3
Assessment of the Model and Its Capacity to Produce Useful Exposure Metrics

The central question before the committee was how the Stellman team’s model for generating herbicide exposure opportunity metrics might best be used in epidemiologic studies of the health of Vietnam veterans. Before addressing that question, the committee judged it appropriate to first assess the strengths and weaknesses of the data and the calculations that are the basis for the Stellman team’s exposure metrics and the infrastructure of their Herbicide Exposure Assessment–Vietnam (HEA-V) software tool. In this chapter, the committee elaborates on the concept of an exposure assessment hierarchy, as introduced in Chapter 2, to serve as the context for its assessment of the Stellman team’s model. The chapter then focuses on (1) the data on geography and herbicide spraying that are the basic infrastructure of the model, (2) the exposure metrics—“hits” and an exposure opportunity index (EOI)—that the HEA-V helps to calculate, and (3) potential refinements of the model. The chapter also addresses concerns that have been raised about some aspects of the data and assumptions on herbicide spraying and the environmental fate and transport of the herbicides.

Use of the model in epidemiologic studies will require researchers to supply data on troop location histories and veterans’ health outcomes. The committee’s examination of these types of data and their acquisition is discussed in Chapter 4.



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3 Assessment of the Model and Its Capacity to Produce Useful Exposure Metrics T he central question before the committee was how the Stellman team’s model for generating herbicide exposure opportunity metrics might best be used in epidemiologic studies of the health of Vietnam veterans. Before addressing that question, the committee judged it appropri- ate to first assess the strengths and weaknesses of the data and the calcula- tions that are the basis for the Stellman team’s exposure metrics and the infrastructure of their Herbicide Exposure Assessment–Vietnam (HEA-V) software tool. In this chapter, the committee elaborates on the concept of an exposure assessment hierarchy, as introduced in Chapter 2, to serve as the context for its assessment of the Stellman team’s model. The chapter then focuses on (1) the data on geography and herbicide spraying that are the basic infrastructure of the model, (2) the exposure metrics—“hits” and an exposure opportunity index (EOI)—that the HEA-V helps to calculate, and (3) potential refinements of the model. The chapter also addresses concerns that have been raised about some aspects of the data and assump- tions on herbicide spraying and the environmental fate and transport of the herbicides. Use of the model in epidemiologic studies will require researchers to supply data on troop location histories and veterans’ health outcomes. The committee’s examination of these types of data and their acquisition is discussed in Chapter 4. 

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 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT AN EXPOSURE ASSESSMENT HIERARCHY FOR VIETNAM VETERANS The Stellman team has developed a geographic information system (GIS) for use in estimating herbicide exposure in Vietnam, and they have also developed the HEA-V, a computerized database engine that facilitates the linking of disparate georeferenced data and the calculation of exposure metrics (HEA-V, 2003). To understand the strengths and limitations of this approach for measuring the opportunity for herbicide exposure, the commit- tee viewed the model in the context of an exposure assessment hierarchy. Placing the Stellman Team’s Model in an Exposure Assessment Hierarchy As noted in Chapter 2, an exposure assessment hierarchy can help illustrate both the relationship between an environmental exposure and a health outcome and the levels at which “exposure” might be measured with greater or lesser accuracy. More specifically, Figure 3-1 illustrates the exposure assessment hierarchy that the committee used to guide its think- ing on herbicide spraying in Vietnam and the level at which the Stellman team’s model operates. The simplest marker of exposure opportunity is presence or absence of a veteran in Vietnam (level 1). Level 2 uses information on proximity to spraying in space and time for military units or individuals. This is primar- ily the level at which the Stellman team’s model operates. The exposure opportunity metrics of hits and EOIs are calculated for geographic loca- tions, and those results can be combined with user-supplied information on the location histories of military units or personnel to calculate hits and EOIs at the unit or person level. A unit-level measurement would in effect assign the same EOI to all individuals within the unit. Hits and EOIs can be considered to serve as proximity-based surrogates of exposure. The proximity-based exposure metrics might be refined by the incorpo- ration of fate and transport models that provide estimates of the concentra- tion of an herbicide in various environmental media (level 3). For example, a spray drift model or estimates of the proportion of the sprayed herbicide that reaches ground level might be used instead of proximity alone. The next level of refinement in estimating exposure (level 4) would require data on individual-level interactions with the environment (e.g., dermal exposure to soil, consumption of local food) to better estimate personal exposures and permit examination of differences among units or individuals present at the same places and times. At the most highly refined level (level 5), information on pharmacokinetics— which relates to the body’s absorption, distribution, metabolism, and elimina-

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 ASSESSMENT OF THE MODEL 1. Presence in Vietnam or not Inputs to Data on location/time of the Model military units and spraying • Spray dates 2. Proximity to spraying in space Potential • Flight path Refinements and time locations (exposure opportunity) • Type of herbicide • Primary and • Volume sprayed secondary drift Fate and transport • Location history • Foliage density model for herbicide for military units • Penetration of or personnel herbicide through foliage 3. Group-level ambient exposure of military units or personnel • Photodegradation characteristics Individual-level behavioral data 4. Exposure of individuals by various routes Pharmacokinetics 5. Individual absorbed doses FIGURE 3-1 An exposure assessment hierarchy showing levels at which herbicide exposure in Vietnam can be assessed. The box on the left shows the inputs to the Stellman team’s model, and the box on the right shows some potential inputs if a revised model were to incorporate fate and transport phenomena. fig 3-1 Type is enlarged from 6.2 points tion of chemicals—would be needed to estimate the doses of a toxic compound to 7 points that individuals receive. Thus advancing through the hierarchy moves closer to measures of a truly biologically relevant dose. TCDD (2,3,7,8-tetrachloro- dibenzo-p-dioxin) levels in serum or tissue have been used as biomarkers of exposure to the TCDD contaminant in Agent Orange and some of the other herbicides used in Vietnam, but comparable biomarkers are not available for any of the herbicides per se, and the usefulness of TCDD levels has receded as the time since exposure in Vietnam has increased. Proximity-Based Surrogates of Exposure in Vietnam The exposure assessment hierarchy is instructive in comparing the exposure metrics generated by the Stellman team’s model and the exposure assessments used in previous epidemiologic studies of Vietnam veterans.

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 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT (See Appendix B for a table summarizing the exposure assessments used in studies of U.S. Vietnam veterans.) In most cases, military personnel were considered “exposed,” not necessarily to herbicides but to the “war experi- ence in total,” if they were present in Vietnam during designated years or were part of specific military units at the division or corps level. In several studies, veterans’ self-reports of herbicide exposure were used as the expo- sure metric. A few studies have included an effort to assess the location of study participants in relation to recorded herbicide spray locations. More detailed exposure assessments, including serum TCDD measurements, have been made for those military personnel who were part of the Operation Ranch Hand units or the Army Chemical Corps, both of which applied herbicides in Vietnam. Proximity-based exposure metrics similar to those developed by the Stellman team were used in a 1986 validation study conducted in con- junction with the planning for a large Agent Orange Exposure Study to be done by the Centers for Disease Control and Prevention (CDC, 1989). The CDC “hits” metric defined an exposure hit as a unit’s presence within 2 kilometers of spraying that occurred within the previous 6 days. CDC also developed a weighted hit score for which the weight was related to the environmental half-life of TCDD. The result was that troops within 2 kilometers of a spray path 1 day after spraying were assigned a higher exposure score than troops in the same location 5 days after spraying. Finally, CDC developed an “area score,” which was based on the number of days a company was in one of five large, heavily sprayed regions of the III Corps Tactical Zone during 1967–1968 (CDC, 1989). Other Uses of Proximity to Source as a Surrogate for Exposure In environmental health studies, it is often necessary to make a retro- spective assessment of a study population’s exposures to an agent of inter- est. When stronger data, such as biomarker measurements for individuals or ambient environmental levels of an agent are unavailable, proximity to the agent has been used as an exposure surrogate. Such studies provide some insight into the usefulness of proximity as an exposure metric for herbicide use in Vietnam. Seveso Studies of the health effects of TCDD exposure from the 1976 indus- trial accident in Seveso, Italy, offer one example of a proximity-based approach to exposure assessment. Subjects were assigned to exposure zones based on the location of their homes, and these exposure zones were defined

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 ASSESSMENT OF THE MODEL by proximity to the plant and measurements of surface soil contamination (Caramaschi et al., 1981). These environmental measurement-based expo- sure zones were associated with rates of chloracne, diabetes, and lymphatic and hematopoetic cancers (Bertazzi et al., 2001). They have also been corre- lated with serum TCDD levels on the basis of blood samples collected after the accident in 1976 and, later, in the 1990s, with serum TCDD concentra- tions being much higher on average in residents of the more highly exposed areas (e.g., Bertazzi et al., 1998; Eskenazi et al., 2004). Agricultural Studies Proximity to the locations of pesticide applications has also been explored as a potential surrogate for exposure in several U.S. studies. In an area of orchard cultivation in Washington State, organophosphate insecti- cide levels in carpet dust and metabolites in urine of children in agricultural families increased with self-reported proximity of homes to crop fields (Lu et al., 2000). Another study of children residing in a similar area of the state found that concentrations of organophosphate insecticide metabolites in urine were not related to proximity to fields but increased during the pesticide application season compared with other times of the year (Koch et al., 2002). In Iowa, over 90 percent of crop acreage (primarily corn and soybeans) is treated with one or more herbicides. Detections of agricultural herbicides and herbicide concentrations in house dust samples increased significantly with increasing acreages of corn or soybean fields within 750 meters of homes (Ward et al., 2006). However, the location of crop acreage within specific buffer distances of 100–500 meters did not explain significantly more of the variation in pesticide level than total acreage within 750 meters (Ward et al., 2006). Another study in Iowa (Curwin et al., 2005) found no relationship between agricultural herbicide and insecticide concentrations in house dust and self-reported proximity to crop fields in nonfarm house- holds; distance was classified in quarter-mile increments, ranging from less than 0.25 miles to more than 1 mile. INFRASTRUCTURE OF THE STELLMAN TEAM’S MODEL In view of the merit of the Stellman team’s proximity-based approach as a reasonable step toward more accurate herbicide exposure assessment, the committee reviewed the components that are the infrastructure of the GIS and the HEA-V software. Three integral databases store basic inputs on dates (filename: DATES), geography (GridPoints), and the data on herbicide spraying (HERBS).

