Executive Summary

From 1962 to 1971, US military forces sprayed herbicides over Vietnam to strip the thick jungle canopy that helped conceal opposition forces, to destroy crops that enemy forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the majority of the herbicides sprayed. The herbicide mixtures used were named according to the color of an identification band painted on the storage drums; one main chemical mixture sprayed was Agent Orange (a 50:50 mixture of 2,4-D and 2,4,5-T). At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, one form of dioxin) was an unintended contaminant from the production of 2,4,5-T and was present in Agent Orange and some other formulations sprayed in Vietnam.

In 1991, because of continuing uncertainty about the long-term health effects on Vietnam veterans of the herbicides sprayed, Congress passed Public Law 102-4 (PL 102-4), the Agent Orange Act of 1991. That legislation directed the Secretary of Veterans Affairs to ask the National Academy of Sciences (NAS) to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various components of those herbicides, including TCDD. The Secretary was also to ask that NAS conduct updates at least every 2 years for 10 years from the date of the first report to review newly available literature and draw conclusions from the overall evidence. PL 107-103, the Veterans Education and Benefits Expansion Act of 2001, extended the updates until 2014.



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Veterans and Agent Orange: Update 2004 Executive Summary From 1962 to 1971, US military forces sprayed herbicides over Vietnam to strip the thick jungle canopy that helped conceal opposition forces, to destroy crops that enemy forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the majority of the herbicides sprayed. The herbicide mixtures used were named according to the color of an identification band painted on the storage drums; one main chemical mixture sprayed was Agent Orange (a 50:50 mixture of 2,4-D and 2,4,5-T). At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, one form of dioxin) was an unintended contaminant from the production of 2,4,5-T and was present in Agent Orange and some other formulations sprayed in Vietnam. In 1991, because of continuing uncertainty about the long-term health effects on Vietnam veterans of the herbicides sprayed, Congress passed Public Law 102-4 (PL 102-4), the Agent Orange Act of 1991. That legislation directed the Secretary of Veterans Affairs to ask the National Academy of Sciences (NAS) to perform a comprehensive evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various components of those herbicides, including TCDD. The Secretary was also to ask that NAS conduct updates at least every 2 years for 10 years from the date of the first report to review newly available literature and draw conclusions from the overall evidence. PL 107-103, the Veterans Education and Benefits Expansion Act of 2001, extended the updates until 2014.

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Veterans and Agent Orange: Update 2004 In response to the request, the Institute of Medicine (IOM) of NAS convened a committee, whose conclusions IOM published in 1994 in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO). The work of later committees resulted in the publication of biennial updates (Update 1996, Update 1998, Update 2000, and Update 2002) and in focused reports on the scientific evidence regarding type 2 diabetes (Type 2 Diabetes), acute myelogenous leukemia in children (Acute Myelogenous Leukemia), and the latency period for respiratory cancer (Respiratory Cancer). This report is the fifth review of recently published scientific evidence regarding associations between health outcomes and exposure to TCDD and other chemical compounds in herbicides used in Vietnam. CHARGE TO THE COMMITTEE In accordance with PL 102-4, the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fifth Biennial Update) was asked to “determine (to the extent that available scientific data permit meaningful determinations)” the following regarding associations between specific health outcomes and exposure to TCDD and other chemical compounds in herbicides: A) whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiological methods used to detect the association; B) the increased risk of the disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and C) whether there exists a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease. In conducting its study, this committee operated independently of the Department of Veterans Affairs (VA) and other government agencies. The committee was not asked to and did not make judgments regarding specific cases in which individual Vietnam veterans have claimed injury from herbicide exposure. This report provides scientific information for the Secretary of Veterans Affairs to consider as VA exercises its responsibilities to Vietnam veterans. The committee was not charged to focus on broader issues, such as the potential costs of compensation for veterans or policies regarding such compensation. COMMITTEE’S APPROACH TO ITS CHARGE To fulfill its charge of assessing whether specific human health effects are associated with exposure to at least one of the herbicides or TCDD, the committee concentrated its review on epidemiologic studies. The committee also consid-

