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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 (referred to in this report as TCDD, the most toxic congener of the tetrachlorodibenzo-p-dioxins [tetraCDDs], also commonly referred to as dioxin). It then reviews several key methodologic issues in human population studies, namely, disease latency, possible misclassification based on exposure, and exposure specificity required for scientific evaluation of studies. 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 esti- mates (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. That method of classification offers simplicity and ease of interpretation. A more refined method assigns each study subject to an expo- sure category, such as high, medium, or low exposure. Disease risk for each group is calculated separately and compared with a reference or nonexposed group. That method can identify the presence or absence of an exposure–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. The metrics integrate quantitative estimates of exposure intensity (such as chemical concentration in air or extent of skin contact) with exposure duration 46

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4 EXPOSURE TO THE HERBICIDES USED IN VIETNAM 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 routes, and their interpretation requires knowledge of pharmacokinetic processes. All those 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. Selection of the specific herbicides to be used was based on tests conducted in the United States and elsewhere that were designed to evaluate their defoliation efficacy (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 dimethylarsinic 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 land, and zones around military bases. In 1974, a National Academy of Sciences committee estimated the amount of herbicides sprayed from helicopters and other aircraft by using records gathered from August 1965 through February 1971 (NAS, 1974). That committee calculated that about 18 million gallons (about 68 million liters) of herbicide were 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 new analysis of spray activities and exposure potential of troops emerged from a recent study overseen by a committee of the Institute of Medicine (IOM) (IOM, 1997, 2003a,b). That work yielded new estimates of the use of military herbicides 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 indicated errors in both types and suggested that additional spraying had taken place but gone unrecorded at the time. The new analyses led to a revision in 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. Herbicides were identified by the color of a band on 55-gal containers and were called Agents Pink, Green, Purple, Orange, White, and 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

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TABLE 3-1 Military Use of Herbicides in Vietnam (1961–1971) 48 Amount Sprayed Concentration of Active Code Name Chemical Constituentsa Ingredienta Years Useda VAO Estimateb Revised Estimatea Pink 60% n-butyl: 40% isobutyl ester of 2,4,5-T 961–1,081 g/L acid 1961, 1965 464,817 L 50,312 L sprayed; equivalent (122,792 gal) 413,852 L additional on procurement records Green n-butyl ester of 2,4,5-T — 1961, 1965 31,071 L 31,026 L on procurement (8,208 gal) records Purple 50% n-butyl ester of 2,4-D, 30% n-butyl ester 1,033 g/L acid equivalent 1962–1965 548,883 L 1,892,733 L of 2,4,5-T, 20% isobutyl ester of 2,4,5-T (145,000 gal) Orange 50% n-butyl ester of 2,4-D, 50% n-butyl ester 1,033 g/L acid equivalent 1965–1970 42,629,013 L 45,677,937 L (could of 2,4,5-T (11,261,429 gal) include Agent Orange II) Orange II 50% n-butyl ester of 2,4-D, 50% isooctyl ester 910 g/L acid equivalent After 1968 — Unknown; at least of 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, 5.7% picloram 2,4-D, 65 g/L picloram (5,246,502 gal) Blue powder Cacodylic acid (dimethylarsinic acid) sodium Acid, 65% active ingredient; 1962–1964 — 25,650 L 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).

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49 EXPOSURE TO THE HERBICIDES USED IN VIETNAM 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. 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. 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 (NAS, 1974). More details on the herbicides used are presented in the initial National Academy of Sciences report (NAS, 1974) and the initial VAO report (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 reaction, a chlorine atom is replaced with an oxygen atom, and this leads to the final TCDD molecule (NAS, 1974). In the class of compounds known as polychlorinated dibenzo-p-dioxins (PCDDs), 75 congeners can occur, depending on the number and placement of the chlorines. 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 measured 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 based on a different process. Its synthesis is based on dichlorophenol, a molecule formed from the reaction of phenol with chlorine (NZIC, 2009). Neither tetrachlorobenzene nor trichlorophenol is formed during this reaction, so TCDD is not normally a byproduct of the syn- thetic 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). 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

