APPENDIX
The Assessment of Exposure to Herbicides Among Vietnam Veterans: A Review and Recommendations for Future Studies

David Kriebel, Michael Stoto, Clifford Weisel, and Susan Rogers

ABSTRACT

In 1991, the U.S. Congress enacted P.L. 102-4, The Agent Orange Act of 1991, which among its provisions mandated a study commissioned by the Department of Veterans Affairs and conducted by the National Academy of Sciences' Institute of Medicine (IOM) to review the existing literature on the human health effects of the herbicides used in Vietnam. A second charge was to review the existing efforts at the assessment of herbicide exposures among Vietnam veterans and make recommendations for future exposure studies. This paper summarizes the investigations conducted by an IOM committee (referred to here as the Agent Orange, or AO, committee) into the problems and prospects for herbicide exposure assessment studies among Vietnam veterans.

The AO committee found that although different approaches have been used to estimate exposure in Vietnam veterans, each of the approaches is limited in its ability to determine precisely the degree and level of individual exposure. The measurement of the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the blood many years after exposure may be useful, especially for detecting group differences. However, because of common background exposures to TCDD, poorly understood variations among individuals in TCDD metabolism, and analytic uncertainty of the analysis, individual TCDD serum levels are usually not meaningful. Furthermore, because not all of the herbicides used in Vietnam contained TCDD, serum TCDD levels are not good indicators of overall exposure to herbicides.

Although definitive data are lacking, the available quantitative and qualitative evidence about herbicide exposure suggests that Vietnam veterans as a group had substantially lower exposure to herbicides and TCDD than the subjects in many occupational studies of herbicide exposure. The participants in "Operation Ranch Hand"—the U.S. Air Force program of aerial spraying of herbicides in South Vietnam—are an exception to this pattern, and it is likely that others among the approximately 3 million men and woman who served in



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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research APPENDIX The Assessment of Exposure to Herbicides Among Vietnam Veterans: A Review and Recommendations for Future Studies David Kriebel, Michael Stoto, Clifford Weisel, and Susan Rogers ABSTRACT In 1991, the U.S. Congress enacted P.L. 102-4, The Agent Orange Act of 1991, which among its provisions mandated a study commissioned by the Department of Veterans Affairs and conducted by the National Academy of Sciences' Institute of Medicine (IOM) to review the existing literature on the human health effects of the herbicides used in Vietnam. A second charge was to review the existing efforts at the assessment of herbicide exposures among Vietnam veterans and make recommendations for future exposure studies. This paper summarizes the investigations conducted by an IOM committee (referred to here as the Agent Orange, or AO, committee) into the problems and prospects for herbicide exposure assessment studies among Vietnam veterans. The AO committee found that although different approaches have been used to estimate exposure in Vietnam veterans, each of the approaches is limited in its ability to determine precisely the degree and level of individual exposure. The measurement of the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the blood many years after exposure may be useful, especially for detecting group differences. However, because of common background exposures to TCDD, poorly understood variations among individuals in TCDD metabolism, and analytic uncertainty of the analysis, individual TCDD serum levels are usually not meaningful. Furthermore, because not all of the herbicides used in Vietnam contained TCDD, serum TCDD levels are not good indicators of overall exposure to herbicides. Although definitive data are lacking, the available quantitative and qualitative evidence about herbicide exposure suggests that Vietnam veterans as a group had substantially lower exposure to herbicides and TCDD than the subjects in many occupational studies of herbicide exposure. The participants in "Operation Ranch Hand"—the U.S. Air Force program of aerial spraying of herbicides in South Vietnam—are an exception to this pattern, and it is likely that others among the approximately 3 million men and woman who served in