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Veterans and Agent Orange: Update 2004 ered controlled laboratory investigations that provide information on whether it is biologically plausible to suppose that the compounds of interest might be related to a given effect. The committee began its evaluation presuming neither the presence nor the absence of associations. To obtain all information potentially relevant to the evaluation of health effects related to herbicide exposure, the present committee, in addition to reviewing studies of Vietnam veterans, reviewed studies of other groups potentially exposed to the constituents of the herbicides used in Vietnam (2,4-D, 2,4,5-T, TCDD, cacodylic acid, and picloram). Those groups include chemical production and agricultural workers, people possibly exposed heavily to herbicides or dioxins as a result of residing near the site of an unintended release or areas used to dispose of toxic waste, and residents of Vietnam. PL 102-4 did not provide a list of specific diseases and conditions suspected of being associated with herbicide exposure. Such a list was developed in VAO on the basis of diseases and conditions that had been mentioned in the scientific literature or in other documents identified through extensive literature searches. The VAO list has been augmented in response to developments in the literature, requests by VA, and concerns of Vietnam veterans. The information that the present committee reviewed was identified through a comprehensive search of relevant databases, including databases covering biologic, medical, toxicologic, chemical, historical, and regulatory information. Literature identification continued through June 1, 2004. More than 3,000 potentially relevant studies were identified in those searches, and more than 550 were reviewed. Additional information came from veterans and other interested persons who testified at public hearings and offered written submissions. To determine whether there is an association between exposure and health outcome, epidemiologists estimate the magnitude of an appropriate measure (such as the relative risk or the odds ratio) that describes the relationship between exposure and disease in a defined population or group. In evaluating the strength of the evidence linking herbicide exposure with a particular outcome, the committee considered whether such estimates of risk might be incorrect (the result of confounding, chance, or bias from errors in selection and measurement) or might accurately represent true associations. It has been the practice of all VAO committees to evaluate all studies according to the same criteria whether or not their subjects are Vietnam veterans and then to weight findings of similar strength and validity equivalently when drawing conclusions. The committee recognizes that an absolute conclusion about the absence of association might never be attained, because, as is generally the case in science, studies of health outcomes after herbicide exposure cannot demonstrate that a purported effect is impossible, only that it is statistically improbable.

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Veterans and Agent Orange: Update 2004 EVIDENCE REVIEWED BY THE COMMITTEE Toxicology Since Update 2002, several experimental studies have been published on the chemical compounds of interest. Some examine particular disease outcomes in animals after exposure to the compounds; others focus more on the mechanism or mode of action by which effects are elicited in cells, tissues, or whole animals. Despite extensive study, the exact mechanisms by which the compounds exert their effects are still unclear. Toxicologic information on disease outcomes in animals can, however, support an association seen in an epidemiologic study by providing evidence that an effect is biologically plausible. Many health effects have been seen in animals after exposure to TCDD or to the herbicides used in Vietnam. Although animal experiments demonstrate that some of the compounds (alone or in conjunction with other treatments) can cause specific cancers, none of the compounds of interest has been shown to act directly by mutating DNA. TCDD is thought to be the most toxic of the compounds, and recent experimental research has shown a great deal about the cellular effects of TCDD. All of the data are consistent with the hypothesis that those effects are mediated by the ability of TCDD to bind a cellular protein, the aryl hydrocarbon receptor, to modulate cell-signaling pathways. However, the exact mechanisms by which those events cause the various effects seen in humans and animals remains unknown. Relevant effects observed in experimental animals, and their relevance to human health outcomes, are discussed as part of the biologic plausibility section for each outcome. Exposure Assessment Assessment of exposure to a toxic substance is an important element in determining whether specific health outcomes are linked to that substance. Under ideal circumstances exposure assessment would quantify the concentration of a substance at its site of action; in human studies that is rarely possible. Exposure estimates, therefore, should be viewed as surrogates for the actual dose. Recent studies of Vietnam veterans, including those of the Ranch Hand and Army Chemical Corps cohorts, have used the measurement of serum blood levels of TCDD as the best available estimator of historical exposures to Agent Orange. This approach has also been used to study health effects in the Seveso population in Italy. Since Update 2002, a study of Korean Vietnam veterans developed an exposure index based on duration of service, troop location relative to herbicide spraying, and individual activity data from questionnaires. The investigators attempted to validate this exposure index with serum blood levels of TCDD, but samples were pooled within presumed exposure categories and only a narrow

