Given the present lack of information, the committee believes that further research aimed at evaluating long-term effects of herbicide exposures on male reproductive organs and on understanding the effects on sex ratio and functional developmental toxicities would be useful.

Because of continuing uncertainty about the long-term health effects of exposure to the herbicides used in Vietnam, Congress passed Public Law 102-4, the Agent Orange Act of 1991, subsequently codified as 38 USC Sec. 1116. This legislation directed the Secretary of Veterans Affairs to request the National Academy of Sciences (NAS) to conduct a comprehensive review and evaluation of scientific and medical information regarding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various chemical components of these herbicides, including dioxin. A committee convened by the Institute of Medicine of the NAS conducted this review, and in 1994 published a comprehensive report entitled Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (henceforth referred to as VAO) (IOM, 1994).

Public Law 102-4 also called for the NAS to conduct subsequent reviews at least every 2 years for a period of 10 years from the date of the first report. The NAS was instructed to conduct a comprehensive review of the evidence that had become available since the previous IOM committee report and to reassess its determinations and estimates of statistical association, risk, and biological plausibility. On completion of VAO, successor committees were formed that produced Veterans and Agent Orange: Update 1996 (hereafter, Update 1996) (IOM, 1996), Veterans and Agent Orange: Update 1998 (hereafter, Update 1998) (IOM, 1999), Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000), and Veterans and Agent Orange: Update 2000 (hereafter, Update 2000) (IOM, 2001).

The committee responsible for Update 2000 concluded that there was limited/ suggestive evidence of an association between exposure to the herbicides used in Vietnam and acute myelogenous leukemia (AML) in the children of veterans. This was a change in classification from previous Veterans and Agent Orange reports, which found inadequate/insufficient evidence to determine whether an association existed for AML and other cancers in the children of veterans. The finding was based in part on a 2000 study of the children of Australian Vietnam veterans by the Australian Institute of Health and Welfare (AIHW).

In May 2001, AIHW announced it had found an error in the way that it calculated the expected incidence of AML that led them to incorrectly conclude that the children of Australian veterans were at a significantly increased risk for the disease. In response to the announcement, the Department of Veterans Affairs

(DVA) requested that IOM convene a committee to revisit the issue of AML in the children of veterans and evaluate updated information from AIHW, other newly available or identified scientific studies, and information developed in previous reviews by IOM committees.

While limited to one health outcome, this report adheres to the format of other Veterans and Agent Orange reports. In conducting its study, the IOM committee operated independently of the DVA 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. Rather, the study provides scientific information for the Secretary of Veterans Affairs to consider as the DVA exercises its responsibilities to Vietnam veterans.

The conclusions in this report are based on cumulative evidence from the scientific literature reviewed in VAO, Update 1996, Update 1998, Update 2000, and information published or identified through October 18, 2001, when the committee completed its deliberations. This report is intended to supplement rather than replace the previous updates; therefore, not all of the information on studies reviewed in those reports has been repeated.

This report begins with a brief overview of the study methodology and the considerations underlying the assessment of research reviewed. This is followed by an evaluation of the epidemiologic evidence, which includes background on the scientific data reviewed in VAO, Update 1996, Update 1998, and Update 2000 and a more thorough discussion of the new information and their interpretation. The reader is referred to relevant sections of the previous reports for additional detail and explanation.

In the Veterans and Agent Orange series of reports, committees have focused most of their efforts on reviewing and interpreting epidemiologic studies in order to evaluate the extent to which the scientific literature does or does not suggest that particular human health effects are associated with exposure to herbicides or dioxin. In this report, the committee weighed the strengths and limitations of the scientific data in VAO, Update 1996, Update 1998, and Update 2000, as well as newly available or identified information, and reached its conclusions by interpreting the new evidence in the context of the whole of the literature. Earlier committees have placed each disease into one of four categories depending on the strength of evidence for an association (see “Categories of Association” below). Here, the discussion and category relate only to acute myelogenous leukemia in the children of veterans, using the same criteria to categorize health outcomes as used in the previous reports.

Consistent with the charge to the Secretary of Veterans Affairs in Public Law 102-4, the categories of association used by the committee are based on “statistical association,” not on causality. Thus, standard criteria used in epidemiology for assessing causality (Hill, 1971) do not strictly apply. The categories are as follows:

• 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, this may constitute sufficient evidence for an association.

