The Utility of Proximity-Based Herbicide Exposure Assessment in Epidemiologic Studies of Vietnam Veterans (2008)

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1 Introduction and Background B etween 1962 and 1971, several herbicides—most notably the ­product known as Agent Orange—were used in Vietnam by U.S. forces and their allies for defoliation of forest areas, destruction of crops, and control of vegetation around the perimeters of troop encampments. Since then many studies have been conducted to examine whether health prob- lems experienced by some Vietnam veterans might be linked to wartime exposure to any of these herbicides or to a contaminant (i.e., 2,3,7,8- ­ etrachlorodibenzo-p-dioxin [TCDD]) that was in some of them. t A fundamental and persisting challenge in these studies has been to determine the amount of herbicide in the wartime environment, identify the military personnel who were exposed to herbicides, distinguish them from personnel who were not exposed, and estimate the herbicide or TCDD dose that exposed individuals received. In response to a recommendation in the Institute of Medicine (IOM) report Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994) that an effort to develop models to reconstruct herbicide exposure be undertaken, the Department of Veterans Affairs (VA) funded and the IOM (1997, 2003a,b) oversaw work by researchers at Columbia University to produce an her- bicide exposure assessment model (Stellman and Stellman, 2003, 2004; Stellman et al., 2003a,b). VA subsequently sought advice from IOM on the use of the exposure assessment model in epidemiologic studies to evaluate the long-term health Throughout this report the term “herbicide” encompasses the TCDD contaminant unless specifically stated otherwise. 13 

14 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT effects of wartime exposure to herbicides. This report presents the conclu- sions and recommendations of the IOM study committee convened to provide this guidance to VA. STUDY CHARGE AND COMMITTEE ACTIVITIES The IOM study requested by VA has the following Statement of Task: A committee will be convened to provide the U.S. Department of Veterans Affairs with advice and suggestions on the best ways to employ the “Agent Orange” exposure assessment model developed by Columbia University researchers in the evaluation of the long-term health effects of wartime exposure to herbicides. VA has requested that the committee include the following in their considerations: • The relevant recommendations for evaluating the model contained in the 1994 report Veterans and Agent Orange. • Approaches to evaluating the exposure model using existing data on health outcomes associated with herbicide or dioxin exposure among Vietnam veterans. • The availability, quality, and usefulness of existing information on Vietnam veterans, including troop locations and health outcome data regarding diseases commonly associated with herbicide exposure (soft tissue sarcoma, non-Hodgkin’s lymphoma, Hodgkin’s disease, or lung and laryngeal cancer, for example) as well as those not currently linked to such exposures (e.g., testicular, colon, or skin cancer). • How such information might be used in studies that would become the basis of further epidemiological research using the exposure reconstruc- tion model. • The role of epidemiologic studies of Vietnam veterans using the new model in informing the evaluation of the association between herbicide exposure and health outcomes performed in the Veterans and Agent Orange–series reports. The committee will prepare a report describing its work and offering find- ings and recommendations. The study committee was selected to include members with expertise in environmental and occupational epidemiology, exposure assessment, environmental health, environmental chemistry, biostatistics, and access to archived military records. The committee met in person four times from March 2007 through August 2007. During these meetings, the committee reviewed and dis- cussed the existing research literature on the topics central to its charge and received information from oral presentations made by the researchers who developed the exposure assessment model, by researchers studying 