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research Vietnam were exposed to herbicides at levels associated with health effects. The difficulty (from the perspective of epidemiologic studies) is that the available data do not readily permit precise quantification of exposure. None of the measures that has been proposed to date would be free of nondifferential misclassification bias. The effect of this bias on risk estimates would likely be to underestimate true effects if they existed, possibly to such an extent that these effects could be missed entirely by future studies. However, it may be possible to develop a valid exposure reconstruction model for epidemiologic studies based on existing records and structured interview data, using principles of historic exposure reconstruction developed by industrial hygienists. Such a model would estimate the likelihood that each veteran was exposed to herbicides in Vietnam, and could possibly quantify the likely degree of exposure. This model would incorporate information in existing military records about herbicide spraying and troop movements. It would also include less formal sources of information on ground and perimeter spraying. INTRODUCTION In 1991, the U.S. Congress enacted P.L. 102-4, The Agent Orange Act of 1991, which attempted to address several of the long-standing concerns of Vietnam veterans concerned with the possibility of lingering health effects from exposure to herbicides during the Vietnam War. One provision of the act required the Department of Veterans Affairs to contract with the National Academy of Sciences' Institute of Medicine (IOM) to conduct a review of the existing literature on the human health effects of the herbicides used in Vietnam. The most prominent of these was Agent Orange (so named because of orange stripes on the barrels used to store and ship the chemical), a 50-50 mixture of the herbicides 2,4,5-T and 2,4-D. The former was contaminated with varying concentrations of numerous dioxins including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The purpose of the review was to assess the strength of the evidence for association between exposure to these herbicides and human disease. The secretary of veterans affairs was then directed by the act to use these findings and other relevant scientific information in making determinations of which, if any, diseases should be considered "service related," and hence compensable for Vietnam veterans. The results of the AO committee's review were published in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994). In 1996, the first biannual update, also mandated by P.L. 102–4, was published as Veterans and Agent Orange: Update 1996 (IOM, 1996). Another provision of P.L. 102–4 requested that the IOM assess the feasibility of further epidemiologic studies of Vietnam veterans. In preparing to respond to this mandate, the IOM committee formed to conduct the review found

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research that exposure assessment was the weakest aspect of existing data on health effects of the herbicides used in Vietnam, and developed a series of recommendations aimed at improving this situation with respect to Vietnam veterans. This paper represents a summary of the findings of the AO committee with regard to exposure assessment of herbicide exposure for Vietnam veterans. After a brief review of the history of herbicide exposures in Vietnam, the article presents an evaluation of the various approaches to exposure assessment that have been used in studies of Vietnam veterans and some of the problems of inaccurate exposure measurement in these studies. Drawing upon the AO committee's evaluation of the available literature and upon information on the military use of herbicides, the paper then summarizes what is known about exposure to herbicides in Vietnam in comparison to other populations with widely different types of exposure (e.g., in factories, of professional herbicide sprayers, from environmental accidents). Finally, proposals for the reconstruction of past exposures to herbicides are discussed and evaluated. This paper draws on and summarizes material published in chapters 3, 6, and 12 of Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam and chapter 5 of Veterans and Agent Orange: Update 1996. HERBICIDE USE IN VIETNAM As background for the consideration of measures of exposure to herbicides in Vietnam that can be used in epidemiologic studies of veterans, both the deployment of troops and the military use of herbicides must be considered. The Military Experience in Vietnam As one historian notes in his account of the Vietnam conflict, "there was no 'typical' U.S. soldier in Vietnam ... the three million Americans who served there went through many varied experiences—partly because the quality of the war varied in different areas of the country, and partly because its nature changed over time" (Karnow, 1991:479). Individual experiences (and potential for exposure to herbicides) also varied according to job assignment, military unit of service, rank, and branch of service. Artillery units, for example, tended to be less mobile than cavalry because of the heavy equipment involved. An individual assigned to base headquarters with an Army personnel position experienced a different tour of duty than an infantry commander, a field engineer, or an officer stationed aboard a Navy vessel off the coast. Personnel assigned to units in the Mekong Delta might slog week after week across paddy fields, while others patrolling the perimeters of major U.S. installations at Danang, Bien Hoa, and Camranh were often targets for sniper attacks (Karnow,

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research 1991). Individuals and units also varied in their consumption of locally grown foods and water from local supplies, as well as in their personal hygiene practices. Estimates of the number of U.S. military personnel who served in Vietnam during this period of herbicide use vary from 2.6 to 3.8 million. The total number of U.S. servicemen and women exposed to herbicides is also not known, although some individuals, such as those of the Air Force Operation Ranch Hand and the Army Chemical Corps (groups that are discussed below), were more likely to have been exposed by the nature of their job assignments. Approximately 50 percent of Vietnam-era veterans served in the Army, 20 percent in the Navy, 20 percent in the Air Force, and the remaining 10 percent in the Marines or Coast Guard (Kulka et al., 1988). Ground forces—the Army and Marines—were likely to experience more of the day-to-day fighting than Navy or Air Force personnel (Card, 1983). Sociological assessments of the American soldier in Vietnam suggest that no one factor is more important in understanding the experiences of the individual veteran than the degree of exposure to combat (Moskos, 1975; Fischer et al., 1980; Martin, 1986; Shafer, 1990). Twenty percent of soldiers sent to Vietnam were assigned to combat units (Shafer, 1990), although surveys of veterans indicate much higher percentages who reported having experienced combat. A survey published by the Veterans Administration indicated that 70 percent of those sampled reported exposure to combat, which meant that they had come under some kind of attack (U.S. Department of Labor, 1990; Karnow, 1991). The CDC Vietnam Experience Study found that 57 percent of Army veterans had served in combat units (i.e., infantry, artillery, armor, cavalry, and engineer; CDC, 1989). Military Use of Herbicides in Vietnam From 1962 to 1971, the U.S. Air Force sprayed nearly 19 million gallons of herbicides in Vietnam, of which at least 11 million gallons was Agent Orange, in a military project called Operation Ranch Hand. An additional quantity (1.6 million gallons has been documented) of herbicides was applied to base perimeters, roadways, and communication lines by helicopter and surface sprayings from riverboats, trucks, or backpacks. Special forces troops also performed an unknown, but relatively small, amount of spraying in support of their operations. Military documents report the use of herbicides over areas of Laos, particularly near the Vietnam border and along the Ho Chi Minh Trail. The purpose of the operation in Laos was to expose foot trails, roads, and other lines of communication that led into Vietnam. Herbicide operations began in December 1965; within a 6-month period, more than 200,000 gallons of

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research herbicide had been sprayed over approximately 1,500 km of roads and trails in Laos (Collins, 1967). Operation Ranch Hand The major defoliation program in Vietnam—Operation Ranch Hand—began on December 4, 1961, when President Kennedy authorized the secretary of defense to test the military effectiveness of the defoliation of several lines of communication (MACV, 1968). The first major operation, to clear enemy infiltration routes, was carried out over the mangrove forests in the Ca Mau peninsula in the southernmost region of the Mekong Delta in September 1962 (Dux and Young, 1980). Operation Ranch Hand had two primary objectives: (1) defoliation of trees and plants to improve visibility for military operations, and (2) destruction of essential enemy food supplies. Targets for defoliation by Ranch Hand included base camps and fire support bases (specifically constructed sites for storage of artillery in support of combat operations), lines of communication, enemy infiltration routes, and enemy base camps. Clearance of these areas improved aerial observation, opened roads to free travel, and hindered enemy ambushes. All large-area defoliation missions were flown exclusively by Ranch Hand crews (Collins, 1967). According to Department of Defense (DoD) records, the aerial application of herbicides was accomplished by spraying from C-123 fixed-wing aircraft and helicopters (UH-1 and H-34). During 1967–1968, requirements for herbicide missions increased to the point that the number of available C-123 aircraft was not sufficient to complete all approved targets within the desired time frame (MACV, 1968). In order to permit a more timely response to defoliation requirements, helicopter operations were recommended for smaller targets, such as in support of local base defense, maintenance of deforested areas, and the uncovering of known small ambush sites along lines of communication (MACV, 1968). As Ranch Hand operations declined in 1970–1971, the number of helicopter herbicide operations increased and gradually became the only aerial means of herbicide delivery. With the buildup of American troops in 1965, Operation Ranch Hand also intensified: the number of C-123 aircraft assigned to the operation increased from 3 to 12 (36 aircraft were assigned to the program from 1967 until it was phased out in 1971); permanent personnel were assigned to the team (Dux and Young, 1980); and the number of missions increased nearly 16-fold from 107 in 1962 to more than 1,600 in 1967 (Huddle, 1969; NAS, 1974). Typical missions early in the conflict included 3 to 4 aircraft, increasing to as many as 19 in the later years. The operation of a single aircraft was termed a sortie. In the period from 1966 through 1968, more than one sortie per day was often common. During the first 6 months of 1968, the 24 C-123 aircraft assigned to Ranch Hand averaged nearly 39 sorties per day (Young et al., 1978). All missions within a

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research target area formed a project (Young and Reggiani, 1988). Ranch Hand missions were also frequent targets of ground fire due to the low altitude and slow speed of the aircraft, and flights required fighter cover for protection (Collins, 1967; Warren, 1968; Spey, 1993). As early as 1963, fighter cover was used in conjunction with defoliation missions to provide mission protection. In 1966, it was reported that nearly one-third (29 percent) of all C-123 defoliation sorties received "hits" from ground fire. The ratio of hits per sortie decreased in later years with improved fighter tactics (Warren, 1968). The helicopter delivery system was also particularly vulnerable to ground fire because of the slow delivery speed (Collins, 1967). The normal altitude of the C-123 for spray application was 150 feet, flying at a speed of 130 to 150 knots, and producing a swath width of 80 in per aircraft (MRI, 1967; NAS, 1974). Under these ideal conditions, a 1,000-gallon tank permitted a 3-to 4-minute spray time at a total distance of about 8.7 statute miles, or about 340 acres treated per aircraft, with a deposition rate of 3 gallons per acre (Young et al., 1978). In addition to aircraft altitude and speed, distribution of the spray was also affected by climate, wind, terrain, and turbulence from the aircraft. Although missions generally were flown in the early morning when the wind was calm, to minimize spray drift, the NAS (1974) study showed that crop damage resulting from drift on defoliation missions was greater than that caused by crop destruction missions—indicating that widespread crop damage resulted from drift. Tschirley (1967) estimated that in a moist, tropical, triple-canopy forest, approximately 80 percent of the spray droplets were intercepted by the uppermost canopy, 14 percent fell to the inner level, and only 6 percent reached ground-level vegetation. Air turbulence from the aircraft also helped to distribute spray droplets throughout the foliage and was an important factor in the dispersal of the spray (MRI, 1967). Four major herbicide compounds were used in the Ranch Hand herbicide formulations—2,4-D (2,4-dichlorophenoxyacetic acid), 2,4,5-T (2,4,5-trichlorophenoxyacetic acid), picloram, and cacodylic acid. Which of these four major chemicals was chosen for a specific application depended on the desired effects. 2,4-D and 2,4,5-T are chlorinated phenoxy acids, and each is effective against a wide array of broadleaf plant species (Irish et al., 1969). They persist in soil only a few weeks (Buckingham, 1982). Picloram, like 2,4-D and 2,4,5-T, regulates plant growth. Compared to 2,4-D, picloram is more mobile, and therefore better able to penetrate the plant's roots and be transported throughout the plant's tissues. Unlike the phenoxy herbicides, picloram is extremely persistent in soils. The fourth compound, cacodylic acid, contains an organic form of arsenic. Cacodylic acid is a desiccant, causing a plant's tissues to lose their moisture and eventually killing the plant. It is a contact herbicide that is rapidly rendered ineffective in soil.

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research These compounds have been used worldwide for the control of weeds and unwanted vegetation, although the application of 2,4,5-T is no longer permitted in the United States following a series of Environmental Protection Agency directives in the 1970s. 2,3,7,8-TCDD is a contaminant of 2,4,5-T, but not of 2,4-D, and is a very toxic material. Of all the herbicides used in South Vietnam, only Agent Orange was formulated differently from the materials for commercial application that were readily available in the United States (Young et al., 1978). The levels of TCDD found in any given lot of 2,4,5-T depend on the manufacturing process (Young et al., 1976), and different manufacturers produced 2,4,5-T with various concentrations of TCDD. The primary source of 2,4,5-T in the herbicides used in Vietnam was Agent Orange. It is the unknown concentration of TCDD in Agent Orange that is of particular concern. TCDD concentrations in individual shipments were not recorded, and levels of TCDD varied in sampled inventories of herbicides containing 2,4,5-T. Analysis of the TCDD concentration in stocks of Agent Orange remaining after the conflict, which had either been returned from South Vietnam or had been procured but not shipped, ranged from less than 0.05 to almost 50 parts per million (ppm), averaging 1.98 and 2.99 ppm in two sets of samples (NAS, 1974; Young et al., 1978). Comparable manufacturing standards for domestic use of 2,4,5-T in 1974 required that TCDD levels be less than 0.05 ppm (NAS, 1974). Therefore, depending on which stocks were sampled, the level of dioxin contamination in Agent Orange could have been up to 1,000 times higher than the level of dioxin found in phenoxy herbicides domestically available at the time. For each herbicide mission, the date, number of gallons sprayed, and type of herbicide, NAS produced maps showing how many times any hectare had been sprayed due to repetition or overlapping of herbicide applications. Figure A-1, for instance, depicts the extent of spraying conducted in the Rung Sat Special Zone during 1966 and 1967 using data from the HERBS tapes—a digitally stored log of spraying missions created by DoD. Areas designated as defoliation targets were much more likely to be sprayed repeatedly than targets of crop destruction missions. Less than 10 percent of the targets for crop destruction missions were sprayed more than once, and the intervals were usually 6 to 12 months; one-third of the areas classified as defoliation were resprayed, and approximately 70 percent received the second spray within 6 months of the initial spray (NAS, 1974). One limitation of the HERBS tapes, and the maps generated from them, is that the plotted lines represent the center of each mission. The assumed swath width for a sortie was 80 m. Typical missions consisted of three aircraft, and some as many as 12 to 16; these differences in effective spray area are not reflected by the maps.

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research Figure A-1. Herbicide spray missions (1966–1967) in the Rung Sat Special Zone. Data from HERBS tape include date of mission, number of gallons, and type of herbicide agent. SOURCE: NAS, 1974.

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research Much of the currently available information on the military use of herbicides in South Vietnam during the period 1962 to 1971—the chemical formulations used, the quantities applied, the operational procedures for aerial spray missions, and the aircraft used—was compiled in the 1970s and early 1980s from military records kept during the conflict, DoD technical reports, and procurement records. In 1974, the National Academy of Sciences' Committee to Review the Ecological Consequences of Herbicides in Vietnam evaluated the available DoD records of herbicide spray missions conducted from 1965 to 1971. During the Vietnam era, thousands of pieces of information on fixed-wing herbicide spray missions were compiled and recorded on the HERBS data tapes. The HERBS tapes are considered to contain the most complete, accurate, and authoritative compilation of data available on aerial fixed-wing herbicide operations conducted in Vietnam (Dashiell, 1973). Non-Ranch Hand Spraying of Herbicides Herbicides were applied by a variety of methods other than fixed-wing aerial spraying. An unknown, but smaller, quantity of herbicides was applied around base perimeters and lines of communication to improve visibility and reduce the likelihood of enemy ambush. Records of these smaller-scale uses of herbicides were not systematically logged and do not appear on the HERBS tapes. A review of various Army records and military reports identified the use of an additional 1.6 million gallons of herbicides, and information on these sprays was subsequently recorded on the Services HERBS tapes. Together these tapes of herbicide sprays account for approximately 20 million gallons of herbicides used in Vietnam from 1962 to 1971. The U.S. Army Chemical Corps, using hand equipment and H-34-type helicopters, conducted smaller spray operations, such as defoliation around Special Forces camps; clearance of perimeters surrounding airfields, depots, and other bases; and small-scale crop destruction (Warren, 1968; Thomas and Kang, 1990). Twenty-two Army Chemical Corps units were assigned to South Vietnam between 1966 and 1971. Approximately 2,900 veterans who served in the Army Chemical Corps in Vietnam between 1966 and 1971 have been identified from unit morning reports. Men serving in these units were trained in the preparation and application of chemicals, as well as in the cleaning and maintenance of the spray equipment (Thomas and Kang, 1990, Dalager and Kang, 1995). Units and individuals other than the members of the Air Force Ranch Hand and Army Chemical Corps were also likely to have handled or sprayed herbicides around bases or lines of communication. For example, Navy riverine patrols were reported to have used herbicides for clearance of inland waterways. Engineering personnel required the use of herbicides for removal of underbrush

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research and dense growth in constructing fire support bases. It is estimated that 10 to 12 percent of the total volume of herbicides was dispensed from the ground by spraying from backpacks, boats, trucks, and buffalo turbines (NAS, 1974). The buffalo turbine was a trailer-mounted spray system used for roadside spraying and perimeter applications, which essentially ''shot'' the herbicide with a velocity up to 240 km/hour and a volume of 280 m3 /min (Young and Reggiani, 1988). Hand spray units consisted of a backpack type of dispenser with a capacity of 3 gallons (Collins, 1967). Although the Air Force maintained complete records of its Operation Ranch Hand fixed-wing herbicide missions, documentation of spraying conducted on the ground by boat, truck, or backpack and authorized at the unit level was less systematic. Authorization for herbicide missions by helicopter or surface spraying from riverboats, trucks, and hand-operated backpacks was delegated to the Republic of Vietnam and U.S. authorities at the Corps level; these operations required only the approval of the unit commanders or senior advisors. "Free-spraying" areas, including the Demilitarized Zone (DMZ) at the seventeenth parallel and the first 100 meters outside base camps, were also exempt from Ranch Hand regulations (NAS, 1974). This delegation of authority for spraying to the Corps level reduced the lag time that existed from proposal to completion of small defoliation projects, such as around depots, airfields, and outposts (Collins, 1967). However, because these helicopter and ground sprays were less rigidly controlled than fixed-wing aerial sprayings, the recording of such sprays was not as systematic as those of Operation Ranch Hand. According to official documents, the "small-scale use of herbicides, for example around friendly base perimeters, was at the discretion of area commanders. Such uses seemed so obvious and so uncontroversial at the time that little thought was given to any detailed or permanent record of the uses or results" (U.S. Army, 1972). DoD took few precautions to prevent troops' exposure to herbicides since they were considered to be a low-level health hazard. Precautions prescribed were consistent with those applied in the domestic use of herbicides existing before the Vietnam conflict (U.S. GAO, 1979). The Army added that exposure of ground troops was very unlikely since DoD personnel did not enter a Ranch Hand-sprayed area until approximately 4 to 6 weeks after the mission, when defoliation was complete and the herbicide had biodegraded or photodegraded (U.S. Army, 1972). The restriction placed on troops' entering a previously sprayed area was primarily for operational reasons, to prevent troops from being injured by the fighter aircraft that often accompanied the herbicide-spraying aircraft (U.S. GAO, 1979). Although some information is documented in military records, it is impossible to determine accurately from military records alone the extent of spraying conducted on the ground or the number of personnel involved in these operations with potential herbicide exposure. An unknown number of non-Ranch Hand personnel likely received various degrees of exposure to herbicides.

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research Young and Reggiani (1988) report that the actual number "may be in the thousands since at least 100 helicopter spray equipment units were used in South Vietnam, and most military bases had vehicle-mounted and backpack spray units available for use in routine vegetation control programs." The dregs of the 55-gallon drums were pumped into smaller drums and sent to military camps for local defoliation of crops and control of perimeter foliage (Dux and Young, 1980). A 1979 study by the U.S. General Accounting Office (U.S. GAO, 1979) examined the military defoliation operation in the Con Thieu province of I Corps between January 1966 and December 1969. During this period, more than 2 million gallons of herbicides were sprayed in I Corps. By using average troop strength and turnover figures, an estimated 218,000 Marine infantry personnel were determined to have been assigned to I Corps between 1966 and 1969. By randomly selecting 276 of 976 Marine monthly battalion reports, the GAO tracked troop movement and compared troop locations with herbicide mission data. Nearly 26,000 U.S. Marines and Navy medical personnel were identified who entered within a radius of 2.5 km of the defoliated target areas within I day of spraying; 4,300 troops were identified as being within 0.5 km of the flight path; 11,700 were within 2.5 km within 4 weeks. In the Khe Sanh-Thon Son Lam area, an estimated 4,300–8,000 troops were within 0.5 km of the sprayed area within I day of spraying; within 28 days, 33,600–45,300 troops were determined to have been within 2.5 km of the defoliation target. Army records were found to lack sufficient information, so that estimates of the number of Army personnel close to sprayed areas could not be calculated. The GAO report concluded that "the chances that ground troops were exposed to herbicide Orange are higher than the DoD previously acknowledged ... the group of personnel most likely to have been exposed could include ground troops as well as herbicide handlers and aircraft crew members" (U.S. GAO, 1979). Geographical Distribution of Herbicide Sprays South Vietnam was divided into four combat tactical zones, from I Corps lying south of the DMZ to IV Corps in the Mekong Delta region (Figure A-2). Although spraying occurred in most provinces of Vietnam, certain areas of the country were subject to more intensive spraying. The herbicide mission maps (Figure A-3) indicate that defoliation missions were not uniformly distributed but were concentrated in certain geographical areas—along transportation routes, in occupied areas around Saigon, and on infiltration routes along the Laotian and Cambodian borders and the DMZ where enemy attacks were likely (U.S. Army, 1972). Primary target areas for crop destruction missions were in I Corps and along the upland and mountain valleys of II Corps (NAS, 1974). The military purposes of these missions were to deny food to the enemy, to redirect enemy

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research from records of herbicide shipments to various military bases, and would consider the type of terrain, typical foliage of the locations, and military mission of the bases and troops located there. Surveys and interviews of Vietnam veterans, stratified by location and period of service, might also provide useful information on situations in which herbicide spraying was prevalent and, if validated, may be incorporated into the exposure reconstruction model. Development of the Exposure Reconstruction Model As conceptualized by the AO committee, this new effort would model the conditions under which herbicides were used in Vietnam and would consider the following information: troop location—based on all available military records, including morning reports, daily journals, situation reports, intelligence summaries, Operational Report Lessons Learned, and combat operations after-action reports; aerial spray mission data—from the HERBS and Services HERBS tapes; estimated ground spraying activity—not based solely on existing records (discussed in more detail below); estimated exposure opportunity factors—including the identification of occupations involving the handling of herbicides, and considerations of how likely troops were to have heavier exposure through eating local food, bathing or drinking local water, contact with contaminated soil, and so on.; military indications for herbicide use—systematic, historic reviews of the conditions under which military use of herbicides was warranted, including information on typical use patterns in those situations such as the Army survey of military commanders conducted in 1971 (U.S. Army, 1972); and. considerations of the composition and environmental fate of herbicides —including changes in the TCDD content of herbicides over time, the persistence of TCDD and herbicides in the environment, and the degree of likely penetration of the herbicides into the ground. Once an exposure reconstruction model has been developed, it should be possible to estimate an exposure score for the large numbers of veterans needed for epidemiologic studies. Ground spraying, although probably representing a smaller quantity of herbicide than aerial spraying, may actually have resulted in heavier human exposures since it probably was done in closer proximity to ground troops, at higher application rates (i.e., number of gallons per acre), and potentially by less well-trained individuals than Ranch Hand spraying. This spraying was often performed around camp perimeters and along communication routes in response

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research to enemy attack or during relocation to a new fire base. Thus, troops may often have remained in the area during spraying or passed through it soon afterward. Ground spraying could reportedly be approved by unit commanders at the Corps level, and the spraying does not appear to have been documented as carefully as the aerial missions of Air Force Ranch Hands. To incorporate estimates of exposure from ground spraying, the AO committee suggested the development of a subsidiary estimation model for this source of exposure. Because ground spraying data are incomplete, this model would be based on a series of factors likely to determine the extent of ground spraying in Vietnam. From testimony presented to the AO committee, it appears that the following factors might have been important determinants of this activity: region and date of military service, terrain, type of vegetation, intensity of enemy activity, any existing data on shipment of herbicides to different regions, and size of military base. Through structured interviews with military personnel who served in various regions and various military units, data would be gathered to permit the development of a model predicting the likelihood and intensity of ground spraying around base perimeters, fire camps, and along roads for different areas and times. A partial check on the utility of this model could be accomplished by comparing its predictions to the limited ground spraying data that do exist in the Services HERBS tapes. This proposal incorporates ideas for exposure reconstruction previously described by others (Bricker, 1981; Erickson et al., 1984a; Stanton, 1989; Lewis, 1993). Evaluation of the Exposure Reconstruction Model The overall exposure reconstruction model could be evaluated in several ways. First, model developers would determine whether the data used in the exposure reconstruction model are internally consistent. This involves checking whether existing spraying records indicate more spraying in areas where it was likely to have been militarily useful from the point of view of terrain, foliage, and military mission. It would also be possible to cross-check the estimated spraying intensity data with a systematic survey of the recollections of veterans who served in particular areas. In a second method of evaluation, exposure estimates based on the reconstruction model would be compared with serum TCDD measurements for a random sample of veterans, stratified according to records-based measures. Although the AO committee concluded that group differences can be useful in confirming that exposure measures reflect the differences in prior exposure, the absence of group differences cannot be interpreted to indicate that groups were not exposed earlier. Serum TCDD measurements should not, therefore, be regarded as a gold standard—a perfect measure of herbicide exposure. In addition to the problems with interpreting serum TCDD measures discussed

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Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research above, some of the herbicides used in Vietnam, such as Agent White, did not contain TCDD, so it is possible for a veteran to have been exposed to a large amount of Agent White without having an elevated serum TCDD level at any time. A third evaluation of the exposure estimation strategy would be to assess the association between the exposure reconstruction estimates and the incidence of health outcomes that are believed to be associated with herbicides. One would expect a positive association between the exposure reconstruction measure and those outcomes found by the AO committee to have sufficient evidence for a statistical association. Because there are sufficient data from occupational studies to suggest an association between herbicides and/or TCDD and non-Hodgkin's lymphoma, one would expect to see a positive association between this cancer and the new exposure reconstruction model data. It might be possible to reanalyze the CDC Selected Cancers Study (CDC, 1990) data, for instance, with data from the proposed exposure reconstruction model rather than with the simple exposure measures that were used in the original study. If such an association were found, it could be interpreted as positive evidence for the validity of the new exposure model. If no association were found, it would not be clear whether this was due to problems in the new exposure measure, to small sample sizes or low average herbicide exposure even in those exposed, or to the lack of a real association between herbicides and non-Hodgkin's lymphoma. The task of exposure estimation for a diffuse class of agents to which up to 3 million persons may have been exposed nearly 30 years ago in wartime is inherently difficult. The AO committee recommended that any exposure reconstruction model be thoroughly evaluated before it is used in epidemiologic studies. Because of the complexity of this task, and the political sensitivity of any studies of Vietnam veterans, the AO committee further recommended that this evaluation be conducted by an independent, nongovernmental scientific panel with expertise in historic exposure reconstruction and epidemiology. REFERENCES Air Force Health Study (AFHS). 1991. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. Albanese RA. 1991. The chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin and U.S. Army Vietnam-era veterans. Chemosphere 22:597–603. Axelson O, Westberg H, eds. 1992. First seminar on occupational exposure assessment: on the concepts of exposure and dose. American Journal of Industrial Medicine 21:1–132.

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