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0 VETERANS AND AGENT ORANGE: UPDATE 2008 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-tri- chlorophenoxide) 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 these 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 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 not be present at over 0.05 ppm (NAS, 1974). Until recently, data from Young and Gough have been used to estimate the amount of TCDD in the various herbicide formulations (Gough, 1986; Young,

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1 EXPOSURE TO THE HERBICIDES USED IN VIETNAM 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 the formulations used in 1965–1970, whereas mean TCDD concentrations in Agents Pink and Green were estimated at 66 ppm. Gough (1986) estimated that about 167 kg of TCDD was sprayed in Vietnam over a 6-year period. A new 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 that the earlier estimates of TCDD contamination in the herbicide formula- tions were too low, noting that the original estimates were based on samples at the lower end of the distribution of concentration values. They concluded that mean TCDD concentrations in Agent Orange were closer to 13 ppm than to the earlier estimates 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 exposure among US military personnel who served in Vietnam has been a great 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 exposures, 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 and the lack of records of individual behaviors. In accord with Congress’s mandated presumption of herbicide expo- sure for 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 com- pounds through mixing, loading, spraying, and clean-up activities had relatively high exposures to herbicides. The US Environmental Protection Agency refers to such personnel as pesticide handlers and provides special guidance for prevent- ing or minimizing 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 in-

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2 VETERANS AND AGENT ORANGE: UPDATE 2008 volved in fixed-wing aircraft spraying activities (often referred to as Operation Ranch Hand), and members of the US Army Chemical Corps (ACC) who used hand-operated equipment and helicopters to conduct smaller-scale operations, including defoliation around special-forces camps; clearing of 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. However, they 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 per- sonnel did not typically use chemical-protective gloves, coveralls, or protective aprons, so substantial skin exposure almost certainly occurred in these popula- tions 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 subpopulation to receive special attention with regard to herbicide exposure. In the Air Force Health Study (AFHS), the 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 in it relied on military spray records for the TCDD-containing herbicides (Agents Orange, Purple, Pink, Green) and helped to identify the members of the cohort. The subjects were fur- ther characterized by military occupation, and exposure in the cohort and com- parison 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 concentrations in the Ranch Hand subjects and in the comparison group (AFHS, 1991). Several methods for estimating herbicide exposure of members of the cohort were de- veloped 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). The IOM has issued a compre- hensive review of the AFHS with recommendations for the use of the extensive data collected in the project (IOM, 2006). Members of the ACC performed chemical operations on the ground and by helicopter and were thereby involved in the direct handling and distribution of herbicides in Vietnam. They were identified for detailed study of health effects

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 EXPOSURE TO THE HERBICIDES USED IN VIETNAM 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 in 1996 from 50 Vietnam veterans showed an association between those who reported spraying herbicides and higher 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 last 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-reported contact with herbicides or military service records with aerial-spray data to produce an “exposure opportunity” index. 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 veterans. Those studies were conducted carefully and provided reasonable estimates based on available data, but no means of testing the validity of the estimates were avail- able 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 con- centrations in adipose tissue to dioxin concentrations in blood (Kahn et al., 1988). At the same time, the Center for Disease Control undertook what came to be called the Agent Orange Validation 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 significant difference in TCDD serum concentrations among the groups. A review of a preliminary report of the work by an advisory panel established through the 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 serum measurements (IOM, 1987).

