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10 Conclusions and Recommendations SYNOPSIS OF COMMITTEE CONCLUSIONS The committee weighed the strengths and limitations of the epidemiologic evidence reviewed in this report and in previous Veterans and Agent Orange (VAO) reports. Although the studies published since Update 2006 are the subject of detailed evaluation here, the committee drew its conclusions in the context of the entire body of literature. The contribution of recent publications to the evidence database was substantial, but the committee did not weigh them more heavily merely because they were new. Epidemiologic methods and analytic capabilities have improved, but many of the recent studies were also particularly useful for the committee’s purpose because they produced results in terms of serum TCDD concentrations or because their findings consisted of observations on the aging population of primary concern, Vietnam veterans. The committee also notes that experimental data related to biologic plausibility of health condi- tions statistically associated with exposure to the components of Agent Orange has gradually emerged since the beginning of this series of VAO reports. These findings now better inform decisions about how to categorize the degree of as- sociation for individual conditions; a footnote to this effect has been added to Table 10-1. On the basis of its evaluation of veterans, occupational, and environmental studies, the committee assigned each health outcome to one of four categories of relative certainty of association with exposure to the herbicides that were used in Vietnam or to any of their components or contaminants (with no intention of specifying particular chemicals). Changes made by the current committee to the 61

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62 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 10-1 Summary from Seenth Biennial Update of Findings in Occupational, Environmental, and Veterans Studies Regarding the Association Between Specific Health Outcomes and Exposure to Herbicidesa Sufficient Evidence of an Association Epidemiologic evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between exposure to herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. b For example, if several small studies that are free of bias and confounding show an association that is consistent in magnitude and direction, there could be sufficient evidence of an association. There is sufficient evidence of an association between exposure to the chemicals of interest and the following health outcomes: Soft-tissue sarcoma (including heart) Non-Hodgkin’s lymphoma Chronic lymphocytic leukemia (including hairy cell leukemia and other chronic B-cell leukemias) (category clarification since Update 2006) Hodgkin’s disease Chloracne Limited or Suggestive Evidence of an Association Epidemiologic evidence suggests an association between exposure to herbicides and the outcome, but a firm conclusion is limited because chance, bias, and confounding could not be ruled out with confidence.b For example, a well-conducted study with strong findings in accord with less compelling results from studies of populations with similar exposures could constitute such evidence. There is limited or suggestive evidence of an association between exposure to the chemicals of interest and the following health outcomes: Laryngeal cancer Cancer of the lung, bronchus, or trachea Prostate cancer Multiple myeloma AL amyloidosis Early-onset transient peripheral neuropathy Parkinson’s disease (category change from Update 2006) Porphyria cutanea tarda Hypertension Ischemic heart disease (category change from Update 2006) Type 2 diabetes (mellitus) Spina bifida in offspring of exposed people Inadequate or Insufficient Evidence to Determine an Association The available epidemiologic studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to control for confounding, have inadequate exposure assessment, or fail to address latency. There is inadequate or insufficient evidence to determine association between exposure to the chemicals of interest and the following health outcomes that were explicitly reviewed: Cancers of the oral cavity (including lips and tongue), pharynx (including tonsils), or nasal cavity (including ears and sinuses) Cancers of the pleura, mediastinum, and other unspecified sites in the respiratory system and intrathoracic organs continued

