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Veterans and Agent Orange: Update 2006 (2007)

Chapter: 5 Exposure Assessment

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5 Exposure Assessment Assessment of human exposure to four specific herbicides (2,4-dichloro- phenoxyacetic acid [2,4-D], 2,4,5-trichlorophenoxyacetic acid [2,4,5-T], 4-amino- 3,5-trichloropicolinic acid [picloram], and cacodylic acid [dimethyl-arsinic acid or DMA]) and the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a key element in determining whether specific health outcomes are linked to these chemicals. In this chapter we review information on occupational and environ- mental exposures to these herbicides and TCDD, including exposure of Vietnam veterans. We discuss exposure assessments from selected epidemiologic studies introduced in Chapter 4 and provide 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 Vet- erans and Agent Orange (VAO; IOM, 1994); additional information concerning exposure assessment is located Chapter 5 of the updates (IOM, 1996, 1999, 2001, 2003a, 2005). Reviews of the most recent studies of the absorption, distribution, metabolism, and excretion of herbicides and TCDD can be found in their respec- tive sections on toxicokinetics in Chapter 3 of this report. EXPOSURE ASSESSMENT IN EPIDEMIOLOGIC STUDIES An ideal exposure assessment would provide quantification of the concentra- tion of a chemical at the site of toxic action in the tissue of an organism. In studies of human populations, however, it is rarely possible to measure those concentra- tions. Instead, exposure assessments are based on questionnaires and interviews, occupational and public records, or measurements in environmental media and 214

EXPOSURE ASSESSMENT 215 in biologic specimens. Table 5-1 provides a guide to exposure monitoring and assessment methods used in selected epidemiologic studies of the health effects of the herbicides applied in Vietnam by US military forces and TCDD. Exposure assessments based on measurements of an environmental contami- nant provide estimates of the amount of the contaminant that contacts a body barrier over a defined period. Exposure can occur through inhalation, skin con- tact, 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, and their interpretation is usually complex. Knowledge of pharmacokinetics is essential for linking measurements at the time of sampling with past exposures. Quantitative assessments based on environmental or biologic samples are not always available for epidemiologic studies, so investigators often rely on a mixture of qualitative and quantitative information to derive estimates (Armstrong et al., 1994; Checkoway et al., 2004). The most basic approach compares members of a presumably exposed group with the general population or with a non-exposed group. This method of classification offers simplicity and ease of interpretation. A more refined method assigns each study subject to an exposure category, such as high, medium, and low exposure. Disease risk for each group is cal- culated separately and compared with a reference or non-exposed group. This method can identify the presence or absence of a dose–response trend. In some cases, more detailed information is available for quantitative exposure estimates, and these can be used to construct what are sometimes called exposure metrics. These metrics integrate quantitative estimates of exposure intensity (such as chemical concentration in air or extent of skin contact) with exposure duration to produce an estimate of cumulative exposure. 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 a defined exposure period 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 extreme, an individual exposed to a chemical that is stored in the body may continue to experience “internal exposure” for years, even if exposure from the environment has ceased. Defining the proper time frame for duration of exposure represents a challenge in the assessment of exposure for epidemiologic studies. Occupational-exposure studies use work histories, job titles, and workplace measurements of contaminant concentration; this information is often combined to create a job–exposure matrix (JEM) wherein a quantitative exposure estimate is assigned to each job or task, and the time spent on each job or task is calculated.

216 TABLE 5-1 Exposure Monitoring and Assessment Methods Used in Selected Epidemiologic Studies of the Health Effects of Herbicides Applied in Vietnam by US Military Forces and 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Ontario US Agri- New Seveso Army NIOSH Dow Farm cultural Zealand Seveso Women’s Air Force Chemical Australian Cohort Cohort Health Health Herbicide Area Health Health Corps Veteran Exposure Method Study Study Study Study Sprayers Study Study Study Study Study Job title x x x x x x x x Self-reported chemical use x x x x Exposure duration x x x x x x x Exposure categories x x x x x x Review of records x x x Job–exposure matrix x x Proximity to source x x x Soil sampling x Air sampling x 2,4-D concentration in urine x TCDD concentration in serum x x x x x

EXPOSURE ASSESSMENT 217 This approach may also incorporate exposure-mitigating factors, such as process changes, engineering controls, and the use of protective clothing. The production- worker cohort analysis conducted by the US National Institute for Occupational Safety and Health (NIOSH) included these methods (Table 5-1). Many environmental-exposure studies use proximity to the source of a con- taminant to classify exposure (Table 5-1). If an industrial facility emits a contami- nant, 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; the zones established were calibrated by the collection of soil samples. In general, it is difficult to use this type of information to classify the exposures of individuals with confidence. Such assessments can be refined to include analyses of exposure pathways (how chemicals move from the source through the environment) and personal behaviors (how individuals interact with their environment). Biologic markers of exposure can provide important information for use in occupational and environmental studies, permitting assignment of a quantitative exposure estimate to each person in a study group. The most important marker in the context of Vietnam veterans’ exposure to Agent Orange is the measurement of TCDD in serum, although it should be noted that TCDD and Agent Orange are not synonymous. The absorption, distribution, and metabolism of TCDD have been studied over the last 20 years. In the late 1980s, the Centers for Dis- ease 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 (Table 5-1). Studies of the patterns of individual chlorinated hydrocarbons observed in the tissues of people exposed to specific sources (Pless-Mulloli et al., 2005) sug- gest that the profiles are not sufficiently distinct to permit discrimination from general urban background exposure. Exposure Misclassification Exposure misclassification in epidemiologic studies can affect estimates of risk. A typical situation is a case–control study in which the reported measure- ment of exposure can be misclassified for either or both groups. The simplest situation to consider is classification of exposure into just two levels, for example ever or never exposed. If the probability of exposure misclassification is the same (i.e., non-differential) between cases and controls, then it can be shown that the estimated association between disease and exposure is biased towards the null value. In other words, one would expect the true association to be stronger than the association actually observed. However, if the probability of misclassification

218 VETERANS AND AGENT ORANGE: UPDATE 2006 is different for cases and controls, then bias in the estimated association can occur in either direction. In this case, the true association might be stronger or weaker than the association observed. The situation when exposure is classified into more than two levels is some- what more complicated. Dosemeci et al. (1990) have demonstrated that for this situation, the slope of a dose–response trend is not necessarily attenuated towards the null value, even if the probability of misclassification is the same for the two groups of subjects being compared, so the observed trend in disease risk across the several levels of exposure may be either an over-estimate or an under-estimate of the true trend in risk. The probabilities of misclassification typically are unknown at the start of the study. If one had perfect knowledge of the misclassification probabilities, statisti- cal adjustment still will not necessarily lead to a result that is more significant than the unadjusted analysis, even if the misclassification probabilities are non- differential between the comparison groups. Analyses in which adjustments have been made for exposure misclassification should not be assumed to increase the certainty that an association is present. The situation is even more complicated when one has to estimate the probabilities of misclassification from the study data themselves. Finally, it is important to consider the effect of exposure misclassification on the statistical significance of the result. Greenland and Gustafson (2006) have shown that if one adjusts for exposure misclassification when the exposure is represented as binary (e.g., ever and never exposed), the resulting association is not necessarily more significant than in the unadjusted estimate. This result re- mains true even though the observed magnitude of the association (for example, the relative risk) might be increased, as indicated previously. Exposure to Dioxin-like Compounds A major focus of the work of the current VAO update has been the analysis of studies concerning exposure to a single compound: TCDD, which is one of several of tetrachlorodibenzo dioxins. The committee recognizes that under real-world conditions exposure to TCDD virtually never occurs in isolation and that there are hundreds of similar compounds to which humans might be exposed, among them other polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocar- bons (PAHs). Exposure to TCDD is almost always accompanied by exposure to one or more of these other compounds. The literature on these other compounds, particularly PCBs and PAHs, was not reviewed systematically by the committee, unless TCDD was identified as an important component of the exposure. We took this approach for two reasons. First, exposure of Vietnam veterans to significant amounts of these other compounds, as compared to exposure to TCDD, has not been documented. Second, the most important mechanism for TCDD toxicity

