12

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 2008 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 considerable, 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 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations or total toxic equivalents (TEQs), which take into account exposure to all dioxin-like chemicals (DLCs), 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 conditions statistically associated with exposure to the components of Agent Orange have gradually emerged since the beginning of this series of VAO reports. These findings now better inform decisions about how to categorize the degree of association for individual conditions, so a footnote to this effect was added to Tables 1-1 and 12-1 by the committee for Update 2008. The current committee has added an additional notation to Table 12-1 indicating the correspondence of the lymphohematopoietic cancers (LHCs) that have been found to have evidence of an association with herbicide exposure and the biologic understanding of the clonal derivation of



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12 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 2008 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 evi - dence database was considerable, 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 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) concentrations or total toxic equivalents (TEQs), which take into account exposure to all dioxin-like chemi - cals (DLCs), 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 conditions statistically associated with exposure to the components of Agent Orange have gradually emerged since the beginning of this series of VAO reports. These findings now better inform decisions about how to categorize the degree of association for indi- vidual conditions, so a footnote to this effect was added to Tables 1-1 and 12-1 by the committee for Update 2008. The current committee has added an additional notation to Table 12-1 indicating the correspondence of the lymphohematopoietic cancers (LHCs) that have been found to have evidence of an association with herbicide exposure and the biologic understanding of the clonal derivation of 759

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760 VETERANS AND AGENT ORANGE: UPDATE 2010 LHCs that is the basis of the World Health Organization’s classification system for these neoplasms. 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 categorizations determined by the committee for Update 2008 (as presented in Table 1-1) are noted in boldface in Table 12-1. The terminology of “early-onset transient peripheral neuropathy” was adopted in Update 2004 as a replacement for the terminology of “acute and sub- acute peripheral neuropathy” used in Update 1996. Update 1996, the first VAO report to find “limited or suggestive evidence of association” with exposure to the chemicals of interest for this health outcome, also noted in the body of the report that this was a “transient” effect. When US Department of Veterans Affairs (VA) declared this outcome to be presumptively associated with service in Vietnam, its definition included the temporal constraints that symptoms develop within weeks or months of exposure to an herbicide and resolve within 2 years of the date of onset (VA, 1996; see Note 2 at end of Final Rule). Thus, currently qualifying cases are contingent upon when symptoms arise relative to when exposure oc- curred and that the symptoms are transitory in nature, with recent claims being extremely unlikely. A thorough review of the existing literature in populations with members experiencing early-onset peripheral neuropathy, however, indicates that some individuals continue to manifest neuropathy symptoms long after ex - ternal exposure has ceased, demonstrating that early-onset peripheral neuropathy is not necessarily a transient condition. Based on this literature, the committee elected to delete the word transient to recognize that symptoms of early-onset peripheral neuropathy may be protracted and recovery from those symptoms may be incomplete. The changes to the classifications made since the previous update are bolded here in Table 12-1 and in Table S-1 in the Summary. Although VA did not find hypertension to be presumptively related to service in Vietnam (VA, 2010), on the basis of the total weight of available evidence, the current committee reaffirmed the conclusion of the committees for Update 2006 and for Update 2008 to categorize hypertension as having limited/suggestive evidence of association. 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 12-1 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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761 CONCLUSIONS AND RECOMMENDATIONS TABLE 12-1 Summary from Eighth Biennial Update of Findings in Occupational, Environmental, and Veterans Studies Regarding the Association Between Specific Health Outcomes and Exposure to Herbicides a Sufficient Evidence of 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 (CLL) (including hairy cell leukemia and other chronic B-cell leukemias) * Hodgkin’s disease Chloracne Limited or Suggestive Evidence of 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 peripheral neuropathy (category clarification from Update 2008) Porphyria cutanea tarda Parkinson’s disease Hypertension Ischemic heart disease Type 2 diabetes (mellitus) Spina bifida in offspring of exposed people Inadequate or Insufficient Evidence to Determine 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 within the respiratory system and intrathoracic organs Esophageal cancer Stomach cancer continued

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762 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 12-1 Continued Colorectal cancer (including small intestine and anus) Hepatobiliary cancers (liver, gallbladder, and bile ducts) Pancreatic cancer Bone and joint cancer Melanoma Non-melanoma 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) Leukemia (other than all chronic B-cell leukemias, including CLL and hairy cell leukemia) Cancers at other and unspecified sites Infertility Spontaneous abortion (other than for 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 myeloid leukemia) in offspring of exposed people Neurobehavioral disorders (cognitive and neuropsychiatric) Neurodegenerative diseases, excluding Parkinson’s disease Chronic peripheral nervous system disorders Hearing loss (newly addressed health outcome) Respiratory disorders (wheeze or asthma, chronic obstructive pulmonary disease, and farmer’s lung) Gastrointestinal, metabolic, and digestive disorders (changes in liver 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 Eye problems (newly addressed health outcome) Bone conditions (newly addressed health outcome) 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.

