workers (69% of the overall cohort).

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Veterans and Agent Orange: Update 2002 The exposure assessment for the subcohort was based on a job–exposure matrix (Piacitelli and Marlow, 1997). The matrix 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 (exclusion of nonexposed workers) and uncertainty (exclusion of workers with incomplete information) and improved accuracy (more detailed information on daily exposure). Most recently, 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 were identified with serum TCDD greater than 10 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 of each worker. Results of the analysis were used to estimate serum TCDD over time due to occupational exposure for all 3,538 workers in the subcohort defined in 1999. International Agency for Research on Cancer Cohort A multisite study by the International Agency for Research on Cancer 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 factories producing chlorophenoxy herbicides or chlorinated phenols and for spraying cohorts. These were completed with the assistance of industrial hygienists, workers, and factory personnel. Industry and production records were also used. Job histories were examined when available. Workers were classified as exposed, probably exposed, exposure unknown, or nonexposed. Exposed workers (N = 13,482) comprised 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

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Veterans and Agent Orange: Update 2002 were deemed probably exposed on the basis of professional judgment. Workers with no exposure information (N = 541) were classified as “exposure unknown.” Nonexposed workers (N = 3,951) were those never employed in parts of factories that produced chlorophenoxy herbicides or chlorinated phenols and those who never sprayed chlorophenoxy herbicides. Review of the later analysis indicated that the lack of detailed exposure information on workers prevented meaningful classification beyond exposed and nonexposed. An expanded and updated version of this cohort study was published in 1997 (Kogevinas et al., 1997). The expanded cohort added herbicide production workers in 12 plants in the United States (the NIOSH cohort) and four plants in Germany. Exposure was reconstructed by using 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: those exposed to TCDD or higher-chlorinated dioxins (N = 13,831), those not exposed to TCDD or higher-chlorinated dioxins (N = 7,553), and those with unknown exposure to TCDD or higher-chlorinated dioxins (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 methods were not described. No new studies of the full cohort have been reported since Update 2000. Researchers have also conducted studies of various subgroups of the IARC cohort. Flesch-Janys et al. (1995) did an update of 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 with serum or adipose measurements of PCDD/F. The authors then regressed the estimated PCDD/F exposure of these workers at the end of their exposure against the length of time they worked in each production department in the plant. The authors also estimated the contribution of the time worked in each production department to the PCDD/F exposure. The working-time “ weights” were then used with the work histories of the remainder of the cohort to estimate the PCDD/F exposure of each cohort member at the end of the person's exposure. The epidemiologic analysis used the estimated TCDD doses. Becher et al. (1996) report an analysis of several German cohorts, including the Boehringer-Ingelheim cohort described above, a cohort from the BASF Ludwigshafen plant that did not include those involved in the 1953 accident, and a cohort from a Bayer plant in Uerdingen and a Bayer plant in Dormagen. All the plants were involved in the production of phenoxy herbicides or chlorophenols. Exposure assessment involved the estimation of duration of employment from the start of work in a department with suspected exposure until the end of em-

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Veterans and Agent Orange: Update 2002 ployment at the plant; it could have included some periods without exposure. Analysis was based on time since first exposure. Hooiveld et al. (1998) reported on an update of a mortality study of workers at two chemical factories in the Netherlands. The study included analysis by estimated maximal serum TCDD concentration. That was estimated for each member of the cohort by measuring serum TCDD of 144 subjects, including production workers known to be exposed to dioxins, workers in herbicide production, nonexposed production workers, and workers known to be exposed as a result of an accident that occurred in 1963. Assuming first-order TCDD elimination with an estimated half-life of 7.1 years, TCDDmax was extrapolated for a group of 47 workers; then a regression model was constructed to estimate the effect of exposure as a result of the accident, of duration of employment in the main production department, and of time of first exposure before (or after) 1970 on the estimated TCDDmax for each cohort member. Dow Cohorts Workers at Dow Chemical Co. facilities who manufactured, formulated, or packaged 2,4-D have been the subject of a cohort analysis since 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. The job–exposure matrix was merged with employee work histories to assign an exposure magnitude to each employee 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 the job was held and then summing the products across all jobs. A 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 these facilities does not appear to have been factored into the exposure estimates. It is not clear to what extent the use of air measurements alone provides 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 was apparently 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 these studies modified the exposure-assessment procedures of the original study. A cohort study of manufacturing workers exposed to pentachlorophenol was also conducted by Dow (Ramlow et al., 1996). Exposure assessment was based on consideration of the available industrial-hygiene and process data, including process and job-description information obtained from veteran employees, process and engineering controls change information, industrial-hygiene surface-