EXPOSURE ASSESSMENT 219 involves its ability to bind to and activate the aryl hydrocarbon receptor (AhR). Many of these other compounds act by different or multiple mechanisms, so it is difficult to attribute toxic effects from such exposures to TCDD. Exposure to mixtures of dioxin-like compounds presents a particularly dif- ficult challenge for toxicology and risk assessment. The total toxicity equivalency quotient (TEQ) method uses the sum of the relative toxicities of dioxin-like compounds in a mixture to express the overall toxicity of the mixture as a single TCDD-toxic equivalent value. This approach has come into common use by regulatory agencies around the world, and most agencies in the United States, including the Environmental Protection Agency, support its use as providing a reasonable estimate of toxicity for complex mixtures. World Health Organization values (Van den Berg et al., 2006) are most often cited and generally accepted. Calculation of a TEQ value for a mixture of dioxin-like compounds requires that each specific dioxin-like compound in the mixture be assigned a toxicity equivalency factor (TEF) relative to the toxicity of TCDD. This determination is based on an evaluation of existing biologic and biochemical data. These data are of variable quality, and their evaluation includes scientific judgment and expert opinion, so the resulting TEFs are by no means precise. Furthermore, the TEQ method is based on the premise that the toxic and biologic responses of dioxin- like compounds are mediated through the AhR mechanism. Available data support this premise, but data on some compounds are incomplete. The TEQ method also has several important limitations. It is not able to account for possible synergistic or antagonistic interactions among compounds, possible actions or interactions of compounds that are not mediated by the AhR mechanism, and exposures to di- etary flavonoids and other phytochemicals that bind the AhR (Ashida et al., 2000; Ciolino et al., 1999; Quadri et al., 2000). For some mixtures the risk posed by non-dioxin-like compounds that can act as AhR antagonists (e.g., non-coplanar PCBs) is not assessed (Safe, 1997–1998). It should also be noted that the kinetics and metabolism of each dioxin-like compound might differ considerably from the others, and complete data on tissue concentrations often are unavailable. Finally, extrapolation of TEF values derived from blood or adipose tissue samples to a meaningful target dose can carry considerable uncertainty. Considering the many difficulties of interpreting exposures to chemical mixtures relative to the exposure of veterans to Agent Orange and other herbicides in Vietnam, the committee’s analyses have focused primarily on TCDD exposures. Background levels of TEQ overall are thought to have declined along with a decline in PCB levels in the environment (e.g., Schneider et al., 2001). There have also been apparent declines in the background levels of TCDD itself (Aylward and Hays, 2002). However, such declines may be influenced by local differences in specific sources.

220 VETERANS AND AGENT ORANGE: UPDATE 2006 Exposure Specificity for the Herbicides Used in Vietnam Only a limited number of herbicidal compounds were used as defoliants dur- ing the Vietnam War: esters and salts of 2,4-D and 2,4,5-T, cacodylic acid, and picloram, as combined in various formulations. Many scientific studies reviewed by the committee have reported exposures to broad categories of chemicals rather than to these specific compounds. These categories are presented in Table 5-2, along with their relevance to the committee’s charge. The information in Table 5-2 represents the current committee’s thinking, and has helped to guide our evaluation of studies. Because the body of evidence available for consideration was substantially more limited, previous committees cast a somewhat wider net by having slightly less stringent criteria for exposure specificity. A large number of studies have examined the relationship between exposure to “pesticides” and adverse health outcomes, while others have used the category of “herbicides” without identifying specific compounds. A careful reading of a scientific report often reveals that none of the compounds of interest (those used in Vietnam as mentioned above) contributed to the exposures of the study population, so such studies can be excluded from consideration. But in many cases the situation will be more ambiguous. For example, reports that define exposure in the broad category of “pesticides” with no further information have little relevance to the committee’s charge to determine associations between exposures to herbicides used in Vietnam and adverse health outcomes. Reports TABLE 5-2 Current Committee Guidance for the Classification of Exposure Information in Epidemiologic Studies That Focus on the Use of Pesticides or Herbicides, and Relevance of the Information to the Committee’s Charge to Evaluate Exposures to 2,4-D, 2,4,5-T (phenoxy herbicides), Cacodylic Acid, and Picloram* Relevance to Specificity of Exposure Committee’s Reported in Study Additional Information Charge Pesticides Chemicals of interest were not used or no Not relevant additional information Chemicals of interest were used Relevant Herbicides Chemicals of interest were not used Not relevant No additional information Limited relevance Chemicals of interest were used Relevant Phenoxy herbicides Highly relevant 2,4-D or 2,4,5-T Highly relevant * None of the epidemiologic studies reviewed by the committee to date have specified exposure to cacodylic acid or picloram.

EXPOSURE ASSESSMENT 221 that define exposure in the more restricted category of “herbicides” are of greater relevance, but are of limited value unless it is clear from additional information that exposure to one or more of the herbicides used in Vietnam occurred within the study population (e.g., the published report indicates that the chemicals of interest were among the pesticide or herbicides used by the study population; the lead investigator of a published report has been contacted and has indicated that the chemicals of interest were among the chemicals used; the chemicals of interest are used commonly for the crop(s) identified in the study; the chemicals of interest are used commonly for a specific purpose, such as removal of weeds and shrubs along highways). Among the various chemical classes of herbicides that have been identified in published studies reviewed by the committee, only phenoxy herbicides, and particularly 2,4-D and 2,4,5-T, are directly relevant to the exposures experienced by US military forces in Vietnam. The committee retained some studies on un- specified pesticides for the neurologic health effects section of this report; their results have been entered in the corresponding outcome-specific tables. However, such studies tend to contribute little to the evidence considered by the committee. The many studies that provide chemical-specific exposure information are far more informative for the committee’s purposes. OCCUPATIONAL EXPOSURE TO HERBICIDES AND TCDD The committee reviewed many epidemiologic studies of occupationally ex- posed groups for evidence of an association between health risks and exposure to TCDD or to the herbicides used in Vietnam, primarily the phenoxy herbicides 2,4-D and 2,4,5-T. TCDD is an unwanted byproduct of 2,4,5-T production, but not of 2,4-D production. Other contaminants including other dioxins (e.g., 1,3,6,8-tetrachlorodibenzo-p-dioxin) have been reported at low levels in 2,4-D, however those identified do not possess the toxicity of TCDD (ATSDR, 1998; Huston, 1972; Norström et al., 1979). In reviewing these studies, the committee considered two types of exposure separately: exposure to 2,4-D or 2,4,5-T and exposure to TCDD from 2,4,5-T or other sources. This separation is necessary because some health effects could be associated with exposure to 2,4-D or 2,4,5-T in the absence of substantial TCDD exposure. After recognition of the problem of dioxin contamination in phenoxy herbicides, production conditions were modi- fied to minimize contamination, but use of the products most subject to containing specifically TCDD (2,4,5-T and Silvex) were banned. As a result, study subjects exposed to phenoxy herbicides only after the late 1970s would not be assumed to have been at elevated risk for exposure to TCDD. This distinction is particularly important for workers in agriculture and forestry, where exposure is primarily the result of mixing, loading, and applying herbicides. In addition to these occupational groups the committee considered studies of occupational exposure to dioxins, focusing primarily on workers in

222 VETERANS AND AGENT ORANGE: UPDATE 2006 chemical plants that produced phenoxy herbicides or chlorophenols, which tend to be contaminated with PCDDs. Waste-incineration workers were also included in the occupation category, because they can come into contact with dioxin-like compounds while handling byproducts of incineration. Other occupationally exposed groups include pulp-and-paper workers exposed to dioxins through bleaching processes that use chlorinated compounds, and sawmill workers ex- posed to chlorinated dioxins that can be contaminants of chlorophenates used as wood preservatives. Production Work US National Institute for Occupational Safety and Health Cohort Study One extensive set of data on chemical production workers potentially con- taminated 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 in- dustrial-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 a correlation (Pearson correlation efficient 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: 1 year, 1 to 5 years, 5 to 15 years, and 15 years. In some cases, information on duration of exposure was not available, 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 percent of the overall cohort). The exposure assessment for the subcohort was based on a JEM (Piacitelli

EXPOSURE ASSESSMENT 223 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 incom- plete 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 ppt (parts per trillion), as measured in 1988. The investigators conducted a regression analysis 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 phar- macokinetic 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 concentration 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 dose–response stud- ies for three occupational cohorts: the NIOSH cohort (Fingerhut et al., 1991), the Hamburg cohort (Flesch-Janys et al., 1998), and the BASF cohort (Ott and Zober, 1996). That analysis incorporated recent exposure data for the NIOSH cohort generated by Steenland et al. (2001). Aylward et al. (2005a) applied a concentration- and age-dependent elimina- tion model to the NIOSH cohort data to determine the impact of these factors on estimates of serum TCDD concentrations. The authors found that their model produced a better fit to serum sampling data than first-order models did. Dose rates varied by a factor of 50 among different combinations of input parameters, elimination models, and regression models. The authors concluded that earlier dose reconstruction efforts may have under-estimated peak exposure levels in these populations. Aylward et al. (2005b) also applied this model to serial mea- surements of serum lipid TCDD concentrations from 36 adults from Seveso, Italy, and 3 adults from Vienna, Austria. They concluded that a large degree of uncer- tainty is characteristic of back-calculated dose estimates of peak TCDD exposure, and recommended that further analyses explicitly recognize this uncertainty. Lawson et al. (2004) continued the NIOSH cross-sectional medical study reported by Sweeney et al. (1989, 1993). They compared serum lipid TCDD concentrations from the NIOSH cohort with those in a reference population,

224 VETERANS AND AGENT ORANGE: UPDATE 2006 and examined three birth outcomes of offspring: birth weight, preterm deliv- ery, and birth defects. TCDD exposures at conception were estimated using physiologically-based pharmacokinetic modeling approaches (Dankovic et al., 1995; Thomaseth and Salvan, 1998). No other reports on the cohort have been published since Update 2004. 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 working 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 workers manufacturing chlorophenoxy herbicides or chlorinated phenols and for herbicide sprayers, and were completed with the assistance of industrial hygienists. Information from production records and 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 individuals known to have sprayed chlorophenoxy herbicides and all who worked in particular aspects of chemical production. Two subcohorts (n 416) had no job titles available, but worked in chemical production facilities that were likely to produce TCDD exposure, so they 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 chlo- rophenoxy herbicides or chlorinated phenols and those who had never sprayed chlorophenoxy herbicides. An expanded and updated analysis of the IARC cohort was published in 1997 (Kogevinas et al., 1997). The researchers added herbicide production work- ers from 12 plants in the United States (the NIOSH cohort) and from four plants in Germany. 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 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 a quantitative exposure assessment based on blood or adipose measurements of polychlorinated dibenzo-p-dioxins

EXPOSURE ASSESSMENT 225 and furans (PCDD/Fs). The authors estimated maximum PCDD/F exposure for 190 workers 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 then regressed the estimated maximum PCDD/F exposures of the workers against the length of time they worked in each produc- tion department in the plant. 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. These values were then used to estimate TCDD doses in the population. Becher et al. (1996) conducted an analysis of several German cohorts, in- cluding 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 cohorts from a Bayer plant in Uerdingen and a Bayer plant in Dormagen. All the plants were involved in production of phenoxy herbicides or chlorophenols. Exposure assessment involved estimates of dura- tion of employment from the start of work in a department where exposure was possible until the end of employment at the plant. Analysis was based on time since first exposure. Hooiveld et al. (1998) updated the mortality experience of production work- ers from two chemical factories in the Netherlands with known exposure to dioxins: workers in herbicide production, non-exposed production workers, and workers known to have been 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, measured TCDD levels were extrapolated to the time of maximum TCDD exposure for a group of 47 workers. A regression model then estimated the effect on estimated maximum TCDD exposure for each cohort member attributable to exposure as a result of the accident, duration of employment in the main produc- tion department, and time of first exposure before (or after) 1970. Since Update 2004, a follow-up study on the mortality experience of the small subcohort of the IARC cohort from New Zealand has been published (’t Mannetje et al., 2005). No direct data on levels of exposure were available for either the production workers or the herbicide sprayers. Exposure categories for production workers were based on job codes, while estimates for sprayers were based on exposure history questionnaires. Dow Cohort Studies Workers at Dow Chemical Company facilities where 2,4-D was manufac- tured, formulated, or packaged have been the focus of a cohort analysis since the 1980s (Bond et al., 1988). Industrial hygienists developed a JEM 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 em- ployee work histories to assign an estimate of exposure to each job assignment. A

226 VETERANS AND AGENT ORANGE: UPDATE 2006 cumulative dose was then developed for each of the 878 employees by multiply- ing the representative eight-hour 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. 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 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. Bio- logic monitoring of 2,4-D apparently was not included 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. Bodner et al. (2003) reported new risk estimates for cancer, using the same assessments. Dow also has conducted a cohort study of its manufacturing workers exposed to PCP (Ramlow et al., 1996). Assessment of exposure for this 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-control 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 air- borne PCP in the flaking–prilling–packaging area; the industrial-hygiene data suggested about a 3-fold difference between the areas of highest to lowest poten- tial 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. Cumulative PCP and TCDD exposure indices 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. Since Update 2004, Dow researchers have published a study of serum dioxin levels measured in 2002 in former chlorophenol workers (Collins et al., 2006). Most of the workers in this study were included in the NIOSH and IARC cohorts. The authors used these data to estimate worker exposures at the time of exposure termination using several different pharmacokinetic models. They concluded that their findings were consistent with other studies reporting high serum dioxin levels among chlorophenol workers after occupational exposures. Waste Incineration Worker Studies Four studies of waste incineration workers have been published recently. A study of infectious waste incineration plant workers in Japan used serum dioxin levels to document higher exposures of workers than of controls (Kumagai and Koda, 2005). A second study in Japan examined the association between serum dioxin levels and oxidative DNA-damage markers in municipal waste incinera- tion workers (Yoshida et al., 2006).

EXPOSURE ASSESSMENT 227 Researchers in South Korea compared plasma protein levels for 31 waste incineration workers with those of 33 unexposed subjects (Kang et al., 2005). A second Korean study evaluated immunologic and reproductive toxicities in 31 waste-incinerator workers in comparison to 84 control subjects (Oh et al., 2005). Rather than measuring serum dioxin levels, both studies inferred dioxin exposure levels for individual workers on the basis of dioxin concentrations in air and also estimated exposures to PAHs by analyzing two urinary metabolites: 1-hydroxypyrene and 2-napthol. Other Production-Worker Studies Several other studies of chemical production workers have relied on job titles as recorded in individual work histories and company personnel records to clas- sify exposure to TCDD (Coggon et al., 1986, 1991; Cook et al., 1986; Ott et al., 1980; Zack and Gaffey, 1983; Zober et al., 1990). Similarly, TCDD 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 (Bueno de Mesquita et al., 1993; Garaj-Vrhovac and Zeljezic, 2002; Manz et al., 1991). Since Update 2004, no additional studies of other cohorts of production workers have been published. Agriculture, Forestry, and Other Outdoor Work In occupational studies of agricultural workers various methods have been used to estimate exposure to herbicides or TCDD. The simplest method derives 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 whether a worker was exposed to a specific agent. In some studies of agricultural workers, examina- tion of differences in occupational practices has allowed 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). In other studies, county of residence was used as a surrogate for 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). In other studies, exposure was estimated according to 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). Other studies used self-reported infor- mation on exposure that recounted direct handling of an 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). Another set

228 VETERANS AND AGENT ORANGE: UPDATE 2006 of studies validated self-reported information with written records, signed state- ments, 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 work- ers, are likely to have been exposed to herbicides and other compounds (see Table C-1 in Appendix C for a summary of studies). Exposure of those groups has been classified by approaches similar to those noted above for agricultural workers, for example, by using the number of years employed, job category, and occupational title. Ontario Farm Family Health Study The Ontario Farm Family Health Study has produced several reports on exposure to phenoxyacetic acid herbicides, 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 build- ing pesticides. Subjects were asked whether they participated in those activities during each month, and their exposure classifications were based on activities in 3-month periods. The exposure classification was refined with answers to ques- tions 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 pro- vided semen and urine samples for 2,4-D analysis. The Ontario Farm Family Health Study also examined the effect of exposure to pesticides, including 2,4-D, on time to pregnancy (Curtis et al., 1999) and on the risk of spontaneous abortion (Arbuckle et al., 1999b, 2001). About 2,000 farm couples participated in the study. Exposure information was pooled from inter- views 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). Assum- ing 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 per- cent and a specificity of 86 percent. In multivariate models, the variables for pes- ticide formulation, protective clothing and gear, application equipment, handling practice, and personal-hygiene practice were valuable as predictors of urinary herbicide concentrations in the first 24 hours after application was initiated.

EXPOSURE ASSESSMENT 229 Since Update 2004, three additional publications have reported results from the Ontario Farm Family Health Study. Urinary concentrations of 2,4-D and 2-methyl-4-chlorophenoxyacetic acid (MCPA) were measured in samples from farm applicators (Arbuckle et al., 2005) and for women living on Ontario farms (Arbuckle and Ritter, 2005). Indirect sources of herbicide exposure for farm families were evaluated through wipe sampling of surfaces and drinking water samples (Arbuckle et al., 2006). The Agricultural Health Study The Agricultural Health Study (AHS) in the United States enrolled approxi- mately 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 has been based primarily on questionnaire data collected at the time of enrollment and in periodic follow-ups. Dosemeci et al. (2002) pub- lished 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. This quantitative approach has potential to improve the accuracy of exposure classification for the cohort, but has not yet been used in published epidemiologic studies. Since Update 2004, eight epidemiologic studies have been published on the AHS cohort. All have developed pesticide exposure estimates or exposure categories from self-administered questionnaires (Alavanja et al., 2004, 2005; Blair et al., 2005; De Roos et al., 2005; Engel et al., 2005; Farr et al., 2004, 2006; Kirrane et al., 2005). Three additional publications discuss pesticide use patterns in this population (Hoppin, 2005; Kirrane et al., 2004; Samanic et al., 2005). The AHS questionnaire collected detailed information regarding herbicide use, with 2,4-D being the most commonly reported herbicide. United Farm Workers of America (UFW) Population Studies California researchers evaluated breast cancer risk (Mills and Yang, 2005) and lymphohematopoietic cancer risk (Mills et al., 2005) in members of the United Farm Workers of America (UFW). The exposed populations were defined as those who had ever been a UFW member. Exposure estimates to specific pesti- cides, including 2,4-D, were developed through linkage of job histories with the California Pesticide Use Reporting Database. Other Agricultural Worker Studies A study of Canadian farmers examined pesticide exposures of men (McDuffie et al., 2001). Data were collected by questionnaires that included information on specific chemicals (including 2,4-D), frequency of application, and dura- tion of exposure. A small validation study (n 27) was performed to test the

230 VETERANS AND AGENT ORANGE: UPDATE 2006 self-reported pesticide-use data against records of purchases. The investigators reported an “excellent concordance” between the two sources, but they did not provide a statistical analysis. Ruder et al. (2004) and Carreon et al. (2005) evaluated farm pesticide ex- posure in men and women, respectively, in relation to the incidence of gilomas as part of the Upper Midwest Health Study. Self-reported lifetime agricultural pesticide exposures were collected by telephone interview, including specific questions on phenoxy herbicides and 2,4-D. Mandel et al. (2005) reported urinary biomonitoring results for farm families in Minnesota and South Carolina as a part of the CropLife America’s Farm Fam- ily Pesticide Exposure Study. The peak geometric mean concentration of 2,4-D was 64 ppb. Lee et al. (2004) used a telephone interview of cases and control or their next-of-kin in a Nebraska study to determine the extent of agricultural use of pesticides, including 2,4,5-T and 2,4-D. Fritschi et al. (2005) used a computer- assisted telephone interview and occupational histories reviewed by an industrial hygienist to estimate exposures to phenoxy herbicides in an Australian study. Cur- win et al. (2005) measured 2,4-D concentrations in urine and hand-wipe samples to characterize exposures among farmers and non-farmers in Iowa. Other studies of the agricultural use of pesticides do not provide specific information on exposure to 2,4-D, TCDD, or other compounds relevant to Viet- nam veterans’ exposure (Bell et al., 2001a,b; Chiu et al., 2004; Duell et al., 2001; Garry et al., 2003; Gorell et al., 2004; Hanke et al., 2003; Van Wijngaarden et al., 2003). A series of papers from a recent workshop focused on methods of assessing pesticide exposure in farmworker populations (Arcury et al., 2006; Barr et al., 2006a,b; Hoppin et al., 2006; Quandt et al., 2006). These publications provide a helpful review of current methodological issues in exposure science for these populations, but do not address directly the VAO compounds of interest. Commercial Herbicide Sprayers Studies of commercial herbicide applicators are relevant because they can be presumed to have had 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. Employment records also can be used to extract information on which compounds are sprayed. One surrogate indicator of herbicide exposure is the receipt of a license to spray. Several studies have specifically identified licensed or registered pesticide and herbicide applicators (Blair et al., 1983; Smith et al., 1981, 1982; Swaen

EXPOSURE ASSESSMENT 231 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 commit- tee examined, however, and many applicators were known to have applied many kinds of herbicides, pesticides, and other substances. In addition, herbicide spray- ing is generally a seasonal occupation, and information is not always available on possible exposure-related activities during the rest of the year. Several studies have evaluated various herbicide exposures: type of exposure, routes of entry, and routes of excretion (Ferry et al., 1982; Frank et al., 1985; Kolmodin-Hedman and Erne, 1980; Kolmodin-Hedman et al., 1983; Lavy et al., 1980a,b; Libich et al., 1984). Those studies appear to show that the major route of exposure is dermal absorption, with 2–4 percent of the chemical that contacts the skin being absorbed into the body during a normal workday. Air concentra- tions 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 in ground crews was 0.1–5 mg/day; for air crews the value was lower. 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 from self-administered questionnaires. Urine samples were collected throughout the spraying season (24-hour 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. Only one study has provided information on serum TCDD concentrations in herbicide applicators. Smith et al. (1992) analyzed blood from nine professional spray applicators in New Zealand who first sprayed before 1960 and were also spraying in 1984. The duration of spraying varied from 80 to 370 months. Serum TCDD was 3–131 ppt on a lipid basis (mean 53 ppt). The corresponding val- ues for age-matched controls were 2–11 ppt (mean 6 ppt). Serum TCDD was positively correlated with the number of months of professional spraying. Since Update 2004, another study of New Zealand herbicide sprayers was published (’t Mannetje et al., 2005). This study population also included herbicide production workers and is a subcohort of the IARC cohort, which was discussed earlier in the section on production workers. Pulp, Paper, and Sawmill Work Pulp, paper, and sawmill workers are likely to be exposed to TCDD and chlo- rinated phenols occurring during the bleaching process. Depending on the type of paper mill or pulping operation and the product manufactured, pulp and paper production workers are also likely to be exposed to toxic compounds in addition to those of concern for the VAO series (Henneberger et al., 1989; Jappinen and Pukkala, 1991; Robinson et al., 1986; Solet et al., 1989). One study of a cohort of Danish paper mill workers (Rix et al., 1998) presented no direct measures of oc-

232 VETERANS AND AGENT ORANGE: UPDATE 2006 cupational exposure, and the qualitative assessment of compounds used by each department did not include chlorinated organic compounds, although chlorine, chlorine dioxide, and hypochlorite were used. In the past, workers in sawmills might have been exposed to pentachloro- phenates, which are contaminated with higher-chlorinated PCDDs (Cl6–Cl8), or to tetrachlorophenates, which are less contaminated with higher-chlorinated PCDDs. Wood is dipped into those chemical preservatives 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. ENVIRONMENTAL EXPOSURES TO HERBICIDES AND TCDD The committee reviewed several new studies of TCDD-exposed populations associated with industrial facilities, including recent investigations at Seveso, Italy. The committee also reviewed exposure studies related to Agent Orange use in Vietnam. Industrial Sources Seveso, Italy A large industrial accident involving environmental exposure to TCDD oc- curred in Seveso in July 1976 as the result of an uncontrolled reaction during trichlorophenol production. Various indicators, including TCDD measurements in soil, have been used as indicators of individual exposure. Three areas were defined around the release point on the basis of soil sampling for TCDD (Bertazzi et al., 1989). Zone A was the most heavily contaminated; all residents were evacuated within 20 days. Zone B was less contaminated; women in the first tri- mester and all children were urged to avoid it during daytime. Zone R had some contamination; consumption of crops grown there was prohibited. Data on serum TCDD concentrations in Zone A residents have been pre- sented by Mocarelli et al. (1990, 1991) and by CDC (1988a). In those with severe chloracne (n 10), TCDD was 828–56,000 ppt of lipid weight. Those without chloracne (n 10) had TCDD 1,770–10,400 ppt. TCDD was undetectable in all control subjects but one. The highest of those concentrations exceeded any that had been estimated at the time for TCDD-exposed workers on the basis of back- ward extrapolation and a half-life of 7 years. Data on nearby soil concentrations, number of days a person stayed in Zone A, and whether local food was consumed were considered in evaluating TCDD. That none of those data correlated with serum TCDD suggested strongly that the exposure of importance was from fallout on the day of the accident. The presence and degree of chloracne did correlate with TCDD. Adults seemed much less likely than children to develop chloracne after acute exposure, but surveillance bias could have affected that finding. Recent

EXPOSURE ASSESSMENT 233 updates (Bertazzi et al., 1998, 2001) have not changed the exposure-assessment approach. As part of the Seveso Women’s Health Study (SWHS), Eskenazi et al. (2001) tested the validity of exposure classification by zone. Investigators measured se- rum TCDD in samples collected between 1976 and 1980 from 601 residents (97 from Zone A; 504 from Zone B). A questionnaire the women completed between 1996 and 1998 included age, chloracne history, animal mortality, consumption of homegrown food, and location at the time of the explosion. Participants did not know their TCDD concentrations at the time of the interview, although most knew their zone of residence. Interviewers and TCDD analysts were blinded to participants’ zone of residence. Zone of residence explained 24 percent of the variability in serum TCDD. Addition of the questionnaire data improved the regression model, explaining 42 percent of the variance. Those findings dem- onstrate a significant association between zone of residence and serum TCDD, but much of the variability in TCDD concentrations is still unexplained by the models. A number of studies of the Seveso population have used lipid-adjusted serum TCDD concentrations as the primary exposure metric (Baccarelli et al., 2002; Eskenazi et al., 2002a,b, 2003, 2004; Landi et al., 2003). Fattore et al. (2003) measured current air concentrations of PCDDs in Zones A and B, and compared them with measurements from a control area near Milan. The authors concluded that release from PCDD-contaminated soil does not add appreciably to air con- centrations in the Seveso study area. Finally, Weiss et al. (2003) collected breast milk from 12 mothers in Seveso to compare TCDD concentrations with those from a control population near Milan. The investigators reported that the TCDD concentrations in human milk from mothers in Seveso were two times higher than were those in controls. The authors concluded that breastfed children in the Seveso area are likely to have higher body burdens of TCDD than are children from other areas. Since Update 2004, five reports have been published on dioxin exposure in the Seveso population. Baccarelli et al. (2005a) used serum TCDD concentrations to evaluate chloracne cases. Bacarelli et al. (2005b) reviewed statistical strate- gies for handing non-detectable readings in dioxin measurement datasets. They recommended that a distribution-based multiple imputation method be used to analyze environmental data when substantial proportions of observations have non-detectable readings. In the SWHS, Warner et al. (2004) used serum dioxin concentrations to evaluate effects on age at menarche, while Eskanazi et al. (2005) used serum dioxin concentrations to evaluate effects on age at the onset of menopause. Warner et al. (2005) compared a chemical-activated luciferase-gene expression bioassay to an isotope dilution high-resolution gas chromatography/ high-resolution mass spectrometry assay to measure dioxin-like toxicity equiva- lents for 78 women residing near Seveso, and found similar results from the two methods.

234 VETERANS AND AGENT ORANGE: UPDATE 2006 Chapaevsk, Russia Researchers in the Samara region of Russia have identified a chemical plant in Chapaevsk as a major source of TCDD pollution (Revich et al., 2001). From 1967 to 1987 the plant produced -hexachlorocyclohexane (lindane) and its derivatives. Since then, the plant has produced various crop-protection products. Dioxins have been detected in air, soil, drinking water, and cows’ milk. However, the researchers do not describe air-, soil-, or water-sampling methods. The num- ber of samples analyzed was small for some media (2 drinking-water samples, 7 breast-milk samples pooled from 40 women, and 14 blood samples) and unre- ported for others (air, soil, and vegetables). Results from the samples suggested higher concentrations of dioxin around the center of Chapaevsk compared with those from outlying areas. That conclusion was based primarily on concentrations measured in soil: 141 ng TEQ/kg soil less than 2 km from the plant, compared with 37 ng TEQ/kg soil 2–7 km from the plant, and 4 ng TEQ/kg soil 7–10 km from the plant. Concentrations outside the city (10–15 km from the plant) were approximately 1 ng TEQ/kg soil. The authors also compared measurements from Chapaevsk with those from other Russian cities with industrial facilities. The data presented do not allow direct comparison of dioxin concentrations in soil as a function of distance from the industrial facilities. However, the highest TCDD concentrations in the Chapaevsk study (those nearest the plant) were higher than were the maximum concentrations reported by four other studies referenced in the article. Residence in the city of Chapaevsk was used as a surrogate for exposure in the epidemiologic analyses presented in the report. No attempt was made to create exposure categories based on residential location within the city or with occupational or lifestyle factors that might have influenced TCDD exposure. Akhmedkhanov et al. (2002) sampled 24 volunteers from this same popula- tion for lipid-adjusted serum dioxin concentrations. Residents living near the plant ( 5 km) had higher concentrations than did those who lived farther from the plant. It was not clear whether the analysis included adjustments for age, body-mass index, or education, all of which are significant predictors of dioxin concentrations. No new studies have been published since Update 2004. Other Studies Several reports have provided information on environmental exposure to TCDD in the Times Beach area of Missouri (Andrews et al., 1989; Patterson et al., 1986). In 1971, TCDD-contaminated sludge from a hexachlorophene pro- duction facility was mixed with waste oil and sprayed in various community areas for dust control. Soil contamination in some samples exceeded 100 ppb. Among the Missouri sites with the highest TCDD soil concentrations was the Quail Run mobile-home park. Residents were considered exposed if they had lived in the park for at least 6 months during the time that contamination occurred (Hoffman

EXPOSURE ASSESSMENT 235 et al., 1986). Other investigations of Times Beach have estimated exposure risk on the basis of residents’ reported occupational and recreational activities in the sprayed area. Exposure estimates have been based on duration of residence and TCDD soil concentrations. Andrews et al. (1989) provided the most extensive data on human adipose- tissue TCDD in 128 non-exposed control subjects compared to concentrations in 51 exposed persons who had ridden or cared for horses at arenas sprayed with TCDD-contaminated oil, who lived in areas where the oil had been sprayed, who were involved in trichlorophenol (TCP) production, or who were involved in TCP non-production activities, such as laboratory or maintenance work. Persons were considered exposed if they lived near, worked with, or had other contact for at least 2 years with soil contaminated with TCDD at 20–100 parts per billion (ppb) or for 6 months or more with soil contaminated with TCDD above 100 ppb. Of the exposed-population samples, 87 percent had adipose tissue TCDD concentra- tions below 200 ppt; however, TCDD concentrations in seven of the 51 exposed persons were 250–750 ppt. In non-exposed persons, adipose-tissue TCDD ranged from undetectable to 20 ppt, with a median of 6 ppt. On the basis of a 7-year half-life, it is calculated that two study participants would have had adipose-tissue TCDD near 3,000 ppt at the time of the last date of exposure. Several epidemiologic studies have been conducted in association with industrial-facility emissions, or in regions with documented variation in dioxin exposures. Viel et al. (2000) reported on an investigation of apparent clusters of cases of soft-tissue sarcoma and non-Hodgkin’s lymphoma in the vicinity of a municipal solid-waste incinerator in Doubs, France. The presumptive source of TCDD in the region is a municipal solid-waste incinerator in the Besançon elec- toral ward in western Doubs. Dioxin emissions from the incinerator were mea- sured in international toxicity equivalent (I-TEQ) units at 16.3 nanograms (ng) I-TEQ per cubic meter (m3), far in excess of the European Union (EU) standard of 0.1 ng I-TEQ/m3. TCDD concentrations in cows’ milk measured at three farms near the incinerator were well below the EU guideline of 6 ng I-TEQ/kg of fat, but the concentrations were highest at the farm closest to the incinerator. Combustion records for the Zeeburg area of Amsterdam in the Netherlands were used as a surrogate for exposure to dioxins in a study of orofacial clefts (ten Tusscher et al., 2000). Location downwind or upwind of an incineration source was used to define exposed and reference groups for the study. A study of soft- tissue sarcomas in the general population was conducted in northern Italy around the city of Mantua (Costani et al., 2000). Several industrial facilities are in Man- tua, and residential proximity to them was presumed to result in increased TCDD exposure, but TCDD was not measured in the environment or in human tissues. A study of dioxin exposure pathways in Belgium focused on long-time resi- dents in the vicinity of two municipal-waste incinerators (Fierens et al., 2003a). Residents near a rural incinerator had significantly higher serum dioxin concen- trations than did a control group (38 vs 24 pg TEQ/g of fat). Concentrations in

236 VETERANS AND AGENT ORANGE: UPDATE 2006 residents living near the incinerators increased proportionately with intake of local-animal fat. A second study (Fierens et al., 2003b) measured dioxin body burden in 257 people who had been environmentally exposed, with the object of determining whether dioxin and PCB exposures were associated with type 2 diabetes and endometriosis. No difference in body burden was found between women with endometriosis and women in a control group, but the risk of type 2 diabetes was significantly higher for those with higher body burdens of dioxin- like compounds and PCBs. Another study of the correlation between dioxin-like compounds in Italian and Belgian women and the risk of endometriosis used measurements of TCDD and other dioxins in blood (De Felip et al., 2004). There was no difference in body burden among women with endometriosis and a control group, but dioxin concentrations were substantially higher in the control groups of women from Belgium than in a similar group from Italy (45 vs. 18 pg TEQ/g, lipid-adjusted, respectively). Since Update 2004, Bloom et al. (2006) measured serum dioxin levels in New York sports fishermen as part of a study of thyroid function. Also, a methodological study by Petreas et al. (2004) found generally quite high cor- relations between concentrations of dioxins and related compounds in breast and abdominal fat within the same woman, which suggested that they could be used interchangeably in epidemiological studies. The same study, however, also found that adjusting concentrations according to lipid content rather than weight of the fat samples is important because of the presence of non-lipid components in these samples. Studies in Vietnam Studies of exposure to herbicides among the residents of Vietnam have com- pared unexposed residents of the South with residents of the North (Constable and Hatch, 1985). Other studies have attempted to identify wives of North Viet- namese veterans who served in South Vietnam. Records of herbicide spraying have been used to refine exposure measurements, comparing individuals who lived in sprayed villages in the South with those living in unsprayed villages. In some studies, village residents were considered exposed if an herbicide mission had passed within 10 km of the village center (Dai et al., 1990). Other criteria for classifying exposure included length of residence in a sprayed area and the number of times the area reportedly had been sprayed. A small number of studies provide information on TCDD concentrations in Vietnamese civilians exposed during the war. Schecter et al. (1986) detected TCDD in 12 of 15 samples of adipose tissue taken during surgery or autopsy in South Vietnam during 1984. The concentrations in the positive samples were 3–103 ppt. TCDD was not detected in nine samples from residents of North Vietnam who had never been to South Vietnam; detection sensitivity was 2–3 ppt. Analysis of three breast-milk samples collected in 1973 from Vietnamese women