INTRODUCTION AND BACKGROUND 15 dioxin and herbicide contamination in the United States and Vietnam, and by representatives from VA, the Centers for Disease Control and Prevention (CDC), and veterans service organizations. (See Appendix A for the agendas of the information-gathering meetings.) In addition, the committee met via a conference call to complete its deliberations. Despite the name of the committee, it is important to note that the herbicide exposure assessment model that was reviewed is not an exposure reconstruction model. To the committee, “exposure reconstruction” sug- gests the possibility of arriving at a retrospective estimate of the quantity of herbicide that individuals or groups were exposed to, or even the dose they might have received. Instead, the model produces metrics based on proximity to herbicide spraying that are only surrogates for exposure. Further­more, the committee was not charged with conducting analyses using the exposure assessment model or with conducting an assessment of the scientific evidence on associations between any specific health effects and exposure to herbicides used in Vietnam. A BRIEF HISTORY This chapter provides readers with brief background information on the size of the population of U.S. military personnel who served in Vietnam, the herbicides used there, the response to concerns about potential health effects of exposure to these herbicides, and findings from other IOM studies on associations between health effects and herbicide exposure. U.S. Military Personnel in Vietnam U.S. military troops were present in Vietnam from the 1950s until 1973 (IOM, 1994). Herbicides were in use from 1962 through 1971, making persons who served during that period the population of interest for epide- miologic studies. Table 1-1 shows (fiscal) year-end troop levels in Vietnam for 1960–1973, based on data currently available from the Department of Defense (DoD, 2007). Although data on the numbers of troops present in Vietnam have been available (if not always entirely consistent) since the end of the war, identifying specific individuals who served there has been more challenging. A computerized roster of approximately 3 million military personnel who are thought to have served in Vietnam was not compiled by DoD and VA until the mid-1990s (Kang, 2007). This roster is discussed further in Chapter 5. Summary data on the length of time individuals served in Vietnam do not appear to have been compiled. The U.S. Army had an individual rota- tion policy with 1-year tours in South Vietnam (The U.S. Army in Vietnam, 2005; DePue, 2006). The Marine Corps adopted an individual rotation 

16 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT TABLE 1-1  U.S. Troop Levels in Vietnam, by Branch of Service, 1960–1973a Year Total Army Navy Marine Corps Air Forceb 1960 794 558 98 21 117 1961 959 701 105 20 133 1962 8,464 6,747 338 720 659 1963 15,575 10,878 606 233 3,858 1964 17,033 10,892 574 761 4,806 1965 124,363 75,025 1,691 37,179 10,468 1966 305,183 192,975 9,109 58,624 44,475 1967 437,103 294,962 12,784 74,660 54,697 1968 537,377 354,212 38,388 83,873 60,904 1969 510,054 345,423 33,708 71,239 59,684 1970 390,278 294,088 19,497 29,962 46,731 1971 212,925 167,304 10,308 459 34,854 1972 35,292 21,212 1,997 1,290 10,793 1973 265 31 3 167 64 aStatuson September 30 of each year. The data include only land-based personnel. bThese data are based on the permanent duty location of individuals and thus differ from Air Force deployment data by command, which reflect the headquarters location of organizational units. SOURCE: DoD, 2007. policy in 1965, and Marines served a 12- or 13-month tour in Vietnam (USMC, 1985). The number of service members who served multiple tours is not known. Herbicide Use in Vietnam Use of herbicides for defoliation and crop destruction was authorized by the U.S. government in late 1961 and terminated in 1971. Herbicides were also used to clear vegetation around military bases. Application of herbi- cides was accomplished primarily by the U.S. Air Force in aerial spraying using fixed-wing aircraft in Operation Ranch Hand. Army Chemical Corps personnel were responsible for smaller operations that included helicopter spraying as well as ground spraying using a variety of specialized and impro- vised equipment. Herbicides were probably also handled and used by other personnel, such as Navy riverine patrols and the engineering personnel who were responsible for constructing fire support bases (IOM, 1994). Several different herbicides were used in Vietnam. Most were given designations (e.g., Orange, White, Pink) based on the color of the iden- tification band on their storage drums. Listed in Table 1-2 are the most 

