3

Exposure to the Herbicides Used in Vietnam

Assessment of human exposure is a key element in addressing two of the charges that guide the work of this committee. This chapter first presents background information on the military use of herbicides in Vietnam from 1961 to 1971 with a review of our knowledge of exposures of those who served in Vietnam and of the Vietnamese population to the herbicides and to the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin, which is referred to in this report as TCDD (and commonly referred to as dioxin) and is the most toxic congener of the tetrachlorodibenzo-p-dioxins. It then reviews several key methodologic issues in human population studies; disease latency, possible misclassification based on exposure, and exposure specificity required for scientific evaluation of studies. Further discussion is presented to underscore the difficulties of assessing exposure in the complex environment that characterized Vietnam during the period of interest.

Exposure of human populations can be assessed in a number of ways, including use of historical information, questionnaires and interviews, measurements in environmental media, and measurements in biologic specimens. Researchers often rely on a mixture of qualitative and quantitative information to derive such 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 nonexposed 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, or low exposure—and calculates disease risk for each group separately and compares it with the risk for a reference or nonexposed group; this method can identify the presence or absence of an exposure–response trend. In some cases, more detailed information is avail-



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3 Exposure to the Herbicides Used in Vietnam Assessment of human exposure is a key element in addressing two of the charges that guide the work of this committee. This chapter first presents back - ground information on the military use of herbicides in Vietnam from 1961 to 1971 with a review of our knowledge of exposures of those who served in Viet - nam and of the Vietnamese population to the herbicides and to the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin, which is referred to in this report as TCDD (and commonly referred to as dioxin) and is the most toxic congener of the tetrachlorodibenzo-p-dioxins. It then reviews several key methodologic issues in human population studies; disease latency, possible misclassification based on exposure, and exposure specificity required for scientific evaluation of studies. Further discussion is presented to underscore the difficulties of assessing expo - sure in the complex environment that characterized Vietnam during the period of interest. Exposure of human populations can be assessed in a number of ways, includ- ing use of historical information, questionnaires and interviews, measurements in environmental media, and measurements in biologic specimens. Researchers often rely on a mixture of qualitative and quantitative information to derive such estimates (Armstrong et al., 1994; Checkoway et al., 2004). The most basic ap- proach compares members of a presumably exposed group with the general popu- lation or with a nonexposed 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, or low exposure—and calculates disease risk for each group separately and compares it with the risk for a refer- ence or nonexposed group; this method can identify the presence or absence of an exposure–response trend. In some cases, more detailed information is avail - 54

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55 EXPOSURE TO THE HERBICIDES USED IN VIETNAM able for quantitative exposure estimates that can be used to construct what are sometimes called exposure metrics. The 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. Exposure also can be assessed by measuring chemicals and their metabolites in human tissues. Such biologic markers of exposure integrate absorption from all exposure routes, but their interpretation requires knowledge of pharmacokinetic processes. All those exposure-assessment approaches have been used in studies of Vietnam veterans. MILITARY USE OF HERBICIDES IN VIETNAM Military use of herbicides in Vietnam took place from 1962 through 1971. Tests conducted in the United States and elsewhere designed to evaluate defo - liation efficacy were used to select specific herbicides (IOM, 1994; Young and Newton, 2004). Four compounds were used in the herbicide formulations in Vietnam: 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 4-amino-3,5,6-trichloropicolinic acid (picloram), and dimethyl - arsinic acid (cacodylic acid). The chemical structures of those compounds are presented in Chapter 2 (Figure 2-1). The herbicides were used to defoliate inland hardwood forests, coastal mangrove forests, cultivated lands, and zones around military bases. In 1974, a National Resource Council committee estimated the amount of herbicides sprayed from helicopters and other aircraft by using records gathered from August 1965 through February 1971 (NRC, 1974). That commit - tee calculated that about 18 million gallons (about 68 million liters) of herbicide was sprayed over about 3.6 million acres (about 1.5 million hectares) in Vietnam in that period. The amount of herbicides sprayed on the ground to defoliate the perimeters of base camps and fire bases and the amount sprayed by Navy boats along river banks were not estimated. A revised analysis of spray activities and exposure potential of troops emerged from a study overseen by a committee of the Institute of Medicine (IOM, 1997, 2003a,b). That work yielded new estimates of the amounts of mili- tary herbicides used in Vietnam from 1961 through 1971 (Stellman et al., 2003a). The investigators reanalyzed the original data sources that were used to develop herbicide-use estimates in the 1970s and identified errors that inappropriately removed spraying missions from the dataset. They also added new data on spray- ing missions that took place before 1965. Finally, a comparison of procurement records with spraying records found errors that suggested that additional spraying had taken place but gone unrecorded at the time. The new analyses led to revision of estimates of the amounts of the agents applied, as indicated in Table 3-1. The new research effort estimated that about 77 million liters were applied, about 9 million liters more than the previous estimate.