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6 CONCLUSIONS AND RECOMMENDATIONS TABLE 10-1 Continued Esophageal cancer Stomach cancer Colorectal cancer (including small intestine and anus) Hepatobiliary cancers (liver, gallbladder, and bile ducts) Pancreatic cancer Bone and joint cancer Melanoma Nonmelanoma skin cancer (basal cell and squamous cell) Breast cancer Cancers of reproductive organs (cervix, uterus, ovary, testes, and penis; excluding prostate) Urinary bladder cancer Renal cancer (kidney and renal pelvis) Cancers of brain and nervous system (including eye) Endocrine cancers (thyroid, thymus, and other endocrine organs) Leukemia (other than all chronic B-cell leukemias, including chronic lymphocytic leukemia and hairy cell leukemia) Cancers at other and unspecified sites Infertility Spontaneous abortion (other than after paternal exposure to TCDD, which appears not to be associated)b Neonatal or infant death and stillbirth in offspring of exposed people Low birth weight in offspring of exposed people Birth defects (other than spina bifida) in offspring of exposed people Childhood cancer (including acute myelogenous leukemia) in offspring of exposed people Neurobehavioral disorders (cognitive and neuropsychiatric) Neurodegenerative diseases, excluding Parkinson’s disease Chronic peripheral nervous system disorders Respiratory disorders (wheeze or asthma, chronic obstructive pulmonary disease, and farmer’s lung) Gastrointestinal, metabolic, and digestive disorders (changes in hepatic enzymes, lipid abnormalities, and ulcers) Immune system disorders (immune suppression, allergy, and autoimmunity) Circulatory disorders (other than hypertension and ischemic heart disease) Endometriosis Effects on thyroid homeostasis This committee used a classification that spans the full array of cancers. However, reviews for nonmalignant conditions were conducted only if they were found to have been the subjects of epidemiologic investigation or at the request of the Department of Veterans Affairs. By default, any health outcome on which no epidemiologic information has been found falls into this category. Limited or Suggestive Evidence of No Association Several adequate studies, which cover the full range of human exposure, are consistent in not showing a positive association between any magnitude of exposure to the herbicides of interest and the outcome. A conclusion of “no association” is inevitably limited to the conditions, exposures, and length of observation covered by the available studies. In addition, the possibility of a ery small increase in risk at the exposure studied can neer be excluded. There is limited or suggestive

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64 VETERANS AND AGENT ORANGE: UPDATE 2008 TABLE 10-1 Continued evidence of no association between exposure to the herbicides of interest and the following health outcomes: Spontaneous abortion after paternal exposure to TCDD a Herbicides indicates the following chemicals of interest: 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, or dioxin), cacodylic acid, and picloram. The evidence regarding association was drawn from occupational, environmental, and veteran studies in which people were exposed to the herbicides used in Vietnam, to their components, or to their contaminants. b Evidence for an association is strengthened by experimental data supporting biologic plausibility, but its absence would not detract from the epidemiologic evidence. categorizations determined by the committee for Update 2006 (as presented in Table 1-1) are noted in boldface in Table 10-1. After considering information related to the Department of Veterans Affairs (VA) question about hairy cell leukemia, the committee concluded that not just hairy cell leukemia—like chronic lymphoid leukemia (CLL)—but all chronic B-cell leukemias belong in the category of “sufficient evidence of an associa- tion” with Hodgkin’s disease and non-Hodgkin’s lymphoma (NHL). Because the committee for Update 2006 could not reach consensus, ischemic heart disease had remained in the category of “inadequate or insufficient evidence to determine an association,” but accruing evidence convinced the present committee to move ischemic heart disease from the category of “inadequate or insufficient evidence to determine an association” to the category of “limited or suggestive evidence of an association” with hypertension. The committee for Update 2006 had also been unable to reach consensus about whether the evidence of an association with herbicide exposure reached the level of “limited or suggestive,” but the present committee did not find new evidence to justify moving either melanoma or breast cancer out of the category of “inadequate or insufficient evidence.” Several pieces of new information specifically about the chemicals of interest led the committee to decide that there is now “limited or suggestive” evidence of association for Parkinson’s disease (PD). As mandated by Public Law (PL) 102-4, the distinctions among categories are based on statistical association, not on strict causality. The committee was directed to review the scientific data, not to recommend VA policy; therefore, conclusions reported in Table 10-1 are not intended to imply or suggest policy decisions. The conclusions are related to associations between exposure and out- comes in human populations, not to the likelihood that any individual’s health problem is associated with or caused by the chemicals in question.