• Limited/Suggestive Evidence of an Association. Evidence is suggestive of an association between herbicides and the outcome, but it is limited because chance, bias, and confounding could not be ruled out with confidence. For example, if at least one high-quality study shows a positive association, but the results of other studies are inconsistent, this may constitute limited/suggestive evidence of an association.

• Inadequate/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, if studies fail to control for confounding, contain inadequate exposure assessment, or have inadequate sample size, this may constitute inadequate/ insufficient evidence to determine whether an association exists.

• Limited/Suggestive Evidence of No Association. There are several adequate studies, covering the full range of exposure levels that humans are known to encounter, that are mutually consistent in that they do not show a positive association between exposure to herbicides and the outcome at any level of exposure. A conclusion of “no association” is inevitably limited to the conditions, level of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded.

The committee was charged with the task of summarizing the strength of the scientific evidence concerning the association between herbicide exposure during Vietnam service and acute myelogenous leukemia in the children of those who

served. Public Law 102-4 specifies three scientific determinations concerning diseases that must be made. It charges the committee to:

1. whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriateness of the statistical and epidemiologic methods used to detect the association;

2. the increased risk of the disease associated with exposure to herbicides during service in the Republic of Vietnam during the Vietnam era; and

3. whether there exists a plausible biologic mechanism or other evidence of a causal relationship between herbicide exposure and the disease.

The committee’s judgments have both quantitative and qualitative aspects; they reflect both the evidence examined and the approach taken to evaluate it. The primary considerations are delineated below.

The committee necessarily focused on a pragmatic question: What is the nature of the relevant evidence for or against a statistical association between exposure and the health outcome? The evidentiary base that the committee found to be most helpful derived from epidemiologic studies of populations—that is, investigations in which large groups of people are studied to determine the association between the occurrence of particular diseases and exposure to the substances at issue. To determine whether an association exists, epidemiologists estimate the magnitude of an appropriate quantitative measure (such as the relative risk or the odds ratio) that describes the relationship between exposure and disease in defined populations or groups. However, the use of terms such as “relative risk,” “odds ratio,” or “estimate of relative risk” is not consistent in the literature. In this report, the committee intends relative risk to refer to the results of cohort studies and odds ratio (an estimate of relative risk) to refer to the results of case-control studies. Values of relative risk greater than 1 may indicate a positive or direct association—that is, a situation in which the disease is observed more frequently among persons who are exposed than among those who are not exposed—whereas values between 0 and 1 may indicate a negative or inverse association—that is, a situation in which the disease is observed less frequently among persons who are exposed than among those who are not exposed. A “statistically significant” difference is one that, under the assumptions made in the study and the laws of probability, would be unlikely to occur if there was no true difference.

Determining whether an observed statistical association between exposure and a health outcome is “real” requires additional scrutiny because there may be

alternative explanations for the observed association. These include: error in the design, conduct, or analysis of the investigation; bias, or a systematic tendency to distort the measure of association so that it may not represent the true relation between exposure and outcome; confounding, or distortion of the measure of association because another factor related to both exposure and outcome has not been recognized or taken into account in the analysis; and chance, the effect of random variation, which produces spurious associations that can, with a known probability, sometimes depart widely from the true relation.

Therefore, in deciding whether an association between herbicide exposure and a particular outcome existed, the committee examined the quantitative estimates of risk and assessed them in the context of the strengths and weaknesses of the study that produced them, evaluating whether these estimates might be due to error, bias, confounding, or chance, or were likely to represent a true association.

In pursuing the question of statistical association, the committee recognized that an absolute conclusion about the absence of association might never be attained. As in science generally, studies of health outcomes following herbicide exposure are not capable of demonstrating that the purported association is impossible or could never occur. Any instrument of observation, including epidemiologic studies, has a limit to its resolving power. Hence, in a strict technical sense, the committee could not prove the absolute absence of an association between a health outcome and herbicide or dioxin exposure.