EXPOSURE ASSESSMENT 237 thought to have been exposed to Agent Orange yielded TCDD concentrations of 77–230 ppt on a lipid basis. Blood samples from 43 residents of Bien Hoa City were analyzed for TCDD (Schecter et al., 2002). Bien Hoa City is in the southern part of South Vietnam, and the surrounding area was treated heavily with Agent Orange. The median lipid-normalized TCDD concentration was 67 ppt in those residents, compared with an average of 2 ppt in residents of Hanoi. The study also indicated that TCDD exposure of the population was continuing, presumably through consump- tion of fish and other foods. Schechter et al. (2006) recently reported additional sampling of residents in areas believed to have ongoing TCDD contamination. Blood samples from residents at eight sites were analyzed for TCDD and related compounds. Elevated TCDD concentrations were found in residents from one of these sites; data from a second site were suggestive of elevated exposures; results from the other six sites were similar to those found in the general population in the south of Vietnam. Dwernychuk et al. (2002) collected environmental and food samples, human blood, and breast milk from residents of the Aluoi Valley of central Vietnam. The investigators identified locations where relatively high dioxin concentrations remain in soil or water systems. Dioxin concentrations in soil were particularly high around former air fields and military bases where herbicides were handled. Fish harvested from ponds in these areas were found to contain elevated dioxin concentrations. More recently Dwernychuk (2005) elaborated on the importance of “hot spots” as important locations for future studies and argued that herbicide use at former US military installations was the most likely cause of these hot spots. These studies are not directly relevant to this committee’s task, but they may prove useful in future epidemiologic studies of the Vietnamese population and in the development of risk mitigation policies. MILITARY USE OF HERBICIDES IN VIETNAM Military use of herbicides in Vietnam began in 1962, expanded in 1965 and 1966, and reached a peak between 1967 and 1969. The herbicides were used primarily to defoliate inland hardwood forests, coastal mangrove forests, culti- vated land, and zones around military bases. Using records concerning herbicides sprayed from helicopters and other aircraft from August 1965 to February 1971, a National Academy of Sciences committee (NAS, 1974) calculated that about 17.6 million gallons (66.5 million liters) of herbicide were sprayed over about 3.6 million acres (1.5 million hectares) in Vietnam. It was more difficult to quantify the amounts of herbicides sprayed on the ground to defoliate the perimeters of base camps and fire bases and by Navy boats along river banks. In 1997, a committee convened by IOM issued a request for proposals (RFP) seeking individuals and organizations to develop historical exposure reconstruc- tion approaches suitable for epidemiologic studies of herbicide exposure among

238 VETERANS AND AGENT ORANGE: UPDATE 2006 US veterans during the Vietnam War (IOM, 1997). The RFP resulted in the project, Characterizing Exposure of Veterans to Agent Orange and Other Herbi- cides in Vietnam, which was carried out under contract by a team of researchers from Columbia University’s Mailman School of Public Health. The project yielded new estimates of the use of military herbicides in Viet- nam from 1961 to 1971 (IOM, 2003b,c; Stellman et al., 2003a). Investigators reviewed the original data used in the 1970s to make estimates and identified in- consistencies, data gaps, and typographical errors. They determined the amounts of herbicide applied but not recorded on the data tapes (the so-called HERBS tapes) compiled in the 1970s and clarified data on missions that presumably “dumped” herbicide loads over very short periods before returning to base. The new analyses led to a revision in estimates of the amounts of the agents applied, as indicated in Table 5-3. Previous VAO reports estimated that a total of 67.8 million liters of military herbicides were applied from 1961 to 1971. The new research effort estimated that ~77 million liters was applied; a difference of more than 9 million liters. Four compounds were used in the herbicide formulations: 2,4-D, 2,4,5-T, picloram, and cacodylic acid. The chlorinated phenoxy acids (2,4-D and 2,4,5-T) persist in soil only for a few weeks (Buckingham, 1982). Picloram is more mobile than 2,4-D and 2,4,5-T and is extremely persistent in soils. Cacodylic acid, or dimethylarsinic acid, is an organic form of arsenic. Herbicides were identified by the color of a band on 55-gal containers and called Agents Pink, Green, Purple, Orange, White, and Blue (Table 5-3). Agent Green and Agent Pink were used in 1961 and 1965; Agent Purple was used from 1962 through 1965. Agent Orange was used from 1965 through 1970, and a slightly different formulation (Agent Orange II) probably was used after 1968. Agent White was used from 1966 through 1971. Agent Blue was used in powder form from 1962 through 1964 and as a liquid from 1964 through 1971. Agents Pink, Green, Purple, Orange, and Orange II all contained 2,4,5-T, and were contaminated to some extent with TCDD. Agent White contained 2,4-D and picloram. Agent Blue (powder and liquid) contained cacodylic acid. More details on the herbicides used are presented in the earlier reports (IOM, 1994, 1996, 1999, 2001, 2003a). In addition to the four major compounds, diquat was applied to native grasses and bamboo (Brown, 1962). Soil-applied herbicides also were reportedly used around base camp perimeters, minefields, ammunition storage areas, and other sites where it was necessary to control grasses and woody vegetation (Darrow et al., 1969). Other accounts discuss the use of other herbicides, fungicides, in- secticides, insect repellents, wetting agents, and wood preservatives (Gonzales, 1992). There are no data on the number of military personnel potentially exposed to those substances. TCDD was formed as an unwanted by-product of 2,4,5-T production, but was not formed during 2,4-D production. The concentration of TCDD in any

TABLE 5-3 Military Use of Herbicides in Vietnam (1961–1971) Amount Sprayed Concentration of Active Code Name Chemical Constituentsa Ingredienta Years Useda VAO Estimateb Revised Estimatea Pink 60%–40% n-butyl, 961–1,081 g/L acid 1961, 1965 464,817 L 50,312 L sprayed; isobutyl ester of 2,4,5-T equivalent (122,792 gal) 413,852 L additional on procurement records Green n-butyl ester 2,4,5-T — — 31,071 L 31,026 L shown on (8,208 gal) procurement records Purple 50% n-butyl ester 2,4-D, 1,033 g/L acid equivalent 1962–1965 548,883 L 1,892,733 L 30% n-butyl ester 2,4,5-T, (145,000 gal) 20% isobutyl ester 2,4,5-T Orange 50% n-butyl ester 2,4-D, 1,033 g/L acid equivalent 1965–1970 42,629,013 L 45,677,937 L (could 50% n-butyl ester 2,4,5-T (11,261,429 gal) include Agent Orange II) Orange II 50% n-butyl ester 2,4-D, 910 g/L acid equivalent Post–1968 (?) — Unknown, but at least 50% isooctyl ester 2,4,5-T 3,591,000 L shipped White Acid weight basis: 21.2% triisopropanolamine By acid weight: 240 g/L 1966–1971 19,860,108 L 20,556,525 L salts of 2,4-D and 5.7% picloram 2,4-D and 65 g/L picloram (5,246,502 gal) Blue powder Cacodylic acid (dimethylarsinic acid) and Acid: 65% active ingredient; 1962–1964 — 25,650 L sodium cacodylate salt: 70% active ingredient Blue aqueous 21% sodium cacodylate cacodylic acid to Acid weight: 360 g/L 1964–1971 4,255,952 L 4,715,731 L solution yield at least 26% total acid equivalent by (1,124,307 gal) weight Total, all 67,789,844 L 76,954,766 L (including formulations (17,908,238 gal) procured) a Based on Stellman et al. (2003a). b Based on data from MRI (1967), NAS (1974), and Young and Reggiani (1988). 239

240 VETERANS AND AGENT ORANGE: UPDATE 2006 given lot of 2,4,5-T depended 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 formu- lated differently from the materials for commercial application that were readily available in the United States (Young et al., 1978). TCDD concentrations in in- dividual 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 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). Until recently, data from Young and Gough and coworkers have been used to estimate the amount of TCDD in the various herbicide formulations (Gough, 1986; Young, 1992; Young et al., 1978). Young et al. (1978) estimated that Agents Green, Pink, and Purple used early in the program (through 1965) contained 16 times the mean TCDD content of formulations used between 1965 and 1970. The mean concentration of TCDD in Agent Purple was estimated at 32.8 ppm; in Agents Pink and Green, it was estimated at 65.6 ppm (Young et al., 1978). Gough (1986) estimated that about 167 kg of TCDD was sprayed in Vietnam over a 6-year period. Analysis of archive samples of Agent Purple reported TCDD as high as 45 ppm (Young, 1992). New analyses produced by the Columbia University team have proposed 366 kg of TCDD as a plausible estimate of the total amount of TCDD applied in Vietnam between 1961 and 1971, and the authors argue that the true amount may be higher (Stellman et al., 2003a). EXPOSURE ASSESSMENT IN STUDIES OF VIETNAM VETERANS Different approaches have been used to estimate the exposure of Vietnam veterans, including self-reporting, record-based exposure estimation, and assess- ment of biologic markers of TCDD exposure. Each approach has a limited ability to ascribe individual exposure. Some studies rely on such gross markers as ser- vice in Vietnam—perhaps refined by branch of service, military region, military specialty, or combat experience—as a proxy for exposure to herbicides. Studies of that type include CDC’s Vietnam Experience Study and Selected Cancers Study, VA’s mortality studies, and most studies of veterans conducted by the states. This approach has the potential to miss associations between exposures and health ef- fects, if they exist, because many members of the cohorts presumed to have been exposed to herbicides might not have been exposed. The number of US military personnel who directly handled (mixed, loaded,