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763 CONCLUSIONS AND RECOMMENDATIONS TABLE 12-1 Continued 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 a component of 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 very small increase in risk at the exposure studied can never be excluded. There is limited or suggestive evidence of no association between exposure to the herbicide component of interest and the following health outcomes: Spontaneous abortion and paternal exposure to TCDD aHerbicides 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. bEvidence for an association can be strengthened by experimental data supporting biologic plausi - bility, but its absence would not detract from the epidemiologic evidence. *The committee notes the consistency of these findings with the biologic understanding of the clonal derivation of hymphohematopoietic cancers that is the basis of the World Health Organization classification system (WHO, 2008). 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 uncertain - ties concerning the health effects of the chemicals of interest sprayed in Viet - nam: 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant TCDD, picloram, and cacodylic acid. This chapter summarizes the committee’s recommendations. Although progress continues to be made in understanding the health effects of exposure to the chemicals of interest and in elucidating the mechanisms un - derlying them, gaps in our knowledge remain. The scope of potential research on the chemicals is far reaching, and what follows here is not an exhaustive list of future research that might have value. There are many additional opportuni- ties for progress in such areas as toxicology, exposure assessment, the conduct of continuing or additional epidemiologic studies, and systematic and compre - hensive integration of existing data that have not been explicitly noted here. It is the committee’s conviction, however, that work needs to be undertaken without delay, particularly to address questions regarding chronic obstructive pulmonary disease (COPD); the potential for paternally mediated, clinically defined health outcomes in offspring; and the effective utilization of VA’s medical database.

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764 VETERANS AND AGENT ORANGE: UPDATE 2010 V A 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 De- fense (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 associa- tions with military service in Vietnam. Particular attention should be paid to the feasibility of conducting epidemiologic 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 COPD, brain cancer, tonsil cancer, melanoma, and Alzheimer disease). For very uncommon health outcomes, a case–control design would probably be most appropriate. VA could possibly more effectively utilize its medical database, particu- larly if there is concern regarding a perceived conflict of interest in surveying its own databases, by involving external analysts. For example, an indepen - dent panel could be commissioned to identify and prioritize database infor- mation that would aid the VAO committee in fulfilling its charge to Congress. Alternatively or in addition, VA could establish an external advisory group that could recommend the most efficient mechanisms for mining the medi- cal database information, which could include, but not be limited to, issuing requests for proposals (RFPs) for the conduct of analytic studies related to specific health outcomes of interest. Finally, as noted in Update 2008, data related to the distribution of claims that have been filed by Vietnam veterans could be very informative. Although applications for compensation and appeals constitute a nonrep - resentative, 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 out - comes in the database. The information that had accumulated in VA’s records clearly generated a signal that motivated VA to ask prior VAO committees to make special evaluations of whether several quite specific malignancies were associated with herbicide exposure; ancillary information was adequate to enable the committees to conclude that CLL and hairy-cell leukemia be- long in the category of sufficient evidence of an association, but perhaps an answer for Vietnam veterans concerning tonsil cancer will only be found by a case–control study addressing deployment status and other emerging risk factors such as viral infection. In general, it is the committee’s conviction that improved data linkage and sharing between DOD and VA would greatly enhance the conduct of