INTRODUCTION AND BACKGROUND 17 TABLE 1-2  Herbicides Most Commonly Used in Vietnam Herbicide Principal Constituents Dates of Use Amount Sprayed (liters) Pink 2,4,5-T 1961, 1965 50,312 (plus 413,852 in procurement records) Green 2,4,5-T 1962–1964 31,026 (shown in procurement records) Purple 2,4-D; 2,4,5-T 1962–1965 1,892,733 Orange 2,4-D; 2,4,5-T 1965–1970 45,677,937 (may include Orange II) Orange II 2,4-D; 2,4,5-T After 1968? 3,591,000 (minimum amount shipped) White 2,4-D; picloram 1966–1971 20,556,525 Blue (powder) Cacodylic acid; sodium 1962–1964 25,650 cacodylate Blue (aqueous Sodium cacodylate; 1964–1971 4,715,731 solution) cacodylic acid NOTE: 2,4-D is 2,4-dichlorophenoxyacetic acid; 2,4,5-T is 2,4,5-trichlorophenoxyacetic acid. 2,4,5-T was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). SOURCES: Adapted from Young et al., 1978; Stellman et al., 2003a; IOM, 2007. commonly used herbicides, their principal constituents, their dates of use, and estimates of the amount sprayed. The principal defoliants were Agent Orange and Agent White, whereas crop destruction was often accomplished with Agent Blue. The herbicide amounts in Table 1-2 were estimated from a combination of records on procurement, Ranch Hand spray missions and other opera- tions, and disposal of surplus supplies (Young et al., 1978; Stellman et al., 2003a). The current estimates reflect the results of archival research, most recently by Stellman and colleagues (2003a), to assemble data from military records. Because Ranch Hand spray missions were subject to a formal high- level approval process, those records are considered to be relatively more complete than records of herbicide use in other contexts (e.g., perimeter spraying around military bases), which was authorized and managed by local commanders (IOM, 1994). Emergence of Concerns About Potential Health Effects of Herbicides The herbicides used in Vietnam were similar to products that had been in routine use in the United States and elsewhere for control of unwanted vegetation. In Vietnam, they were generally applied at a rate of 3 gallons per acre to maximize their effectiveness on tropical vegetation (Darrow et al., 1969). Lower application rates of 1 to 1.5 gallons per acre were considered 

18 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT effective for the vegetation types found in the United States (Department of the Army, 1971). By the end of the 1960s, however, concern had arisen that 2,4,5-T posed a hazard to human health. That concern contributed to a decision in 1970 to end the use in Vietnam of the herbicides that contained 2,4,5-T, and all official herbicide use ended in 1971. Remaining herbicide stocks were removed from Vietnam and subsequently destroyed. Investigation had found that herbicides containing 2,4,5-T were con- taminated with TCDD, an unwanted and highly toxic byproduct of the manufacturing process. This included Agent Orange, the herbicide used in greatest quantity in Vietnam, as well as agents Pink, Green, and Purple. In the 1970s, TCDD levels were measured in samples of the remaining stocks of these herbicides, but the TCDD levels found were not necessarily repre- sentative of the contamination levels of the herbicides applied in Vietnam. Furthermore, the TCDD contamination is thought to have varied over time and across manufacturing lots (Young et al., 1976). During the 1970s, concern grew among Vietnam veterans and their families that the veterans were experiencing health problems because of exposure to herbicides in Vietnam, especially to the TCDD-contaminated Agent Orange. Claims for eligibility for health care services and disability compensation posed a challenge for VA: Information about the human health effects of herbicide and TCDD exposure was limited, and in most cases military service records provided no clear means to establish that a veteran had been exposed to an herbicide in Vietnam. Studying Health Effects and Herbicide Exposure Many different efforts have been pursued by Congress, federal agencies, and independent researchers to address the concerns about health effects that might result from herbicide exposure in Vietnam and to establish whether exposure occurred. In the early 1970s, for example, the National Academy of Sciences (NRC, 1974) conducted a broad congressionally mandated review of the effects of herbicide use in Vietnam, which included onsite investigations and initial construction of a computerized database on Ranch Hand spray missions (the HERBS tapes). By the end of the decade, the General Accounting Office (GAO, now named the Govern- ment Accountability Office) had investigated the potential for troops to be exposed to herbicides from Ranch Hand spraying (GAO, 1979). In 1979, the U.S. Air Force initiated a 20-year follow-up study of the health of Ranch Hand personnel (IOM, 2006), whose assignments meant both that they were in frequent proximity to herbicides and that their exposure history would not be representative of most troops who served in Vietnam. VA and subsequently CDC were directed by Congress to conduct large epidemiologic studies of the health effects of herbicide exposure among 