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Veterans and Agent Orange: Update 2002 wipe sample data, area exposure monitoring, and personal breathing-zone data. Jobs with higher estimated potential exposure involved primarily dermal exposure to airborne pentachlorophenol (PCP) in the flaking –prilling–packaging area; the industrial-hygiene data suggest about a 3-fold difference between the potential highest- and lowest-exposure areas. 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 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 summing across all exposed jobs. Other Production-Worker Studies Several other occupational studies of workers involved in chemical production plants have relied on job titles as recorded on individual work histories and company personnel records to classify exposure (Ott et al., 1980; Zack and Gaffey, 1983; Coggon et al., 1986, 1991; Cook et al., 1986; Zober et al., 1990). Similarly, exposure of chemical-plant workers has been characterized by worker involvement in various production processes, such as synthesis, packaging, waste removal, shipping, and plant supervision (Manz et al., 1991; Bueno de Mesquita et al., 1993). Agricultural, Forestry, and Other Outdoor Work Occupational studies of agricultural workers have estimated exposure to herbicides or TCDD with various methods. In the simplest method, data on a person's occupation were derived from death certificates, cancer registries, or hospital records (Burmeister, 1981). Although such information is relatively easy to obtain, it is not possible to estimate duration or intensity of exposure from it or to determine the specific type of herbicide or chemical to which a worker was exposed. Some studies of agricultural workers attempted to investigate differences in occupational practices, allowing identification of subsets of workers who were likely to have had higher herbicide exposure (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 used county of residence as a surrogate of exposure, relying on agricultural censuses of farm production and chemical use to characterize exposure in individual counties (Blair and White, 1985; Cantor, 1982; Gordon and Shy, 1981). Still other studies 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 amounts of herbicides purchased to estimate exposure or

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Veterans and Agent Orange: Update 2002 estimating the acreage sprayed to determine the amount used (Morrison et al., 1992; Wigle et al., 1990). In some cases, self-reported information on exposure was obtained, including direct handling of the herbicide, whether it was applied by tractor or hand-held spray, and what type of protective equipment was worn or what safety precautions were exercised, if any (Hoar et al., 1986; Zahm et al., 1990). Some studies attempted to validate self-reported information by using written records, signed statements, or telephone contacts with co-workers or former employers (Carmelli et al., 1981; Woods and Polissar, 1989). Forestry workers and other outdoor workers, such as highway-maintenance workers, are likely to have been exposed to herbicides and other chemicals to various degrees (see Table 4-1 for summary of studies). Exposure has been classified in a manner similar to that in other studies, for example, by number of years employed, job category, and occupational title. The Ontario Farm Family Health Study has produced several studies 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-reported involvement in five activities associated with pesticide exposure: mixing or applying 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. A man's exposure classification was based on his activities in 3-month windows. The exposure classification was refined with 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 biomarker 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 for 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 the urine analysis), the questionnaire's prediction of exposure, when compared to the urine 2,4-D concentrations, had a sensitivity of 57% and a specificity

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Veterans and Agent Orange: Update 2002 of 86%. In multivariate models, the variables 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. Herbicide and Pesticide Spraying Studies of herbicide sprayers are relevant because it can be presumed that appliers had more sustained exposure to herbicides; however, they were also likely to be exposed to a multiplicity of chemicals, and this would complicate the assessment of any individual or group exposure to specific phenoxy herbicides or TCDD. Some studies have attempted to measure exposure of appliers on the basis of information from work records on acreage sprayed or number of days of spraying. Employment records can also be used to extract information on the chemicals sprayed. One surrogate indicator of herbicide exposure is receipt of a license to spray. Several studies have specifically identified licensed or registered pesticide and herbicide appliers (Blair et al., 1983; Smith et al., 1981, 1982; Swaen et al., 1992; Wiklund et al., 1988b, 1989). Individual estimates of the intensity and frequency of exposure were rarely quantified in the studies that the committee examined, however, and many appliers were known to have applied many kinds of herbicides, pesticides, and other chemicals. In addition, herbicide spraying is generally a seasonal occupation, and information may not be available on possible expo-sure-related activities during the rest of the year. One study provided information on serum TCDD concentrations in herbicide sprayers. Smith et al. (1992) analyzed blood from nine professional spray appliers in New Zealand who first sprayed before 1960 and were also spraying in 1984. The duration of actual spray work varied from 80 to 370 months. Serum TCDD was 3–131 ppt on a lipid basis (mean = 53 ppt). The corresponding values for age-matched controls were 2–11 ppt (mean = 6 ppt). Serum TCDD was positively correlated with the number of months of professional spray application. Several studies have evaluated various herbicide exposures during spraying in terms of type of exposure, routes of entry, and routes of excretion: (Ferry et al., 1982; Frank et al., 1985; Lavy et al., 1980a,b; Libich et al., 1984; Kolmodin-Hedman and Erne, 1980; and Kolmodin-Hedman et al., 1983). On the basis of those studies, it appears that the major route of exposure is dermal absorption, with 2–4% of the chemical that contacts the skin being absorbed into the body during a normal workday. Air concentrations of the herbicides were usually less than 0.2 mg/m3. Absorbed phenoxy acid herbicides are virtually cleared within 1 day, primarily through urinary excretion. Typical measured excretion by ground crews was 0.1–5 mg/day, and that by air crews was less.