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TABLE 3-1 Military Use of Herbicides in Vietnam (1961–1971) 56 Amount Sprayed Concentration of Years Code Name Chemical Constituentsa Active Ingredienta Useda VAO Estimateb Revised Estimatea Pink 60% n-butyl ester 40% isobutyl ester of 1961, 1965 464,817 L 50,312 L sprayed; 413,852 L 961-1,081 g/L acid 2,4,5-T equivalent (122,792 gal) additional on procurement records Green n-butyl ester of 2,4,5-T — 1961, 1965 31,071 L 31,026 L on procurement records (8,208 gal) Purple 50% n-butyl ester of 2,4-D, 30% n-butyl ester 1,033 g/L acid 548,883 L 1,892,733 L 1962-1965 of 2,4,5-T, 20% isobutyl ester of 2,4,5-T equivalent (145,000 gal) Orange 50% n-butyl ester of 2,4-D, 50% n-butyl ester 1,033 g/L acid 42,629,013 L 45,677,937 L (could include 1965-1970 of 2,4,5-T equivalent (11,261,429 gal) Agent Orange II) Orange II 50% n-butyl ester of 2,4-D, 50% isooctyl 910 g/L acid After 1968 — Unknown; at least 3,591,000 L ester of 2,4,5-T equivalent shipped White Acid weight basis: 21.2% triisopropanolamine By acid weight, 240 19,860,108 L 20,556,525 L 1966-1971 salts of 2,4-D, 5.7% picloram g/L 2,4-D, 65 g/L (5,246,502 gal) picloram Blue powder Cacodylic acid (dimethylarsinic acid) sodium Acid, 65% active — 25,650 L 1962-1964 cacodylate ingredient; salt, 70% active ingredient Blue aqueous 21% sodium cacodylate + cacodylic acid to Acid weight, 360 g/L 4,255,952 L 4,715,731 L 1964-1971 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) aBased on Stellman et al. (2003a). bBased on data from MRI (1967), NRC (1974), and Young and Reggiani (1988).

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57 EXPOSURE TO THE HERBICIDES USED IN VIETNAM Herbicides were identified by the color of a band on 55-gal shipping contain- ers and were called Agent Pink, Agent Green, Agent Purple, Agent Orange, Agent White, and Agent Blue. Agent Green and Agent Pink were used in 1961 and 1965, and Agent Purple in 1962–1965. Agent Orange was used in 1965–1970, and a slightly different formulation (Agent Orange II) probably was used after 1968. Agent White was used in 1966–1971. Agent Blue was used in powder form in 1962–1964 and as a liquid in 1964–1971. Agent Pink, Agent Green, Agent Purple, Agent Orange, and Agent 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. The chlorinated phenoxy acids 2,4-D and 2,4,5-T persist in soil for only a few weeks; picloram is much more stable, persisting in soil for years; and cacodylic acid is nonvolatile and stable in sunlight (NRC, 1974). More details on the herbicides used are presented in the initial IOM report, Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO; IOM, 1994). TCDD IN HERBICIDES USED IN VIETNAM TCDD is formed during the manufacture of 2,4,5-T in the following manner: trichlorophenol (2,4,5-TCP), the precursor for the synthesis of 2,4,5-T, is formed by the reaction of tetrachlorobenzene and sodium hydroxide (Figure 3-1a); 2,4,5-T is formed when 2,4,5-TCP reacts with chloroacetic acid (Figure 3-1b); small amounts of TCDD are formed as a byproduct of the intended main reaction (Figure 3-1b) when a molecule of 2,4,5-TCP reacts with the tetrachlorobenzene stock (Figure 3-1c) instead of with chloroacetic acid. For each step in the reac - tion, a chlorine atom is replaced with an oxygen atom, and this leads to the final TCDD molecule (NRC, 1974). In the class of compounds known as polychlo- rinated dibenzo-p-dioxins (PCDDs), 75 congeners can occur, depending on the number and placement of the chlorine atoms. Cochrane et al. (1982) noted that TCDD had been found in pre-1970 samples of 2,4,5-TCP. Other PCDDs—2,7- dichloro-dibenzo-p-dioxin and 1,3,6,8-tetrachloro-dibenzo-p-dioxin—were mea- sured in the same samples. The concentration of TCDD in any given lot of 2,4,5-T depended on the manufacturing process (FAO/UNEP, 2009; Young et al., 1976). The manufacture of 2,4-D is a different process: its synthesis is based on dichlorophenol, a molecule formed from the reaction of phenol with chlo- rine (NZIC, 2009). Neither tetrachlorobenzene nor trichlorophenol is formed during this reaction, so TCDD is not normally a byproduct of the manufactur- ing process. However, other, less toxic PCDDs have been detected in pre-1970 commercial-grade 2,4-D (Cochrane et al., 1982; Rappe et al., 1978; Tosine, 1983). Cochrane et al. (1982) found multiple PCDDs in isooctyl ester, mixed butyl ester, and dimethylamine salt samples of 2,4-D. It has also been noted that cross-contamination of 2,4-D by 2,3,7,8-TCDD occurred in the operations of at least one major manufacturer (Lilienfeld and Gallo, 1989).

