U.S. Veteran Information (non-governmental)

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Agent Orange and
Vietnam Related Research

Non-VA Efforts

CDC Epidemiologic Study (Epidemiologic Studies of the Health of Vietnam Veterans - Mandated by Public Law 97-72 and Public Law 96-151) - This project was actually three studies: the Vietnam Experience Study, designed to evaluate the overall impact of military service in Vietnam on those who served there; the Agent Orange Exposure Study, intended to assess the possible adverse health effects on Vietnam veterans of exposure to the herbicide; and the Selected Cancers Study, designed to determine the risks of developing specific types of cancer among Vietnam veterans. The Department of Veterans Affairs (VA) provided full funding to the Centers for Disease Control (CDC) for this research.

Vietnam Experience Study - There were two components of this study: mortality (death) and morbidity (disease).

The mortality effort (Postservice Mortality Among Vietnam veterans) revealed that total mortality in Vietnam veterans was 17% higher than for other veterans. The excess mortality occurred mainly in the first five years after discharge from active duty and involved motor vehicle accidents, suicide, homicide, and accidental poisonings. Thereafter, mortality among Vietnam veterans was similar to that of other Vietnam-era veterans, except for drug-related deaths, which continued to be elevated. An unexpected finding was a deficit in deaths from diseases of the circulatory system among Vietnam veterans.

The excess in postservice mortality due to external causes among Vietnam veterans was similar to that found among men returning from combat areas after world War II and the Korean War. The results of this study component were published in the Journal of the American Medical Association in February 1987. At the same time, CDC published a comprehensive report on this project.

The morbidity component of the Vietnam Experience Study (Health Status of Vietnam Veterans) indicated that the Vietnam and non-Vietnam veterans studied were similar in terms of level of education, employment, income, marital status, and satisfaction with personal relationships. Certain psychological problems, however, were significantly more common among Vietnam veterans than among non-Vietnam veterans. These included depression, anxiety, and alcohol abuse or dependence. About 15% of Vietnam veterans suffered from combat-related post-traumatic stress disorder at some time during or after military service, and 2.2% had the disorder during the month before the examination. During the telephone interview, Vietnam veterans reported current and past health problems more often than did non-Vietnam veterans, although results of medical examinations showed few current differences in physical health. Vietnam veterans had more hearing loss.

Among a subsample of participants who had semen samples evaluated, Vietnam veterans had lower sperm concentrations and lower average proportions of "normal" sperm cells. Despite differences in sperm characteristics, Vietnam and non-Vietnam veterans fathered similar numbers of children.

Children of Vietnam veterans were not more likely to have birth defects recorded on hospital birth records than were children of non-Vietnam veterans. The rates of total, major, minor, and suspected defects were similar among children of Vietnam and non-Vietnam veterans.

The results of the morbidity component were published in the Journal of the American Medical Association in May 1988. CDC published a report (five volumes plus three supplements) on this study component in January 1989.

Agent Orange Exposure Study - This study was designed to evaluate the health effects, if any, of possible exposure to herbicides (primarily Agent Orange), utilizing information contained in military records. This component was put on hold in January 1986 because of problems related to the exposure assessment of veterans who served in Vietnam. More specifically, it was determined that a study based solely on military records was not possible because of the considerable potential for misclassification of exposure status.

Subsequently, the Centers for Disease Control conducted a TCDD validation study to compare military records-based estimates with current serum dioxin levels. The results of this study led the Domestic Policy Council's Agent Orange Working Group and the Congressional Office of Technology Assessment to conclude that the Agent Orange Exposure Study cannot be conducted. Consequently, this study was canceled.

The results of the validation study were published in the Journal of the American Medical Association in September 1988. The final report was published by CDC in September 1989.

Selected Cancers Study - This study was designed to determine if Vietnam veterans are at increased risk of contracting any of six specific cancers: soft tissue and other sarcomas, non-Hodgkin's lymphomas, Hodgkin's disease, nasal cancer, nasopharyngeal cancer, and liver cancer.

Data collection for this study component began in January 1985. Selected Cancers Study findings, released in March 1990, indicated that Vietnam veterans are at increased relative risk of developing non-Hodgkin's lymphomas. CDC reported that for "men aged 35-59, the age of most Vietnam veterans, the annual risk of developing non-Hodgkin's lymphoma is 1 in 10,000. For Vietnam veterans, the risk appears to be about one and one-half per 10,000."

The higher non-Hodgkin's lymphoma ratio was due to excessive non-Hodgkin's lymphomas among men who served on ships offshore Vietnam. According to the investigators, there was no similar increased risk among veterans who served in locations other than Vietnam. CDC found that Vietnam veterans were not at increased risk for developing any of the other five types of cancers studied.