INTRODUCTION AND BACKGROUND 19 the Vietnam veteran population, but these studies were never completed as planned, in part because of the lack of credible methods of determin- ing herbicide exposure levels among veterans (e.g., CDC, 1988d; IOM, 1994). However, both VA and CDC completed other studies of the health of Vietnam veterans, many of which used service in Vietnam as a surrogate for herbicide exposure (e.g., Kang et al., 1986; Breslin et al., 1988; CDC, 1988a,b,c, 1990a,b,c; Watanabe and Kang, 1996; also see Appendix B). In 1991, Public Law (P.L.) 102-4, known as the Agent Orange Act of 1991, established that Vietnam veterans with chloracne that developed within 1 year of leaving Vietnam, non-Hodgkin’s lymphoma, or certain soft tissue sarcomas would be presumed to have been exposed to an herbicide in Vietnam and therefore be eligible for disability compensation. Among its other provisions, P.L. 102-4 also directed VA to contract with the National Academy of Sciences to conduct biennial reviews of the published scientific literature to assess the strength of the evidence regarding associations between exposure to herbicides (or specific constituent chemi- cal compounds) used in Vietnam and health outcomes of concern. To date seven reviews have been published (IOM, 1994, 1996, 1999, 2001, 2003c, 2005, 2007). These reviews include consideration of evidence from avail- able studies of Vietnam veterans, but they rely more heavily on ­studies of other populations, especially chemical production and agricultural ­workers as well as community residents exposed through environmental contam- ination, including industrial accidents. As directed by P.L. 102-4 (and r ­ eauthorized in P.L. 107-103), VA has used the findings from these reviews to designate additional health conditions as presumed to have a connection to military service in Vietnam (see Table 1-3). The IOM findings and the VA decisions on presumptive connections to military service are all based on evidence of statistical associations between health effects and herbicide exposure, not on evidence that is necessarily strong enough to demonstrate a causal relationship. The Current Study Congress originally sought from the IOM reviews an assessment of the increased risk that Vietnam veterans would have for conditions found to be associated with herbicide exposure. None of the review committees have been able to make quantitative assessments of this risk, in part, because credible direct or proxy measurements of Vietnam veterans’ herbicide expo- sure have not been available. In addition to these broad reviews, IOM committees have also conducted reviews for spe- cific health outcomes (IOM, 2000, 2002, 2004). 

20 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT TABLE 1-3  Conditions Designated by the Department of Veterans Affairs as Presumed to Have Resulted from Exposure to Herbicides Used in Vietnam • Acute and subacute peripheral neuropathy • Prostate cancer • Chloracne • Respiratory cancers • Chronic lymphocytic leukemia   (lung, bronchus, larynx, and trachea) • Hodgkin’s disease • Soft-tissue sarcoma, acute • Multiple myeloma • Spina bifida in offspring of Vietnam veterans • Non-Hodgkin’s lymphoma • Type II diabetes mellitus • Porphyria cutanea tarda SOURCE: VA, 2007. The first of the biennial reviews included a recommendation that this problem be addressed by an attempt to develop an exposure reconstruc- tion model that could be considered valid for use in epidemiologic studies of veterans (IOM, 1994). VA responded to this recommendation by com- missioning the IOM to assess the scientific issues that a research proposal would need to address, oversee the selection of a contractor to conduct the work, monitor progress during the course of the contract, and evaluate the product produced by the contractor (IOM, 1997, 2003a,b). The contract for the work was awarded in 1998 to researchers at the Columbia Uni- versity Mailman School of Public Health (Jeanne Mager Stellman, Ph.D., principal investigator). The project resulted in the development of a software tool called the Herbicide Exposure Assessment–Vietnam (HEA-V). The HEA-V uses a geo- graphic information system (GIS) to link computerized databases contain- ing information on the timing, amount, and locations of herbicide spraying with data on troop locations over time to calculate two metrics—“hits” and an exposure opportunity index (EOI)—representing exposure (HEA-V, 2003; Stellman and Stellman, 2003; Stellman et al., 2003b). These metrics are designed to serve as proxies for herbicide exposure. They account for differences in exposure that are likely to result from differences among individuals or units in their proximity in time and space to sprayed loca- tions. The software and related databases are discussed in more detail in Chapter 2. With the software and databases in hand, VA returned to the IOM for guidance on their use. In a presentation to the committee (Brown, 2007), VA’s interests were described as including obtaining advice on effective use of the model in studies of illnesses previously associated with herbicide exposure and on the usefulness of existing information on Vietnam ­veterans who have died or who have certain diseases. VA was also interested in 