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58 VETERANS AND AGENT ORANGE: UPDATE 2010 a. Trichlorophenol, the precursor for the synthesis of 2,4,5-T, is formed by the reaction of tetrachlorobenzene and sodium hydroxide (NaOH). b. The herbicide 2,4,5-T is formed when a reactive form of trichlorophenol (2,4,5-trichlo - rophenoxide) reacts with chloroacetic acid. c. TCDD is formed when a molecule of trichlorophenol reacts with its own precursor, tetrachlorobenzene. Two intermediate steps are shown in this diagram. At each step, an oxygen–carbon bond forms as a chlorine atom is released. This reaction does not occur in the synthesis of 2,4-D, because the precursors with adjacent chlorines are not used in its production. FIGURE 3-1 TCDD formation during 2,4,5-T production. Figure 3-1abc.eps

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59 EXPOSURE TO THE HERBICIDES USED IN VIETNAM TCDD concentrations in individual herbicide shipments were not recorded but were known to vary from batch to batch and between manufacturers. TCDD concentrations in stocks of Agent Orange remaining after the conflict, which ei - ther 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 2–3 ppm in two sets of samples (NRC, 1974; Young et al., 1978). Comparable manufacturing standards for the domestic use of 2,4,5-T in 1974 required that TCDD not be present at over 0.05 ppm (NRC, 1974). Data from Young and Gough were originally 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 Agent Green, Agent Pink, and Agent Purple—used early in the program (through 1965)—contained 16 times the mean TCDD content of the formulations used in 1965–1970, whereas mean TCDD concentrations in Agent Pink and Agent Green were estimated at 66 ppm. Gough (1986) estimated that about 167 kg of TCDD was sprayed in Vietnam over a 6-year period. Later analysis by researchers at Columbia University benefited from access to military spray records that had not been available earlier and has resulted in substantial revisions of the estimates (Stellman et al., 2003a). The investigators were able to incorporate newly found data on spraying in the early period of the war (1961–1965) and to document that larger volumes of TCDD-containing herbicides were used in Vietnam than had been estimated previously. They also found the earlier estimates of TCDD contamination in the herbicide formulations to be low, noting that the original estimates were based on samples at the lower end of the distribution of concentration. They concluded that the mean TCDD concentration in Agent Orange was closer to 13 ppm than to the earlier estimate of 3 ppm. They therefore proposed 366 kg of TCDD as a plausible estimate of the total amount of TCDD applied in Vietnam during 1961–1971. EXPOSURE OF VIETNAM VETERANS Determination of exposures of US military personnel who served in Vietnam has been perhaps the greatest challenge in the study of health effects associated with herbicides and TCDD. Some military personnel stationed in cities or on large bases may have received little or no herbicide exposure, whereas troops who moved through defoliated areas soon after treatment may have been exposed through soil contact, drinking water, or bathing. Reliable estimates of the magni - tude and duration of such exposures are not possible in most cases, given the lack of contemporaneous chemical measurements, the lack of a full understanding of the movement and behavior of the defoliants in the environment, and the lack of records of individual behaviors and locations. Consequently, most studies have focused on populations that had well-defined tasks that brought them into contact with the agents. It is believed that the subjects of those studies, primarily Air

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60 VETERANS AND AGENT ORANGE: UPDATE 2010 Force personnel involved in fixed-wing aircraft spraying activities (often referred to as Operation Ranch Hand) and members of the US Army Chemical Corps (ACC), may have also had among the highest exposures. As described below, exposures of ground troops are difficult to define, so this group has not been as intensely studied. In accord with Congress’s mandated presumption of herbicide exposure of all Vietnam veterans, VAO committees have treated Vietnam-veteran status as a proxy for some herbicide exposure when no more specific exposure information is available. Exposure of Herbicide Handlers Military personnel who came into direct contact with the herbicidal chemi - cals through mixing, loading, spraying, and clean-up activities had relatively high exposures to them. The US Environmental Protection Agency refers to such per- sonnel as pesticide handlers and provides special guidance for preventing or mini - mizing their exposure during those activities in its worker-protection standard for pesticides (EPA, 1992). The number of US military personnel who handled herbicides directly is not known precisely, but two groups have been identified as high-risk subpopulations among veterans: Air Force personnel involved in Opera- tion Ranch Hand and members of the ACC who used hand-operated equipment and helicopters to conduct smaller-scale operations, including defoliation around special-forces camps; clearing the perimeters of airfields, depots, and other bases; and small-scale crop destruction (NRC, 1980; Thomas and Kang, 1990; Warren, 1968). Additional units and individuals handled or sprayed herbicides around bases or lines of communication; for example, Navy river patrols were reported to have used herbicides to clear inland waterways, and engineering personnel used herbicides to remove underbrush and dense growth in constructing fire-support bases. The latter groups have not been the subject of epidemiologic studies. The herbicides used in Vietnam were not considered to present an important human health hazard at that time, so few precautions were taken to prevent exposure of personnel (GAO, 1978, 1979); that is, military personnel did not typically use chemical-protective gloves, coveralls, or protective aprons, so substantial skin exposure almost certainly occurred in these populations in addition to exposure by inhalation and incidental ingestion (such as by hand-to-mouth contact). The Air Force personnel who participated in Operation Ranch Hand were the first Vietnam-veteran population to receive special attention with regard to herbicide exposure. In the Air Force Health Study (AFHS), job and work history, biomarkers, and health outcomes of members of this Ranch Hand cohort were contrasted with Air Force personnel who had served elsewhere in Southeast Asia during the Vietnam era. The AFHS began in 1979 (IOM, 2006). The exposure index initially proposed relied on military spray records for the TCDD-containing herbicides (Agent Orange, Agent Purple, Agent Pink, and Agent Green), which also helped to identify the members of the cohort. The subjects were further char-

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61 EXPOSURE TO THE HERBICIDES USED IN VIETNAM acterized by military occupation, and exposure in the cohort and the comparison group was evaluated through measurement of TCDD in blood (serum) samples drawn in 1987 or later. A general increase in serum TCDD was detected in people whose jobs involved more frequent handling of herbicides, but there was no clear demarcation between the distributions of serum TCDD concentrations in the Ranch Hand subjects and those in the comparison group (AFHS, 1991). Several methods for estimating herbicide exposure of members of the cohort were developed on the basis of questionnaires and focused on such factors as number of days of skin exposure, percentage of skin area exposed, and the concentration of TCDD in the different herbicidal formulations (Michalek et al., 1995). Most recent analyses of the AFHS data have relied on serum TCDD concentration as the primary exposure metric for epidemiologic classification (Kern et al., 2004; Michalek et al., 2001, 2003; Pavuk et al., 2003). IOM has issued a comprehensive review of the AFHS with recommendations for the use of the extensive data col- lected in the project (IOM, 2006). Members of the ACC performed herbicide-spraying operations on the ground and by helicopter and were thereby involved in the direct handling and distribu - tion of Agent Orange and other herbicides in Vietnam. They were identified for detailed study of health effects related to herbicide exposure only in the late 1980s (Thomas and Kang, 1990). An initial feasibility study recruited Vietnam veterans and nondeployed Vietnam-era veterans from within the ACC (Kang et al., 2001). Blood samples collected from 50 Vietnam veterans in 1996 showed an association between those who reported spraying herbicides and higher serum TCDD concentrations; this finding was confirmed in a follow-up study of a larger fraction of the cohort (Kang et al., 2006). Exposure of Ground Troops In light of the widespread use of herbicides in Vietnam for many years, it is reasonable to assume that many military personnel were inadvertently exposed to the chemicals of concern. Surveys of Vietnam veterans who were not part of the Ranch Hand or ACC groups have indicated that 25–55% believe that they were exposed to herbicides (CDC, 1989a). That view has been supported by govern - ment reports (GAO, 1979) and reiterated by veterans and their representatives in testimony to the VAO committees over the past several years. Numerous attempts were made in the 1980s to characterize herbicide expo - sures of people who served as ground troops in Vietnam (CDC, 1988; Erickson et al., 1984; NRC, 1982; Stellman and Stellman, 1986; Stellman et al., 1988). The efforts combined self-reports of contact with herbicides or military service records with aerial-spray data to produce an “exposure opportunity index” (EOI). For example, Erickson et al. (1984) created five exposure categories based on military records to examine the risks of birth defects among the offspring of vet - erans. Those studies were conducted carefully and provided reasonable estimates

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62 VETERANS AND AGENT ORANGE: UPDATE 2010 based on available data, but no means of testing the validity of the estimates were available at the time. The search for a validation method led to the development of exposure bio - markers in veterans. Initial studies measured concentrations of dioxin in adipose tissue of veterans (Gross et al., 1984; Schecter et al., 1987). A study sponsored by the New Jersey Agent Orange Commission was the first to link dioxin concen- trations in adipose tissue to dioxin concentrations in blood (Kahn et al., 1988). At the same time, the Centers for Disease Control (now the Centers for Disease Control and Prevention) undertook what came to be called the Agent Orange Vali- dation Study, measuring TCDD in the serum portion of blood from a relatively large sample of Vietnam veterans and veterans who served elsewhere during the Vietnam era (CDC, 1989b). The study did not find a statistically significant difference in mean serum TCDD concentrations between the groups. A review of a preliminary report of the work by an advisory panel established through IOM concluded that the long lag between exposure and the serum measurements (about 20 years) called into question the accuracy of exposure classification based on serum concentrations. The panel concluded that estimates based on troop locations and herbicide-spraying activities might be more reliable indicators of exposure than serum measurements (IOM, 1987). The report of the first VAO committee (IOM, 1994) proposed further work on exposure reconstruction and development of a model that could be used to categorize exposures of ground troops. The committee cautioned that serum TCDD measurements not be regarded as a “gold standard” for exposure, that is, as a fully accurate measure of herbicide exposure. Efforts to develop exposure- reconstruction models for US Vietnam veterans are discussed later in this chapter. One other effort to reconstruct exposure has been reported by researchers in the Republic of Korea who developed an exposure index for Korean military per- sonnel who served in Vietnam (Kim et al., 2001, 2003). The exposure index was based on herbicide-spray patterns in military regions in which Korean personnel served during 1964–1973, time–location data on the military units stationed in Vietnam, and an exposure score derived from self-reported activities during ser- vice. The researchers were not successful in an attempt to validate their exposure index with serum dioxin measurements. Exposure of Personnel Who Had Offshore Vietnam Service US Navy riverine units are known to have used herbicides while patrolling inland waterways (IOM, 1994; Zumwalt, 1993), and it is generally acknowledged that estuarine waters became contaminated with herbicides and dioxin as a result of shoreline spraying and runoff from spraying on land. Thus, military personnel who did not serve on land were among those exposed to the chemicals during the Vietnam conflict. In recent years, concern about dioxin exposure via drinking water has arisen among personnel who served offshore but within the territorial

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63 EXPOSURE TO THE HERBICIDES USED IN VIETNAM limits of the Republic of Vietnam on ships that converted seawater to drinking water through distillation. Since the last VAO update, NAS convened the Blue Water Navy Vietnam Veterans and Agent Orange Exposure Committee to address that specific issue; its recently released report (IOM, 2011) found that information to determine the extent of exposure experienced by Blue Water Navy personnel was inadequate, but that there were possible routes of exposure. EXPOSURE OF THE VIETNAMESE POPULATION As summarized by Constable and Hatch (1985), Vietnamese researchers have made a number of attempts to characterize the herbicide exposure of resi- dents of Vietnam in the process of trying to assess adverse reproductive out - comes. Some compared residents of the South with residents of the unsprayed North, and others endeavored to compare South Vietnamese people who lived in sprayed and unsprayed villages, as determined by observed defoliation. For evaluating reproductive outcomes, pregnancy outcomes of North Vietnamese women married to veterans who served in South Vietnam were compared with those of women whose husbands had not. In some cases, records of herbicide spraying have been used to refine exposure measurements. In assessing infant mortality, Dai et al. (1990) considered village residents to have been exposed if a herbicide mission had passed within 10 km of the village center and further classified exposure by length of residence in a sprayed area and the number of times that the area reportedly had been sprayed. A small number of studies have provided information on TCDD concentra- tions in Vietnamese civilians exposed during the war (Schecter et al., 1986, 2002, 2006). Dwernychuk et al. (2002) emphasized the need to evaluate dioxin con- tamination around former air bases in Vietnam. They 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 remained in soil or water systems. Soil dioxin concentra - tions were particularly high around former airfields and military bases where herbicides were handled. Fish harvested from ponds in those areas were found to contain high dioxin concentrations. More recently, Dwernychuk (2005) elabo - rated 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 the hot spots. The Bien Hoa Air Base, considered a hot spot be - cause of the use of chemical defoliants around the base, was the focus of a study examining dioxin contamination in soils in Vietnam (Mai et al., 2007). The study found high soil concentrations but did not involve estimation of the exposure of people who lived in the vicinity of the bases. Since Update 2008, there has been an increase in the number of publi- cations reporting mostly environmental concentrations of dioxins in various areas throughout Vietnam (Brodsky et al., 2009; Feshin et al., 2008; Hatfield

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64 VETERANS AND AGENT ORANGE: UPDATE 2010 Consultants, 2009a,b,c; Nhu et al., 2009; Saito et al., 2010). Taken as a whole, those studies suggest a pervasive exposure to dioxins—not limited to hot spots— through environmental media throughout the country more than a half-century after they were initially deposited. The above 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. MODELS FOR CHARACTERIZING HERBICIDE EXPOSURE IOM, following up on the recommendations contained in the original VAO report (IOM, 1994), issued a request for proposals seeking individuals and orga - nizations to develop historical exposure-reconstruction approaches suitable for epidemiologic studies of herbicide exposure of US veterans during the Vietnam War (IOM, 1997). The request resulted in the project Characterizing Exposure of Veterans to Agent Orange and Other Herbicides in Vietnam. The project was carried out under contract by a team of researchers in Columbia University’s Mailman School of Public Health. The Columbia University project integrated various sources of information concerning spray activities and information on location of military units assigned to Vietnam, all compiled into a database, to generate individualized estimates of the exposure potential of troops serving in Vietnam (Stellman and Stellman, 2003). “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 or mobile), a distance designation (usually in kilometers) to indicate how far a unit might travel in a day, and a notation of the modes of travel available to the unit (by air, by water, or on the ground by truck, tank, or armored personnel carrier). A mobility factor was assigned to every unit that served in Vietnam. The data were combined into a geographic information system (GIS) for Vietnam. Herbicide-spraying records were integrated into the GIS and linked with data on military-unit locations to permit estimation of individual exposure- opportunity scores. The results are the subject of reports by the contractor (Stellman and Stellman, 2003) and the Committee on the Assessment of Wartime Exposure to Herbicides in Vietnam (IOM, 2003a,b). A summary of the findings on 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. The publications have argued that it is feasible to conduct epidemiologic investigations of veterans who served as ground troops during the Vietnam War. IOM later issued a report that examined the feasibility