EXPOSURE ASSESSMENT 241 or applied) herbicides is impossible to determine precisely, but two groups have been identified as high-risk subpopulations among veterans: Air Force personnel involved in fixed-wing aircraft spraying activities known commonly as Operation Ranch Hand, and members of the US Army Chemical Corps involved in using hand-operated equipment and helicopters to conduct smaller (but potentially high-exposure) operations: mixing; defoliation around special forces camps; clearing the 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 also were likely to have handled or sprayed herbicides around bases or lines of communication. Navy river patrols were reported to have used herbicides to clear inland waterways, and engineering personnel used herbi- cides to remove 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. The precautions that were prescribed were consistent with those applied in the domestic use of herbicides before the Vietnam conflict (US GAO, 1979). Young et al. (2004a,b) now allege that care was taken in planning missions to avoid spraying friendly forces. Air Force Health Study Major defoliation activities in Vietnam were conducted by Air Force person- nel as part of Operation Ranch Hand. These veterans became the first subpopu- lation among Vietnam veterans to receive special attention in regard to Agent Orange, and have become known as the Ranch Hand cohort within the Air Force Health Study (AFHS). The AFHS was initiated in 1979 by the Air Force. Results of biologic marker studies of Ranch Hand personnel have been consistent with their being exposed, as a group, to TCDD. When the Ranch Hand cohort was 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 AFHS relied on military records of TCDD-containing herbicides (Agents Orange, Purple, Pink, Green) sprayed as reported in the HERBS tapes for the period starting in 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. 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 of herbicide or TCDD exposure: number of days of skin exposure; the percentage of skin area exposed; and the product of the number of days of skin exposure,

242 VETERANS AND AGENT ORANGE: UPDATE 2006 percentage of skin exposed, and a factor for the concentration of TCDD in the herbicide. A fourth index, which used no information gathered from individual subjects, was calculated by multiplying the volume of herbicide sprayed during a person’s tour of duty by the concentration of TCDD in herbicides sprayed in that period and then dividing the product by the number of crew members in each job specialty at the time. Each of these four models tested was significantly related to serum TCDD, although the models explained only 19–27 percent of the variability in serum TCDD concentrations. 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 percent of the variability in serum TCDD. When the questionnaire-derived indexes were applied within each job classifica- tion, days of skin exposure added statistical significance, but not substantially, to the variability explained by job alone. Most recent AFHS publications have relied on serum dioxin concentration as the primary exposure metric for epidemiologic classification (Akhtar et al., 2004; Barrett et al., 2001, 2003; Michalek et al., 2001a,b,c, 2003; Pavuk et al., 2003). Since Update 2004, four additional publications employing serum dioxin concentrations have examined insulin sensitivity (Kern et al., 2004), post-service mortality (Ketchum and Michalek, 2005), risk of prostate cancer (Pavuk et al., 2006), and cancer risk in Air Force personnel who did not spray Agent Orange (Pavuk et al., 2005). The National Academies of Science recently issued a comprehensive review of the AFHS, together with recommendations for the use of the extensive data and biologic samples collected in the course of this project (IOM, 2006). Army Chemical Corps Studies Members of the US Army Chemical Corps performed chemical operations on the ground and by helicopter and were thereby involved in the direct handling and distribution of herbicides in Vietnam. This population was belatedly identified for detailed study of health effects related to herbicide exposure (Thomas and Kang, 1990). Results of an initial feasibility study were reported by Kang et al. (2001). That study recruited 565 veterans: 284 Vietnam veterans and 281 non-Vietnam- veteran control subjects. Blood samples were collected in 1996 from 50 Vietnam veterans and 50 control veterans, and 95 of the samples met CDC standards for quality assurance and quality. 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). Of the 50 Vietnam veterans sampled, analysis of questionnaire responses indicated that those who reported spraying herbicides had higher TCDD concentrations than did those who reported no spraying ac-

EXPOSURE ASSESSMENT 243 tivities. The authors concluded that Agent Orange exposure was a likely contribu- tor to TCDD concentrations in Vietnam veterans who had a history of spraying herbicides. Since Update 2004, Kang et al. (2006) reported findings from the main study. A health survey was administered by telephone to 1,499 Vietnam veterans and 1,428 non-Vietnam veterans. Exposure to herbicides was assessed by analyzing serum specimens from a sample of 897 veterans for dioxin. Those veterans who reported spraying herbicides had significantly higher TCDD serum levels than did Vietnam veterans and other veterans who did not report herbicide spraying. The final analysis compared Vietnam-veteran sprayers with Vietnam-veteran non- sprayers from the entire study population. Australian Vietnam Veterans Three recent reports update earlier investigations (AIHW, 1999, 2000; CDVA 1998a,b; CIH, 1984a,b,c; Crane et al., 1997a,b; Evatt, 1985; Fett et al., 1987a,b; Forcier et al., 1987) of the health experience of Australian Vietnam veterans. The first two reports compared the incidences of all types of cancer (ADVA, 2005a) and the frequencies of various causes of death (ADVA, 2005b) in all male Aus- tralian Vietnam veterans with the general population. The third study (ADVA, 2005c) compared mortality and cancer incidence in male Army veterans deployed to Vietnam (“National Service” veterans) with their non-deployed counterparts (“National Service non-veterans”). Like previous studies of Australian Vietnam veterans, these reports did not characterize the veterans’ exposure to the herbicides sprayed in Vietnam in any way beyond the fact that they served on land or in Vietnamese waters during May 23, 1962–July 1, 1973. It is the convention of this committee to regard Vietnam veterans in general as being more likely to have received higher exposures to the chemicals of concern than the general public. Korean Vietnam Veterans Military personnel from the Republic of Korea served in Vietnam between 1964 and 1973. Kim et al. (2001) attempted to use serum dioxin concentrations for validating an index estimating group exposure. The study involved 720 veter- ans who served in Vietnam, and 25 veterans who did not serve in Vietnam. The exposure index was based on Agent Orange spray patterns across military regions in which Korean personnel served, time-location data on the military units sta- tioned in Vietnam, and an exposure score derived from self-reported activities during service. A total of 13 pooled samples were submitted to CDC for serum dioxin analysis. One analytic sample was prepared from the pooled blood of the 25 veterans who did not serve in Vietnam. The remaining 12 analytic samples

244 VETERANS AND AGENT ORANGE: UPDATE 2006 were intended to correspond to 12 exposure categories; each was created by pooling blood samples from 60 veterans. The 12 exposure categories ultimately were reduced to 4 exposure groups, each representing a quartile of 180 Vietnam veterans, but characterized by only three serum TCDD measurements. The paper by Kim et al. (2001) reported highly significant Pearson correla- tion coefficients and multiple regression analysis results. The statistical analyses apparently were based on the assignment of the pooled-serum-dioxin value to each individual in the exposure group, thereby inflating the true sample size. The multiple regression analysis evaluated such variables as age, body-mass index, and consumption of tobacco or alcohol. In a subsequent report for the same exposure groups and serum dioxin data, the authors corrected their analysis (Kim et al., 2003). A correlation was observed between serum dioxin concentra- tions and ordinal exposure categories, but the correlation was not statistically significant. The authors attributed the lack of statistical significance to the small sample size, and they noted that the data exhibited a distinct monotone upward trend (average serum dioxin concentrations of 0.3, 0.6, 0.62, 0.78, and 0.87 pg/g [lipid adjusted] for exposure categories 0–4, respectively). The decision to pool blood samples from a large number of persons within each exposure set (Kim et al., 2001) greatly reduced the power of the validation study. Instead of 180 samples for each of the final exposure categories, the pooled analysis produced only 3 samples for each category. The lipid-adjusted serum TCDD concentra- tions from the 12 pooled samples for Vietnam veterans ranged from 0.25 to 1.2 pg/g, whereas the single sample from the non-Vietnam veterans contained 0.3 pg/g. The narrow range of results puts into question the biologic relevance of any differences. Thus, it appears that there was not a clear separation between Korean Vietnam veterans and non-Vietnam veterans. Furthermore, the range of mean values for the four Vietnam-veteran exposure categories was narrow, and all concentrations were relatively low ( 1 pg/g). The relatively low serum dioxin concentrations observed in the 1990s in those individuals are the residual of substantially higher initial concentrations, as has been seen with other Vietnam-veteran groups. How- ever, the concentrations reported in the Korean veterans’ study are significantly lower than those reported for American Vietnam veterans in the 1988 CDC Agent Orange Validation Study, which was nonetheless unable to distinguish Vietnam veterans from non-Vietnam veterans on the basis of serum dioxin assay (CDC, 1988b). The Korean authors were able to construct plausible exposure categories based on military records and self-report, but they were unable to validate those categories with serum dioxin measurements. No additional reports on this population have been published since Update 2004.