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Veterans and Agent Orange: Update 2002 A recent study of Canadian farmers examined pesticide exposures of men (McDuffie et al., 2001). Data on pesticide exposure were collected by questionnaires, including information on specific chemicals (including 2,4-D), frequency of application, and duration of exposure. A small validation study (N = 27) was performed to test the self-reported pesticide-use data against records of purchase. Investigators reported an “excellent concordance” between the two sources, but did not provide a statistical analysis. A study of 98 professional turf sprayers in Canada developed new models to predict 2,4-D dose (Harris et al., 2001). Exposure information was gathered with self-administered questionnaires. Urine samples were collected throughout the spraying season (24-h samples on 2 consecutive days). Estimated 2,4-D doses were developed from the data and used to evaluate the effect of protective clothing and other exposure variables. A number of other studies regarding agricultural use of pesticides published recently do not provide specific information on exposure to 2,4-D, TCDD, or other compounds relevant to Vietnam veterans' exposure (Bell et al., 2001a,b; Duell et al., 2001). Paper and Pulp Mill Work Another occupational group likely to be exposed to TCDD and chlorinated phenols consists of paper and pulp mill workers. They are likely to have received various degrees of exposure as part of the bleaching process in the production of paper products. Pulp and paper production workers are also likely to be exposed to other chemicals in the workplace according to, for example, the type of paper mill or pulping operation and the product manufactured (Henneberger et al., 1989; Jappinen and Pukkala, 1991; Robinson et al., 1986; Solet et al., 1989). In a study of a cohort of Danish paper mill workers (Rix et al., 1998), there were no direct measures of exposure of the workers, and a qualitative assessment of chemicals used in paper manufacture by department does not include chlorinated organic compounds, although chlorine, chlorine dioxide, and hypochlorite were used. No new studies of those populations have been reported since Update 2000. Sawmill Work Workers in sawmills may be exposed to pentachlorophenates, which are contaminated with higher-chlorinated PCDDs (Cl6−Cl8), or tetrachlorophenates, which are less contaminated with higher-chlorinated PCDDs. Wood is dipped in those chemicals and then cut and planed in the mills. Most exposure is dermal, although some exposure can occur by inhalation (Hertzmann et al., 1997; Teschke et al., 1994). No new studies in those populations have been reported since Update 2000.

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Veterans and Agent Orange: Update 2002 vegetation (Darrow et al., 1969). Additional accounts include the use of fungicides, insecticides, wetting agents, wood preservatives, insect repellents, and other herbicides (Gonzales, 1992). The numbers of military personnel potentially exposed to those chemicals are not available. Ground Spraying of Herbicides The number of US military personnel exposed to herbicides is impossible to determine precisely, but most of those assigned to Operation Ranch Hand can be presumed to have been exposed to Agent Orange and other herbicides. In addition, the US Army Chemical Corps, using hand equipment and helicopters, conducted smaller spray operations, such as defoliation around special forces camps; clearance of perimeters of airfields, depots, and other bases; and small-scale crop destruction (Thomas and Kang, 1990; Warren, 1968). Units and individuals other than members of the Air Force Ranch Hand and Army Chemical Corps were also likely to have handled or sprayed herbicides around bases or lines of communication. For example, Navy river patrols were reported to have used herbicides for clearance of inland waterways, and engineering personnel required the use of herbicides for removal of underbrush and dense growth in constructing fire-support bases. Because the herbicides were not considered to present a health hazard, few precautions were taken to prevent troop exposure to the chemicals. The precautions prescribed were consistent with those applied in the domestic use of herbicides that existed before the Vietnam conflict (US GAO, 1979). New information looking into the assessment of wartime exposure to herbicides in Vietnam is being gathered through a research project being overseen by an Institute of Medicine (IOM) committee. This work is being conducted in response to a request for proposals on this topic (IOM, 1997). TCDD in Herbicides Used in Vietnam TCDD is a contaminant of 2,4,5-T. Small quantities of other dioxins are present in 2,4-D. The concentration of TCDD in any given lot of 2,4,5-T depends on the manufacturing process (Young et al., 1976), and different manufacturers produced 2,4,5-T with different concentrations of TCDD. Of all the herbicides used in South Vietnam, only Agent Orange was formulated differently from the materials for commercial application that were readily available in the United States (Young et al., 1978). TCDD concentrations in individual shipments were not recorded, and they varied in sampled inventories of herbicides containing 2,4,5-T. Analysis of the TCDD concentration in stocks of Agent Orange remaining after the conflict, which either had been returned from South Vietnam or had been procured but not shipped, ranged from less than

