Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 250
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 6 Exposure Assessment Assessment of individual exposure to herbicides and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or other chemical compounds found in the herbicides used in Vietnam is a key element in determining whether specific health outcomes are associated with exposure to these compounds. For a variety of reasons, the committee placed particularly heavy emphasis on exposure assessment issues. First, the committee's primary task is to review and evaluate the scientific literature to determine, if possible, whether there is a statistical association between various health effects and herbicide use, taking into consideration the strength of the scientific evidence and the appropriateness of the methods used to detect the association. Estimation of health risks associated with herbicide exposure consists of two primary activities: (1) exposure assessment and (2) assessment of the health effects in exposed individuals. The committee has found in its review that the weakest methodologic aspects complicating the interpretation of the available epidemiologic studies are the definition and quantification of exposure. This chapter describes the criteria used by the committee in assessing the quality and validity of exposure measures. It begins with a description of the role of exposure assessment in epidemiology, followed by a discussion and evaluation of the various approaches that have been used to measure exposure in studies of those occupationally and environmentally exposed to herbicides and TCDD. The next section describes exposure assessment in studies of Vietnam veterans and some of the problems of inaccurate exposure measurement in these studies.
OCR for page 251
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Second, an additional task brought to this committee through its legislative charge was the determination of whether additional studies of Vietnam veterans are feasible. Drawing upon the committee's evaluation of the available literature and upon information on the military use of herbicides (see Chapter 3), this chapter summarizes what is known about exposure to herbicides in Vietnam in comparison to other populations with widely different types of exposure (e.g., in factories, of professional herbicide sprayers, from environmental accidents). Valid measures of exposure are critical to further epidemiologic studies, and this chapter proposes a method for developing such a measure for future studies of Vietnam veterans. A third and related reason for the committee's concern about exposure assessment in epidemiologic studies is that these data are needed to draw inferences on the health effects of exposure in Vietnam veterans from studies of those occupationally and environmentally exposed. Studies of these other groups address the issue of whether herbicides are associated with particular health outcomes, but they have only an indirect bearing on the question of associations in veterans themselves. Exposure data in all groups are needed to translate the results of occupational and environmental studies to estimates of increased risk for Vietnam veterans. AN OVERVIEW OF EXPOSURE ASSESSMENT FOR EPIDEMIOLOGY When epidemiologists assess the potential health risks of exposure to a toxic chemical, they compare the disease experience of groups of people with different levels of exposure to the substance of interest. Accurate risk estimates depend on the ability to accurately identify those who are "exposed" and those who are not. When the concern is with low-level, possibly intermittent exposure to a chemical such as an herbicide, it becomes important not simply to assess exposure as its presence or absence, but to characterize the degree of exposure—its intensity and duration. At root there are three essential steps in epidemiology: assembling a cohort of people with similar, well-defined exposures to some agent, and another cohort identical to the first but with members who lack exposure to the agent; measuring and then comparing the disease experience of each of these cohorts; and, drawing inferences from these comparisons about the risks that may derive from the exposure differences between cohorts. Exposure assessment contributes to the epidemiologic study process in several ways. First, accurate measures of exposure are essential to a study's validity because if there is not a well-defined contrast in exposure among
OCR for page 252
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam the two (or more) groups being studied, then the results cannot be considered meaningful with respect to a judgment about the potential risk to an exposed individual or group. Second, very large groups must be studied in order to identify small risks, and conversely a relatively small study may be able to detect the effect of heavy or sustained exposure to a toxic substance. In this way, a study's precision is also linked to the extent of the exposure involved and the accuracy of its measurement. The strength of an association between an exposure and a disease is just one of the criteria used in evaluating epidemiologic evidence, as described in Chapter 5. Another criterion often used in evaluating an association is whether or not there is evidence that as exposure increases, the risk of the disease also increases (Hill, 1971). This dose-response pattern can be detected only if there is some way to determine the degree of exposure among different cohorts or subcohorts of the study. Inaccurate assessment of exposure can obscure the existence of such a trend and thus make it less likely that a true risk will be identified as such. A recent review, for instance, has found evidence that studies of putative occupational carcinogens are more likely to identify these agents successfully when quantitative exposure data are used, instead of relying on qualitative categories or simply the duration of exposure (Blair and Stewart, 1992). Once a given exposure-disease association has been established, it is often desirable to consider the implications of this risk for some exposed population other than the population with which the study was performed. In making this inference, it is critical to have accurate exposure assessments. If there is a risk of a certain disease in workers occupationally exposed to a herbicide, what would the risk be for a Vietnam veteran who was exposed only occasionally or for just a short period? The proper scale on which to compare these risks is the scale of quantitative exposure. It is useful to view exposure to an environmental agent as a process involving a progression of events that links the chemical in the environment to the ultimate "target" tissue in the human body (Figure 6-1). It is particularly important to distinguish "exposure" from "dose"—words that are often used interchangeably but have quite different meanings. Exposure is the concentration of an agent in the environment in close proximity to a study subject. Depending on a variety of factors, some of this toxin may be taken up by the subject through inhalation, ingestion, or the skin. These routes of exposure then mediate uptake and, along with metabolic characteristics of the subject, determine the dose of the agent that reaches the target tissues in the body. With regard to Vietnam veterans, for instance, it has been suggested that troops who spent days in the field without the possibility of good personal hygiene may have received a larger effective dose from a given exposure. Although it is the toxic dose and not the exposure per se that causes a disease, this dose is rarely measurable, and often, exposure
OCR for page 253
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam FIGURE 6-1 Progression of events from environmental exposure to health effects. Reprinted with permission from Heldref Publications. SOURCE: Sexton et al., 1992. must be used as a proxy for dose. The assumption that exposure approximates dose is not necessarily a bad one, but how strong this correlation actually is depends on the chemical and physical properties of the agent, the route of exposure, and the target tissue. Hierarchy of Exposure Assessment Strategies Exposure has been characterized in many different ways in epidemiologic studies, depending on the availability of data and the hypothesis being tested. One can usefully distinguish a few basic approaches to exposure assessment (Checkoway, 1986; Smith, 1987). The simplest approach compares the members of a class presumably exposed to an agent with the general population or with an "unexposed" group. Occupational studies are often of this type, comparing for example, herbicide production workers to the general population. Vietnam veterans have also been compared to veterans who served during the Vietnam era but did not serve in Vietnam. The advantages of this approach are its simplicity and the ease of interpretation of the results. If there is something fundamental to class membership that increases risk—for example, all "woodworkers" are exposed to wood dust—then studies of this type can effectively identify the increased morbidity or mortality in the group. If, however, only a small fraction of class members are actually substantially exposed to a toxic agent (in all likelihood, as discussed in this chapter, only a fraction of the estimated 2.6 million to 3.8 million veterans who served in Vietnam were substantially exposed to herbicides), then any increased risk from exposure in this subgroup may be lost entirely when the disease risk of the full class (all Vietnam veterans) is assessed. A somewhat more refined method of exposure assessment assigns to
OCR for page 254
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam each cohort member a qualitative degree or level of exposure. This may be done in several different ways. For example, a cohort of herbicide production workers could be divided into subgroups in such a way that those who were likely to have been heavily exposed through their job assignments are placed in one group (e.g., "high exposure"); a second group might be identified who had sustained exposures, but not in those jobs or departments in direct contact with the toxin ("moderate exposure"); and finally, a residual group might contain those with little or no exposure who were nonetheless employed at the production facility ("low exposure"). The disease risk may then be calculated separately for each of these groups compared to a referent or ''unexposed" group. This method has several advantages over the simple exposed/unexposed comparison just described: it should (if the classification of exposure is done without serious errors, see below) yield less diluted risk estimates; provide support for a dose-response trend; and not necessarily require expensive and time-consuming measurements of the actual exposure of each cohort member. Ideally, quantitative estimates should be available on the total exposure history of each subject in the study. When such data are available, it is possible to estimate quantitatively the relationship between a given level of exposure and the degree of risk that is expected to accrue. In occupational epidemiology studies, quantitative exposure data are sometimes developed through a process called historic exposure reconstruction, which is outlined in the following sections. When quantitative estimates of the intensity of exposure are not available, it is sometimes possible to know the duration of exposure for each cohort member. Although less satisfactory, one may nevertheless assume that the intensity of exposure was relatively constant among cohort members so that the total exposure (sometimes called cumulative exposure) is proportional to its duration. Following these assumptions, one would hypothesize that a true risk would increase with the duration of exposure. Epidemiologists generally think of these various exposure assessment strategies in a hierarchy of increasing accuracy: the exposed/unexposed approach being the least accurate, followed by the qualitative classification of level of exposure, and best of all, quantitative estimates of both the intensity and the duration of exposure. It is important to stress that all of these strategies may be valid, but they vary in their precision and in the degree to which they can contribute to the evidence for or against a particular exposure-disease association. Exposure Assessment for Cohort Studies In cohort studies it is sometimes possible to have other data sources available with which to estimate exposure for each study subject without
OCR for page 255
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam directly interviewing the subject. This is especially common in occupational cohort studies in which work records and industrial hygiene data may be available that cover the entire history of the factory being studied. At minimum, it is often possible to know with considerable accuracy the length of time that each cohort member has spent in the industry. Somewhat more precise assessments may be possible if the cohort can be subdivided into those who were employed in one or more areas of the plant where the exposure of interest was heaviest. A variety of approaches have been used to estimate the intensity of exposure in each job or department in an industry. Sometimes industrial hygiene measurements are available, in which statistical models can be used to "fill in the gaps" that inevitably occur in these data (Greife et al., 1988; Hornung, 1991). Often the potentially hazardous chemical is an essential component of an industry's production process, so the relative intensity of exposure can be estimated from data on production rates in each department of the factory being studied (Kalliokoski, 1990). Expert judgment has also been used to estimate relative intensity of exposure (Tankersley et al., 1991). Physical models of the workplace environment, the production process, and the location of workers may be used to estimate likely exposure levels (Schneider et al., 1991). In recent years, considerable research has been done to develop systematic methods of historic reconstruction of exposure—the broad term covering all of these various strategies (Gamble and Spirtas, 1976; Smith, 1987; Bond et al., 1991; Rice, 1991; Smith et al., 1991; Stewart and Herrick, 1991; Tankersley et al., 1991). Three international symposia have been held on the subject (Rappaport and Smith, 1991; Stewart and Herrick, 1991; Axelson and Westberg, 1992). The essential features of historic exposure reconstruction applied to each member of a study cohort are (1) the use of surrogates of past exposure to toxic chemicals (if no measurements are available) to estimate the likely intensity of exposure an individual would have experienced in a particular location (often a job or industrial department) at a particular time; (2) the use of either work records, individual recollections, or a combination of the two to determine which locations or jobs the subject was in for which periods; this information can then be combined with the job/location exposure estimates to build up for each subject an estimated exposure history covering years to decades of past exposure; and (3) summation of individual exposure histories in parameters that can then be used in epidemiologic models to assess exposure-risk associations. Historic exposure reconstruction is a lengthy and expensive process, and the field is still developing. There are however some recent examples of occupational epidemiologic studies in which exposure estimates derived from historic reconstruction have proven superior to those relying on simpler
OCR for page 256
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam measures such as the total duration of exposure (Dement et al., 1983; Stewart et al., 1986; Rinsky et al., 1987; Kriebel, 1988a,b; Seixas, 1990; Blair and Stewart, 1992). Exposure Assessment for Case-Control Studies Often case-control studies must rely on information provided by the study subjects—cases and controls—to estimate exposure histories. The problem of recall bias has already been mentioned, and it is a potentially serious one in case-control studies when subjects are asked directly to recall exposure to a potentially toxic chemical. Some case-control studies reduce the severity of this problem by gathering general data from study subjects, with which more specific exposures can be estimated, that are less likely to be recalled differentially by cases and controls. For example, in occupational case-control studies, it is common to collect from each subject a full occupational history including detailed job information, but not information on chemicals that may have been used in these jobs. Experts on industrial processes such as manufacturing engineers and industrial hygienists then independently develop a job exposure matrix (JEM), which estimates for each job the types of chemicals likely to have been used, and sometimes their likely intensity of use as well (Zahm et al., 1990; Gerin and Siemiatycki, 1991). There is doubtless a good deal of nondifferential misclassification that results from this approach because the JEM approximates the general use of chemicals in occupations and not the specifics of an individual subject's experience. However, recall bias is much less likely to occur because subjects are not asked directly about hazards. An excellent example of this approach is provided by a large multicenter case-control study of hematolymphopoietic cancers being conducted in Italy and focusing on pesticides and solvents risk factors (Miligi and Masala, 1991). In the participating centers, which are located in different agricultural regions, detailed JEMs have been developed by agronomists with long experience in local pest control practices. Subjects who report employment in farming are asked detailed questions about the crops they grew and the pests they treated in the course of their working lives. Local agronomists who advise farmers on pesticide usage then can predict with some reliability which chemicals were used in that particular zone in a particular time period to combat the reported pest. The committee recognized that case-control studies can only rarely provide quantitative estimates of exposure. Nevertheless, they can provide valid information on the existence of an association and the identification of a dose-response trend. An example of this comes from a recent study of non-Hodgkin's lymphoma (NHL) and the use of 2,4-dichlorophenoxyacetic acid (2,4-D) among Nebraska farmers (Zahm et al., 1990). Investigators
OCR for page 257
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam questioned cases and controls extensively about the use of all kinds of pesticides. One question asked how frequently the subjects changed clothes after spraying pesticides. The authors observed that for those reporting 2,4-D use, the risk of NHL was higher among those who tended to change clothes less often. There was a statistically significant trend in the odds ratio over three categories of clothes changing. Thus, although no conclusions can be drawn from this study about the amount of 2,4-D to which subjects were exposed, there are data that strengthen a finding of a statistical association. It must be stressed that these methods of exposure assessment, like the historic reconstruction approach for cohort studies discussed previously, are rarely "confirmed" in a given study by comparison to some "true" measure, since such a measure generally does not exist. As explained below, however, it is unlikely that such methods, conducted in a systematic way, can produce false-positive associations (bias away from the null). On the other hand, it is entirely likely that estimates resulting from these methods may underestimate the true magnitude of risk. Exposure Misclassification Some degree of error is introduced into any exposure measurement. When a cohort member is incorrectly called "exposed," an individual is assigned to the "low-exposure" group when moderate exposure has actually occurred, or a quantitative estimate of exposure is highly inaccurate, then exposure misclassification occurs, which introduces bias into the study results. Epidemiologists distinguish two fundamental kinds of exposure misclassification. Differential (or nonrandom) exposure misclassification occurs when errors in the assignment of exposure are unequally distributed between the diseased and nondiseased groups. A common example of this is recall bias, which may occur in case-control studies if cases and controls are asked directly about their exposure histories, and if cases recall their exposure differently than controls. It has been shown, for example, that mothers of newborns with birth defects (cases) are more apt to report exposure to many prescription and nonprescription drugs than are mothers of normal newborns (controls) (Werler et al., 1989). Differential misclassification is a particularly serious problem because the direction of the bias cannot be determined. That is, the effect of this kind of error in exposure assignment may be to increase artificially the magnitude of an association between exposure and disease (called a bias away from the null) or to reduce the apparent magnitude of association (a bias toward the null). Nondifferential (or random) misclassification occurs when exposure is measured with error but the degree of error is the same for the diseased and
OCR for page 258
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam nondiseased groups. In well-designed epidemiologic studies, investigators are often able to reduce the likelihood that serious differential misclassification has occurred, but nondifferential misclassification is often inevitable because of the imprecision of any exposure measurement tool. It is often possible to determine with some confidence that the likely direction of the bias from nondifferential exposure misclassification will be toward the null (Fleiss and Shrout, 1977; Armstrong and Oakes, 1982; Kupper, 1984; Heedrik and Miller, 1988; Lagakos, 1988). That is, the magnitude of the association estimated with misclassified exposure data will be lower than that of the "true" exposure-disease association. One can think of this phenomenon as "diluting" the true effect, which occurs, for example, when all members of an occupational group are compared to nonmembers to estimate the risk of a toxin to which only some members are actually exposed. For example, consider the relationship between Hodgkin's disease and exposure to Agent Orange, which was studied by the Centers for Disease Control (CDC) in the Selected Cancers Study (CDC, 1990b), but for which the primary exposure variable was Vietnam service, not something more closely related to herbicide exposure. The odds ratio relating Hodgkin's disease to Vietnam service was approximately 1.2, but it was not statistically significant. Suppose that (1) disease status is classified without error; (2) 100 percent of those truly exposed are classified as exposed; and (3) 95 percent of those truly not exposed are classified as not exposed, and this fraction is the same for Hodgkin's disease cases as for the controls in the Selected Cancers Study. Then, by using the method of Kleinbaum and colleagues (1982), the estimated relative risk adjusted for misclassification bias would be 1.6, which represents a tripling of the excess risk. If the percentages in assumptions (2) and (3) were further from 100, the adjusted relative risk would be even higher. Several recent scientific papers have argued that the general principle of nondifferential misclassification producing bias toward the null may not always hold when ordered categorical exposure data (e.g., low, medium, high) are used; however, there is not yet agreement as to how frequent or how severe any bias away from the null may be (Dosemici et al., 1990; Myers and Ehrlich, 1990; Flegal et al., 1991; Wacholder et al., 1991; Birkett, 1992; Brenner, 1992; Delpizzo, 1992). There is general agreement that with continuous quantitative measures of exposure and with dichotomous measures (exposed/unexposed), nondifferential misclassification will bias toward the null. A common method of exposure estimation in occupational cohort studies assigns exposure levels to each job in the factory; then each worker's lifetime exposure is estimated by multiplying the amount of time spent in each job by the exposure intensity for that job. The resulting lifetime cumulative exposure for each cohort member may not be seriously misclassified
OCR for page 259
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam even if there are substantial errors in the job exposure estimates on which the cumulative exposures are based. One reason that the practice of estimating exposure histories from data on the exposure levels in certain jobs and the amount of time spent in each job may be fairly robust against errors in exposure measurement is that if workers move from job to job over the course of their careers, the errors in each of the job exposure estimates tend to cancel one another. Often the process of reconstructing the exposure levels in jobs in the past is only approximate, but as long as the effect of the errors is to sometimes over- and sometimes underestimate the true exposure in the job, then a lifetime exposure estimate will not be strongly affected by these individual job errors. One solution to the problem of misclassification of exposure is to conduct a small validation study in which elaborate and expensive measurements are performed alongside the quicker, more error-prone measurements that will be used in the full study. Analysis of the degree of correlation between the "true" and the approximate measures allows investigators to adjust the risk estimates from the full study for exposure misclassification (Fleiss and Shrout, 1977; Armstrong and Oakes, 1982; Marshall, 1990; Rosner et al., 1990). Biomarkers Biomarkers for TCDD TCDD and other chlorinated dibenzo-p-dioxins and dibenzofurans are found in tissues of non-occupationally exposed humans at part-per-trillion (ppt; nanogram-per-kilogram) levels. Following absorption, TCDD is distributed to tissues with high lipid content. Adipose tissue appears to be the main site of accumulation, although TCDD has been found in all tissue samples that have been examined from autopsy (Ryan et al., 1986). On a whole-weight basis, adipose tissue contains the highest levels, followed by liver, muscle, and kidney; on a lipid basis, the concentrations vary less (Ryan et al., 1986). Normal exposure to TCDD leads to levels in the lipid stores of humans of about 5-6 ppt, as measured in the adipose tissue or the lipid portion of the blood (Needham et al., 1990). Although exposure to TCDD from environmental sources, primarily food (Geyer et al., 1986; Byard, 1987), occurs on a continuing basis, both serum and fat biopsy samples taken from individuals with unusually high exposures indicate that TCDD may remain in the body for many years after exposure. For example, fat biopsy samples taken from three Vietnam veterans believed to have been exposed through herbicide use showed levels of TCDD up to 99 ppt approximately 10 years after exposure occurred. By comparison, veterans with no unusual herbicide exposure had TCDD levels
OCR for page 260
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam between 3 and 15 ppt (Gross et al., 1984). A number of other studies, including the Ranch Hand half-life study, the Missouri civilian study, and the National Institute for Occupational Safety and Health (NIOSH) study, suggest that current serum TCDD levels are useful for distinguishing between groups of individuals that were exposed to TCDD 15 to 20 years ago (CDC, 1989a). For example, Sweeney and colleagues (1990) measured TCDD levels in serum lipids of 143 workers at two chemical plants in New Jersey and Missouri. The median TCDD level in a group of 103 production workers at the New Jersey plant was 84 ppt compared to 11 ppt for a group of eight office workers. The most reliable procedure for measuring serum lipid-associated TCDD was developed by the CDC in 1986 as a substitute for the considerably more difficult surgical procedure required to obtain fat biopsies (Patterson et al., 1987). This procedure involves an extremely sensitive mass spectroscopic technique that permits measurement of TCDD into the low part-perquadrillion levels. A study in which both serum and fat TCDD levels were compared in 50 individuals showed a very high correlation between the two, suggesting that TCDD levels in serum provide a valid measure of TCDD levels in the body (Patterson et al., 1988). The Pointman Project (Kahn et al., 1988), conducted by the New Jersey Agent Orange Commission, confirmed this result. The pharmacokinetics of TCDD in humans—its distribution and passage through the body—are not fully understood, which makes individual serum TCDD levels difficult to interpret and also complicates the interpretation of epidemiologic studies relying on these measures of exposure. As described in Chapter 4, a complex, poorly understood process distributes dioxins among body tissues and slowly clears it from the body. There is evidence that this process is quite variable among humans, so it is difficult to model its behavior and thereby extrapolate backward to estimate the likely concentration of TCDD in fat or blood in the past. It is also assumed that TCDD is removed from the body according to first-order kinetics—that is, for a given period of time, a constant fraction of the TCDD body burden is eliminated—but some evidence suggests the process may be more complicated and may vary as conditions in the body change. Second, the metabolic processes governing this movement and disposition may not be relevant to the determination of the dose of TCDD to the brain or reproductive organs, for example. In the epidemiologist's view, there may be different "causal pathways" linking exposure to the biomarker and exposure to disease. By measuring TCDD levels in 1982 and 1987 from serum samples of 36 Ranch Hand veterans, the median half-life of TCDD in humans was estimated to be 7.1 years, adjusted for background TCDD levels (with a 95 percent confidence interval of 5.8 to 9.6 years) (Pirkle et al., 1989). In this study, the background exposure level of TCDD in serum was taken to be 4
OCR for page 289
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam a model predicting the likelihood and intensity of ground spraying around base perimeters, fire camps, and along roads for different areas and times. A partial check on the utility of this model could be accomplished by comparing its predictions to the limited ground spraying data that do exist in the Services HERBS tapes. This proposal incorporates ideas for exposure reconstruction previously described by others (Bricker, 1981; Erickson et al., 1984a; Stanton, 1989; Lewis, 1993). Evaluation of the Exposure Reconstruction Model The overall exposure reconstruction model can be evaluated in several ways. First, model developers should determine whether the data used in the exposure reconstruction model are internally consistent. This involves checking whether existing spraying records indicate more spraying in areas where it was likely to have been militarily useful from the point of view of terrain, foliage, and military mission. It would also be possible to cross-check the estimated spraying intensity data with a systematic survey of the recollections of veterans who served in particular areas. In a second method of evaluation, exposure estimates based on the reconstruction model should be compared with serum TCDD measurements for a random sample of veterans, stratified according to records-based measures. Although the committee concludes that group differences can be useful in confirming that exposure measures reflect the differences in prior exposure, the absence of group differences cannot be interpreted to indicate that groups were not exposed earlier. Serum TCDD measurements should not, however, be regarded as a gold standard—a perfect measure of herbicide exposure. In addition to the problems with interpreting serum TCDD measures discussed above, some of the herbicides used in Vietnam such as Agent White did not contain TCDD, so it is possible for a veteran to have been exposed to a large amount of Agent White without having an elevated serum TCDD level at any time. A third evaluation of the exposure estimation strategy would be to assess the association between the exposure reconstruction estimates and the incidence of health outcomes that are truly associated with herbicides. One would expect a positive association between the exposure reconstruction measure and those outcomes found in this report to have sufficient evidence for a statistical association. For instance, the non-Hodgkin's lymphoma data from the CDC Selected Cancers Study (CDC, 1990a) and the DVA case-control study (Dalager et al., 1991) can be combined and exposure measures calculated on the basis of the new exposure reconstruction model. Because there are sufficient data from occupational studies to suggest an association between herbicides and/or TCDD and NHL (see Chapter 8), one would expect to see a positive association between this cancer and the new
OCR for page 290
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam exposure reconstruction model data in the combined cases from the CDC and DVA studies. If such an association were found, it could be interpreted as positive evidence for the validity of the new exposure model. If no association were found, it would not be clear whether this was due to problems in the new exposure measure, to small sample sizes or low average herbicide exposure even in those exposed, or to the lack of a real association between herbicides and NHL. Exposure reconstruction models for herbicides in Vietnam must be thoroughly evaluated before epidemiologic studies based upon them proceed. Chapter 12 contains recommendations about how this evaluation should be carried out by an independent, nongovernmental scientific panel with expertise in historic exposure reconstruction and epidemiology, and how the resulting exposure measures should be used in a program of epidemiologic studies of Vietnam veterans. SUMMARY The existing epidemiologic data base reviewed by the committee is severely lacking in quantitative measures of individual exposure to herbicides and TCDD. Assessment of the intensity and duration of individual exposures is a key component in determining whether specific health outcomes are associated with exposure to TCDD or other chemicals found in the herbicides used in Vietnam. Although different approaches have been used to estimate exposure in Vietnam veterans and in others exposed occupationally or environmentally, each of the approaches is limited in its ability to determine precisely the degree and level of individual exposure. New biochemical techniques that can detect small amounts of TCDD in the blood many years after exposure have some merit, especially for detecting group differences. However, because of common background exposures to TCDD, poorly understood variations among individuals in TCDD metabolism, and relatively large measurement errors, individual TCDD serum levels are usually not meaningful. Furthermore, because not all of the herbicides used in Vietnam contained TCDD, serum TCDD levels are not good indicators of overall exposure to herbicides. Although definitive data are lacking, the available quantitative and qualitative evidence about herbicide exposure suggests that Vietnam veterans as a group had substantially lower exposure to herbicides and TCDD than the subjects in many occupational studies. The participants in Operation Ranch Hand are an exception to this pattern, and it is likely that others among the approximately 3 million men and woman who served in Vietnam were exposed to herbicides at levels associated with health effects. It is clear that the military use of herbicides in Vietnam was not uniform either geographically or temporally, and that the movement and behavior of troops also
OCR for page 291
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam varied, so one cannot assume that all troops were equally exposed to herbicides. Thus, in the committee's judgment, a sufficiently large range of exposures may exist among Vietnam veterans to conduct a valid epidemiologic study for certain health outcomes. The difficulty (from the perspective of epidemiologic studies) is that the available data do not precisely quantify individual exposure. None of the measures that the committee has reviewed would be free of nondifferential misclassification bias. The effect of this bias on risk estimates would likely be to underestimate true effects if they existed, possibly to such an extent that these effects could be missed entirely by future studies. The committee believes that it may be possible to develop a valid exposure reconstruction model for epidemiologic studies based on existing records and structured interview data, using principles of historic exposure reconstruction developed by industrial hygienists. Such a model would estimate the likelihood that each individual veteran was exposed to herbicides in Vietnam, and could possibly quantify the likely degree of exposure. This model would incorporate information in existing military records about herbicide spraying (the HERBS and Services HERBS tapes) and troop movements. It would also include less formal sources of information on ground and perimeter spraying from records of herbicide shipments to various military bases, and would consider the type of terrain, typical foliage of the locations, and the military mission of the bases and troops located there. Surveys and interviews of Vietnam veterans, stratified by location and period of service, might also provide useful information on situations in which herbicide spraying was prevalent and, if validated, may be incorporated into the exposure reconstruction model. REFERENCES Air Force Health Study (AFHS). 1991. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. 9 vols. Albanese RA. 1991. The chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin and U.S. Army Vietnam-era veterans. Chemosphere 22:597-603. Andrews JS Jr, Garrett WA Jr, Patterson DG Jr, Needham LL, Roberts DW, Bagby JR, Anderson JE, Hoffman RE, Schramm W. 1989. 2,3,7,8-Tetrachlorodibenzo-p-dioxin levels in adipose tissue of persons with no known exposure and in exposure persons. Chemosphere 18:499-506. Armstrong BG, Oakes D. 1982. Effects of approximation in exposure assessments on estimates of exposure-response relationships. Scandinavian Journal of Work, Environment, and Health Supplement 1:20-23. Axelson O, Westberg H, eds. 1992. First seminar on occupational exposure assessment: on the concepts of exposure and dose. American Journal of Industrial Medicine 21:1-132. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989. Ten year mortality study of the population involved in the Seveso incident in 1976. American Journal of Epidemiology 129:1187-1200.
OCR for page 292
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Birkett NJ. 1992. Effect of nondifferential misclassification on estimates of odds ratios with multiple levels of exposure. American Journal of Epidemiology 136:356-362. Blair A, White DW. 1985. Leukemia cell types and agricultural practices in Nebraska. Archives of Environmental Health 40:211-214. Blair A, Stewart P. 1992. Do quantitative exposure assessments improve risk estimates in occupational studies of cancer? American Journal of Industrial Medicine 21:53-63. Blair A, Grauman DJ, Lubin JH, Fraumeni JF Jr. 1983. Lung cancer and other causes of death among licensed pesticide applicators. Journal of the National Cancer Institute 71:31-37. Bond GG, Cook RR, Brenner FE, McLaren EA. 1987. Evaluation of mortality patterns among chemical workers with chloracne. Chemosphere 16:2117-2121. Bond GG, McLaren EA, Brenner FE, Cook RR. 1989. Incidence of chloracne among chemical workers potentially exposed to chlorinated dioxins. Journal of Occupational Medicine 31:771-774. Bond GG, Bodner KM, Olsen, GW, Burchfiel CM, Cook RR. 1991. Validation of work histories for the purpose of epidemiological studies. Applied Occupational and Environmental Hygiene 6:521-527. Brenner H. 1992. Notes on the assessment of trend in the presence of nondifferential exposure misclassification. Epidemiology 3:420-427. Bricker JG. 1981. Proposed Agent Orange Troop Exposure and Non-Exposure Cohort Selection Concept Paper. Memorandum to the Chairman, AOWG Science Panel. December 4, 1981. Washington, DC: Office of the Assistant Secretary of Defense, Health Affairs. Bueno de Mesquita HB, Doornbos G, van der Kuip DA, Kogevinas M, Winkelmann R. 1993. Occupational exposure to phenoxy herbicides and chlorophenols and cancer mortality in the Netherlands. American Journal of Industrial Medicine 23:289-300. Burmeister LF. 1981. Cancer mortality in Iowa farmers: 1971-1978. Journal of the National Cancer Institute 66:461-464. Byard JL. 1987. The toxicological significance of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds in human adipose tissue. Journal of Toxicology and Environmental health 22: 381-403. Cantor KP. 1982. Farming and mortality from non-Hodgkin's lymphoma: a case-control study. International Journal of Cancer 29:239-247. Carmelli D, Hofherr L, Tomsic J, Morgan RW. 1981. A Case-Control Study of the Relationship Between Exposure to 2,4-D and Spontaneous Abortions in Humans. SRI International. Prepared for the National Forest Products Association and the U.S. Department of Agriculture, Forest Service. Centers for Disease Control (CDC). 1985. Agent Orange Projects Interim Report Number 2: Exposure Assessment for the Agent Orange Study. Atlanta: CDC, Center for Environmental Health, Division of Chronic Disease Control, Agent Orange Projects. Centers for Disease Control. 1988a. Preliminary report: 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure in humans-Seveso, Italy. Morbidity and Mortality Weekly Report 37:733-736. Centers for Disease Control. 1988b. Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in U.S. Army Vietnam-era veterans. Journal of the American Medical Association 260:1249-1254. Centers for Disease Control. 1989a. Comparison of Serum Levels of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin with Indirect Estimates of Agent Orange Exposure Among Vietnam Veterans: Final Report. Atlanta: U.S. Department of Health and Human Services. Centers for Disease Control. Vietnam Experience Study. 1989b. Health Status of Vietnam Veterans. Atlanta: U.S. Department of Health and Human Services. Vols. I-V, Supplements A-C. Centers for Disease Control. 1990a. The association of selected cancers with service in the U.S. military in Vietnam. I. Non-Hodgkin's lymphoma. Archives of Internal Medicine 150:2473-2483.
OCR for page 293
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Centers for Disease Control. 1990b. The association of selected cancers with service in the U.S. military in Vietnam. III. Hodgkin's disease, nasal cancer, nasopharyngeal cancer, and primary liver cancer. Archives of Internal Medicine 150:2495-2505. Checkoway H. 1986. Methods of treatment of exposure data in occupational epidemiology. medicina del Lavoro 77:48-73. Christian R. 1992. Records-Based Measures of Exposure to Herbicides in Vietnam Veterans. Statement to the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. December 8, 1992. Coggon D, Pannett B, Winter PD, Acheson ED, Bonsall J. 1986. Mortality of workers exposed to 2-methyl-4-chlorophenoxyacetic acid. Scandinavian Journal of Work, Environment, and Health 12:448-454. Coggon D, Pannett B, Winter P. 1991. Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine 48:173-178. Collins JJ, Strauss ME, Levinskas GJ, Conner PR. 1993. The mortality experience of workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a trichlorophenol process accident. Epidemiology 4:7-13. Constable JD, Hatch MC. 1985. Reproductive effects of herbicide exposure in Vietnam: recent studies by the Vietnamese and others. Teratogenesis, Carcinogenesis, and Mutagenesis 5:231-250. Cook RR, Townsend JC, Ott MG, Silverstein LG. 1980. Mortality experience of employees exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Journal of Occupational Medicine 22:530-532. Cook RR, Bond GG, Olson RA. 1986. Evaluation of the mortality experience of workers exposed to the chlorinated dioxins. Chemosphere 15:1769-1776. Dai LC, Phuong NTN, Thom LH, Thuy TT, Van NTT, Cam LH, Chi HTK, Thuy LB. 1990. A comparison of infant mortality rates between two Vietnamese villages sprayed by defoliants in wartime and one unsprayed village. Chemosphere 20:1005-1012. Dalager NA, Kang HK. 1993. Mortality among Army Chemical Corps Vietnam veterans occupationally exposed to herbicides. Abstracts of the 26th Annual Meeting of the Society for Epidemiologic Research. Keystone, CO. June 16-18, 1993. Dalager NA, Kang HK, Burt VL, Weatherbee L. 1991. Non-Hodgkin's lymphoma among Vietnam veterans. Journal of Occupational Medicine 33:774-779. Del Corno G, Montesarchio E, Fara GM. 1985. Problems in the assessment of human exposure to tetrachlorodibenzodioxin (TCDD): the marker chloracne. European Journal of Epidemiology 1:139-144. Delpizzo V. 1992. An apparently incongruous exposure-response relationship resulting from the use of job description to assess magnetic field exposure. Scandinavian Journal of Work, Environment, and Health 18:242-245. Dement JM, Harris RL, Symons MJ, Shy CM. 1983. Exposures and mortality among chrysotile asbestos workers . Part II, Mortality. American Journal of Industrial Medicine 4:421-433. Devine OJ, Karon JM, Flanders WD, Needham LL, Patterson DG Jr. 1990. Relationships between concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin serum and personal characteristics in U.S. Army Vietnam veterans. Chemosphere 20:681-691. Dosemici M, Wacholder S, Lubin JH. 1990. Does nondifferential misclassification of exposure always bias a true effect toward the null value? American Journal of Epidemiology 132:746-748. Erickson JD, Mulinare J, McClain PW, Fitch TG, James LM, McClearn AB, Adams MJ. 1984a. Vietnam Veterans' Risks for Fathering Babies with Birth Defects. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control. Erickson JD, Mulinare J, McClain PW, Fitch TG, James LM, McClearn AB, Adams MJ Jr. 1984b. Vietnam veterans' risks for fathering babies with birth defects. Journal of the American Medical Association. 252:903-912.
OCR for page 294
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Ferry DG, Gazeley LR, Edwards IR. 1982. 2,4,5-T absorption in chemical applicators. Proceedings of the University Otago Medical School 60:31-34. Fingerhut MA, Sweeney MH, Patterson DG Jr, Piacitelli LA, Morris JA, Marlow DA, Hornung RW, Cameron LW, Connally LB, Needham LL, Halperin WE. 1989. Levels of 2,3,7,8-TCDD in the serum of U.S. chemical workers exposed to dioxin-contaminated products: Interim results. Chemosphere 19:835-840. Fingerhut MA, Halperin WE, Marlow DA, Piacitelli LA, Honchar PA, Sweeney MH, Greife AL, Dill PA, Steenland K, Suruda AJ. 1991. Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. New England Journal of Medicine 324:212-218. Flanders WD, Lin L, Pirkle JL, Caudill SP. 1992. Assessing the direction of causality in cross-sectional studies. American Journal of Epidemiology 135:926-935. Flegal KM, Keyl PM, Nieto FJ. 1991. Differential misclassification arising from nondifferential errors in exposure measurement. American Journal of Epidemiology 134:1233-1240. Fleiss JL, Shrout PE. 1977. The effects of measurement errors on some multivariate procedures. American Journal of Public Health 67:1188-1191. Frank R, Campbell RA, Sirons GJ. 1985. Forestry workers involved in aerial application of 2,4-dichlorophenoxyacetic acid (2,4-D): exposure and urinary excretion. Archives of Environmental Contamination and Toxicology 14:427-435. Gamble J, Spirtas R. 1976. Job classification and utilization of complete work histories in occupational epidemiology. Journal of Occupational Medicine 18:399-404. Gerin M, Siemiatycki J. 1991. The occupational questionnaire in retrospective epidemiologic studies: recent approaches in community-based studies. Applied Occupational and Environmental Hygiene 6:495-501. Geyer H, Scheunert I, Korte F. 1986. Bioconcentration potential of organic environmental chemicals in humans. Regulatory Toxicology and Pharmacology 6:313-347. Gordon JE, Shy CM. 1981. Agricultural chemical use and congenital cleft lip and/or palate. Archives of Environmental Health 36:213-221. Greife AL, Hornung RW, Stayner LG, Steenland KN. 1988. Development of a model for use in estimating exposure to ethylene oxide in a retrospective cohort mortality study. Scandinavian Journal of Work, Environment, and Health 14 (Supplement 1):29-30. Gross ML, Lay JO, Lippstreu D, Lyon PA, Kangas N, Harless RL, Taylor SE. 1984. 2,3,7,8-Tetrachlorodibenzo-p-dioxin levels in adipose tissue of Vietnam veterans. Environmental Research 33:261. Hansen ES, Hasle H, Lander F. 1992. A cohort study on cancer incidence among Danish gardeners. American Journal of Industrial Medicine 21:651-660. Heedrik D, Miller BG. 1988. Weak associations in occupational epidemiology: adjustment for exposure estimation error. International Journal of Epidemiology 17(suppl):970-974. Henneberger PK, Ferris BG Jr, Monson RR. 1989. Mortality among pulp and paper workers in Berlin, New Hampshire. British Journal of Industrial Medicine 46:658-664. Hill AB. 1971. Principles of Medical Statistics, 9th ed. New York: Oxford University Press. Hoar SK, Blair A, Holmes FF, Boysen CD, Robel RJ, Hoover R, Fraumeni JF. 1986. Agricultural herbicide use and risk of lymphoma and soft tissue sarcoma. Journal of the American Medical Association 256:1141-1147. Hoffman RE, Stehr-Green PA, Webb KB, Evans RG, Knutsen AP, Schramm WF, Staake JL, Gibson BB, Steinberg KK. 1986. Health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of the American Medical Association 255:2031-2038. Hornung R. 1991. Statistical evaluation of exposure assessment strategies. Applied Occupational and Environmental Hygiene 6:516-520. Institute of Medicine. 1987. Review of Comparison of Serum Levels of 2,3,7,8-TCDD with Indirect Estimates of Agent Orange Exposure in Vietnam Veterans. Fifth Letter Report.
OCR for page 295
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Washington, DC: IOM, Advisory Committee on the CDC Study of the Health of Vietnam Veterans. Jappinen P, Pukkala E. 1991. Cancer incidence among pulp and paper workers exposed to organic chlorinated compounds formed during chlorine pulp bleaching. Scandinavian Journal of Work, Environment, and Health 17:356-359. Kahn PC, Gochfeld M, Nygren M, Hansson M, Rappe C, Velez H, Ghent-Guenther T, Wilson WP. 1988. Dioxins and dibenzofurans in blood and adipose tissue of Agent Orange-exposed Vietnam veterans and matched controls. Journal of the American Medical Association 259:1661-1667. Kahn PC, Gochfeld M, Lewis WW. 1992. Dibenzodioxin and Dibenzofuran Congener Levels in Four Groups of Vietnam Veterans Who Did Not Handle Agent Orange. The Pointman II Project. New Jersey Agent Orange Commission. Kalliokoski P. 1990. Estimating long-term exposure levels in process-type industries using production rates. American Industrial Hygiene Journal 51:310-312. Kang HK, Watanabe KK, Breen J, Remmers J, Conomos MG, Stanley J, Flicker M. 1991. Dioxins and dibenzofurans in adipose tissue of U.S. Vietnam veterans and controls. American Journal of Public Health 81:344-349. Kleinbaum DG, Kupper LL, Morgenstern H. 1982. Epidemiologic Research: Principles and Quantitative Methods. London: Lifetime Learning Publications. Kolmodin-Hedman B, Erne K. 1980. Estimation of occupational exposure to phenoxy acids (2,4-D and 2,4,5-T). Archives of Toxicology Supplement 4:318-321. Kolmodin-Hedman B, Hoglund S, Akerblom M. 1983. Studies on phenoxy acid herbicides. I. Field study. Occupational exposure to phenoxy acid herbicides (MCPA, dichlorprop, mecoprop and 2,4-D) in agriculture. Archives of Toxicology 54:257-265. Kriebel D, Sprince N, Eisen E, Greaves I. 1988a. Pulmonary function in beryllium workers: assessment of exposure. British Journal of Industrial Medicine 45:83-92. Kriebel D, Sprince N, Eisen E, Greaves I, Feldman H, Greene R. 1988b. Beryllium exposure and pulmonary function: a cross-sectional study of beryllium workers. British Journal of Industrial Medicine 45:167-173. Kupper LL. 1984. Effects of the use of unreliable surrogate variables on the validity of epidemiologic research studies. American Journal of Epidemiology 120:643-648. Lagakos SW. 1988. Effects of mismodelling and mismeasuring explanatory variables on tests of their association with a response variable. Statistics in Medicine 7:257-274. Lavy TL, Shepard JS, Mattice JD. 1980a. Exposure measurements of applicators spraying 2,4,5-trichlorophenoxy acetic acid in the forest. Journal of Agricultural and Food Chemistry 28:626-630. Lavy TL, Shepard JS, Bouchard DC. 1980b. Field worker exposure and helicopter spray pattern of 2,4,5-T. Bulletin of Environmental Contamination and Toxicology 24:90-96. Lewis W. 1993. The Vietnam Experience. Presentation to the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. February 8, 1993. Libich S, To JC, Frank R, Sirons GJ. 1984. Occupational exposure of herbicide applicators to herbicides used along electric power transmission line right-of-way. American Industrial Hygiene Association Journal 45:56-62. Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H. 1991. Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet 338:959-964. Marshall RJ. 1990. Validation study methods for estimating exposure proportions and odds ratios with misclassified data. Journal of Clinical Epidemiology 43:941-947. Michalek JE, Tripathi RC. 1992. Predicting Checkmark Patterns in the Air Force Health Study. Brooks AFB, TX: Armstrong Laboratory. Miligi L, Masala G. 1991. Methods of exposure assessment for community-based studies:
OCR for page 296
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam aspects inherent to the validation of questionnaires. Applied Occupational and Environmental Hygiene 6:502-507. Mocarelli P, Patterson DG Jr, Marocchi A, Needham LL. 1990. Pilot study (phase II) for determining polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in serum of Seveso, Italy residents collected at the time of exposure: future plans. Chemosphere 20:967-974. Mocarelli P, Needham LL, Marocchi A, Patterson DG Jr, Brambilla P, Gerthoux PM, Meazza L, Carreri V. 1991. Serum concentrations of 2,3,7,8-tetrachlorobdibenzo-p-dioxin and test results from selected residents of Seveso, Italy. Journal of Toxicology and Environmental Health 32:357-366. Morrison HI, Semenci RM, