The committee's review of the existing literature has identified some health outcomes having likely or possible associations with herbicide and/or TCDD exposure and other outcomes for which the data are simply insufficient (Chapters 8 through 11). Even where an association with herbicide exposure is likely, the magnitude of the risk remains uncertain, especially for Vietnam veterans. Given this scientific uncertainty, the second part of the committee's charge—to assess the need for continued research efforts—is timely and appropriate.
As stated in Public Law 102-4, the committee must consider the available scientific evidence, the value and relevance of scientific information that could result from additional studies, and the cost and feasibility of carrying out such studies. Consistent with this mandate, two considerations have guided the committee's research recommendations. First, as discussed in Chapter 6, the interpretation of existing epidemiologic studies is compromised by the frequent lack of appropriate individual measures of exposure to herbicides or TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin). This is especially true for studies of Vietnam veterans, yet the committee believes that there may be substantial numbers of veterans who have been exposed to levels of herbicides equivalent to workers in the occupational studies that the committee reviewed. However, as outlined in Chapter 6, the committee believes that it is possible to develop better exposure measures for Vietnam veterans, for use in any future research efforts. Second, as Chapters 8 through 11 have shown, substantial scientific uncertainty about the health effects of herbicides and TCDD remain, especially with regard to Vietnam
veterans, despite the number of existing studies. Thus, the committee concluded that a series of epidemiologic studies of Vietnam veterans could yield valuable information if a new, valid exposure reconstruction model could be developed.
The committee's research recommendations focus on studies in Vietnam veterans rather than on general toxicologic research or on epidemiologic studies of occupationally or environmentally exposed populations. The substantial amount of research on the toxicology and epidemiology of herbicides and herbicide components already under way in the United States and abroad, although not targeted specifically to Vietnam veterans, is likely to contribute to the knowledge of potential health effects in veterans.
ANALYSES OF EXISTING DATA AND RESEARCH PROGRAMS
Much can be learned by reanalysis of existing data and by more in-depth analysis of data from ongoing research programs that investigate the health of Vietnam veterans. Studies of particular interest include the Air Force Ranch Hand study and the Department of Veterans Affairs (DVA; formerly the Veterans Administration) studies of other highly exposed Vietnam veterans such as members of the Army Chemical Corps.
Studies of Highly Exposed Vietnam Veterans
Recommendation 1. The committee endorses continued follow-up of the Air Force Ranch Hand cohort and its comparison group, and recommends that members of the Army Chemical Corps and an appropriate comparison group be followed in a similar study. An independent, nongovernmental scientific panel should be established to review and approve a new, expanded research protocol for both study populations, and to commission and direct a common analysis of the results.
The Ranch Hand cohort includes the Vietnam veterans with the highest documented exposure to herbicides, and the committee endorses continuation of the planned follow-up, including both mortality and morbidity studies. Because they will be available at three points in time, the serum TCDD measurements from this study are particularly important to better understand TCDD metabolism and to assess its use as a biomarker to further analyze health effects. Studies of individual characteristics and other factors affecting TCDD metabolism are particularly important and should be encouraged. This knowledge will lead to more appropriate analyses of the Ranch Hand data and other studies that use serum TCDD gathered years after exposure as a biomarker.
A major limitation of the Ranch Hand study, however, is the small size
of the cohort—1,261 men at the start of the study, 995 who completed the 1987 physical exam (Michalek et al., 1990). Studies of other groups, in addition to the Ranch Hand, that may also have been highly exposed to herbicides in Vietnam would be valuable. One such group is the Army Chemical Corps, which has been studied by the DVA (Thomas and Kang, 1990).
Members of the Army Chemical Corps were responsible for the storage, preparation, and handling of herbicides and other chemicals. Although they were exposed to a wider range of chemicals, the level and intensity of herbicide exposure may have been similar to those of the Ranch Hand cohort. In their first study, Thomas and Kang (1990) identified 894 members of this group and obtained vital status for 745. According to a recent abstract, Dalager and Kang (1993) have now identified 2,954 Army veterans who held chemical operation positions in Vietnam. Continued follow-up of the members of this group would substantially increase the size of the highly exposed population of Vietnam veterans and would yield greater statistical power to detect less common health outcomes. Prompt collection and storage of biological samples and determination of serum TCDD levels for these additional highly exposed veterans would enhance future epidemiologic studies of health outcomes.
Further study of both groups is likely to yield information on a number of health outcomes for which additional research is needed. Priorities for specific health outcomes are discussed after recommendation 6. However, to be useful for this purpose, a common protocol must be followed for both groups. Thus, it is important that a new and expanded protocol for both study populations be developed to include sufficient data for assessing health outcomes.