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Veterans and Agent Orange: Update 2004 range of TCCD concentrations was measured across these categories. All concentrations were less than one picogram TCDD per gram of serum (lipid-adjusted). In 1997, a committee convened by IOM on behalf of the VA requested research proposals designed to reconstruct exposures of US veterans who served as ground troops in Vietnam. This request resulted in a project called “Characterizing Exposure of Veterans to Agent Orange and Other Herbicides in Vietnam”. Since Update 2002, a final report of this work has been published by IOM. This report presents an “exposure-opportunity index” based on records of herbicide spraying and troop movements. The IOM committee’s review of the report concluded that the exposure-opportunity index holds promise for epidemiologic investigations of this population. Epidemiology The health outcomes reviewed by the committee are categorized as cancer, reproductive and developmental effects, neurologic disorders, and other health effects. This section briefly summarizes the relevant epidemiologic studies published on those health outcomes since Update 2002. In the health outcomes chapters, this new literature was evaluated and considered in the context of the previous reviews to derive comprehensive updated conclusions integrating the entire body of information. Cancer Since Update 2002, several cohort studies were published that investigated multiple cancer outcomes. Cancer incidence and mortality were compared between the Ranch Hand cohort and the Air Force control cohort of Vietnam veterans; an excess incidence of melanoma was observed in some subgroups of the Ranch Hand Air Force veterans, but analyses did not establish this outcome in the entire cohort, and an increase in the incidence of, but not mortality from, prostate cancer was observed. A pilot case-control study of prostate cancer among Vietnam-era veterans found an elevated, but non-significant increase associated with reported Agent Orange exposure. An update of a cohort of Dow Chemical Company workers and a study of pesticide appliers in Iowa and North Carolina both also found an increase in prostate cancer, while a cancer mortality study of Dutch herbicide appliers showed only an increase in “all skin cancers.” An ecological study of Japanese municipalities with and without waste incinerators had negative findings for cancer mortality overall. Case-control studies of soft-tissue sarcoma in Italian and Finnish populations had opposing results concerning residential exposure to the chemicals of interest. No other increases in cancer incidence or mortality were reported in association with the chemicals of interest.

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Veterans and Agent Orange: Update 2004 Reproductive and Developmental Effects Two environmental studies addressed birth defects: One examined proximity to municipal solid waste incinerators in France, and the other reviewed countywide use of agricultural pesticides in four US states. Neither presented additional information on the occurrence of spina bifida. The French study reported associations with facial clefts and renal abnormalities, and the US study presented results for circulatory and respiratory anomalies; the exposure assessment in each study was ecological. One relatively small study of time-to-conception presented results that suggested a connection with infertility, but the assessment of herbicide exposure was nonspecific. Two ecological studies addressed outcomes that are tangentially related to fertility (sperm quality and regularity of menstrual cycling). One study investigating spontaneous abortion among women exposed during the Seveso accident reported no relationship with serum TCDD concentrations. Studies of birth weight and gestational duration for the pregnancies of Polish farm women and of Seveso residents presented data suggestive of a connection, but compromised by design limitations. A single study of cancers among the offspring of pesticide appliers presented indeterminate results for this quite nonspecific outcome category. One new study of pesticide production workers reported a suggestion of a reduced sex ratio (fewer-than-expected male offspring) for the children of male, but not female, workers. Neurologic Disorders Since Update 2002, cognitive outcomes have been investigated in a study of elderly residents of Bordeaux, France; in an updated cohort of Czech workers; in an ecological study of a community adjacent to a wood treatment plant; and in two studies of Vietnam veterans, one of US Ranch Hands and one of Korean veterans. Only the Bordeaux study reported an increase in cognitive disorders, but it did not implicate the compounds of interest to this report. Three publications examined possible associations with Parkinson’s disease. Although some associations were reported, the limitations of those studies (particularly the lack of information on the compounds of interest) do not permit conclusive interpretation. One study reported a higher rate of peripheral neuropathy among Korean Vietnam veterans than was found among veterans who did not serve in Vietnam, but the results were unrelated to estimated dioxin exposures. Although the committee carefully reviewed the available literature on peripheral neuropathy, neither the new report nor the previous epidemiologic literature convincingly indicates an association between exposure and persistent neuropathy in veterans who do not have diabetes. Peripheral neuropathy is seen secondary to diabetes, for which an association with the compounds of interest has been noted. It is not possible to determine from the available literature whether observed increases in peripheral neuropathy are primary effects from dioxin exposure or secondary to diabetes.