INTRODUCTION AND BACKGROUND 21 advice on planning future research using the model, guiding researchers to the potentially most fruitful areas, and alerting researchers to the challenges in doing studies using the model. ISSUES IN ASSESSING HERBICIDE EXPOSURE IN VIETNAM FOR EPIDEMIOLOGIC STUDIES The committee identified four considerations as being central to its task. First, it was essential to be clear about the nature of the exposure assessment model and what it does and does not claim to do. The com­ mittee approached the model as a means of generating a quantitative representation of opportunity for herbicide exposure, not actual environ- mental levels, personal exposure levels, or biological dose levels. Although direct measurement of individual doses or exposure levels is the ideal, many ­studies of environmental and occupational health hazards must rely on proxy measures similar in concept to the direct hits metric or the EOI metric produced by the Stellman team’s model (i.e., inferred exposure based on spatial and temporal proximity of the persons at risk to a source of the agent), as discussed in Chapter 3. For example, location of residence has been used as a proxy for exposure to ambient air pollution, recognizing that there will nonetheless be variation in individual exposure depending on factors such as the indoor environment and time–activity patterns (e.g., Briggs, 2003; Colvile et al., 2003). Second, the committee gave careful consideration to the informa- tion needed to use the model. This included gaining an understanding of strengths and limitations of data on herbicide spraying, troop locations, and health outcomes. Issues of access to and usability of these data were also important. The committee notes that although attention in past studies has often focused on TCDD, the spraying database includes information on all herbicides for which records were available, and the committee made its assessment from this broader perspective. Third, the committee considered the feasibility of a validation study to determine whether the metrics produced (“direct hits” and EOI) and the tools used to generate them “worked,” that is, whether they locate spray- ing and troops accurately (opportunity for exposure) and whether doing so is related to actual exposure (through comparisons with other sources of information on exposure, such as blood levels or environmental samples). The goal of environmental epidemiology is the assessment of associations between exposure to a substance in the environment and a health outcome of interest. Research often advances through successive approximations of exposure, so that the utility of the model is defined in part by the methods it improves upon and does not depend solely on how closely the model approaches absolute accuracy. 

22 PROXIMITY-BASED HERBICIDE EXPOSURE ASSESSMENT Fourth, with the nature of the model and its metrics clearly in mind, the committee considered the potential contributions and pitfalls from using it in epidemiologic studies. Of particular interest in those deliberations were the potential to study Vietnam veterans directly, the degree to which expo- sure classification might be improved if the model was to be used, and the appropriate interpretation of the results of any such studies. THE COMMITTEE’S REPORT The remainder of the report presents the committee’s findings and conclusions concerning use of the exposure assessment model and the committee’s recommendations regarding epidemiologic studies that might be considered. Chapter 2 reviews the essential features of the model devel- oped by the Stellman team. Chapter 3 presents the committee’s assessment of the model within the context of an exposure hierarchy, with a review of key components of the model and the measures of exposure opportunity that the model can generate. Chapter 4 discusses the accessibility of data on military units and personnel needed to conduct studies using the model. Chapter 5 concludes the report with the committee’s assessment of and recommendations concerning the development of epidemiologic studies that incorporate use of the exposure assessment model. REFERENCES Breslin, P., H. K. Kang, Y. Lee, V. Burt, and B. Shepard. 1988. Proportionate mortality study of US Army and US Marine Corps veterans of the Vietnam War. Journal of Occupational Medicine 30(5):412–419. Briggs, D. 2003. Environmental measurement and modeling: Geographical information sys- tems. In Exposure assessment in occupational and environmental epidemiology, edited by M. J. Nieuwenhuijsen. New York: Oxford University Press. Brown, M. 2007. Charge to the NAS/IOM Committee on Making Best Use of the Agent ­ range Exposure Reconstruction Model. Written comments submitted to the Committee O on Making Best Use of the Agent Orange Exposure Reconstruction Model, Meeting 1, March 8, Washington, DC. CDC (Centers for Disease Control and Prevention). 1988a. Health status of Vietnam vet- erans: I. Psychosocial characteristics. Journal of the American Medical Association 259(18):2701–2707. CDC. 1988b. Health status of Vietnam veterans: II. Physical health. Journal of the American Medical Association 259(18):2708–2714. CDC. 1988c. Health status of Vietnam veterans: III. Reproductive outcomes and child health. Journal of the American Medical Association 259(18):2715–2719. CDC. 1988d. 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. 1990a. The association of selected cancers with service in the U.S. military in Vietnam: I. Non-Hodgkin’s lymphoma. Archives of Internal Medicine 150:2473–2483. 