The high participation rate of veterans in the Ranch Hand study (84 percent) is a credit to both the Air Force and the Ranch Hands themselves. However, the study could benefit from improved methods of analysis and presentation of results both for existing data and for data obtained in the future. Difficulties with interpreting these analyses, as exemplified in the recent reproductive effects report from the Ranch Hand study (AFHS, 1992), along with specific suggestions for further analyses, appear in Appendix C.
As a committee of the National Academy of Sciences noted in a review of the proposed protocol for the Ranch Hand study (NRC, 1980), public perception of the federal government's interest in the outcome of the study results suggests the need for studies of the health of Vietnam veterans to be conducted by a nongovernmental organization. Ranch Hand's excellent participation rate argues that components of the Department of Defense (DOD) or the DVA continue to conduct the follow-up examinations of the Ranch Hand and Army Chemical Corps cohorts. However, an independent, nongovernmental scientific panel is needed to oversee the analyses of the
resulting data in order to satisfy the public's concern about impartiality and scientific credibility. Such a panel could commission others to perform the analyses or arrange to conduct the analyses itself. The panel should also ensure that data from the study are made available to others for secondary analyses within a reasonable time frame and with appropriate safeguards for individual confidentiality.
FEASIBILITY OF NEW EPIDEMIOLOGIC STUDIES OF VIETNAM VETERANS
As discussed in Chapter 6, one of the major problems with the interpretation of existing studies is the frequent lack of appropriate measures of exposure to herbicides or TCDD; however, the committee finds that it may be possible to develop better exposure measures for Vietnam veterans. In particular, Chapter 6 proposes measures that are not dependent on serum TCDD levels (which the committee finds inappropriate for the full range of herbicide exposures) but instead recommends the use of less formal sources of historical information about base perimeter spraying and other relevant exposures, as discussed below in Recommendation 4. Thus, the committee concludes that certain further research efforts using new measures of exposure to herbicides in Vietnam are both necessary and potentially feasible. However, each of the possible measures that the committee has considered involves some degree of nondifferential misclassification bias, and the effect of this bias on risk estimates would likely be to underestimate true effects if they existed, possibly to the point that they would not be detected. In particular, the committee recommends that the following steps be taken prior to undertaking new epidemiologic studies of Vietnam veterans, for the reasons described below.
Recommendation 2. The Department of Defense and the Department of Veterans Affairs should identify Vietnam service in the computerized index of their records.
Chapter 3 notes that Vietnam service is not a ''flagged item" on the computerized index of military personnel records archived at the National Personnel Records Center in St. Louis, Missouri, which is maintained by the General Services Administration under an agreement with the Department of Defense. Therefore, the computerized index of the record system does not allow for searches or selection of records of individuals who have served in Vietnam. The lack of an indicator of Vietnam service complicates every epidemiologic study based on military records and leads to methodologic inconsistencies among studies in defining the population under consideration. Adding this indicator to the computerized data base would facilitate future mortality studies based on computerized records, thereby increasing
accuracy and decreasing cost, and would also simplify other epidemiologic studies of health outcomes in Vietnam veterans. All servicemen and women who were stationed in Vietnam or in the Vietnam theater during the Vietnam era should be identified in the records.
Recommendation 3. Biomarkers for herbicide exposure should be developed further.
Considerable uncertainty remains about the use of current or future serum TCDD levels as indicators of past exposure to TCDD in Vietnam veterans. Further research on the toxicokinetics of TCDD is needed to permit more accurate extrapolation from current serum TCDD measurements to past exposures. The multiple serum measurements from the Ranch Hand study group and other highly exposed groups should be particularly useful in this research.
An individual's serum TCDD level, however, is at best an indicator of past exposure to TCDD; it does not necessarily reflect general exposure to all herbicides used in Vietnam. Further refinement of currently available TCDD biomarkers and improved understanding of TCDD metabolism so that these measures can be appropriately included in statistical analyses, as well as development of new biomarkers for exposure to herbicides per se, would also be useful.
Recommendation 4. A nongovernmental organization with appropriate experience in historical exposure reconstruction should be commissioned to develop and test models of herbicide exposure for use in studies of Vietnam veterans.