Because of the difficulty in estimating Agent Orange exposure in individual veterans (see Agent Orange Exposure Study entry above), CDC only indirectly evaluated the effects of such exposure for the Selected Cancers Study. The study did not find any evidence that the increased risk of non-Hodgkin's lymphomas might be due to Agent Orange exposure. In fact, the pattern of risk among subgroups of Vietnam veterans seems to be the opposite of the use of Agent Orange in Vietnam.

CDC published a "Final Report" on this study in September 1990. The study results were also published in the Archives of Internal Medicine in December 1990.

As a result of the findings of the Selected Cancers Study, Secretary Derwinski announced that VA would recognize non-Hodgkin's lymphomas as service-connected for Vietnam veterans. For additional information about this decision, see gent Orange Brief, B3.

Questions concerning the conduct of the studies described above should be referred to the Centers for Disease Control and Prevention, Atlanta, Georgia 30333.

Air Force Health Study (An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides) - In 1979, the Air Force began this epidemiologic study to determine whether long-term adverse health effects exist following contact with herbicides and whether these medical problems can be attributed to occupational exposure to Agent Orange.

The 20-year study consists of mortality and morbidity components with associated follow-up efforts plus reproductive outcome assessments. The investigation focuses on the Air Force personnel attached to Operation Ranch Hand, who were responsible for the great majority of herbicide spraying missions. Members of the Ranch Hand unit had frequent and repeated exposure to Agent Orange. Individuals in the comparison group served in numerous flying organizations that transported cargo to, from, and within Vietnam but were not involved in the aerial Agent Orange spray operations.

Air Force investigators have issued a series of reports, beginning in 1983, describing the study results. The mortality analyses have not shown any differences between the observed and expected number of Ranch Hand deaths from all causes. There were significantly increased Ranch Hand deaths due to digestive diseases. The 1991 mortality report revealed an increased number of deaths due to circulatory system diseases among the non-flying enlisted personnel. This new finding is being investigated further.

Because of the "healthy veteran effect," (that is, only healthy people are allowed to serve in our Armed Forces) both groups are surviving significantly longer than similarly aged civilians.

The initial morbidity assessments showed only minor differences between the Ranch Hands and the comparisons, and these differences were not considered to be indicators of dioxin-related disease. The 1995 update indicated a possible association between dioxin and diabetes and a relationship between dioxin exposure and heart disease.

A report on reproductive outcomes released in 1992 suggested that there is no adverse relationship between dioxin levels and reproductive outcomes. Investigators also reported no relationship between dioxin levels and sperm count or percentage of abnormal sperm.

Mortality reports were published in 1983, 1984, 1985, 1986, 1989, and 1991. Morbidity assessments were released in 1984, 1987, 1990, and 1995. Additional follow-up examinations are scheduled for 1997 and 2002. An evaluation of the relationship between paternal serum dioxin in Ranch Hand veterans and reproductive outcomes was published in 1995.

For additional information regarding the Air Force Health Study, contact the Office of the Surgeon, Bolling Air Force Base, Washington, DC 20332-7050.

CDC Birth Defects Study (Vietnam Veterans' Risks for Fathering Babies with Birth Defects) - This study, conducted by the Centers for Disease Control with funding from VA, Department of Defense, and the Department of Health and Human Services, assessed Vietnam veterans' risks for fathering babies with major structural birth defects. Information regarding military service in Vietnam was obtained from interviews with mothers and fathers of babies in case and control groups and from review of military records.

Vietnam veterans did not have an increased risk of fathering babies with defects. Vietnam veterans who had greater estimated opportunities for Agent Orange exposure were not at greater risk for fathering babies with all types of defects combined. The study results were published in the Journal of the American Medical Association in August 1984. CDC published a comprehensive report of the study findings in August 1984.

Agricultural Herbicide Use and Risk of Lymphoma and Soft-Tissue Sarcoma - This population-based case-control study of soft-tissue sarcoma, Hodgkin's disease, and non-Hodgkin's lymphomas in Kansas found farm herbicide use to be associated with non-Hodgkin's lymphomas.

This National Cancer Institute study indicated that the relative risk of non-Hodgkin's lymphomas increased significantly with number of days of herbicide exposure per year and latency. Men exposed to herbicides more than 20 days per year (regardless of the number of years of herbicide use) had a 6-fold increased risk of non-Hodgkin's lymphomas relative to non-farmers. Excess risk was associated primarily with long-term use of the herbicide 2,4-D, one of the ingredients of Agent Orange. (This ingredient did not contain the contaminant of Agent Orange known as TCDD or dioxin which has caused a variety of illnesses in laboratory animals.) Soft tissue sarcomas were not associated with herbicide exposure. This study supports findings from Sweden and the U.S. that suggest non-Hodgkin's lymphomas are associated with farm herbicide use.