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765 CONCLUSIONS AND RECOMMENDATIONS military epidemiology and the meaningfulness of its results. The committee does endorse the efforts DOD is making to improve collection of exposure data during current deployments, so the impasses associated with missing exposure information will not impede investigations of health consequences in future veterans, as has been the case for Vietnam veterans. For optimal use, however, such DOD information on a veteran’s combat experience needs to be readily connected with future medical events, much of which resides with VA. Available information should be gleaned from existing cohort studies. • In 2006, the Committee on the Disposition of the Air Force Health Study (AFHS) (IOM, 2006) recommended that all data from the AFHS be retained and suggested mechanisms by which those data could be made available to researchers. Since that time, the Institute of Medicine (IOM) Medical Follow-up Agency (MFUA) became custodian of the data and biologic speci- mens (PL 109-364; 120 Stat. 2290); the specimens are now in storage at the Wright-Patterson Air Force Base under the MFUA’s aegis and funding has been provided for IOM to maintain and manage the materials and to make them available as a resource for research. What is required is a strong com - mitment 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 concern 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 understanding of health issues of Vietnam veterans exposed to herbicides. Comprehensive longitudinal analyses of the data collected in the various medical-cycle examinations, data on medical interventions (such as hospitalizations and emergency-department visits), data on cancer inci - dence, data on mortality, and other data on exposure should be conducted to investigate further some of or all of the health outcomes that may be associ - ated with the exposures under consideration in this report; conclusions about melanoma in particular remain in limbo. Of course, distillation of existing data could be further enhanced by incorporation of new results derived by assays of the biologic samples. 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 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 re-

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766 VETERANS AND AGENT ORANGE: UPDATE 2010 sources devoted to it, because it represents our best opportunity to understand the health effects of exposure to TCDD and the herbicides used in Vietnam. The new report (Cypel and Kang, 2010) revisiting the mortality experience of this group through 2005 was valuable input to this update; similar follow- up of their morbidity profile would be extremely useful, as in resolving some of the issues concerning COPD raised by the recent publication. 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) 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 Readjust- ment 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. The VA Office of Inspector General (VAOIG, 2005) ruled that “the Study was not properly, planned, procured, or managed” but directed that it be completed and that provisions be made to avoid the previous problems. Because baseline information is available on symptoms and chronic health problems in the original cohort, the commit - tee thinks that completion of the NVVLS could generate useful information for future updates and concurs that serious consideration should be given to restarting the study. On May 5, 2011, at a hearing of the House Veterans’ Affairs Committee, the chair of the VAO committee for Update 2008 had the privilege of testifying in support of reviving the NVVLS. The committee was pleased to learn that VA has reinitiated this 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 impor- tant source of epidemiologic data, the committee recommends that studies of the NIOSH cohort be extended. 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 exposures with specific health conditions.

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767 CONCLUSIONS AND RECOMMENDATIONS Possible health effects in offspring following paternal exposure merit • further investigation. The rapidly expanding field of epigenetics is revealing the molecular basis by which environmental agents can modify gene expression without changing DNA sequence long after exposure occurs, even in subsequent generations—at least in the case of maternal exposure to certain chemicals. There is a growing body of evidence that TCDD can induce epigenetic changes in animal models, but there remains extremely limited data on the risk of paternal exposure to xenobiotics in general, and the VAO chemicals of interest in particular, resulting in adverse effects on their offspring. VAO committees have been monitoring studies of morphological birth defects and cancer in the offspring of exposed parents, but this committee identified two major information gaps to assessing the link between expo - sure of Vietnam veterans to the chemicals of interest and the development of disease in their offspring: (1) a paucity of studies of the endpoints that VAO committees have been monitoring related to paternal exposure in the absence of maternal exposure, and (2) a failure to systematically review defined clinical health conditions that are manifested later in life by the offspring. While it now appears more physiologically possible for paternal exposure to cause changes in the offspring, the last of the few publications on birth defects among the offspring of male Vietnam veterans was published before the report on the children of female Vietnam veterans (Kang et al., 2000), and none of the epidemiology studies recently reviewed by this committee assessed the role of paternal exposure in the occurrence of such effects. Thus, most of the available epidemiology studies are not relevant to the primary exposure group of concern: male Vietnam veterans. In addition, the epide - miology studies of maternal exposure and adverse effects in offspring other than morphological birth defects and cancer reviewed by this committee did not assess specific diseases in the offspring, but rather they measured physi- ological biomarkers that might or might not predict the potential for disease development later in life. Based on these information gaps, the present committee recommends renewed effort to conduct epidemiology studies on all the developmental effects in offspring that may be associated with paternal exposure. In ad- dition, new studies should evaluate offspring for defined clinical health conditions that develop later in life, focusing on those organ systems that have shown the greatest impact following maternal exposure, including neurologic, immune, and endocrine. Lastly, while the committee recognizes that there is evidence that environmental exposures can affect subsequent generations through fetal and germ-line modifications, epidemiologic inves - tigation designed to associate toxicant exposures to health effects manifested in later generations will be even more challenging to conduct than research on adverse effects on the first generation. Thus, the committee recommends