EXPOSURE ASSESSMENT 245 Other Vietnam Veterans Surveys of US Vietnam veterans who were not part of the Ranch Hand or Army Chemical Corps groups indicate that 25–55 percent believe they were ex- posed to herbicides (CDC, 1989; Erickson et al., 1984a,b; Stellman and Stellman, 1986). Several attempts have been made to estimate exposure of Vietnam veter- ans who were not part of the Ranch Hand or Army Chemical Corps groups. In 1983, the US government asked the CDC to conduct a study of possible long- term health effects in Vietnam veterans exposed to Agent Orange. The CDC Agent 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 valid- ity 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 study based on the number of Agent Orange hits they were thought to have experienced, as derived from the number of days on which their company was located within 2 km and 6 days of a recorded Agent Orange spraying event. 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. Only two veterans had concentrations above 20 ppt. The “low” exposure group consisted of 298 Vietnam veterans, the “medium” exposure group had 157 Vietnam veterans, and the “high” exposure group had 191 Vietnam veterans. The distribution of TCDD measurements was nearly identical for the control group of 97 non-Vietnam veterans. The CDC validation study concluded that study subjects could not be distinguished from controls on the basis of serum TCDD. In addition, neither record-derived estimates of exposure nor self-reported exposure to herbicides could predict Vietnam veterans with currently high serum TCDD (CDC, 1988b). The report concluded that it was unlikely that military records alone could be used to identify a large number of veterans who might have been heavily exposed to TCDD in Vietnam. The serum TCDD measurements for Vietnam veterans also suggested that exposure to TCDD in Vietnam was substantially less, on 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

246 VETERANS AND AGENT ORANGE: UPDATE 2006 evaluated by the committee. This assessment of average exposure does not pre- clude the possibility of heavily exposed subgroups of Vietnam veterans. The aforementioned 1997 IOM RFP for historical exposure reconstruction has led to the development of new methods for estimating Vietnam veterans’ exposures to Agent Orange. The Columbia University project integrated various sources of information concerning spray activities to generate individualized estimates of the exposure potential of troops serving in Vietnam (Stellman and Stellman, 2003). Location data for military units assigned to Vietnam were com- piled into a database developed from five primary and secondary sources: the Unit Identification Code list (a reference list of units serving in Vietnam created and used by the Army); a command post list (data on division level of the command locations for army personnel); Army Post Office lists (compilations of locations down to and including battalion size and other selected units that were updated on a monthly basis); troop strength reports (data assembled by the US Military Assistance Command on troop allocations, updated on a monthly basis and gen- erally collected on the battalion level); and order of battle information (data on command post, arrival and departure dates, and authorized strength of many but not all units). For units that served in the III Corps Tactical Zone between 1966 and 1969, battalion-tracking data were also available. These are data on the grid coordinate locations of battalion-sized units derived from Daily Journals, which recorded the company locations over 24-hour periods. “Mobility factor” analysis, a new concept for studying troop movement, was developed for use in reconstructing herbicide-exposure histories. The analysis is a three-part classification system for characterizing the location and movement of military units in Vietnam. It comprises a mobility designation (stable, mobile, or elements mobile), a distance designation (usually in a range of kilometers) to indicate how far the unit might travel in a day, and a notation of the modes of travel available to the unit (air; ground—truck, tank, or armored personnel carrier; or water). A mobility factor was assigned to every unit that served in Vietnam. All of these data were combined into a geographic information system (GIS) for Vietnam with 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 argue that it is now fea- sible to conduct epidemiologic investigations of veterans who served as ground troops during the Vietnam War A different perspective has been put forth in a series of papers (Young and

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256 VETERANS AND AGENT ORANGE: UPDATE 2006 McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, Robson D, Skinnider LF, Choi NW. 2001. Non-Hodgkin’s lymphoma and specific pesticide exposures in men: Cross-Canada study of pesticides and health. Cancer Epidemiology, Biomarkers and Prevention 10(11):1153–1163. Michalek JE, Wolfe WH, Miner JC, Papa TM, Pirkle JL. 1995. Indices of TCDD exposure and TCDD body burden in veterans of Operation Ranch Hand. Journal of Exposure Analysis and Environ- mental Epidemiology 5(2):209–223. Michalek JE, Ketchum N, Longnecker MP. 2001a. Serum dioxin and hepatic abnormalities in veterans of Operation Ranch Hand. Annals of Epidemiology 11(5):304–311. Michalek JE, Akhtar FZ, Arezzo JC, Garabrant DH, Albers JW. 2001b. Serum dioxin and peripheral neuropathy in veterans of Operation Ranch Hand. Neurotoxicology 22:479–490. Michalek JE, Akhtar FZ, Longnecker MP, Burton JE. 2001c. Relation of serum 2,3,7,8-tetrachloro- dibenzo-p-dioxin (TCDD) level to hematological examination results in veterans of Operation Ranch Hand. Archives of Environmental Health 56(5):396–405. Michalek JE, Ketchum NS, Tripathi RC. 2003. Diabetes mellitus and 2,3,7,8-tetrachlorodibenzo-p- dioxin elimination in veterans of Operation Ranch Hand. Journal of Toxicology and Environ- mental Health, Part A 66(3):211–221. Mills PK, Yang R. 2005. Breast cancer risk in Hispanic agricultural workers in California. Interna- tional Journal of Occupational and Environmental Health 11(2):123–131. Mills PK, Yang R, Riordan D. 2005. Lymphohematopoietic cancers in the United Farm Workers of America (UFW), 1988–2001. Cancer Causes and Control 16(7):823–830. Mocarelli P, Patterson DG Jr, Marocchi A, Needham LL. 1990. Pilot study (phase II) for determining polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in serum of Seveso, Italy residents collected at the time of exposure: Future plans. Chemosphere 20:967–974. Mocarelli P, Needham LL, Marocchi A, Patterson DG Jr, Brambilla P, Gerthoux PM, Meazza L, Carreri V. 1991. Serum concentrations of 2,3,7,8-tetrachlorobdibenzo-p-dioxin and test results from selected residents of Seveso, Italy. Journal of Toxicology and Environmental Health 32:357–366. Morrison HI, Semenci RM, Morison D, Magwood S, Mao Y. 1992. Brain cancer and farming in western Canada. Neuroepidemiology 11:267–276. MRI (Midwest Research Institute). 1967. Assessment of Ecological Effects of Extensive or Repeated Use of Herbicides. MRI Project No. 3103-B. Kansas City, MO: MRI. NTIS AD-824-314. Musicco M, Sant M, Molinari S, Filippini G, Gatta G, Berrino F. 1988. A case–control study of brain gliomas and occupational exposure to chemical carcinogens: The risks to farmers. American Journal of Epidemiology 128:778–785. NAS (National Academy of Sciences). 1974. The Effects of Herbicides in South Vietnam. Washington, DC: National Academy Press. Norström A, Rappe C, Lindahl R, Buser HR. 1979. Analysis of some older Scandinavian formulations of 2,4-dichlorophenoxy acetic acid for contents of chlorinated dibenzo-p-dioxins and dibenzo- furans. Scandanavian Journal of Work, Environment and Health 5:375–378. Oh E, Lee E, Im H, Kang HS, Jung WW, Won NH, Kim EM, Sul D. 2005. Evaluation of immuno- and reproductive toxicities and association between immunotoxicological and genotoxicological parameters in waste incineration workers. Toxicology 210(1):65–80. Ott MG, Zober A. 1996. Cause specific mortality and cancer incidence among employees exposure to 2,3,7,8-TCDD after a 1953 reactor accident. Occupational and Environmental Medicine 53:606–612. Ott MG, Holder BB, Olson RD. 1980. A mortality analysis of employees engaged in the manufacture of 2,4,5-trichlorophenoxyacetic acid. Journal of Occupational Medicine 22:47–50.

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From 1962 to 1971, the U.S. military sprayed herbicides over Vietnam to strip the thick jungle canopy that could conceal opposition forces, to destroy crops that those forces might depend on, and to clear tall grasses and bushes from the perimeters of U.S. base camps and outlying fire-support bases.

In response to concerns and continuing uncertainty about the long-term health effects of the sprayed herbicides on Vietnam veterans, Veterans and Agent Orange provides a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange and other herbicides used in Vietnam. The 2006 report is the seventh volume in this series of biennial updates. It will be of interest to policy makers and physicians in the federal government, veterans and their families, veterans' organizations, researchers, and health professionals.

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