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Veterans and Agent Orange: Update 2004 Other Health Effects Several studies have investigated health effects other than those classified as cancer, reproductive and developmental effects, or neurological disorders. The incidence of chloracne; increases in uroporphyrins; changes in immune parameters; and increased hypertension, valvular heart disease, and ischemic heart disease were observed to be higher in Korean Vietnam veterans who served in Vietnam than in those who did not. The study’s limitations, however, do not permit conclusions to be drawn based only on its data. Changes in immune parameters also were seen in studies of residents of Seveso. Some respiratory effects were suggested by a study of people living near a wood treatment plant, but there was no evidence that those effects were specifically related to the compounds of interest. Several other studies presented evidence of additional effects, but none was of high enough quality or sufficiently relevant to the compounds of interest to affect the conclusions of previous reviews. COMMITTEE’S CONCLUSIONS Health Outcomes The present committee weighed the strengths and limitations of the epidemiologic evidence reviewed in this report and in previous Veterans and Agent Orange reports. Its conclusions were drawn from the new evidence in the context of the entire body of literature. It assigned each health outcome to one of four categories on the basis of the evidence. Table ES-1 defines these categories and gives criteria for assigning a health outcome to each of them. Based on the committee’s evaluation of occupational, environmental, and veterans studies, this table also lists the relative weight of evidence for association between particular health outcomes and exposure to the herbicides that were used in Vietnam or to any of their components or contaminants (with no intention of specifying a particular chemical). After careful consideration, the present committee did not change the categorization of health outcomes in this report from Update 2002. It did, however, modify the previous terminology of “acute and subacute” transient peripheral neuropathy to “early-onset” transient peripheral neuropathy as being more reflective of the intended properties of the condition’s symptoms, rather than suggesting the conditions of exposure. As mandated by PL 102-4, the distinctions among categories are based on statistical association, not on causality. The committee was directed to review the scientific data, not to recommend VA policy; therefore, conclusions reported in Table ES-1 are not intended to imply or suggest policy decisions. The conclusions are related to associations between exposure and outcomes in human populations, not to the likelihood that any individual’s health problem is associated with or caused by the herbicides in question.

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Veterans and Agent Orange: Update 2004 TABLE ES-1 Summary of Findings in Occupational, Environmental, and Veterans’ Studies Regarding the Association Between Specific Health Outcomes and Exposure to Herbicidesa Sufficient Evidence of an Association Evidence is sufficient to conclude that there is a positive association. That is, a positive association has been observed between herbicides and the outcome in studies in which chance, bias, and confounding could be ruled out with reasonable confidence. For example, if several small studies that are free from bias and confounding show an association that is consistent in magnitude and direction, there may be sufficient evidence of an association. There is sufficient evidence of an association between exposure to herbicides and the following health outcomes: Chronic lymphocytic leukemia (CLL) Soft-tissue sarcoma Non-Hodgkin’s lymphoma Hodgkin’s disease Chloracne Limited or Suggestive Evidence of an Association Evidence is suggestive of an association between herbicides and the outcome but is limited because chance, bias, and confounding could not be ruled out with confidence. For example, at least one high-quality study shows a positive association, but the results of other studies are inconsistent. There is limited or suggestive evidence of an association between exposure to herbicides and the following health outcomes: Respiratory cancer (lung and bronchus, larynx, and trachea) Prostate cancer Multiple myeloma Early-onset transient peripheral neuropathyb Porphyria cutanea tarda Type 2 diabetes (mellitis) Spina bifida in offspring of exposed individuals Inadequate or Insufficient Evidence to Determine Whether an Association Exists The available 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 whether an association exists between exposure to herbicides and the following health outcomes: Hepatobiliary cancer Oral, nasal, and pharyngeal cancer Bone and joint cancer Skin cancers (melanoma, basal cell, and squamous cell) Breast cancer Female reproductive cancer (cervix, uterus, ovary) Testicular cancer Urinary bladder cancer Renal cancer Leukemia (other than CLL) Abnormal sperm characteristics and infertility Spontaneous abortion Neonatal or infant death and stillbirth in offspring of exposed individuals