The results of the study were published in the Journal of the American Medical Association in Setember 1986.

Soft Tissue Sarcoma and Non-Hodgkin's Lymphoma in Relation to Phenoxyherbicide and Chlorinated Phenol Exposure in Western Washington - This National Cancer Institute-funded population-based case-control study was conducted in western Washington State to evaluate the relationship between occupational exposure of men aged 20-79 to certain herbicides and other chemicals and the risks of developing soft tissue sarcomas and non-Hodgkin's lymphomas. Occupational histories and other information were obtained by personal interviews for 128 soft tissue sarcoma cases and 576 non-Hodgkin's lymphoma cases, diagnosed between 1981 and 1984, for 694 randomly selected controls without cancer.

The results demonstrated small but significantly increased risks of developing non-Hodgkin's lymphomas in association with some occupational activities where certain herbicides have been used in combination with other types of chemicals, particularly for prolonged periods. They do not demonstrate a positive association between increased cancer risks and exposure to any specific herbicide alone. Moreover, these findings provide no evidence of increased risks of developing non-Hodgkin's lymphomas associated with chlorinated phenol exposure or of developing soft tissue sarcomas associated with exposure to either class of chemical.

The results were published in the Journal of the National Cancer Institute in May 1987.

In addition to the scientific investigations described above, the Department of Agriculture, Environmental Protection Agency, Armed Forces Institute of Pathology, National Cancer Institute, National Institute for Occupational Safety and Health, and several other Federal agencies are doing or have completed research to discover more about the possible adverse health effects of exposure to Agent Orange and other herbicides used in Vietnam.

According to the final report issued by the Domestic Policy Council's Agent Orange Working Group in 1994, there are 38 ongoing projects and 189 completed projects. The report indicates that over $127 million has been spent on the completed projects and an additional $86 has been spent on the ongoing projects. The report added that an additional $70 million will be required to complete ongoing projects.

A number of States have also conducted research on Agent Orange and Vietnam veterans. Mortality studies of Vietnam veterans were completed in New York, Wisconsin, West Virginia, and Massachusetts. Studies and/or surveys have also been done in Iowa, New Jersey, and several other States. The American Legion also did a study. That veterans group, in concert with two other organizations, sponsored a review of herbicide literature in 1990.

The Department of Veterans Affairs also is closely monitoring research being conducted in other countries as well as studies being done throughout the United States.

NAS Report (Veterans and Agent Orange - Health Effects of Herbicides Used in Vietnam) - In 1992, the National Academy of Sciences (NAS), a non-governmental organization, agreed to conduct a multi-year review of all relevant scientific research and provide advice to the Secretary of Veterans Affairs on a wide range of issues relative to herbicides and dioxin. The NAS review is being undertaken in accordance with Public Law 102-4, the Agent Orange Act of 1991, signed by the President on February 6, 1991. The initial NAS report was released in July 1993. The NAS found "sufficient evidence" to conclude that there is a positive association between herbicides and (1) soft tissues sarcoma, (2) non-Hodgkin's lymphoma, (3) Hodgkin's disease, (4) chloracne, and (5) porphyria cutanea tarda (in genetically susceptible individuals).

The NAS also found "limited/suggestive evidence" of an association between exposure to herbicides used in Vietnam and three other types of cancer: respiratory cancers (including lung, larynx, and trachea), prostate cancer, and multiple myeloma.

For most conditions reviewed, the NAS concluded that there was "inadequate/insufficient evidence" to determine whether an association exists. The NAS Committee included the following diseases and disorders in this third category: hepatobiliary cancers, nasal/nasopharyngeal cancer, bone cancer, female reproductive cancers (breast, cervical, uterine, ovarian), renal cancer, testicular cancer, leukemia, spontaneous abortion, birth defects, neonatal/infant death and stillbirths, low birthweight, childhood cancer in offspring, abnormal sperm parameters and infertility, cognitive and neuropsychiatric disorders, motor/coordination dysfunction, peripheral nervous system disorders, metabolic and digestive disorders (diabetes, changes in liver enzymes, lipid abnormalities, ulcers), immune system disorders (immune modulation and autoimmunity), circulatory disorders, and respiratory disorders.

For a small group of cancers, the NAS found "limited/suggested evidence" that there is "no association" with herbicides used in Vietnam. This category included skin cancer, gastrointestinal tumors (stomach cancer, pancreatic cancer, colon cancer, rectal cancer), bladder cancer, and brain tumors. The Committee report noted, however, that even for these conditions "the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded."