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0 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT Time and Geography Time references are essential in the calculation of the exposure metrics. Each date from January 1, 1961, through December 31, 1975, has been assigned four unique integer values corresponding to its day, week, month, and year within that 15-year period. The integer values facilitate the date- related calculations. As noted in Chapter 2, the model uses a GIS that is based on a grid that covers all of South Vietnam (as well as sprayed areas in Cambodia and Laos). The grid uses fixed intervals of 0.01° of latitude and longitude, which results in 176,060 cells of approximately 1.2 square kilometers each (Stellman and Stellman, 2003). The coordinates of the southwest corner of a cell serve as the reference point, and each cell is assigned a unique iden- tification number in the GridPoints database. Calculations of distance are made from the centroid of a cell, which is reported as being no more than 800 meters from any of the cell’s corners (Stellman and Stellman, 2003). These two databases are straightforward tools and are subject to little potential error or uncertainty. The committee notes, however, that the loca- tion data in military records from the Vietnam era, such as those for spray missions or sites of military encampments, were recorded with map coor- dinates in a version of the Universal Transverse Mercator (UTM) system used by the military, rather than in coordinates of latitude and longitude. The UTM values were converted to latitude and longitude using software from what is now the National Geospatial-Intelligence Agency (Stellman, 2007). Herbicide Spraying The third integral data component in the GIS is the information that the Stellman team has assembled on herbicide spraying. The data elements of the HEA-V HERBS file include information on when and where each her- bicide mission took place, how the mission was conducted (e.g., fixed-wing aircraft or other means), what herbicide was used, and how much herbicide was used. Of particular interest to the committee in thinking about generat- ing exposure opportunity metrics were the nature and quality of the data on the location of spraying and the amount of herbicide applied. Stellman and colleagues (2003a) have described assembling this data- base by cleaning, combining, and reconciling data on spraying from several sources, including records on Operation Ranch Hand missions and U.S. Army helicopter and ground spraying activities (sources known as the HERBS and Services HERBS tapes); newly identified data from the National Archives; and data relating to aborted missions, emergency dumps, leaks, crashes, and other herbicide releases that were not part of standard spray-

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 ASSESSMENT OF THE MODEL ing missions. They report having examined and reconciled multiple versions of previously compiled data on Ranch Hand missions, original U.S. Air Force records that included Daily Air Activities Reports (DAARs), and the contents of Air Force “project folders,” which could include maps, after- action reports, and other documentation of groups of spraying missions (Stellman and Stellman, 2003). Mission Records The HEA-V HERBS file contains information on 9,141 separate spray- ing missions, of which 5,957 (65 percent) are recorded as Ranch Hand flights by C-123 fixed-wing aircraft. Records of these missions are consid- ered relatively complete, especially for 1965–1971, in part because of the formal, high-level approval process for those missions (U.S. Army, 1985; Stellman et al., 2003a; Young et al., 2004a). Also included in the HEA-V file is what is recognized as incomplete information on U.S. Army helicopter and ground spraying activities (U.S. Army, 1985; Stanton, 1989; IOM, 1994). A review of the file showed that it has records for 2,108 helicopter missions and 446 missions that used ground spraying equipment. (The delivery method is not specified for the remaining 630 missions, 70 percent of which were recorded as being for perimeter spraying around base camps, fire bases, air bases, and other fixed military camps.) Records of helicopter missions were kept with Ranch Hand records beginning in 1968, but ground spraying was not tracked as part of a permanent record system (Stanton, 1989). Information on herbicide use by the U.S. Navy, U.S. Marine Corps, Vietnamese, and other allied forces is not known to be available. The Stellman team’s comparisons of spraying records with procurement records show disparities in both directions—in some cases (e.g., Agent Pink) it would appear that more herbicide was pro- cured than documentation shows was sprayed, while in others (e.g., Agent Purple) it appears that more was sprayed than surviving records would indicate was procured (Stellman and Stellman, 2004). Location of Herbicide Spraying The location data in the HEA-V HERBS database identify the mission’s region (the Corps Tactical Zone, e.g., III Corps) and sometimes the province in which the mission originated. A review of the file showed that for approximately 99 percent of the fixed-wing missions, UTM coordinates are available for the starting and ending points of the mission and for interme- diate points at which the flight path changed or the spray was turned on or off. About 50 percent of helicopter missions and 60 percent of ground spraying missions are represented by a single UTM coordinate.

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 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT The HEA-V system represents the flight path for a mission by straight lines between the known UTM points (Stellman and Stellman, 2003), but actual routes may have curved to follow the path of a target such as a road or waterway. The Stellman team reported plans to use information on the nature of target areas to impute more realistic flight paths (Stellman and Stellman, 2004), but this work has not yet been completed (Stellman, 2007). The records also include the number of fixed-wing planes flown in a given mission: 4.6 percent of these missions were flown with one aircraft, 21 percent with two, 44 percent with three, 11 percent with four, and 19 percent with five or more planes. The number of planes flown on a mis- sion is a factor in the size of the area sprayed. Although the current version of the HEA-V does not account for differences among missions in the total width of their flight paths, the Stellman team has explored ways in which the information might be incorporated (Stellman, 2007). Herbicide Agents and Volume Estimates The HEA-V HERBS database identifies the herbicide used in a mission and the amount dispensed (the “gallonage”). “Incidents” that would have affected the dispersal of herbicide (e.g., an aborted flight, leaks) are identified as well. The Stellman team (2003b) reported that Agent Orange accounted for 62 percent of the total documented volume of herbicide used (approxi- mately 12 million out of 19.5 million gallons), with 28 percent being Agent White, 6 percent being Agent Blue, 3 percent being other known herbicides, and 1 percent unknown agents. Although Stellman and colleagues (2003a) discuss the amount and variability of the TCDD contamination that may have been present in some of these herbicides (discussed later in this chap- ter), the HEA-V data do not incorporate any explicit estimates of TCDD levels for individual spray missions. The available records show that 95 percent of the herbicide used was applied via the missions flown by fixed-wing aircraft as part of Operation Ranch Hand (Stellman et al., 2003a). The Stellman team’s database shows that, overall, data on the amount of herbicide used are missing for 781 (8.5 percent) of the missions. The data are missing for only 0.9 percent of fixed-wing missions but for 33 percent of ground spraying missions. As with the data on the location of spraying, the information on the herbicide agents and volumes sprayed appears to reflect the Stellman team’s review of multiple sources, including attempts to reconcile herbicide pro- curement records with records of use and destruction of remaining stocks of these products (Stellman et al., 2003a). The magnitude of a separate set of volume estimates that were based on procurement and disposition records for 1965–1971 (17.4 million gallons of agents Orange, White, and Blue combined) (see Young et al., 1978) is similar to the amount in the Stellman

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 ASSESSMENT OF THE MODEL team’s data drawn from Ranch Hand files for the same period (17.5 million gallons). The Stellman team’s data include an additional 1.6 million gallons in records covering the period before 1965 and the use of other agents. EVALUATION OF THE INFRASTRUCTURE OF THE STELLMAN TEAM’S MODEL In evaluating the infrastructure of the Stellman team’s model, the issues of principal concern to the committee included the general completeness of the data, the completeness of data on herbicide spraying conducted sepa- rately from Ranch Hand flights, the potential for errors in the location of spraying arising from errors or imprecision in UTM coordinates or from the representation of flight paths as straight lines, and the appropriateness of assumptions about the extent of the area considered exposed to herbicide by a given mission. The committee included in its considerations limitations of the model noted by the Stellman team (e.g., Stellman and Stellman, 2004) as well as concerns about aspects of the model that have been raised by others (e.g., Young and Newton, 2004; Young et al., 2004a,b; Ross and Ginevan, 2007; Young, 2007; Ginevan et al., 2008). Completeness of Data Efforts have been made since the early 1970s to compile information about herbicide use in Vietnam. Records from the Vietnam War are known to vary in their quality and completeness (Shaughnessy, 1991; Young et al., 2004a; Boylan, 2007). Much of the data on which the HEA-V HERBS file is based were originally recorded by field units and forwarded to the Chemical Operations Division of the central military command in Vietnam. A 1971 audit of an early version of the Ranch Hand spraying data characterized the statistical quality of the data as good; but it found that 2 percent of the records had missing data, 6 percent had “serious” tran- scription or measurement errors, and 23 percent had errors in the length of the track sprayed (Heizer, 1971). An assessment of the Ranch Hand records by a National Academy of Sciences committee (NRC, 1974) concluded that the data as a whole were reliable despite inaccuracies in some records. That committee’s comparisons of flight path coordinates from a sample of records with aerial photographs suggested good agreement for defoliation missions. The Stellman team has described a substantial review of various types of original records as part of its 1998–2003 work to develop its GIS and exposure opportunity model (Stellman and Stellman, 2003). The work was done in consultation with the Army unit now known as the Joint Services Records Research Center (JSRRC). The Stellman team used information

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 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT they collected to fill in missing data on spraying records and to identify and correct errors when possible. In comparisons between the compiled records on spray missions and separate archival records on 60 percent of Ranch Hand target areas, spray paths of related missions were found to generally fall within these identified target areas (Stellman et al., 2003b). Because the Air Force target data and the mission flight path database are independent of each other and generally corroborate each other, the Stellman team sees them as providing some validation of the spray location data (Stellman et al., 2003b). The committee is persuaded that the Stellman team’s HERBS database is as complete a record of herbicide spraying as currently exists. However, the data appear to be more complete for the Air Force Ranch Hand mis- sions than for spraying conducted by other services or by other means, such as helicopter or ground spraying. Because formal reporting for Army heli- copter spraying is described as having started in 1968 (U.S. Army, 1985), the records on helicopter spraying are presumed to be more complete for the 1968–1971 period than for earlier years. To the committee’s knowledge, factors influencing the availability of non-Ranch Hand spraying records have not been identified in any systematic way; it is therefore not possible to judge whether the available data are relatively representative or whether they may under-represent spraying activities in certain areas or time periods. The IOM committee that oversaw the Stellman team’s work for VA reached a similar conclusion (IOM, 2003). Accuracy of Flight Path Data The Stellman team notes (Stellman and Stellman, 2004) that flight paths are represented with straight-line segments but that this assumption may not always hold. Young and colleagues (2004a) point to DAARs for reports that aircraft may have adopted zigzag flight patterns in response to enemy fire. The straight-line assumption may also not hold when the flight path followed features such as a river or a highway, with variations of as much as a kilometer or more from recorded locations suggested (Young et al., 2004a). Anecdotal evidence suggests that aircraft crews navigated by a combination of visual orientation and maps that were precise to no better than 120–240 meters (Young et al., 2004a). The committee heard concerns that the Stellman team’s EOI calcula- tions take into account an excessively wide area (up to 5 kilometers) on either side of a flight path (Ross and Ginevan, 2007; Ginevan et al., 2008). This issue is discussed again later in the chapter, but the committee notes here that considering the wider area when assessing exposure opportunity would seem to address, at least to some extent, the concern that true flight paths may have deviated from the straight lines used in the model. Missions

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 ASSESSMENT OF THE MODEL flown with multiple aircraft also would have contributed to variation in the width of the area where herbicide was applied. Accuracy in locating herbicide spraying is essential for effective assess- ment of exposure, but the concerns that have been raised do not appear to point to major misrepresentations of locations in the spraying database. Other Issues It has been noted that troops on the ground may have mistaken the frequent aerial spraying of insecticide (e.g., malathion) for herbicide spray- ing (Young et al., 2004a; Cecil and Young, 2008). Young and colleagues (2004a) point to reports that between 1966 and 1972 more than 3.5 million liters of malathion were sprayed over approximately 6 million hectares of South Vietnam and that by 1970 malathion was being sprayed at 9-day intervals. The committee did not attempt to determine whether records exist that document the flight paths of insecticide spray missions. If they do, it would be appropriate to consider adding that data to the Stellman team’s GIS. THE STELLMAN TEAM’S EXPOSURE OPPORTUNITY METRICS As previously described, the Stellman team’s model produces two expo- sure metrics that are based on proximity to herbicide spraying: hits and the EOI. The hits metric represents direct exposure, and the EOI incorporates consideration of indirect exposure from previous spraying. The model uses a two-stage approach to calculate the exposure values. The first stage relies on the datasets that the committee has described as the infrastructure of the model. The data on the location and date of each spraying mission are used to calculate a hit and an EOI value for each indi- vidual cell in the GIS grid that falls within 5 kilometers of that mission’s spray path. These geographically based exposure calculations are stored, along with essential information about the associated spray mission, as individual records for each cell exposed to spraying during that mission. The database containing all this information (Exposure_Master) contains approximately 1.45 million records and is an integral part of the HEA-V tool. At the second stage, this geographic exposure database is used in combination with user-supplied information on the location histories of military units, individual military personnel, or other study subjects to calculate exposure scores for the period that the units or the individuals spent in Vietnam.

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 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT military herbicides used in Vietnam, but it is not prominent in PCDDs generated by combustion. TCDD and related compounds have very low water solubility and are lipophilic. Following aerial spraying, waste incineration, or other atmospheric releases, the compounds may be deposited on plants, on soil, and in bodies of water and their sediments. They can also enter water and sediments from such sources as effluent discharge and soil runoff. Although TCDD can be degraded by sunlight, it is otherwise highly persistent in the environment and can accumulate in the fatty tissue of some fish and mammals. Studies carried out at Eglin Air Force Base in Florida indicated that even though 99 percent of the TCDD applied was photodegraded, TCDD was still detectable in test plots several years after application (Young and Newton, 2004). The half-life of TCDD has been estimated at 9–15 years in surface soil and 25–100 years in subsurface soil (Paustenbach et al., 1992). In sediments, TCDD has been found to persist over decades (Bopp et al., 1991). An investigation in one area of Vietnam found that TCDD levels were somewhat elevated in soil samples from locations where aerial spraying had occurred 30 years earlier (Dwernychuk et al., 2002). The same investiga- tion also found that soil samples from Special Forces bases in the area had significantly higher concentrations of TCDD than the soil samples collected from flight paths. The higher levels in the base areas were attributed to her- bicide spillage and disposal. A separate analysis of soil and sediment from areas at and around the site of the Da Nang Airbase, which was a base used for Operation Ranch Hand missions, found very high levels of TCDD (365,000 ppt) in soil samples from specific sites where herbicides had been stored or airplanes’ spray tanks had been loaded (Hatfield Consultants and Office of the National Steering Committee 33, MNRE, 2007). Because of the persistence of TCDD and other PCDDs, samples of undisturbed soil or sediment can provide a historical record of their deposi- tion (e.g., Czuczwa and Hites, 1984, 1986; Baker and Hites, 2000). Com- parisons of TCDD and PCDD levels found in areas that were sprayed and areas that were not may offer some qualitative insight into past exposure sources. However, several factors hinder the use of data on current TCDD concentrations to validate the Stellman team’s model. With sediment cores from a lake or delta, the historical profile of the total levels of TCDD depos- ited over the watershed does not adequately indicate localized variations in soil deposition. In addition, the precision with which TCDD deposition in sediments can be dated is limited and may be no better than 2 to 5 years (e.g., Frignani et al., 2004). Therefore sediment analysis could only be used to validate the estimates of exposure opportunity generated by the Stellman team’s model on very broad geographic and temporal scales. With soil analysis, the range of 9 to 15 years for the estimated half-life of TCDD in surface soil and the use of herbicides extending over a 10-year

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 ASSESSMENT OF THE MODEL period mean that present-day TCDD levels may reflect levels that were anywhere from 3.4 to 15 times higher during the war. There are also likely to have been other sources of TCDD and PCDD deposition over the more than 45 years since herbicide spraying began, including contributions from open burning of waste during and after the war, burning of materials con- taining polychlorinated biphenyls, and long-range atmospheric transport of TCDD and PCDDs. As a result, it may be difficult to isolate the contribu- tions of TCDD from war-era herbicides except in areas where they were extensively used. For the herbicides themselves that were used in Vietnam, virtually no opportunity exists to test for residues. The principal components of Agent Orange, the military herbicide used most extensively, were 2,4-D and 2,4,5-T in various formulations. Unlike TCDD, these compounds are fairly water soluble and not persistent. For example, 2,4-T has a half-life in soil of approximately 6 days and in aerobic aquatic environments of 15 days (EPA, 2005). Similarly, malathion, which was sprayed to control mosquitoes and potentially confused with herbicide spraying, has a half life of 11 days or less in soil and up to 2 weeks in an aerobic aquatic environ- ment (EPA, 2006). As a result, no major accumulation of these compounds in soil and sediment is likely. Utility of Serum and Adipose TCDD Measurements In humans, an initial rapid rate of elimination of TCDD is followed by a slower rate that results in an estimated half-life of 7–10 years (e.g., Michalek et al., 2002). As it has been more than 35 years since any U.S. military personnel were exposed to TCDD in Vietnam, studies conducted now may not be able to reliably distinguish TCDD exposure in Vietnam from background exposure in the United States from other sources (e.g., combustion or food). The IOM committee that oversaw the Stellman team’s work for VA reached a similar conclusion (IOM, 2003). Some previous studies have explored the correlation between measures of exposure and TCDD levels in tissue samples. These studies have used various approaches to exposure measurement and have had varying results. CDC Study In 1987, CDC (1988, 1989) measured TCDD levels in serum samples from 646 enlisted Vietnam veterans with a pay grade between E1 and E5 and only one tour of duty in Vietnam (average 320 days) who served in one of five combat battalions in III Corps during 1967–1968. Comparison samples were drawn from 97 U.S. Army veterans of the same era who did not serve in Vietnam (CDC, 1988). The Vietnam veterans were selected to

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 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT represent low, medium, and high categories of exposure, which were defined on the basis of the number of hits. (As described above, a hit was defined as a person’s company being located within 2 kilometers of a recorded Agent Orange spraying mission within 6 days after the spraying.) Subjects in the high exposure category had five or more hits. Fifty-four percent of the Vietnam veterans enrolled in the study had at least one hit, and 30 percent had five or more. The analysis used this exposure measure as well as two others, all of which were based on proximity in space and time to Agent Orange spraying, as the Stellman team’s measures are. Although a range of TCDD levels was found in this study, the serum levels of those who served in Vietnam, which ranged from non-detectable levels to 45 ng/g lipid, were not significantly different from the levels among veterans with no Vietnam service (range: non-detectable levels to 25 ng/g lipid) (CDC, 1988). Only 4 percent of the Vietnam veterans had TCDD levels above 8 ng/g lipid. There was also no significant trend in serum TCDD levels by exposure score category. The lack of relationship between serum TCDD levels and exposure scores was an important factor in the cancellation of the larger CDC study of the long-term health effects of exposure to Agent Orange (CDC, 1989). There are several reasons why the CDC study may have failed to detect a difference in TCDD serum concentrations between the veterans who served in Vietnam and those who did not. The TCDD concentrations in Agent Orange used during the exposure period studied may have been relatively low. Contamination levels could vary by production run and manufacturer and were found to range from 0.05 to 50 ppm, averaging 1.98 and 2.99 in two sets of samples (NRC, 1974; Young et al., 1978). It is also possible that the study selection criterion requiring a single tour of duty may have undersampled subjects with high exposure opportu- nity, limiting the power of the study to detect differences. Only 30 percent of the Vietnam veterans tested had hit scores of 5 or greater (i.e., being in locations within 2 kilometers of spraying that had occurred in the previous 6 days five or more times). Differences in pharmacokinetics between veterans due to differences in metabolism, body composition, or weight change, could have influenced the rate at which TCDD was eliminated. Furthermore, the pharmacokinetics of TCDD is more complicated than the simple first-order models assumed in the CDC study as the basis for power calculations (e.g., Michalek et al., 2002; Emond et al., 2005). However, elevated serum and adipose tissue levels of TCDD have been used elsewhere to document higher exposure (e.g., Flesch-Janys et al., 1998; Michalek et al., 2002). Another possibility is that most American military personnel who served in Vietnam did not have high TCDD exposure. The range of expo- sure opportunity scores seen for most Vietnam veterans may not represent

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 ASSESSMENT OF THE MODEL significant elevations in TCDD exposure. The lack of correlation between exposure score and TCDD serum levels could also mean that the exposure score is a poor surrogate for TCDD exposure. Residents of Vietnam Comparisons have also been made between TCDD levels and EOIs for two groups of Vietnamese (Verger et al., 1994; Kramarova et al., 1998; Stellman and Stellman, 2003). In one comparison, adipose tissue samples from 25 participants in a cancer case-control study conducted in Ho Chi Minh City were analyzed for TCDD and other PCDDs and PCDFs (Stellman and Stellman, 2003). These subjects were recruited in 1993–1997 for a study supervised by the International Agency for Research on Cancer (IARC). Of the analyzed samples (from a mix of cases and controls), 11 had detectable TCDD levels, ranging from 1.0 to 4.2 pg/g lipid. The Stellman team (Stellman and Stellman, 2003) computed EOI values for the study subjects on the basis of geocoded residential histories. Seven subjects had an EOI of zero; scores for the others ranged from 295 to 7.7 × 105. The Pearson correlation coefficient between the TCDD levels and the EOI (both log-transformed) was 0.23 and not significantly different from zero, but no sample had both a high TCDD level and a low EOI (Stellman and Stellman, 2003). A second study examined 27 Vietnamese men admitted for abdominal surgery in Ho Chi Minh City in 1989; all patients were born before 1953 (Verger et al., 1994). TCDD concentrations in adipose tissue samples (range: non-detectable levels to 49.6 pg/g lipid) were compared with EOI scores (range: 0 to 9,868) computed based on residential history and an earlier version of the Stellman team’s model. The Spearman correlation coefficient for all samples was 0.32, p = 0.10 (with log transformation: Pearson r = 0.36, p = 0.07). Restricting the analysis to the 22 subjects with non-zero EOIs increased the correlation (Spearman = 0.44, p = 0.04; Pearson = 0.50, p = 0.02) (Verger et al., 1994; Stellman and Stellman, 2003). The committee sees the data on Vietnamese residents as providing weak evidence that the EOI can serve as a predictor of TCDD concentrations in people. It is unclear whether these results can be generalized to U.S. vet- erans because the Vietnamese study subjects could have been exposed to TCDD for long periods of time, including extended exposure via the food chain, a route less likely for American military personnel. TESTING AND REFINING THE STELLMAN TEAM’S MODEL The Stellman team’s model for herbicide exposure in Vietnam counts direct exposure events and also produces a quantitative representation of

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 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT indirect exposure that takes account of the quantity of herbicide sprayed, the distance from the spray path, and, by using an environmental decay factor for the herbicides, the time since spraying. The committee notes first that the exposure assessment model and metrics developed by the Stellman team are one approach but not necessarily the only approach that might be followed for a proximity-based assessment of exposure opportunity. Other approaches might be explored, possibly without requiring collection of additional data. There are also several possible expansions of the model and the GIS databases, each of which has advantages and disadvantages. For exam- ple, the Stellman team (Stellman et al., 2003b) has described developing other geocoded databases that might be used to refine exposure estimates. Examples of these databases include locations of inhabited places during the period of the Vietnam War, roadways and other constructed features, locations of military sites, and soil types. Only the database on soil types was available to the committee for examination. Aerial spray drift dispersion models might also be useful. For example, the AgDRIFT (Teske et al., 2002) and AGDISP models (Bilanin et al., 1989) use inputs such as the type of aircraft and spray nozzle, characteristics of the spray material, spraying height, swath width, wind speed and direc- tion, and temperature to estimate the percentage of the spray that deposits at various distances from the flight path. For application to spraying in Vietnam, inputs such as weather conditions are likely to be available from the DAARs, but they would have varied relatively little if official operating procedures were followed. Those procedures specified that spraying flights take place in clear weather, with wind speeds of no more than 10 miles per hour, and that herbicide be dispensed at an altitude of 150 feet at a constant delivery rate of 3 gallons/acre (MACV, 1969; Stellman and Stellman, 2003; Young et al., 2004a). Other factors such as the types of vegetation, characteristics of the ini- tial and remaining canopy, and meteorological parameters that could affect the ground-level deposition, photodegradation rate, and the availability of herbicide in the topsoil could also be incorporated into a more detailed exposure model that might use the Stellman team’s EOI or the spraying location data in the GIS as a starting point. Consideration of secondary drift (e.g., through evaporation from treated plant materials or transport of aerosolized particles) might further improve estimation of exposure. However, the committee is not aware of any currently existing secondary drift models that could be directly applied. Rather, such models would need to be developed. Although use of spray drift models or incorporation of other factors could potentially result in improved quantification of herbicide deposition, it is unclear whether they would result in changes in the relative ranking of

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 ASSESSMENT OF THE MODEL exposures among military personnel or units. It is also unclear how much of the historical data needed to use these more advanced spray deposition models would be available in the military records. No “gold standard” exists for use in testing the accuracy of retro- spectively estimated exposure of veterans to herbicides in Vietnam using the Stellman team’s hits or EOI score, alternative simple proximity-based measures (e.g., incorporating other distance functions), or approaches that use the Stellman team’s infrastructure as a foundation for more elaborate fate and transport modeling (e.g., primary and secondary drift). Thus the committee sees it as essential that sensitivity analyses be done to compare various approaches to estimating exposure. The exposure measures they produce should be compared with each other to see how assigned exposures are changed, particularly rank orderings. The impact of assumptions (e.g., distance functions, decay rates) should be examined in the same way. CONCLUSIONS Based on its review of the Stellman team’s herbicide exposure assess- ment model, the committee reached several conclusions. 1. Using a surrogate of exposure that is based on individuals’ or military units’ proximity in space and time to herbicide spray paths is a reasonable exposure assessment strategy. This approach is a clear improve- ment over the cruder measures of exposure or opportunity for exposure, such as those based on service in Vietnam, that have been used in some past studies of the potential effects of herbicide exposure on the health of Vietnam veterans. Such proximity-based surrogates are similar to exposure measures commonly used in occupational health studies (e.g., job title) and in environmental studies of proximity to sources of exposure. 2. The Stellman team’s databases and GIS provide a useful basis for estimating proximity-based surrogates of exposure to herbicides in Viet- nam. Because of the availability of relatively more complete data on spray- ing by fixed-wing aircraft, the model is currently better suited to examining proximity to that type of spraying than to spraying from ground equipment or helicopters. The uncertainty about the completeness of the data on heli- copter and ground spraying should be taken into consideration, especially when studying stable units, which may have had limited exposure to fixed- wing spraying. 3. The Stellman team’s hits and EOI scores have value in that they move further along the exposure assessment hierarchy than exposure assess- ment based only on presence in Vietnam. However, the methods by which the hits and EOI scores are calculated have the potential for significant exposure misclassification, and so these metrics must be used with caution.

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0 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT Other proximity-based approaches with the potential for estimating exposure scores more accurately should be explored. Moving from exposure metrics based on spray and troop location data to more accurate exposure and dose metrics would require the incorporation of additional data, such as herbicide fate and transport, individual behavior, and pharmacokinetics. 4. Fate and transport processes not incorporated into the current version of the Stellman team’s model (e.g., width of the spray swath, con- centration of contaminants, primary and secondary drift, soil conditions, initial and remaining canopy, and photodegradation) will affect estimates of exposure to herbicides and their contaminants. Incorporating these phenomena into an exposure model could possibly reduce exposure mis- classification but would require additional data that may or may not be available. However, the relatively coarse resolution of the military UTM system used in military records and the Stellman team’s GIS grid map of Vietnam may limit, to some extent, the benefits of adding fine-scale fate and transport modeling. 5. Regardless of the exposure model used, sensitivity analyses are nec- essary to determine the impact of model assumptions regarding decreases in herbicide concentration with distance and time on the exposure assignments generated. Such studies provide important information on the stability of the proposed exposure opportunity measures. 6. Given the significant uncertainties about the levels of TCDD con- tamination over time and from different lots of the herbicides used in Viet- nam, proximity-based exposure models may be better suited to studies of the health effects of herbicides in general rather than TCDD specifically. 7. It is not feasible to validate the exposure scores produced by the Stellman team’s model, or any other proximity-based model, by compari- sons with biomarker or soil samples because of the passage of time and the unavailability of archived environmental or biological samples. RESEARCH OPPORTUNITIES From its review of the Stellman team’s model, the committee identified two areas where it urges further investigation. 1. Efforts should be made to improve and refine the Stellman team’s model by exploring alternative formulations of the proximity-based expo- sure metrics and by incorporating alternative or additional model parameters that account for more aspects of herbicide fate and transport in the environ- ment. Further development of the model will require an assessment of the additional data needed and of the availability of these data. 2. The sensitivity of the Stellman team’s model’s results to changes in parameter values should be assessed systematically. The committee specifi-

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 ASSESSMENT OF THE MODEL cally urges attention to effects of potential inaccuracies in the data on the location of herbicide application or troop presence. It is also important to investigate, especially with any attempt to add refinements to the existing model, the effect of assumptions on factors such as spray swath, the con- centration of the TCDD contamination, primary and secondary drift, soil conditions, initial and remaining canopy, and photodegradation of sprayed herbicide. Although the committee concluded, based on the information it reviewed, that direct validation of the accuracy of exposure assignment is not feasible, it encourages efforts to quantify the degree of accuracy and incorporate those estimates into the sensitivity analysis. REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 1998. Toxicological profile for chlorinated dibenzo-p-dioxins. Atlanta, GA: U.S. Department of Health and Human Services. Baker, J. I., and R. A. Hites. 2000. Siskiwit Lake revisited: Time trend of polychlorinated dibenzo-p-dioxins and dibenzofuran deposited at Isle Royale, Michigan. Environmental Science and Technology 34:2887–2891. Bertazzi, P. A., I. Bernucci, G. Brambilla, D. Consonni, and A. C. Pesatori. 1998. The Seveso studies on early and long-term effects of dioxin exposure: A review. Environmental Health Perspectives 106(S2):625–633. Bertazzi, P. A., D. Consonni, S. Bachetti, M. Rubagotti, A. Baccarelli, C. Zocchetti, and A. C. Pesatori. 2001. Health effects of dioxin exposure: A 20-year mortality study. American Journal of Epidemiology 153(11):1031–1044. Bilanin, A. J., M. E. Teske, J. W. Barry, and R. B. Ekblad. 1989. AGDISP: The aircraft spray dispersion model, code development and experimental validation. Transactions of the American Society of Agricultural Engineers 32:327–334. Bopp, R. F., M. L. Gross, H. Tong, H. J. Simpson, S. J. Monson, B. L. Deck, and F. C. Moser. 1991. A major incident of dioxin contamination: Sediments of New Jersey estuaries. Environmental Science and Technology 25(5):951–956. Boylan, R. 2007. Accessing military unit records at the College Park Archives. Oral presenta- tion to the IOM Committee on Making Best Use of the Agent Orange Reconstruction Model, Meeting 2, April 30–May 1, Washington, DC. Caramaschi, F., G. del Corno, C. Favaretti, S. E. Giambelluca, E. Montesarchio, and G. M. Fara. 1981. Chloracne following environmental contamination by TCDD in Seveso, Italy. Inter- national Journal of Epidemiology 10(2):135–143. CDC (Centers for Disease Control and Prevention). 1988. Serum 2,3,7,8-tetrachlorodibenzo- p-dioxin levels in U.S. Army Vietnam-era veterans. Journal of the American Medical Association 260(9):1249–1254. CDC. 1989. Comparison of serum levels of ,,,-tetrachlorodibenzo-p-dioxin with indirect estimates of Agent Orange exposure among Vietnam veterans: Final report. Atlanta, GA: Agent Orange Projects, Center for Environmental Health and Injury Control. Cecil, P. F., Sr., and A. L. Young. 2008. Operation FLYSWATTER: A war within a war. Envi- ronmental Science and Pollution Research 15(1):3–7. Curwin, B. D., M. J. Hein, W. T. Sanderson, M. G. Nishioka, S. J. Reynolds, E. M. Ward, and M. C. Alavanja. 2005. Pesticide contamination inside farm and nonfarm homes. Journal of Occupational and Environmental Hygiene 2(7):357–367.

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 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT Teske, M. E., S. L. Bird, D. M. Esterly, T. B. Curbishly, S. L. Ray, and S. G. Perry. 2002. AgDRIFT®: A model for estimating near-field spray drift from aerial applications. Envi- ronmental Toxicology and Chemistry 21(3):659–671. U.S. Army. 1985. Services HERBS Tape. Report No. AD-A160 563. Washington, DC: U.S. Army and Joint Services Environmental Support Group. Verger, P., S. Cordier, L. T. B. Thuy, D. Bard, L. C. Dai, P. H. Phiet, M. F. Gonnord, and L. Abenhaim. 1994. Correlation between dioxin levels in adipose tissue and estimated exposure to Agent Orange in South Vietnamese residents. Environmental Research 65:226–242. Ward, M. H., J. Lubin, J. Giglierano, J. S. Colt, C. Wolter, N. Bekiroglu, D. Camann, P. Hartge, and J. R. Nuckols. 2006. Proximity to crops and residential exposure to agri- cultural herbicides in Iowa. Environmental Health Perspectives 114(6):893–897. Young, A. L. 2007. Public statement to the Committee on Making Best Use of the Agent Orange Exposure Reconstruction Model, Meeting 2, April 30–May 1, Washington, DC. Young, A. L., and M. Newton. 2004. Long overlooked historical information on Agent Orange and TCDD following massive applications of 2,4,5-T-containing herbicides, Eglin Air Force Base, Florida. Environmental Science and Pollution Research 11(4):209–221. Young, A. L., J. A. Calcagni, C. E. Thalken, and J. W. Tremblay. 1978. The toxicology, envi- ronmental fate, and human risk of Herbicide Orange and its associated dioxin. OEHL TR-78-92, Final Report. Brooks Air Force Base, TX: U.S. Air Force Occupational and Environmental Health Laboratory. Young, A. L., P. F. Cecil, and J. F. Guilmartin, Jr. 2004a. Assessing possible exposure of ground troops to Agent Orange during the Vietnam War: The use of contemporary military records. Environmental Science and Pollution Research 11(6):349–358. Young, A. L., J. P. Giesy, P. D. Jones, and M. Newton. 2004b. Environmental fate and bioavail- ability of Agent Orange and its associated dioxin during the Vietnam War. Environmental Science and Pollution Research 11(6):359–370.