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6 CONCLUSIONS AND RECOMMENDATIONS COMMITTEE RECOMMENDATIONS As part of its charge, the committee was asked to make recommendations concerning the need, if any, for additional scientific studies to resolve uncertainties concerning the health effects of the chemicals of interest sprayed in Vietnam: 2,4- dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), picloram, and cacodylic acid. This chapter summarizes the committee’s recommendations. Although great strides have been made over the last several years in un- derstanding the health effects of exposure to the chemicals of interest and in elucidating the mechanisms underlying them, gaps in our knowledge remain. The scope of potential research on the chemicals is wide, and what follows here is not an exhaustive list of future research that might have value. There are many additional opportunities for progress in such subjects as toxicology, exposure assessment, the conduct of continuing or additional epidemiologic studies, and systematic and comprehensive integration of existing data that have not been explicitly noted here. It is the committee’s conviction, however, that work needs to be undertaken promptly, particularly to address questions regarding several health outcomes, most urgently tonsil cancer, melanoma, paternally mediated transgenerational effects, and PD. • The current definition of Vietnam service is not supported by existing data. The evidence that this committee has reviewed makes limiting Vietnam ser- ice to those who set foot on Vietnamese soil seem inappropriate. The ongoing series of hearings and appeals in the US Court of Appeals for Veterans Claims (Haas . Nicholson) reflect the controversy. As discussed in Chapter 3, there is little reason to believe that exposure of US military personnel to the herbicides sprayed in Vietnam was limited to those who actually set foot in the Republic of Vietnam. Having reviewed the Australian report (NRCET, 2002) on the fate of TCDD when seawater is distilled to produce drinking water, the committee is convinced that this use of seawater would provide a feasible route of exposure of personnel in the Blue Water Navy, which might have been supplemented by drift from herbicide spraying. The epidemiologic evidence itself supports a broader definition of Vietnam serice to serve as a surrogate for presumed exposure to Agent Orange or other herbicides sprayed in Vietnam. For instance, the Centers for Disease Control and Prevention (CDC, 1990) study of selected cancers in Vietnam veterans found that the risk of the “classic AO cancer” NHL was highest and most significant in Blue Water Navy veterans. More recently, the Air Force Health Study (AFHS) has demonstrated that TCDD concentrations in Vietnam-era veterans deployed to Southeast Asia, not just the “Vietnam veteran” Ranch Hand subjects, are gener- ally higher than US background concentrations (although notably lower than in Ranch Hand sprayers themselves).

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66 VETERANS AND AGENT ORANGE: UPDATE 2008 The present committee notes that all previous VAO committees have consid- ered information on naval Vietnam veterans to pertain to possible Agent Orange exposure when evaluating the full spectrum of health outcomes. The present committee finds that exposure assignment to be appropriate. No new studies con- sidered in this update contained Navy-specific information, but such information has been factored into the evolving conclusions of VAO committees. Given the available evidence, the committee recommends that members of the Blue Water Navy should not be excluded from the set of Vietnam-era veterans with presumed herbicide exposure. • VA should evaluate possibilities for studying health outcomes in Vietnam- era veterans by using the existing administrative and health-services databases. The original VAO committee recommended that the Department of Defense (DOD) and VA identify Vietnam service in the computerized index of records. Linking that information with the VA electronic medical-record and associated administrative databases, such as discharge-diagnosis and pharmacy-use records, should make it possible to assemble epidemiologic information on common health conditions for evaluation of possible associations with military service in Vietnam. Particular attention should be paid to the feasibility of conducting epide- miologic studies of conditions that have been noted to be of special interest but on which the current evidence is inadequate or insufficient to determine whether there is an association with herbicide exposure (such as tonsil and breast can- cers, melanoma, amyotrophic lateral sclerosis, lupus, ischemic heart disease, and stroke). For very uncommon health outcomes, a case–control design would probably be most appropriate. Although applications for compensation and appeals constitute a nonrepre- sentative, self-selected sample that is influenced by which conditions are already judged to be service-related, an effort to use existing VA information should include a more systematic review of the distribution of health outcomes in the database. To evaluate whether Vietnam veterans actually have experienced an increase in tonsil cancer, the next logical step would be for VA to identify the veterans with tonsil cancer that are already in the system and examine the biopsy results to classify the form (origin) of tonsil cancer better. Given the low incidence of this rare condition, a typical epidemiologic study in the general population would not be useful. Determining whether the lymphatic nature of the tonsil plays a role in a substantial proportion of tonsil cancers would guide planning of the next steps for research. A portion of the Neurotoxin Exposure Treatment Research Program (NETRP) is related to the pathogenesis and etiology of several conditions, including PD, and has been funded since 1997. Originally housed in the US Army Military