Exposure assessment has been a weak aspect of most epidemiologic studies of Vietnam veterans. The military reports and personal testimony reviewed by the committee suggest that a sufficient range of exposure to herbicides may exist among Vietnam veterans for valid epidemiologic studies of certain health outcomes, and the committee believes that it is possible to develop valid exposure reconstruction models for epidemiologic studies using methods of historical exposure reconstruction. Such models would estimate the likelihood that each individual veteran was exposed to herbicides in Vietnam and possibly quantify their degree of exposure. These models (described in more detail in Chapter 6) would incorporate information from existing military records about troop movements and herbicide spraying (including, but not limited to, the HERBS and Services HERBS tapes). The models must also include less formal sources of historical information about ground and perimeter spraying, such as records of herbicide shipments to individual bases from the major shipping depots, and consideration of the types of terrain, typical foliage, and military mission of the bases or troops located there. Supplemental information gathered from
surveys of military officers with first-hand knowledge of herbicide operations in Vietnam, such as the 1971 survey conducted by the Army (U.S. Army, 1972) could also be incorporated into the exposure model.
Historical exposure reconstruction is a well-developed specialty in occupational health research that requires substantial professional judgment. The committee recommends that the DVA arrange for a nongovernmental organization with appropriate experience in historical exposure reconstruction to develop and test potential models of herbicide exposure for use in studies of Vietnam veterans. This group will need access to DOD and DVA records to carry out this work.
Recommendation 5. The exposure reconstruction models developed according to Recommendation 4 should be evaluated by an independent, nongovernmental scientific panel established for this purpose.
Herbicide exposure reconstruction models for Vietnam veterans must be evaluated thoroughly before epidemiologic studies based on these models proceed. The committee has identified three possible approaches to such an evaluation, which are discussed in more detail in Chapter 6: (1) internal consistency checks, (2) comparisons of model exposure measures with serum TCDD measurements, and (3) assessment of the association between exposure reconstruction measures and health outcomes shown in occupational or environmental studies to be associated with herbicides. Scientific judgment is required in interpreting the results of such an evaluation, so the committee cannot specify explicit criteria for acceptance or rejection of the new exposure reconstruction models in advance of their development and testing.
The committee recommends that an independent, nongovernmental scientific panel be established to review the results of the proposed evaluation studies and judge the validity and feasibility of the exposure reconstruction models. This panel should have expertise in historical exposure reconstruction and epidemiology. To maintain the public and scientific credibility of the study, the panel members should be nongovernmental and independent of the organization that develops the exposure reconstruction models.
Recommendation 6. If the scientific committee proposed in Recommendation 5 determines that a valid exposure reconstruction model is feasible, the Department of Veterans Affairs and other government agencies should facilitate additional epidemiologic studies of veterans.
A number of possible epidemiologic studies could provide additional information on the health effects of exposure to herbicides in Vietnam beyond what is already known. Highest research priority should be given to those health effects for which additional study is likely to change the balance of the evidence for or against an association. This includes
health outcomes for which current evidence is limited/suggestive of an association (lung and respiratory cancers, prostate cancer, and multiple myeloma);
health outcomes for which current evidence is insufficient or inadequate to determine whether an association exists, but which, in the committee's judgment, are plausible based on animal toxicologic data (such as nasal/nasopharyngeal cancer) or for which there are known associations with related chemical compounds in humans (such as liver cancer and polychlorinated biphenyls);
health outcomes for which the typical age at onset has not yet been reached by members of the Vietnam veteran cohort (such as prostate cancer).
The committee also recommends that priority be given to additional research on reproductive outcomes that would help clarify the possible effects of herbicides. Since Vietnam veterans are expected to have relatively few additional children because of their age, reanalyses of existing reproductive data, especially those based on registries, with the new exposure reconstruction measures proposed in this chapter, would be especially relevant. In particular, the committee believes that extensive reanalysis of the Ranch Hand reproductive data could shed additional light on these questions (see Chapter 9 Appendix C).
Although there is sufficient evidence of an association between occupational or environmental exposure to herbicides and non-Hodgkin's lymphoma, Hodgkin's disease, and soft tissue sarcomas, the existing information on dose-response relationships is incomplete, especially with regard to Vietnam veterans. If a valid exposure reconstruction method can be developed, it might be applied to the exposure data available from existing case-control studies to provide additional dose-response evaluations. Further refinement of the clinical and pathological definitions of soft tissue sarcomas in epidemiologic studies would also help to determine which of the specific cancers in this class are associated with herbicides and/or TCDD.
The exposure reconstruction models to be developed could be used in either case-control or cohort studies. The type of study design will depend on the health outcome being investigated. Rare health effects, for instance, will likely require case-control studies, as described in Chapter 5.