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4 VETERANS AND AGENT ORANGE: UPDATE 2008 The report of the 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. Recent 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 (Kim et al., 2001, 2003). They developed an exposure index for Korean military personnel who served in Vietnam. The exposure in- dex 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 service. 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. A particular concern for the personnel has been possible contamination of drinking water. Most vessels serving offshore but within the territorial limits of the Republic of Vietnam converted seawater to drinking water through distillation. Higher than expected mortality among Royal Australian Navy Vietnam vet- erans prompted a study of potable-water contamination on ships offshore dur- ing the Vietnam conflict (Mueller et al., 2001, 2002). Specifically, the study investigated the potential for naval personnel to ingest TCDD and cacodylic acid in drinking water. The study focused on the evaporative distillation process that was used to produce potable water from surrounding estuarine waters. The study found that codistillation of dioxins was observable in all experiments con- ducted and that distillation increased the concentration of dioxins in the distillate compared with the concentration in the source water. The study also found that dimethylarsenic acid did not codistill to a great extent during evaporation and concluded that drinking water on ships was unlikely to have been contaminated with this herbicide. In a follow-up discussion of the study with its authors, it was noted that vessels would take up water for distillation as close to shore as possible to minimize salt content (Wells, 2006). On the basis of that study and other evidence, the Australian Department of Veterans Affairs determined that Royal Australian Navy personnel who served offshore were exposed to dioxins

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 EXPOSURE TO THE HERBICIDES USED IN VIETNAM that resulted from herbicide spraying in Vietnam even if they did not go ashore during their tour of duty (ADVA, 2005). The current committee engaged Steven Hawthorne as a consultant to review the Mueller et al. (2002) publication and to comment generally on the abil- ity of organic compounds to codistill during the production of potable water. Hawthorne is an environmental chemist at the University of North Dakota’s Energy and Environmental Research Center and has specific expertise in the study of organic emissions from water (Hawthorne et al., 1985). He affirmed the findings of the Australian study, citing Henry’s law for an explanation of how contaminants with low water solubility would evaporate from water and not- ing that the distillation process would enhance the process by adding heat and reducing pressure (SB Hawthorne, University of North Dakota Energy Research Center, personal communication on October 23, 2008). No measurements of dioxin concentrations in seawater were collected during the Vietnam conflict, so it is not possible to ascertain the extent to which drinking water on US vessels may have been contaminated through distillation processes. However, it seems likely that vessels with such distillation processes that traveled near land or even at some distance from river deltas would periodically collect water that contained dioxin. Thus, a presumption of exposure of military personnel serving on those vessels is not unreasonable. In its charge to the original VAO committee, the Department of Veterans Affairs asked the committee to include military personnel who served in inland waterways, offshore of the Republic of Vietnam, and in the airspace above the Republic of Vietnam. A presumption of exposure to Agent Orange and other herbicides used as defoliants applied to each of those groups as well as to those who served on land. In light of the findings of the Australian study regarding potential drinking-water contamination and those serving offshore, the presump- tion seems well founded. EXPOSURE OF THE VIETNAMESE POPULATION Studies of exposure to herbicides among the residents of South Vietnam have compared nonexposed residents of the South with residents of the North (Constable and Hatch, 1985). Other studies have attempted to identify wives of veterans of North Vietnam who served in South Vietnam. Records of herbicide spraying have been used to refine exposure measurements, comparing people who lived in sprayed villages in the South with those living in unsprayed villages. In some studies, village residents were considered exposed if a 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 have provided information on TCDD concentra- tions in Vietnamese civilians exposed during the war (Schecter et al., 1986, 2002,

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6 VETERANS AND AGENT ORANGE: UPDATE 2008 2006). Dwernychuk et al. (2002) have emphasized the need to evaluate dioxin contamination around former air bases in Vietnam. They collected environmen- tal 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 concen- trations were particularly high around former air fields 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 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. The only new study of dioxin in Vietnam reviewed by the committee ex- amined dioxin contamination in soils (Mai et al., 2007). The study focused on the Bien Hoa Air Base, considered a hot spot because of the use of chemical defoliants around the base, and found high dioxin concentrations. The study did not involve estimates of exposure of the population living in the vicinity of the bases. NEW 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 or- ganizations to develop historical exposure-reconstruction approaches suitable for epidemiologic studies of herbicide exposure among US veterans during the Vietnam War (IOM, 1997). The request resulted in the project Characterizing Ex- posure 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 to generate individual- ized estimates of the exposure potential of troops serving in Vietnam (Stellman and Stellman, 2003). Location data on military units assigned to Vietnam were compiled into a database. “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 a range of kilometers) to indicate how far a unit might travel in a day, and a notation of the modes of travel available to the unit (air; ground by truck, tank, or armored personnel carrier; or water). 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