This question, which is pertinent principally (but not exclusively) if there is evidence for a positive association between exposure and a health outcome, concerns the likely magnitude of the association in Vietnam veterans exposed to herbicides. The most desirable evidence in answering this type of question involves knowledge of the rate of occurrence of the disease in those Vietnam veterans who were actually exposed to herbicides, the rate in those who were not exposed (the “background” rate of the disease in the population of Vietnam veterans), and the degree to which any other differences between exposed and unexposed groups of veterans influence the difference in rates. When exposure levels among Vietnam veterans have not been adequately determined, which has been the case in most studies, this question is very difficult to answer. The committees have found the available evidence sufficient for drawing conclusions about the association between herbicide exposure and a number of health outcomes. However, the lack of good data on Vietnam veterans per se, especially with regard to herbicide exposure, has complicated the assessment of the increased risk of disease among individuals exposed to herbicides during service in Vietnam. By considering the magnitude of the association observed in other cohorts, the quality and results of studies of veterans, and other principles of

epidemiologic research, the present committee has formulated a qualitative judgment regarding the risk of disease among Vietnam veterans. Indeed, most of the evidence on which the findings in this and other reports are based comes from studies of people exposed to dioxin or herbicides in occupational and environmental settings rather than from studies of Vietnam veterans.

Chapters 3 and 8 of Update 2000 include reviews of the previously available cellular, animal, and human evidence that provides the basis for the assessment of biologic plausibility—the extent to which a statistical association is consistent with existing biological or medical knowledge. The likelihood that a given chemical exposure-health outcome relationship reflects a true association in humans is addressed in the context of: research regarding the mechanism of interaction between the chemical and biological systems; evidence in animal studies; evidence of an association between exposure and health outcome occurrence in humans; and/or evidence that a given outcome is associated with occupational or environmental chemical exposures. It must be recognized, however, that a lack of data in support of a plausible biologic mechanism does not rule out the possibility that a causal relationship does exist.

It has been well documented in biomedical research that studies with a statistically significant finding are more likely to be published than studies with nonsignificant results (see, for example, Song et al., 2000). Thus, evaluations of disease-exposure associations that are based solely on the published literature could be biased in favor of a positive association. In general, however, for reports of overall associations with exposure, the committee did not consider the risk of publication bias to be high among studies of herbicide exposure and health risks. The committee took this position because there are numerous published studies showing no positive association; because it examined a substantial amount of unpublished material; and because the committee felt that publicity surrounding the issue of exposure to herbicides, particularly regarding Vietnam veterans, has been so intense that any studies showing no association would be unlikely to be viewed as unimportant by the investigators, journal referees, and editors. In short, the pressure to publish such “negative” findings would be considerable.

Assessment of individual exposure to herbicides and dioxin is a key element in determining whether specific health outcomes are linked to these compounds. The committee responsible for producing VAO found that the definition and

quantification of exposure are the weakest methodologic aspects of the epidemiologic studies. Although different approaches have been used to estimate exposure among Vietnam veterans, each approach is limited in its ability to determine precisely the chemical type, amount, and duration of individual exposure.

A separate effort by another Institute of Medicine committee is facilitating the development and evaluation of models of herbicide exposure for use in studies of Vietnam veterans. That committee authored and disseminated a Request for Proposals for exposure assessment research in 1997 (IOM, 1997) and is carrying out scientific oversight of the research.

Although definitive data are presently lacking, the available evidence suggests that Vietnam veterans as a group had substantially lower exposure to herbicides and dioxin than did the subjects in many occupational studies. Participants in Operation Ranch Hand and members of the Army Chemical Corps are exceptions to this pattern, and it is likely that there are others who served in Vietnam who had exposures comparable in intensity to members of the occupationally exposed cohorts. Although it is currently not possible to identify this heavily exposed fraction of Vietnam veterans, the exposure assessment research effort presently under way may allow progress to be made on this important question.

The American Cancer Society (ACS) estimates that approximately 8,600 children under the age of 15 will be diagnosed with cancers in the United States in 2001. Leukemias, which are cancers of the white blood cells, are the most common of these cancers. They account for about one-third of all childhood cases, with nearly 2,700 children projected to be diagnosed in 2001 (ACS, 2001). Of these, about 2,000 cases will be acute lymphocytic leukemia (ALL) and most of the rest will be acute myelogenous leukemia. Chronic leukemias are very rarely seen in children.

Acute myelogenous leukemia (AML)³ is a cancer of the bone marrow cells that form two types of white blood cells called granulocytes and monocytes. There are several different forms of AML that are primarily distinguished by how the affected cells appear under the microscope. According to a recent review paper (Langmuir et al., 2001) AML is the seventh most common malignancy among children. The highest rates of incidence are found in those 2 years of age (12 cases per one million), but this rate decreases to 3.8 cases per one million by the age of 9. After this age the incidence rises again to 9 cases per one million at