The cost of these epidemiologic studies will depend on the study design. A design based on an exposure reconstruction model applied to computerized troop location records using existing mortality data or health outcome data could be relatively inexpensive. Adding detailed record review by experts or analysis of clinical or morbidity data would substantially increase costs. A study design involving serum TCDD measurements would also increase cost, if current costs for the biochemical assays are not reduced.
Although the number of women Vietnam veterans may be too small to provide adequate statistical power in a study by themselves, the committee believes that women Vietnam veterans should be included in Vietnam veteran studies whenever appropriate.
The committee recognizes that the recommendations for development of a historical exposure reconstruction model and its use in epidemiologic studies might seem at variance with the Centers for Disease Control (CDC) (Pirkle, 1993), White House Agent Orange Working Group (AOWG) (Young et al., 1986), and Office of Technology Assessment (OTA) (Gibbons, 1987) conclusions with regard to the congressionally mandated Agent Orange Study. The committee has come to a different conclusion for four reasons: First, the CDC-AOWG-OTA conclusions were based in large part on serum TCDD measurements, which the committee feels are insufficient for validating exposure to herbicides used in Vietnam, as explained in Chapter 6. Second, the arguments underlying the earlier conclusion that individuals in combat units were widely dispersed and that troop movement data are incomplete imply that exposure measurements may be imprecise, not that they are invalid. However, these arguments do suggest that historical reconstruction of exposure will have some degree of nondifferential misclassification bias, and the effect of this bias on risk estimates would likely be to underestimate true effects if they existed, possibly to the point that they would not be detected. Third, the committee is proposing the use of more, but less formal, information on exposure than was considered in 1986. This includes the development and use of informal information on perimeter spraying, which might account for more meaningful herbicide exposure than the aerial spraying documented on the HERBS tapes. Finally, the committee does not know whether the approach it proposes will prove valid or whether new methods will identify a sufficient number of highly exposed Vietnam veterans for an epidemiologic study. In the committee's judgment, however, the likelihood that this approach will be successful is sufficient for it to be recommended.
MANDATED RESEARCH EFFORTS
For the purposes of further research on the health effects of Vietnam service, Public Law 102-4 mandates that the DVA establish four specific programs: (1) a scientific research feasibility studies program; (2) a system to compile and analyze clinical data obtained in connection with the examination and treatment of certain Vietnam veterans; (3) a tissue archiving system; and (4) a program of blood testing for certain Vietnam era veterans. These programs are subject to initiation, continuance, or discontinuation depending on the findings of this Institute of Medicine report, as well as logistical and funding considerations, and the committee is charged with
making recommendations about specific mandates. The DVA has no specific plans for any of these research efforts beyond the minimal descriptions given in the law, so the committee is able to comment on them in only the broadest terms.
With regard to the need for a series of scientific "studies on the feasibility of conducting additional scientific research on" health hazards resulting from exposure to TCDD and herbicides used in Vietnam, the research mandate in section 8 of Public Law 102-4, the committee feels that a series of epidemiologic studies of veterans could yield valuable information if a new, valid exposure reconstruction model can be developed. The committee finds value in continuing the existing Ranch Hand study and expanding it to include Army Chemical Corps veterans. As discussed above, however, these studies should be carried out with some independence from government agencies.
Section 6 of Public Law 102-4 requires the DVA to "compile and analyze, on a continuing basis, all clinical data" that (1) are obtained in connection with examinations and treatment furnished by the DVA to certain veterans, and (2) are likely to be scientifically useful in determining the association between disabilities experienced by these veterans and exposure to TCDD or herbicides. Such a system, called the Agent Orange Registry (see Chapter 2), currently exists. Section 7 of the law calls for the establishment of a system for the collection and storage of voluntarily contributed samples of blood and tissue of veterans who served in Vietnam.
Stored biological samples and clinical data offer some promise for future research efforts. They could, for instance, form the basis for future nested case-control studies of particular diseases. For example, as Vietnam veterans age, studies of the incidence of prostate cancer could compare TCDD levels in stored serum for men with and without the disease. The benefit of such a program is that the cost of storing serum (approximately $50 per veteran per year) is substantially less than that of measuring its TCDD level (almost $1,000 per sample with current technology). It is also possible that new scientific assays or other measurement methods developed in the next 10 to 20 years could be applied to stored serum and tissue, and the resulting analyses might shed light on some of the remaining uncertainty.