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65 EXPOSURE TO THE HERBICIDES USED IN VIETNAM of using the Agent Orange Reconstruction Model developed by Columbia Uni- versity (IOM, 2008). The report concluded that “despite the shortcomings of the exposure assessment model in its current form and the inherent limitations in the approach, the committee agreed that the model holds promise for support - ing informative epidemiologic studies of herbicides and health among Vietnam veterans and that it should be used to conduct studies.” A different perspective has been put forth by Young and colleagues in a se - ries of papers (Young et al., 2004a,b). They have argued that ground troops had little direct contact with herbicide sprays and that TCDD residues in Vietnam had low bioavailability. Those conclusions were based on analyses of previ - ously unpublished military records and environmental-fate studies. They have also argued that direct exposures of ground troops were relatively low because herbicide-spraying missions were carefully planned, and spraying occurred only when friendly forces were not in the target area. Since Update 2008, a pair of industry-sponsored papers that used a math- ematical model of herbicide dispersion and deposition from aerial spraying concluded that actual ground deposition of Agent Orange was many orders of magnitude lower than that predicted by previous exposure estimations proposed for use in evaluating ground-troop health effects (Ginevan et al., 2009a,b). The new papers first undertook a quantitative evaluation of the Stellman EOI model (Stellman and Stellman, 2004; Stellman et al., 2003a,b) recommended for pos - sible use in an epidemiologic evaluation of ground troops by IOM (2008). The new evaluation revealed frequent and substantial inconsistencies in the calculated EOI based in part on the use of a central equation “contrary to a large body of pesticide exposure assessment practice,” the general imprecision of spray-flight path records, the use of 1.2-km2 exposure cells in the model, and “unknown computational errors” in the model. The analyses demonstrated unexpected and unexplained 1,000-fold differences in model output for sample flight paths that appear to be in all respects equivalent. The authors propose the use of the AgDRIFT Tier III model as a more accurate and appropriate estimator of ground- troop potential exposures. That model uses a combination of standard Lagrangian and Gaussian techniques in combination with empirically derived information, such as aerosol penetration through a forest canopy, to estimate ground-level exposure. The AgDRIFT Tier III model is purportedly validated and used by the US Forest Service to plan aerial application of various agents to forests. The AgDRIFT model predicts a much smaller area of impact under the spray path and Agent Orange concentrations lower by several orders of magnitude than the EOI estimates for the same set of sample flight paths. That effect is particularly pronounced at points distant from the spray path; the AgDRIFT model predicts Agent Orange exposures up to 20 orders of magnitude lower than the EOI model at a point 4 km away from the flight-path centerline. Finally, the authors point out that the use of any exposure model for ground troops will be severely limited by the imprecision of spatial and temporal measures of troop movements.

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66 VETERANS AND AGENT ORANGE: UPDATE 2010 Exposure assessment of human populations is difficult. It is most reliable in situations in which there is a single or predominant source of contamination or a single route of exposure that occurs over a short period, such as the atomic bomb studies used to assess the health effects of radiation exposure. Accurate and reliable assessment is far more problematic in situations with multiple dispersed sources of contamination or multiple routes of exposure that occur over an ex- tended period many years in the past. Exposure-assessment studies for the Ranch Hand and ACC cohort studies approach the former scenario in their relative simplicity and ease. Nonetheless, attempts to quantify exposures to date, even at the level of serum biomarkers of exposure, have been less than satisfactory. In the case of ground troops, which more nearly approaches the latter scenario, few studies have characterized exposure beyond “in-theater” vs “not-in-theater” comparisons. Considerable work has been done by National Academies commit - tees and others to develop ground-troop exposure assessments based on num - bers, patterns, and timing of aerial spray missions combined with troop-location information. Although previously recommended by earlier VAO committees, the Stellman model has not yet been applied in a study evaluating the health of ground troops. The focus on aerial spraying as the primary exposure, however, may be misplaced. To ascribe a health effect to an exposure in an epidemiologic study accurately, one must account for all sources and routes of exposure—a concept now popularly termed total exposure assessment. In the Vietnam theater, there were undoubtedly multiple sources and routes of TCDD exposure of ground troops other than being directly under an aerial-spray mission. The relative magnitudes of those sources and whether the aerial spray route predominated are unknown and now prob- ably unknowable. For instance, troops in the field commonly collected drinking water from streams. Some of those streams are still highly polluted with TCDD. Although the ultimate source of the TCDD in the streams may have been aerial spraying, the concentration of TCDD in the water would not necessarily be cor- related with spray mission exposure estimates and could conceivably far exceed the “direct exposure” estimates, depending on the terrain, rainfall, timing of water collection, and other unknown factors. The dynamic nature of TCDD released into the environment is largely unknown quantitatively, so an exposure assessment that accounts for all sources of TCDD exposure is impossible. In addition, an assess - ment of total exposure must include an understanding of coexposures that could confound TCDD exposure analyses or otherwise directly account for an observed health effect. Studies have not factored coexposures into health risk estimates. METHODOLOGIC ISSUES IN EXPOSURE ASSESSMENT Analyses of Vietnam-veteran studies have been an important source of in- formation for understanding associations between the herbicides used in Vietnam and specific health outcomes, but, as discussed in Chapter 2, the committee has