INTRODUCTION AND BACKGROUND 23 CDC. 1990b. The association of selected cancers with service in the U.S. military in Vietnam: II. Soft-tissue and other sarcomas. Archives of Internal Medicine 150:2485–2492. CDC. 1990c. The association of selected cancers with service in the U.S. military in Vietnam: III. Hodgkin’s disease, nasal cancer, nasopharyngeal cancer, and primary liver cancer. Archives of Internal Medicine 150:2495–2505. Colvile, R., D. Briggs, and M. J. Nieuwenhuijsen. 2003. Environmental measurement and modeling: Introduction and source dispersion modeling. In Exposure assessment in ­ ccupational and environmental epidemiology, edited by M. J. Nieuwenhuijsen. New o York: Oxford University Press. Darrow, R. A., K. R. Irish, and C. E. Hinarik. 1969. Herbicides used in Southeast Asia. Technical Report SAOQ-TR-69-11078. Fort Detrick, MD: U.S. Army Plant Sciences Laboratories. Department of the Army. 1971. Tactical employment of herbicides. Field Manual FM 3-3. Washington, DC: Department of the Army. DePue, M. 2006. Vietnam War: The individual rotation policy. Vietnam Magazine. http:// www.historynet.com/magazines/vietnam/4632961.html (accessed September 20, 2007). DoD (U.S. Department of Defense). 2007. Military personnel historical reports. http://siadapp. dmdc.osd.mil/personnel/MILITARY/history/309hist.htm (accessed August 2, 2007). GAO (General Accounting Office). 1979. U.S. ground troops in South Vietnam were in areas sprayed with Herbicide Orange. FPCD-80-23. Washington, DC: U.S. Government Print- ing Office. HEA-V (Herbicide Exposure Assessment–Vietnam). 2003. CD-ROM, version 1.0.2. Software and accompanying electronic documentation. New York: Columbia University. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health effects of herbicides used in Vietnam. Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1997. Characterizing exposure of veterans to Agent Orange and other herbicides used in Vietnam: Scientific considerations regarding a request for proposals for research. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2000. Veterans and Agent Orange: Herbicide/dioxin exposure and Type 2 diabetes. Washington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2002. Veterans and Agent Orange: Herbicide/dioxin exposure and acute myelogenous leukemia in the children of Vietnam veterans. Washington, DC: National Academy Press. IOM. 2003a. Characterizing exposure of veterans to Agent Orange and other herbicides used in Vietnam: Interim findings and recommendations. Washington, DC: The National Academies Press. IOM. 2003b. Characterizing exposure of veterans to Agent Orange and other herbicides used in Vietnam: Final report. Washington, DC: The National Academies Press. IOM. 2003c. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. IOM. 2004. Veterans and Agent Orange: Length of presumptive period for association between exposure and respiratory cancer. Washington, DC: The National Academies Press. IOM. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. 

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