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Veterans and Agent Orange: Update 2002 0.05 ppm to almost 50 ppm and averaged 1.98 and 2.99 ppm in two sets of samples (NAS, 1974; Young et al., 1978). Comparable manufacturing standards for the domestic use of 2,4,5-T in 1974 required that TCDD be present at less than 0.05 ppm (NAS, 1974). Agents Green, Pink, and Purple—used early in the program (before 1965)— contained 16 times the mean TCDD content of formulations used during 1965– 1970 (Young et al., 1978). Analysis of archive samples of Agent Purple reported TCDD as high as 45 ppm (Young, 1992). The mean concentration of TCDD in Agent Purple was estimated to be 32.8 ppm; that in Agents Pink and Green, 65.6 ppm (Young et al., 1978). It has been estimated that about 368 lbs of TCDD was sprayed in Vietnam over a 6-year period (Gough, 1986). EXPOSURE ASSESSMENT IN STUDIES OF VIETNAM VETERANS Different approaches have been used to estimate the exposure of Vietnam veterans, including self-reported exposures, record-based exposure estimates, and biomarkers of TCDD exposure. Each approach is limited in its ability to determine individual exposure. Some studies rely on such gross markers as service in Vietnam—perhaps enhanced by branch of service, military region, military specialty, or combat experience —as proxies for exposure to herbicides. Studies of that type include the CDC Vietnam Experience Study and Selected Cancers Study, Department of Veterans Affairs mortality studies, and most studies of veterans conducted by states. This approach almost surely dilutes the health effects of herbicides because many members of the cohort presumed to be exposed to herbicides may, in reality, not have been. Ranch Hand Studies Job title while in the military has been shown to be a valid exposure classification for Air Force Ranch Hand personnel, who were responsible for aerial spraying of herbicides. Biomarker studies of the Ranch Hand personnel are consistent with their exposure to TCDD as a group. When the Ranch Hand cohort was further classified by military occupation, a general increase in serum TCDD was detected for jobs that involved more frequent handling of herbicides (AFHS, 1991). The exposure index initially proposed in the Air Force Ranch Hand study relied on military records of TCDD-containing herbicides (Agents Orange, Purple, Pink, and Green) sprayed as reported in the HERBS tapes for the period starting July 1965 and on military procurement records and dissemination information for the period before July 1965. In 1991, the exposure index was compared with the results of the Ranch Hand serum TCDD analysis. The exposure index and the TCDD body burden correlated weakly.