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67 EXPOSURE TO THE HERBICIDES USED IN VIETNAM extended its review of the scientific literature to other populations in which expo - sure could be estimated with greater accuracy. Those populations are discussed in detail in Chapter 5. We focus here on several key methodologic issues that com - plicate development of accurate estimates of exposure of the Vietnam-veteran population and the other study populations discussed in this report: the latent period between exposure and disease, exposure misclassification, and exposure specificity. Latency The temporal relationship between exposure and disease is complex and often difficult to define in studies of human populations. Many diseases do not ap- pear immediately after exposure. Cancer, for example, might not appear for many years after exposure. The time between a defined exposure period and the occur- rence of disease is often referred to as a latent period (IOM, 2004). Exposures can be brief (sometimes referred to as acute exposures) or protracted (sometimes referred to as chronic exposures). At one extreme, an exposure can be the result of a single event, as in an accidental poisoning. At the other extreme, a person 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. The definition of the proper timeframe for duration of exposure constitutes a challenge to exposure scientists. Misclassification Exposure misclassification in epidemiologic studies can affect estimates of risk. A typical situation is in a case–control study in which the reported mea - surement of exposure of either group or both groups can be misclassified. The simplest situation to consider is one in which the exposure is classified into just two levels, for example, ever vs never exposed. If the probability of exposure misclassification is the same in cases and controls (that is, nondifferential), it can be shown that the estimated association between disease and exposure is biased toward the null value; in other words, one would expect the true association to be stronger than the observed association. However, if the probability of misclas - sification is different between cases and controls, bias in the estimated association can occur in either direction, and the true association might be stronger or weaker than the observed association. The situation in which exposure is classified into more than two levels is somewhat more complicated. Dosemeci et al. (1990) have demonstrated that in that situation the slope of a dose–response trend is not necessarily attenuated to - ward the null value even if the probability of misclassification is the same in the two groups of subjects being compared; the observed trend in disease risk across the several levels of exposure may be either an overestimate or an underestimate

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68 VETERANS AND AGENT ORANGE: UPDATE 2010 of the true trend in risk. Greenland and Gustafson (2006) have discussed the effect of exposure misclassification on the statistical significance of the result, demonstrating that if one adjusts for exposure misclassification when the expo - sure is represented as binary (for example, ever vs never exposed), the resulting association is not necessarily more significant than in the unadjusted estimate. That result remains true even though the observed magnitude of the association (for example, the relative risk) might be increased. Specificity Incorporation of findings of studies of persons exposed to components of the herbicides sprayed in Vietnam requires some decisions about their relative contributions to the VAO project’s evidentiary database. Only a few herbicidal chemicals were used as defoliants during the Vietnam conflict: esters and salts of 2,4-D and 2,4,5-T, cacodylic acid, and picloram in various formulations. Many scientific studies reviewed by the committee report exposures to broad categories of chemicals rather than to those specific chemicals. The categories are presented in Table 3-2 with their relevance to the committee’s charge. The information in Tables 3-2 and 3-3 represents the committee’s current thinking with respect to their relevance and has helped to guide its evaluation of epidemiologic studies. Earlier VAO committees did not address the issue of exposure specificity in exactly this manner. The committee for VAO and the first several updates gave more weight to results based solely on job title (for example, “farmer” with no additional information) than have the committees for the last three updates but entirely excluded findings from the Yusho and Yucheng polychlorinated biphenyl (PCB) poisonings, whereas recent committees have factored in results that are now more commonly expressed in terms of individual dioxin-like PCB congeners. Many studies have examined the relationship between exposure to “pesti- cides” and adverse health outcomes, and others have used the category of “her- bicides” without identifying specific chemicals. A careful reading of a scientific report often reveals that none of the chemicals of interest (those used in Vietnam, as delineated above) contributed to the exposures of the study population, so such studies could be excluded from consideration. But in many cases, the situation is more ambiguous. For example, reports that define exposure in the broad category of “pesticides” with no further information have little relevance to the commit - tee’s charge to determine associations between exposures to herbicides used in Vietnam and adverse health outcomes. Reports that define exposure in the more restricted category of “herbicides” are of greater relevance but are of little value unless it is clear from additional information that exposure to one or more of the herbicides used in Vietnam occurred in the study population—for example, if the published report indicates that the chemicals of interest were among the pesti - cides or herbicides used by the study population, the lead author of a published