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768 VETERANS AND AGENT ORANGE: UPDATE 2010 development of epidemiologic protocols to address the logistical challenge of determining whether adverse effects are being manifested in later generations as a result of paternal exposure: consideration must be given to (a) the mini - mum sample size needed to detect changes if present; (b) the most sensitive and reliable outcome measures that should be included; and (c) the need for animal studies to provide mechanistic insight into documented epidemiologi- cal associations. The best cohorts for revealing potential associations would be those with known, well-characterized exposure information. Another ap - proach could be adopting a case–control approach and exploring whether information about Vietnam exposure or specific herbicide exposure could be ascertained in any of the many birth cohorts that have been established in the past several decades. To hone in on a paternal effect, however, it will be necessary to establish that the mothers did not have the opportunity for other than background exposure to the chemicals of interest. 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 concen - trations of DLCs with certain health outcomes, including obesity, hypertri - glyceridemia, type 2 diabetes, hypertension, and ischemic heart disease. The first four of those outcomes are key criteria for the diagnosis of metabolic syndrome, and the fifth 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 mul - tiple health outcomes that define metabolic syndrome should be analyzed as a group. One cross-sectional study reviewed for this update was highly infor- mative in that regard (Uemura et al., 2009), and use of the Ranch Hand and Army Chemical Corps cohorts for these types of analyses are recommended. There is a need for epidemiology studies on the incidence of COPD and • measuring immune/inflammation biomarkers of disease. The committee recommends two key areas that require additional study in humans: the relationship of exposure to the chemicals of interest with (1) the incidence of COPD and (2) meaningful biomarkers of immune/inflam- matory diseases. A recent study on Army Chemical Corps personnel reviewed by this committee reported a high risk of mortality resulting from COPD (Cypel and Kang, 2010); however, numerous factors made it difficult to interpret the strength of this association, including the lack of adjustment for smoking sta- tus, the inconsistency inherent in the diagnosis of COPD, and the likelihood of comorbidities that could contribute to death from COPD. Nonetheless, the committee was greatly concerned about the level of risk reported in this study and urges that studies be conducted to evaluate the incidence of COPD in

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769 CONCLUSIONS AND RECOMMENDATIONS exposed populations, emphasizing the importance of adjusting for smoking and establishing the appropriate functional diagnosis of COPD. In addition, the present committee recognizes that great strides have been made in recent years to elucidate the mechanisms underlying TCDD- induced changes in the immune system; specifically acknowledging that new biomarkers of immune/inflammatory disease have been identified from laboratory-based animal studies. Although various immune system biomark - ers have been measured in human epidemiology studies, it is critical in the future that these biomarkers be the most predictive for risk of disease and not just those that are most readily measured. Thus, the committee urges the measurement in human studies of meaningful biomarkers of immune/ inflammatory disease, such as Fox p3+ T regulatory cells, Th17 cells, and dendritic cells; interleukin 6 elevations; frequency and duration of specific types of infections; and inflammatory cytokines under resting and challenged conditions. 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, B-cell cancers, and paternally mediated effects in offspring) could provide valuable information related to the risk of disease in Vietnam veterans and their children. The development of animal models of various chronic health conditions and their progression would be useful for understanding the pos- sible contributions of the chemicals of interest to compromise the health of aging Vietnam veterans. Specifically, determining the mechanism by which dioxin-like chemicals induce B-cell cancers and how exposure to dioxin-like chemicals alters the susceptibility to developing obesity and components of metabolic syndrome would fill important knowledge gaps. Furthermore, ani - mal models elucidating the impact of paternal exposure on the development of disease in offspring would be very informative, particularly in identifying the timing and duration of exposure that is most critical and the susceptibility of specific organ systems to disease development in offspring later in life. The predecessors of this committee have made similar recommendations concerning the need for additional research to resolve outstanding questions. This committee remains particularly concerned about COPD, hypertension, mela- noma, tonsil cancer, Alzheimer disease, and paternally transmitted effects to offspring. In closing, the current committee notes that there has been little or no action toward implementing such investigations that would address veterans’ concerns and scientific insights needed to inform decision-making by future VAO committees. Table 12-2 provides a terse summary of the committee’s current priorities for future research.

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770 VETERANS AND AGENT ORANGE: UPDATE 2010 TABLE 12-2 Research Needs Relevant Chapter Committee Research Recommendation Chapter 4 • Develop new animal models to elucidate mechanisms of diseases and Biologic Plausibility disease progression (particularly for cardiovascular disease, B-cell cancers, obesity and the components of metabolic syndrome, and paternally mediated effects in offspring). • Conduct toxicologic investigation of the potential for the chemicals of interest (particularly TCDD) to induce epigenetic modifications, with special attention to the capacity for paternal transmission of such effects. • Conduct more research to identify a biologic mechanism by which the chemicals of interest may cause Parkinson disease. Chapter 5 • Glean available information from existing cohort studies, particularly Epidemiologic Study those of Vietnam veterans (Air Force Health Study, Army Chemical Populations Corps cohort, female Vietnam veterans, National Vietnam Veterans Longitudinal Study), the National Institutes of Safety and Health and International Agency for Research on Cancer cohorts of dioxin workers, the Agricultural Health Study, and the Seveso cohort. • Link information in its electronic medical-record system, in its claims files, and in other associated administrative databases to assemble epidemiologic information on common health conditions for evaluation of possible associations with military service in Vietnam. Chapter 6 • Include immunologic biomarkers in future studies of other health Immune Outcomes outcomes that may involve compromised immune function as an intermediate step in the development of overt pathology. Chapter 7 • Evaluate the occurrence of several neoplastic conditions (brain cancer, Cancer Outcomes tonsil cancer, melanoma, and myelodysplastic syndrome) in Vietnam-era veterans by using existing VA administrative and health-services databases. • Perform a comprehensive analysis of melanoma in the entire AFHS data set to resolve ambiguity remaining in currently published results. Chapter 8 • Conduct studies of defined clinical health conditions in mature offspring Reproductive or following exposure of either parent, rather than more investigations Developmental of physiological biomarkers that may merely be predictive of disease Outcomes development later in life. • Develop epidemiologic protocols to address the logistical challenge of determining whether adverse effects are being manifested in later generations as a result of paternal exposure (in the absence of maternal exposure). Chapter 9 • Evaluate possibilities for studying neurodegenerative outcomes (such Neurologic Outcomes as amyotrophic lateral sclerosis and Alzheimer disease) in Vietnam-era veterans by using the existing VA administrative and health-services databases. • Conduct investigation relating PD incidence to exposure in the Vietnam- veteran population, including studies of biologic plausibility. Chapter 10 • Analyze the emergence of the individual health outcomes constituting Cardiovascular metabolic syndrome in association with exposure to the chemicals of Outcomes interest. • Analyze the incidence of the multiple health outcomes that define metabolic syndrome as a group. Chapter 11 • Conduct epidemiology studies on the incidence of COPD and measure Other Health meaningful immune/inflammation biomarkers of disease. Outcomes • Study the incidence of COPD among Vietnam-era veterans by using the existing VA administrative and health-services databases.

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771 CONCLUSIONS AND RECOMMENDATIONS REFERENCES1 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. Cypel Y, Kang H. 2010. Mortality patterns of Army Chemical Corps veterans who were occupation - ally exposed to herbicides in Vietnam. Annals of Epidemiology 20(5):339–346. IOM (Institute of Medicine). 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. Kang HK, Mahan CM, Lee KY, Magee CA, Mather SH, Matanoski G. 2000. Pregnancy outcomes among US women Vietnam veterans. American Journal of Industrial Medicine 38(4):447–454. Uemura H, Arisawa K, Hiyoshi M, Kitayama A, Takami H, Sewachika F, Dakeshita S, Nii K, Satoh H, Sumiyoshi Y, Morinaga K, Kodama K, Suzuki TI, Nagai M, Suzuki T. 2009. Prevalence of metabolic syndrome associated with body burden levels of dioxin and related compounds among Japan’s general population. Environmental Health Perspectives 117(4):568–573. VA (Department of Veterans Affairs). 1996. Diseases associated with exposure to certain herbicide agents (prostate cancer and acute and subacute peripheral neuropathy): Final rule. Federal Register 61(217):57587–57589. VA. 2010. Health effects not associated with exposure to certain herbicide agents. Federal Register 75(109):32540–32553. 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. WHO (World Health Organization). 2008. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue (4th edition). Lyon, France: World Health Organization. 1 Throughout 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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