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Veterans and Agent Orange: Update 2002 Michalek et al. (1995) developed several indexes of herbicide exposure for members of the Ranch Hand cohort and tried to relate them to the measurements of serum TCDD from 1987 to 1992. Self-administered questionnaires completed by veterans of Operation Ranch Hand were used to develop three indexes for herbicide or TCDD exposure: number of days of skin exposure, percentage of skin area exposed, and the product of number of days of skin exposure, percentage of skin exposed, and a factor for the concentration of TCDD in the herbicide. A fourth index used no information gathered from individual subjects. It was calculated by multiplying the volume of herbicide sprayed during a specific individual's tour of duty by the concentration of TCDD in herbicides sprayed in that period and dividing the product by the number of crew members in each job specialty at that time. Each of the four models tested was significantly related to serum TCDD, although each explained only 19–27% of the variability in serum TCDD. Days of skin exposure had the highest correlation. Military job classification (non-Ranch Hand combat troops, Ranch Hand administrators, Ranch Hand flight engineers, and Ranch Hand ground crew), which is separate from the four indexes, explained 60% of the variability in serum TCDD. When the questionnaire-derived indexes were applied within each job classification, days of skin exposure added statistically significantly, but not substantially, to the variability explained by job alone. Recent studies of the same population have used serum TCDD as the primary exposure index to examine possible associations with hepatic abnormalities, peripheral neuropathies, hematologic disorders, and cognitive functioning (Barrett et al., 2001; Michalek et al., 2001a,b,c). Army Chemical Corps Studies Members of the US Army Chemical Corps performed ground and helicopter chemical operations and were thereby involved in the direct handling and distribution of herbicides in Vietnam. This population has only recently been identified for detailed study of health effects related to herbicide exposure (Thomas and Kang, 1990). Results of an initial feasibility study were reported recently (Kang et al., 2001). It recruited 565 veterans: 284 Vietnam veterans and 281 non-Vietnam veteran controls. Blood samples were collected from 50 Vietnam veterans and 50 control veterans, and 95 of the samples met quality-assurance –quality-control standards set by the CDC laboratory. Comparison of the entire Vietnam cohort with the entire non-Vietnam cohort showed that the geometric mean TCDD concentrations did not differ significantly (p = 0.6). Analysis of questionnaire responses indicated that the Vietnam veterans who reported spraying herbicides had higher TCDD concentrations than those who reported no spraying activities. The authors concluded that Agent Orange exposure was a likely contributor to

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Veterans and Agent Orange: Update 2002 TCDD concentrations in Vietnam veterans with a history of spraying herbicides. The main study of 5,000 Vietnam veterans, including analysis of an additional 900 blood specimens, continues. Other Vietnam Veterans Surveys of Vietnam veterans who were not part of the Ranch Hand or Army Chemical Corps groups indicate that 25–55% believe that they were exposed to herbicides (CDC, 1989; Erickson et al., 1984a,b; Stellman and Stellman, 1986). A few attempts have been made to estimate exposure of the Vietnam veterans who were not part of the Ranch Hand or Army Chemical Corps groups. In 1983, CDC was assigned by the US government to conduct a study of the possible long-term health effects of Vietnam veterans' exposures to Agent Orange. The CDC Agent Orange study (CDC, 1985) attempted to classify veterans' exposure to herbicides that occurred during military service. 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 nonrandom sample of Vietnam veterans and Vietnam-era veterans who did not serve in Vietnam (CDC, 1988b). Vietnam veterans were selected for further study on the basis of their 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 included 298 veterans, the “medium” exposure group 157 veterans, and the “high” exposure group 191 veterans. Blood samples were obtained from 66% of Vietnam veterans (N = 646) and 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 was 4 ppt, with a range of less than 1 to 45 ppt, and two veterans had concentrations above 20 ppt; the distributions of these measurements were nearly identical with those in the control group of 97 non-Vietnam veterans. In other words, the CDC validation study found 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 study 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.

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Veterans and Agent Orange: Update 2002 In addition, the serum TCDD measurements in Vietnam veterans suggest that the exposure to TCDD in Vietnam was substantially less, on the average, than that of persons exposed as a result of the industrial explosion in Seveso, or of the heavily exposed occupational workers that are the focus of many of the studies evaluated by the committee. This estimation of average exposure does not preclude the existence of a heavily exposed subgroup of Vietnam veterans. In 1997, a committee convened by IOM developed a request for proposals (RFP) seeking individuals and organizations capable of conducting research to develop one or more historical exposure reconstruction approaches suitable for epidemiologic studies of herbicide exposure among US veterans during the Vietnam War (IOM, 1997). The RFP resulted in a project called “Characterizing Exposure of Veterans to Agent Orange and Other Herbicides in Vietnam” (Stellman, 2002). The project, initiated in 1998, has created a geographic information system (GIS) for Vietnam with a grid resolution of 0.01 degree latitude and 0.01 degree longitude. Herbicide-spray records from US military agencies have been integrated into the GIS and used to produce an exposure-opportunity index. The data will be linked with data on military-unit locations to permit estimation of exposure-opportunity scores for individuals. The results of the project will be published in the peer-reviewed literature in the next two years. 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. 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(6):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(6):406–414. Armstrong BK, White E, Saracci R. 1994. Principles of Exposure Assessment in Epidemiology. New York, Oxford University Press. Barrett DH, Morris RD, Akhtar FZ, Michalek JE. 2001. Serum dioxin and cognitive functioning among veterans of Operation Ranch Hand. Neurotoxicology 22(4):491–502. Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindorf K, Manz A, Wahrendorf J. 1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes and Control 7(3):312–321.

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