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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
ever, it is not at present known whether or not such associations are indicative of a causal pathway from dioxin exposure to Type 2 diabetes. Other observed effects include alteration of glucose transport in a variety of cells, modulation of protein kinase C activity, reduction in adipose tissue lipoprotein lipase in guinea pigs, hypertriglyceridemia in rabbits, and down-regulation of low-density lipoprotein receptors on the plasma membrane in guinea pig hepatocytes.
Three recent studies of humans add to that evidence by reporting a compensatory metabolic relation between dioxin and insulin regulation in Air Force Health Study (AFHS) participants, an apparent association between serum dioxin levels and fasting glucose levels among nondiabetic AFHS comparison group members with less than 10 parts per trillion (ppt) serum dioxin, and an elevated incidence of hyperinsulinemia among a group of nondiabetics with serum TCDD levels greater than 15 ppt. These studies, however, have methodologic limitations—primarily, inadequate measures of individual characteristics such as percentage of body fat at the time of exposure—that prevent more definitive conclusions from being drawn.
INTRODUCTION
Background
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. 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 called 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 (IOM, 1996) and Veterans andAgent Orange: Update 1998 (IOM, 1999). IOM is now convening a committee to review publications from 1998 to 2000 to form revised assessments, if indicated, of the cumulative evidence and issue a 2000 update.
In 1999, in response to a request from the Department of Veterans Affairs, IOM called together a committee to conduct an interim review of the scientific evidence regarding one of the conditions addressed in the Veterans and Agent
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
ever, it is not at present known whether or not such associations are indicative of a causal pathway from dioxin exposure to Type 2 diabetes. Other observed effects include alteration of glucose transport in a variety of cells, modulation of protein kinase C activity, reduction in adipose tissue lipoprotein lipase in guinea pigs, hypertriglyceridemia in rabbits, and down-regulation of low-density lipoprotein receptors on the plasma membrane in guinea pig hepatocytes.
Three recent studies of humans add to that evidence by reporting a compensatory metabolic relation between dioxin and insulin regulation in Air Force Health Study (AFHS) participants, an apparent association between serum dioxin levels and fasting glucose levels among nondiabetic AFHS comparison group members with less than 10 parts per trillion (ppt) serum dioxin, and an elevated incidence of hyperinsulinemia among a group of nondiabetics with serum TCDD levels greater than 15 ppt. These studies, however, have methodologic limitations—primarily, inadequate measures of individual characteristics such as percentage of body fat at the time of exposure—that prevent more definitive conclusions from being drawn.
INTRODUCTION
Background
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. 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 called 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 (IOM, 1996) and Veterans and Agent Orange: Update 1998 (IOM, 1999). IOM is now convening a committee to review publications from 1998 to 2000 to form revised assessments, if indicated, of the cumulative evidence and issue a 2000 update.
In 1999, in response to a request from the Department of Veterans Affairs, IOM called together a committee to conduct an interim review of the scientific evidence regarding one of the conditions addressed in the Veterans and Agent
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
Orange series of reports: Type 2 diabetes. The committee consisted of individuals responsible for the Update 1998 report plus recognized experts in the field of Type 2 diabetes. They conducted two workshops to hear researchers in the field present information on their past and ongoing investigations, and reviewed material published since the deliberations of the Update 1998 committee.
While limited to one health outcome, this report adheres to the format of the update series' directions from Congress via the Secretary of Veterans Affairs. 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.
Organization and Framework
The conclusions in this report are based on cumulative evidence from the scientific literature reviewed in VAO, Update 1996, and Update 1998 and relevant papers published since the deliberations of the Update 1998 committee were completed. This present update is intended to supplement rather than replace the previous reports; therefore, not all of the information on studies reviewed in those reports has been repeated. Appendix B of this report reproduces the review of diabetes studies presented in Update 1998.
The 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, and Update 1998, and a more thorough discussion of the newly published data 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, and Update 1998, as well as the newly published scientific data, 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 Type 2 diabetes, using the same criteria to categorize health outcomes as used in the previous reports.
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
Categories of Association
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 not showing 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.
Methodologic Considerations in Evaluating the Evidence
Questions Addressed
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 Type 2 diabetes. Public Law 102-4 specifies three
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
scientific determinations concerning diseases that must be made. It charges the committee to:
. . . determine (to the extent that available scientific data permit meaningful determinations):
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;
the increased risk of each disease among those exposed to herbicides during service in the Republic of Vietnam during the Vietnam era; and
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.
Is Herbicide Exposure Statistically Associated with the Health Outcome?
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 harmful association—whereas values between 0 and 1 may indicate a negative or inverse association—that is, a protective association. 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
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
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 evaluated 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 may never be attained. As in science generally, studies of health outcomes following herbicide exposure are not capable of demonstrating that the purported effect 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 a health outcome associated with herbicide or dioxin exposure.
What Is the Increased Risk of the Outcome in Question Among Those Exposed to Herbicides in Vietnam?
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 that have been made 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.
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
Is There a Plausible Biologic Mechanism?
Chapter 3 and Chapter 11 of Update 1998 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.
Publication Bias
It has been well documented (Song et al., 2000) in biomedical research that studies with a statistically significant finding are more likely to be published than studies with nonsignificant results. 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. In short, the pressure to publish such “negative” findings would be considerable.
Exposure Assessment
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 intensity 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 Re-
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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes
quest 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.
Issues Related to the Epidemiologic Study of Exposure to Herbicides and Type 2 Diabetes
In addition to the difficulties of exposure ascertainment common to nearly all studies of herbicide exposure and human health effects, some research issues relate specifically to the study of diabetes. These begin with the case definition of diabetes itself. Unlike certain tumors whose diagnosis is defined by the presence of specific cell types, a diagnosis of diabetes is based on a continuum of metabolic activity, with a threshold set at a specific value for purposes of definition. The accepted normative value has been reset in recent years, from a fasting plasma glucose level of ≥140 mg/dl to a level of ≥126 mg/dl (WHO, 1980; ADA, 1997). Additional uncertainty is added by normal laboratory measurement and intraindividual variability that create an error range around the cut-off. Also, heath care providers use an array of interrelated assessment tools and acquire differing amounts of interview information from patients. The “Background” section of the diabetes discussion in Chapter 11 of Update 1998—reproduced in Appendix B in this report—provides more detailed information on the disease itself.
The accuracy of death certificate coding of diabetes compounds the issue of diagnostic definition. Underlying cause and associated causes of death are coded according to internationally endorsed guidelines based on information written on the death certificate by the medical authority present at or soon after the death. For all diseases, the extent to which that person knows the medical history of the decedent influences the assignment of the underlying cause of death and the nature of associated, contributing, and otherwise present medical conditions that are noted on the death certificate. Prevalence of diabetes at death substantially exceeds its designation as underlying cause of death, a methodologic challenge addressed by Steenland and colleagues (1992, 1999) and discussed later in this report.
Type 2 diabetes, also called non-insulin-dependent diabetes mellitus, is usually an adult-onset condition with incidence rates increasing with age. Type 2 diabetes prevalence per 1,000 males is 12.2 at ages 25–44 and 101.4 at ages 65 and older (Kenny et al., 1995). The Vietnam veteran cohort has only recently entered the age range with sufficient incidence for accurate study. Therefore, past studies
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