To be scientifically valid, however, a study based on stored biological samples or clinical data must be designed with a sampling plan appropriate for the hypotheses to be tested (see, e.g., NRC, 1991). Stored samples are valuable, for instance, in identified high-exposure cohorts, such as the Ranch Hands, the Army Chemical Corps, and perhaps other study groups, so that health effects can be compared to their level of TCDD exposure. By contrast, storage of biological samples or medical records from self-selected individuals, or from those who feel that they are suffering from disabilities
due to herbicide exposure, is unlikely to yield scientifically valid information on the health effects of herbicides; any epidemiologic study based on these data would suffer from misclassification bias (see Chapter 5).
Over the last 15 to 20 years, the sampling and storage of human biologic specimens for later analysis in scientific studies have received increasing attention. A 1993 conference on human tissue monitoring and specimen banking, sponsored by the U.S. Environmental Protection Agency and the University of North Carolina School of Public Health, Chapel Hill, explored state-of-the-art banking techniques, design, and ethical considerations. Human tissue banks in the United States and abroad have become a valuable resource for obtaining baseline or historical measurements of toxic substances, and for monitoring and assessing trends in human exposure to environmental or occupational chemicals. Results obtained to date indicate that human tissue monitoring may become increasingly informative, provided that difficult issues of system design, quality control, and ethics are resolved.
Balancing the strengths and weaknesses of stored biological samples and clinical data for research purposes, the committee feels that systems of this sort have scientific value, but only to the extent that they are components of specific, well-designed studies. In the absence of a clear study design to guide such activities—and without resolution of the design, quality control, and ethical issues—the committee does not recommend the establishment of the clinical data and tissue archiving systems described in sections 6 and 7 of the law at this time.
The final mandate in Public Law 102-4 (section 9) on which the committee must comment calls for testing the serum TCDD levels of Vietnam veterans who apply for medical care or file a disability compensation claim. The purpose of this mandate is not stated in the legislation. If research purposes are contemplated, the committee's discussion about tissue archiving systems applies, and such a program would not be recommended at this time. It is also possible that this program is intended to provide information on individual exposure to TCDD and/or herbicides to aid in individual compensation decisions. The committee cannot make recommendations for DVA policy, but notes that the finding in Chapter 6 that individual TCDD serum levels are usually not meaningful (because of common background exposures to TCDD, poorly understood variations among individuals in TCDD metabolism, relatively large measurement errors, and exposure to herbicides that did not contain TCDD) might apply to this mandate.
OTHER DIOXIN (TCDD)/HERBICIDE STUDIES
Basic toxicologic research on TCDD will further enhance knowledge of its possible human health effects. The committee recommends that basic
research be undertaken to investigate possible differences in sensitivity among humans to TCDD-mediated toxicity. Additionally, mechanistic studies focused on identifying possible predisposing molecular or genetic factors for TCDD-associated effects would be highly significant for risk assessment purposes.
It may be possible to learn more about the health effects of the herbicides used in Vietnam by studying occupationally exposed workers than by studying veterans, because the amount and intensity of exposure to TCDD and herbicides experienced by Vietnam veterans were probably small compared to the exposures of production workers, agricultural workers, and herbicide sprayers. Furthermore, records on which to base exposure measures for some occupational groups may be better than those for veterans. Thus, although the committee is not in a position to make detailed recommendations about the conduct of occupational studies, it notes the potential value of such studies to the DVA and other government agencies. In particular, the committee has found that the occupational studies being conducted by the National Institute for Occupational Safety and Health in the United States and the International Agency for Research on Cancer in Europe and elsewhere (see Chapter 7) have contributed substantially to the evidence base for some health outcomes that the committee reviewed, and the committee endorses continuing follow-up and analysis of these cohorts. Making available the individual level exposure and outcome data from these two studies would be valuable; these data could be pooled and analyzed further with comparable exposure groups and outcome measures. Additional, carefully conducted epidemiologic studies—with adequate sample size to detect elevated associations—of the reproductive history of individuals with occupational or environmental exposure to herbicides and dioxin are also needed.
Studies of the Vietnamese population exposed to herbicides are also possible and potentially useful. These studies might include Vietnamese still in Vietnam or perhaps even those now in the United States. Accurate disease ascertainment and exposure reconstruction may pose difficult problems, however. The actual exposure of this group to herbicides would be extremely difficult to determine accurately because (1) serious problems with recall bias are likely; (2) given war conditions, documents about location during the war in Vietnam are unlikely to be completely available or reliable; and (3) the Vietnamese in question may have relocated in the intervening decades. Current serum TCDD measures may not be practical or relevant for the same reasons discussed above for U.S. veterans. Before significant resources are committed to studies of the Vietnamese population, the committee recommends that feasibility studies of both exposure reconstruction and disease outcome monitoring be conducted.
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