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69 EXPOSURE TO THE HERBICIDES USED IN VIETNAM TABLE 3-2 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 and 2,4,5-T (Phenoxy Herbicides), Cacodylic Acid, and Picloram Specificity of Exposure Relevance to Reported in Study Additional Information Committee’s Charge Pesticides Chemicals of interest were not used, or there was Not relevant no additional information Chemicals of interest were used Limited relevance Herbicides Chemicals of interest were not used Not relevant There was 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 acida Cacodylic — Highly relevant Picloram — Highly relevant aNone of the epidemiologic studies reviewed by the committee to date has specified exposure to cacodylic acid. TABLE 3-3 Current Committee Guidance for the Classification of Exposure Information in Epidemiologic Studies That Focus on Exposure to Dioxin-like Chemicals and Relevance of the Information to the Committee’s Charge Specificity of Exposure Relevance to Reported in Study Additional Information Committee’s Charge Dioxin-like chemicals Exposure to PCBs or polychlorinated Limited relevance dibenzofuron (PCDF) Dioxin-like chemicals Results expressed in terms of (total) toxic Highly relevant equivalents (TEQs) or concentrations of individual congeners recognized as having dioxin- like activitya TCDD or mixture of Established on the basis of environmental Highly relevant PCDDs sampling or work histories TCDD or mixture of Concentrations in tissues of a subset of Very highly relevant PCDDs participants (preferably soon after exposure) TCDD or mixture of Concentrations in tissues of individual Most informative PCDDs participants (preferably soon after exposure) aThe values of toxic equivalency factors for individual dioxin-like chemicals, which are weighted by concentration and summed to derive TEQs are presented in Table 4-2.

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70 VETERANS AND AGENT ORANGE: UPDATE 2010 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 crops identified in the study, or 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, phenoxy herbicides, particularly 2,4-D and 2,4,5-T, are directly relevant to the exposures experienced by US military forces in Vietnam. On the basis of the assumption that compounds with similar chemical structure may have analogous biologic activity, information on the effects of other chemicals in the phenoxy herbicide class—such as Silvex, 2-methyl-4-chlorophenoxyacetic acid, 2-(2-methyl-4-chlorophenoxy) propionic acid (Mecoprop), and dicamba—has been factored into the committee’s delib- erations with somewhat less weight. The very few epidemiologic findings on exposure to picloram or cacodylic acid have been regarded as highly relevant. The committee has decided to include many studies that report on unspecified herbicides in their health-effects sections, and their results have been entered into the health-outcome–specific tables; however, these studies tend to contribute little to the evidence considered by the committee. The many studies that provide chemical-specific exposure information are believed to be far more informative for the committee’s purposes. A similar issue arises in the evaluation of studies that document exposure to dioxin-like compounds. Most “dioxin” studies reviewed by the committee have focused on TCDD, but TCDD is only one of a number of PCDDs. The committee recognizes that in real-world conditions exposure to TCDD virtu - ally never occurs in isolation and that there are hundreds of similar compounds to which humans might be exposed, including other PCDDs, polychlorinated dibenzofurans (PCDFs), and PCBs. Exposure to TCDD is almost always ac- companied by exposure to one or more of the other compounds. The literature on the other compounds, particularly PCBs, has not been reviewed systemati- cally by the committee unless TCDD was identified as an important component of the exposure or the risks of health effects were expressed in terms of toxicity equivalent quotients (TEQs), which are the sums of toxicity equivalency fac - tors for individual dioxin-like compounds as measured by activity with the aryl hydrocarbon receptor (AHR). The committee took that approach for two reasons. First, exposure of Vietnam veterans to substantial amounts of the other chemicals, relative to exposure to TCDD has not been documented. Second, the most impor- tant mechanism for TCDD toxicity involves its ability to bind to and activate the AHR. Many of the other chemicals act by different or multiple mechanisms, so it is difficult to attribute toxic effects after such exposures specifically to TCDD. Furthermore, people’s environmental exposures to dioxin-like chemicals and their non–dioxin-like counterparts are to mixtures of components that tend to be corre- lated, so it is not surprising that specific chemicals measured in a person’s serum also tend to be correlated; this means that it will be difficult for epidemiologic

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