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 EXPOSURE TO THE HERBICIDES USED IN VIETNAM 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 War- time Exposure to Herbicides in Vietnam (IOM, 2003a,b). 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. The publications have argued that it is now feasible to conduct epidemiologic investigations of veterans who served as ground troops during the Vietnam War. A different perspective has been put forth by Young and colleagues in a series 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 previously unpub- lished military records and environmental-fate studies. They have also argued that ground-troop exposures 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 2006, IOM has issued a report that examined the feasibil- ity of using the Agent Orange Reconstruction Model developed by Columbia University (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.” 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 extended its review of the scientific literature to other populations in which ex- posure could be estimated with greater accuracy. Those populations are discussed in detail in Chapter 5. We focus here on several key methodologic issues that complicate development of accurate exposure estimates in the Vietnam-veteran population and in 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

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8 VETERANS AND AGENT ORANGE: UPDATE 2008 appear immediately after exposure. In the case of cancer, for example, the disease may not appear for many years after exposure. The time between a defined expo- sure 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, 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, non-differential), then 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 associa- tion to be stronger than the association observed. However, if the probability of misclassification is different between cases and controls, 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 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 toward the null value even if the probability of misclassification is the same in the two groups of subjects being compared; in other words, the observed trend in disease risk across the several levels of exposure may be either an overestimate or an underestimate 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 exposure 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 Only a few herbicidal compounds 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

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9 EXPOSURE TO THE HERBICIDES USED IN VIETNAM various formulations. Many scientific studies reviewed by the committee have reported exposures to broad categories of chemicals rather than to those specific compounds. The categories are presented in Table 3-2, with their relevance to the committee’s charge. The information in Table 3-2 represents the current committee’s thinking and has helped to guide our evaluation of epidemiologic studies. Previous VAO committees did not necessarily address the issue of expo- sure specificity in this manner. 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 compounds. A careful reading of a scientific report often reveals that none of the compounds of interest (those used in Viet- nam, as delineated above) contributed to the exposures of the study population, so such studies could be excluded from consideration. But in many cases, the situ- ation is 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 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, 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 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 Limited relevance 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 Cacodylic acida Highly relevant Picloram Highly relevant aNone of the epidemiologic studies reviewed by the committee to date have specified exposure to cacodylic acid.

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60 VETERANS AND AGENT ORANGE: UPDATE 2008 if the published report indicates that the chemicals of interest were among the pesticides or herbicides used by the study population, the lead author of a pub- lished 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 (MCPA), 2-(2-methyl-4-chlorophenoxy) propionic acid (MCPP, Mecoprop), and dicamba—has been factored into the committee’s deliberations with somewhat less weight. The very few epidemio- logic 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 the discussions in the 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 commit- tee recognizes that in 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, including other PCDDs, polychlorinated dibenzofu- rans, and polychlorinated biphenyls (PCBs). Exposure to TCDD is almost always accompanied by exposure to one or more of the other compounds. The literature on the other compounds, particularly PCBs, was not reviewed systematically 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 equiva- lent quotients, which are the sums of toxicity equivalency factors for individual dioxin-like compounds as measured by activity with the aryl hydrocarbon recep- tor (AHR). We took that approach for two reasons. First, exposure of Vietnam veterans to substantial amounts of the other compounds, relative to exposure to TCDD, has not been documented. Second, the most important mechanism for TCDD toxicity involves its ability to bind to and activate the AHR. Many of the other compounds act by different or multiple mechanisms, so it is difficult to at- tribute toxic effects after such exposures to TCDD.

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