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6 CONCLUSIONS AND RECOMMENDATIONS Operational Medicine Research Program, the NETRP has recently moved to the Telemedicine and Advanced Technology Research Center under the US Army Medical Research and Materiel Command. Perhaps coordination with that effort and with the resources of VA’s appeals and medical records would be a produc- tive means of addressing whether an increased risk of PD is being manifested in Vietnam veterans. • Available information should be gleaned from existing cohort studies. The present committee joins the committee for Update 2006 in concurring with the recommendations of the Committee on the Disposition of the Air Force Health Study (IOM, 2006). The latter committee made strong recommendations regarding the retention of all data from the AFHS and suggested mechanisms by which the data could be made available to researchers. We reiterate that committee’s statement that “no other epidemiologic dataset on Vietnam veterans contains as detailed information over as long a time period, the data appear to be of high quality and the specimens well preserved, and analysis of the assets has contributed to the literature addressing the health of Vietnam veterans.” Congress directed the Institute of Medicine (IOM) Medical Follow-up Agency (MFUA) to become custodian of the data and biologic specimens in 2006 (PL 109-364; 120 Stat. 2290); the specimens are now in storage at the Wright-Patterson Air Force Base under the MFUA’s aegis. The MFUA is pursuing the funding that PL 110- 389, §803 directed VA to provide to IOM to maintain and manage the materials and make them available as a resource for research. What is required is a strong commitment by the federal government to provide sufficient funds to develop the infrastructure necessary to meet the goals of further research using this invaluable database. Moreover, dedicated funding is required so that focused analyses can be carried out by independent investigators, especially as related to the research questions that concerns the present committee. The investment would be a small fraction of the $143 million invested to date in the AFHS. Such research could clarify the various issues and would reap substantial benefits in the understand- ing of health issues of Vietnam veterans exposed to herbicides. Comprehensive longitudinal analysis of the data collected in the various medical-cycle examina- tions, data on medical interventions (such as hospitalizations and emergency- department visits), data on cancer incidence, data on mortality, and other data on exposure could be used profitably to investigate further some of or all of the health outcomes that may be associated with the exposures under consideration in this report. The present committee believes strongly that a complete analysis of the melanoma findings should be performed because an unambiguous interpreta- tion is not possible on the basis of the papers published to date (Akhtar et al., 2004; Pavuk et al., 2005). Members of the Army Chemical Corps (ACC) constitute the largest cohort of Vietnam veterans exposed directly to herbicides and TCDD. They were involved in the handling and distribution of the chemicals in Vietnam. ACC veterans who reported spraying herbicides as part of their duties have been shown to have

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68 VETERANS AND AGENT ORANGE: UPDATE 2008 increased serum TCDD concentrations; this highly exposed population has also been shown to be at increased risk for several diseases. The population should be the focus of additional study, with new resources devoted to it, because it repre- sents our best opportunity to understand the health effects of exposure to TCDD and the herbicides used in Vietnam. Few data on the women who served in Vietnam are available. The cohort of nurses studied by Kang et al. (2000) largely exhausted the source population. The mortality study of the population (Cypel and Kang, 2008) reviewed in the present update was helpful, but additional follow-up of the health status of the group and determination of their TCDD concentrations would be worthwhile. At the direction of Congress, the National Vietnam Veterans Readjustment Study (1986–1988) investigated primarily psychiatric sequelae in a representative cohort of about 1,600 men and women. In 2000, Congress mandated (PL 106- 419) that VA assess the current physical and mental well-being of the members of that cohort. In 2001, VA contracted for the work, named the National Vietnam Veterans Longitudinal Study (NVVLS), but progress ceased within 2 years. VA’s Inspector General (VAOIG, 2005) ruled that “the Study was not properly, planned, procured, or managed,” but directed that it be completed and that provi- sions be made to avoid the previous problems. Because baseline information is available on symptoms and chronic health problems in the original cohort, the committee thinks that completion of the NVVLS could generate useful informa- tion for future updates and concurs that serious consideration should be given to restarting the study. Starting in 1978, the National Institute for Occupational Safety and Health (NIOSH) began to study US workers potentially exposed to TCDD. A total of 5,132 workers in 12 large manufacturing companies were included in the NIOSH cohort. The cohort has been a source of data extremely valuable in assessing the health effects associated with TCDD exposure. The studies have included high- quality exposure assessment, and evaluations of a wide array of health outcomes have been published. Given its value as an important source of epidemiologic data, the committee recommends that studies of the NIOSH cohort be extended. Although the committee concluded that there is limited or suggestive evi- dence that the occurrence of Parkinson’s disease is associated with the chemicals of interest, it would still be desirable to investigate whether the apparent incon- sistencies in the results for incident and prevalent cases in the Agricultural Health Study (Kamel et al., 2007b) could be resolved. The committee recommends that the researchers conducting that ongoing study apply the analytic method described in Copas and Farewell (2008) to this dataset. The committee also notes that future analyses of health outcomes in those and other important study populations should be as specific as possible because generic findings, such as those for “all respiratory outcomes,” are not useful in addressing the committee’s charge of determining associations of herbicide ex- posures with specific health conditions.

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69 CONCLUSIONS AND RECOMMENDATIONS • The exposure-reconstruction study should be put to use. IOM’s Committee on the Assessment of Wartime Exposure to Herbicides in Vietnam oversaw the development of a model of herbicide exposure of Viet- nam veterans (the “Stellman model”), which has been described in detail (IOM, 2003a,b). The present committee endorses the finding in the recent report (IOM, 2008) of the Committee on Making Best Use of the Agent Orange Reconstruc- tion Model that the model should be incorporated into new epidemiologic studies where feasible. • Studies of the Vietnamese population would be worthwhile. As discussed in earlier updates, the Vietnamese are an under studied popula- tion. Although there are likely to be serious logistical challenges, the many Viet- namese people who had substantial exposure constitute a potentially informative study sample. It will be important to include appropriate exposure measures, such as tissue TCDD concentrations, in studying Vietnamese residents. Because such research has the potential to close a number of gaps in the understanding of the long-term health consequences of exposure to TCDD and the herbicides used in Vietnam, the committee endorses action toward developing collaborative programs of research. • Possible effects in offspring of exposed people merit further investigation. The assessment of any link between exposure of Vietnam veterans to the chemicals of interest and birth defects or developmental disease in their offspring presents distinct challenges. VA should review all the possible cognitive and developmental effects in offspring of veterans. Such a review should include the possibility of effects in grandchildren, which are of growing concern to veterans and their families. A recent meta-analysis of Agent Orange exposure and birth defects in both Vietnamese and non-Vietnamese populations (Ngo et al., 2006) found the studies of non-Vietnamese subjects (that is, Vietnam veterans) overall showed significant association, pointing to the need to examine closely both the biologic plausibility of paternally mediated birth defects and the existing epide- miologic evidence. Reviews have also focused on epidemiologic studies of data from birth-defects registries and from parental reports of birth defects. Those studies often exclude alterations in function that could appear later in a child’s life, such as alterations in neurologic function, endocrine function, or reproduc- tive capacity. The findings of the AFHS on birth defects in veterans’ offspring have not yet been (and, if funding is not provided, may never be) formally and systematically integrated and analyzed in a longitudinal fashion. Most etiologic research has focused on the effects of maternal and fetal exposures, but some work addressing paternal exposures has been discussed in previous reviews. With increasing concern about male reproductive function, increasing numbers of epidemiologic studies of the role of paternal exposures in

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660 VETERANS AND AGENT ORANGE: UPDATE 2008 the risk of birth defects are being published. This work is particularly relevant in assessing health outcomes in offspring of a largely male service population. The plausibility of birth defects arising from parental exposure, especially from paternal exposure, merits careful review in light of newly hypothesized epigen- etic mechanisms (such as heritable forms of gamete imprinting) that might make paternal transmission of a TCDD effect more plausible. The committee recom- mends that an ad hoc group be established to review current mechanistic studies that could further knowledge of a possible paternally mediated link between ex- posure to the chemicals of interest and health conditions (including birth defects) in offspring. Given the sparseness of the data on birth defects in the children of Vietnam veterans, the committee also recommends that the ad hoc group conduct meta-analyses of existing epidemiologic studies of male populations exposed to TCDD, 2,4-D, or 2,4,5-T and the risk of birth defects in their offspring. • Potential emergence of metabolic syndrome should be analyzed. Within the study populations reviewed, the committee recognized a possible interrelationship among the reported associations of serum concentrations of dioxin-like compounds with certain health outcomes, including hypertriglyceri- demia, type 2 diabetes, hypertension, and ischemic heart disease. The first three of those outcomes are key criteria for the diagnosis of metabolic syndrome, and the fourth is a major consequence of it. Thus, the committee recommends that— in addition to analysis of the association of exposure to the chemicals of interest with individual health outcomes—the incidence of multiple health outcomes that define metabolic syndrome should be analyzed as a group. • There is a need for new animal models to elucidate mechanisms of dis- eases and disease progression. The committee believes that experimental research in the mechanisms that underlie human health outcomes (particularly cardiovascular disease and trans- generational effects) could provide valuable information related to the risk of disease in Vietnam veterans. The central role of the aryl hydrocarbon receptor (AHR) in animal models is clear, and AHR gene differences in animals clearly af- fect susceptibility to the effects of TCDD. Although work on the AHR in humans has been sparse, variations in this specific genetic factor alone are likely to affect human susceptibility to the toxic effects of TCDD, dioxin-like chemicals, and herbicide formulations that contain these chemicals. In addition, recent research makes it clear that variations in the genetic regulation of the expression or activ- ity of other factors, including proteins that interact with the AHR and the gene products that are regulated by the AHR, are critical in determining susceptibility to the effects of TCDD and the types of toxic effects observed. Studies addressing the identification, distribution, and functional consequences of polymorphisms of the AHR and the other cofactors in human populations should be pursued. The committee expects that investigations of mitochondrial disease and epigenetic

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661 CONCLUSIONS AND RECOMMENDATIONS mechanisms will have important implications for health effects of concern in Vietnam veterans. The committee notes that although its predecessors have made similar rec- ommendations, there has been little or no action toward implementing several investigations that the committee regards as imperative. Those projects need to be undertaken to address veterans concerns and to meet the scientific needs of future VAO committees to resolve outstanding questions, particularly with regard to PD, tonsil cancer, and melanoma. VA and DOD are in the unique position of being able to study the very population that is of concern. Focused study of Vietnam veterans themselves would be especially appropriate for extremely rare conditions, such as tonsil cancer, which appears anecdotally to be occurring at an unusual rate in Vietnam veterans and in connection with which the study of surrogate populations (even with a case–control design) might exclude factors that are important for the military situation. REFERENCES1 Akhtar FZ, Garabrant DH, Ketchum NS, Michalek JE. 2004. Cancer in US Air Force veterans of the Vietnam war. Journal of Occupational and Enironmental Medicine 46(2):123–136. CDC (Centers for Disease Control and Prevention). 1990. The association of selected cancers with service in the US military in Vietnam. I. Non-Hodgkin’s lymphoma. Archies of Internal Medi- cine 150:2473–2483. Copas AJ, Farewell VT. 2008. Incorporating retrospective data into an analysis of time to illness. Biostatistics 2(1):1–12. Cypel Y, Kang H. 2008. Mortality patterns among women Vietnam-era veterans: Results of a retro- spective cohort study. Annals of Epidemiology 18(3):244–252. IOM (Institute of Medicine). 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. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. IOM. 2008. The Utility of Proximity-Based Herbicide Exposure Assessment in Epidemiologic Studies of Vietnam Veterans. Washington, DC: The National Academies Press. Kamel F, Tanner C, Umbach D, Hoppin J, Alavanja M, Blair A, Comyns K, Goldman S, Korell M, Langston J, Ross G, Sandler D. 2007b. Pesticide exposure and self-reported Parkinson’s disease in the Agricultural Health Study. American Journal of Epidemiology 165(4):364–374. Kang HK, Mahan CM, Lee KY, Magee CA, Mather SH, Matanoski G. 2000. Pregnancy out- comes among US women Vietnam veterans. American Journal of Industrial Medicine 38(4): 447–454. 1Throughout the report the same alphabetic indicator following year of publication is used con- sistently for the same article when there were multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.

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662 VETERANS AND AGENT ORANGE: UPDATE 2008 Ngo AD, Taylor R, Roberts CL, Nguyen TV. 2006. Association between Agent Orange and birth defects: Systematic review and meta-analysis. International Journal of Epidemiology 35(5): 1220–1230. NRCET (National Research Centre for Environmental Toxicology). 2002. Examination of the Poten- tial Exposure of Royal Australian Nay (RAN) Personnel to Polychlorinated Dibenzodioxins and Polychlorinated Dibenzofurans Via Drinking Water. Brisbane, Australia. Pavuk M, Michalek JE, Schecter A, Ketchum NS, Akhtar FZ, Fox KA. 2005. Did TCDD exposure or service in Southeast Asia increase the risk of cancer in Air Force Vietnam veterans who did not spray Agent Orange? Journal of Occupational and Enironmental Medicine 47(4):335–342. VAOIG (Department of Veterans’ Affairs Office of Inspector General). 2005. Audit of VA Acquisition Practices for the National Vietnam Veterans Longitudinal Study (Report No. 04-02330-212). Washington, DC.