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Veterans and Agent Orange: Update 2004 Low birthweight in offspring of exposed individuals Birth defects (other than spina bifida) in offspring of exposed individuals Childhood cancer (including acute myelogenous leukemia) in offspring of exposed individuals Neurobehavioral disorders (cognitive and neuropsychiatric) Movement disorders, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS) Chronic peripheral nervous system disorders Respiratory disorders Gastrointestinal, metabolic, and digestive disorders (changes in liver enzymes, lipid abnormalities, ulcers) Immune system disorders (immune suppression, autoimmunity) Circulatory disorders AL amyloidosis Endometriosis Effects on thyroid homeostasis Limited or Suggestive Evidence of No Association Several adequate studies, covering the full range of levels of exposure that human beings are known to encounter, are consistent in not showing a positive association between any magnitude of exposure to herbicides and the outcome. A conclusion of “no association” is inevitably limited to the conditions, exposure, 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 herbicides and the following health outcomes: Gastrointestinal tumors (esophagus, stomach, pancreas, colon, rectum) Brain tumors a Herbicides indicates the following chemicals of interest: 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, or dioxin), cacodylic acid, and picloram. The evidence regarding association was drawn from occupational, environmental, and veterans studies in which individuals were exposed to the herbicides used in Vietnam, to their components, or to their contaminants. b For clarity, this committee has changed the nomenclature from “acute and subacute” to “early-onset” transient peripheral neuropathy. Risk in Vietnam Veterans There have been numerous health studies of Vietnam veterans, but most have been hampered by relatively poor measures of exposure to herbicides or TCDD and by other methodologic problems. In light of those problems, many conclusions regarding associations between exposure to the chemicals of interest and disease are based on studies of people exposed in various occupational and environmental settings rather than on studies of Vietnam veterans. The committee believes that there is sufficient evidence to reach general conclusions about asso-

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Veterans and Agent Orange: Update 2004 ciations between herbicide exposure and the health outcomes, but the lack of adequate exposure data on Vietnam veterans themselves makes it difficult to estimate the degree of increased risk of disease in Vietnam veterans, as a group or individually. Thus, quantification of the actual risks experienced by veterans exposed to the compounds of interest during the Vietnam War is not possible. Because of those limitations, only general assertions can be made about risks to Vietnam veterans, depending upon which category of the association has been attributed to a given health outcome. When there is “limited or suggestive evidence of no association” between herbicide exposure and a health outcome, the evidence suggests that there is no increased risk of the outcome among Vietnam veterans that is attributable to exposure to the compounds of interest, but that conclusion is limited to the conditions, exposures, and lengths of observation covered by the studies reviewed by the committee. Even qualitative estimates are not possible when there is “inadequate or insufficient” evidence of an association. For outcomes categorized as having “sufficient” or “limited or suggestive” evidence of an association with herbicide exposure, the lack of exposure information for Vietnam veterans prevents calculation of precise risk estimates. RESEARCH RECOMMENDATIONS IOM has been asked to make recommendations concerning the need, if any, for additional scientific studies to resolve continuing scientific uncertainties about the health effects of the herbicides and their contaminants used in Vietnam. Great strides have been made over the past several years in understanding the health effects of exposure to TCDD and to the herbicides used in Vietnam and in elucidating the mechanisms that underlie those effects, but there are still important gaps in our knowledge. On the basis of its review of the epidemiologic evidence and consideration of the quality of exposure information available in existing studies, especially of Vietnam veterans, the present committee concludes that continuation of epidemiologic studies of veterans could yield valuable information. Another population that has been understudied is the Vietnamese, including those who served in the military during the war and civilians. Anecdotal evidence and studies published in non-English-language journals suggest an array of long-term health effects that could potentially be related to the chemicals used by US troops in Vietnam. Although the explicit purpose of the newly established exposure database was to determine exposures of US service personnel who spent time in Vietnam, the possibility of using it to identify study populations among Vietnamese residents should be considered.