The greatest problem encountered in the review was a severe lack of information about the exposure of individual Vietnam veterans to herbicides. Except for particular groups, such as the individuals directly involved in spraying operations, information on the extent of herbicide exposure among veterans is practically nonexistent. Consequently, most studies evaluated by the NAS did not involve Vietnam veterans. Rather, the NAS focused on studies of people who were exposed to herbicides as a result of their jobs or as a result of contact in the environment.

These types of exposures often were at high levels and for long periods of time. Assessing health risks for Vietnam veterans is complicated by the fact that the levels of exposure were extremely wide ranging. While most Vietnam veterans probably had lower exposure levels, some may have experienced levels as high as that of occupational or agricultural exposures. What is uncertain is how many veterans may have been exposed to those higher levels and who those individuals are.

The NAS concluded that a series of epidemiologic studies of veterans could yield valuable information if a new, valid exposure reconstruction model could be developed. The NAS urged the continuation of the Air Force Health Study of Ranch Hand personnel and the expansion of that investigation to include Army Chemical Corps veterans.

The NAS's research recommendations emphasized epidemiologic studies of Vietnam veterans, rather than general toxicologic or epidemiologic studies of occupationally or environmentally exposed populations. A substantial amount of research on the toxicology of herbicides and herbicide components is already under way in the United States and abroad. Many of the studies on which the NAS's conclusions are based have been published since 1991. Although not targeted specifically to Vietnam veterans, it is likely that this ongoing research will also contribute to the knowledge of potential health effects in this population.

The NAS made the following specific recommendations regarding epidemiologic studies of Vietnam veterans:

Recommendation 1. The NAS 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.

Recommendation 2. The Department of Defense and the Department of Veterans Affairs should identify Vietnam service in the computerized index of their records.

Recommendation 3. Biomarkers for herbicide exposure should be developed further.

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.

Recommendation 5. The exposure reconstruction models developed according to Recommendation 4 should be evaluated by an independent, nongovernmental scientific panel established for this purpose.

Recommendation 6. If the scientific panel 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.

The NAS also recommended that priority be given to additional research on reproductive effects that would help clarify the possible effects of herbicides. In particular, the NAS concluded that extensive reanalysis of the Ranch Hand reproductive data could shed additional light on these questions.

The NAS report noted that although there is sufficient evidence of an association between occupational or environmental exposures to herbicides and several conditions, 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. Additional 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 or TCDD.

The NAS observed that its 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, White House Agent Orange Working Group, and Congressional Office of Technology Assessment conclusions made in 1986 regarding the congressionally mandated Agent Orange Study. The NAS offered four reasons for the different conclusion:

  1. the 1986 conclusions were based in large part on serum TCDD measurements, which the NAS thinks are insufficient for validating exposure to herbicides used in Vietnam;
  2. 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 nondifferential misclassification errors that will lead to underestimates of the relative risk of health outcomes if an association is in fact present;
  3. the NAS 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; and
  4. the NAS 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 NAS's judgment, however, the likelihood that this approach will be successful is sufficient for it to be recommended.

The law that mandated the NAS review (Public Law 102-4, the Agent Orange Act of 1991), required that NAS include in the initial NAS report an evaluation of the feasibility and cost-effectiveness of four specific programs that might be implemented by VA. The NAS conclusions are described below.

Section 6 of that legislation requires VA to compile and analyze, on a continuing basis, all clinical data that

  1. are obtained in connection with VA examinations and treatment of Vietnam veterans, and
  2. are likely to be scientifically useful in determining the association between disabilities experienced by these veterans and exposure to dioxin or herbicides.

The NAS report indicated that such a system, called the Agent Orange Registry, currently exists.

Section 7 concerned the establishment of a system for the collection and storage of voluntarily contributed samples of blood and tissue of veterans who served in Vietnam. Balancing the strengths and weaknesses stored biological samples and clinical data for research purposes, the Committee concluded 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 important design, quality control, and ethical issues regarding tissue banks, the NAS did not recommend the establishment at this time of the clinical data (Section 6) and tissue archiving (Section 7) systems described in the law.

Section 8 related to the feasibility of conducting additional scientific research on health hazards resulting from exposure to dioxin and herbicides used in Vietnam. As stated above, the NAS concluded that a series of epidemiologic studies of veterans could yield valuable information if a new, valid exposure reconstruction model can be constructed.

Section 9 would require VA to test for dioxin (TCDD) in any blood sample voluntarily provided by Vietnam veterans who seek VA health care under priority eligibility based on exposure to Agent Orange. The NAS report noted that the purpose of this idea was not stated in the legislation and is unclear. If research purposes are contemplated, the NAS's conclusions about tissue archiving are applicable, and the NAS would not recommend such a program at this time. The NAS realized that such a program might be intended to provide information on individual exposure to dioxins or herbicides to aid in individual compensation decisions. The NAS cannot make recommendations for VA policy but noted that individual TCDD serum levels in Vietnam veterans are usually not meaningful because of common backgrounds exposures to TCDD, poorly understood variations in TCDD metabolism, relatively large measurement errors, and exposure to herbicides that did not contain TCDD.

Follow-up reports by the NAS are planned for once every two years for ten years following the initial report (to the extent appropriations are available).

NAS Report (Veterans and Agent Orange: Update 1996) - The first NAS update was considerably shorter than the initial publication (384 pages compared to 832 pages). Unlike the 1992 report, it did not include research recommendations. The same four categories were used to classify health outcomes according to the likelihood of a positiveassociation with herbicide exposure, based on all available research data.

In its initial report, the NAS included the following conditions in category one (sufficient evidence of an association): soft-tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, chloracne, and porphyria cutanea tarda (PCT), in genetically susceptible individuals. The 1996 update dropped PCT to category two (limited/suggestive evidence of an association). The other four conditions remained in category one, and no additional health outcomes were included in this category.

In the initial report, the NAS included only three health outcomes in category two: prostate cancer, multiple myeloma, and respiratory cancers. Six outcomes were placed in this category in the update. In addition to these three cancers and PCT, the NAS included the following in category two: acute and subacute peripheral neuropathy in Vietnam veterans and spina bifida in the children of Vietnam veterans.

The first report included peripheral neuropathy among "peripheral nervous system disorders," finding that there is inadequate/insufficient evidence to determine whether an association exists (category three). Similarly, spina bifida was grouped with all other birth defects, and the NAS declared that there is inadequate/insufficient evidence to determine whether an association exists.

In the update, the NAS concluded that birth defects (except spina bifida) as well as chronic peripheral nervous systems disorders should remain in category three. Most conditions evaluated in 1996 report (as well as in the 1993 effort) were listed in category three. In the 1996 report the following outcomes were listed in this NAS category: hepatobiliary cancers, nasal/nasopharyngeal cancer, bone cancer, female reproductive cancers (cervical, uterine, ovarian), breast cancer, renal cancer, testicular cancer, leukemia, spontaneous abortion, birth defects (other than spina bifida), neonatal/infant death and stillbirths, low birthweight, childhood cancer in offspring, abnormal sperm parameters and infertility, cognitive and neuropsychiatric disorders, motor/coordination dysfunction, chronic peripheral nervous system disorders, metabolic and digestive disorders (diabetes, changes in liver enzymes, lipid abnormalities, immune systems disorders (immune suppression and autoimmunity), ulcers), circulatory disorders, respiraory disorders, and skin cancer.

The 1996 list for category three is very similar to the list in the 1993 report. The changes are the two noted above (that is, peripheral nervous system disorders and birth defects) plus an elevation of skin cancer from category four.

Few health outcomes were included in category four (limited/suggestive evidence of no association). The 1996 report included gastrointestinal tumors (stomach cancer, pancreatic cancer, colon cancer, rectal cancer), bladder cancer, and brain tumors. The only change from the earlier NAS report in this category was the elevation of skin cancer to category three.

In two years, as required by the Agent Orange Act of 1991, the NAS will re-evaluate current scientific evidence in conjunction with an assessment of new information regarding the possible long-term health consequences of herbicide exposure.

Single copies of the NAS books were distributed to all VA medical center libraries: Organizations or individuals interested in purchasing these documents can contact the publisher: National Academy Press, 2101 Constitution Avenue, N.W. Box 285, Washington, DC 20055. The telephone numbers are 1-800-624-6242 and 202-334-3313. The NAS is a private, nonprofit society of distinguished scholars engaged in scientific and engineering research. Established in 1863, the NAS is dedicated to the furtherance of science and technology and to their use for the promotion of general public welfare.

Where can a veteran get more information about Agent Orange research and studies on related matters?

Information on these subjects can be obtained at the VA medical center libraries, from the Registry Physician or Agent Orange Coordinator at every VA medical center, or from the Environmental Agents Service, (131), Department of Veterans Affairs, 810 Vermont Avenue, N.W., Washington, DC 20420.

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Department of Veterans Affairs
Agent Orange Brief
Prepared by the Environmental Agents Service
VA Central Office, Washington, DC       January 1997

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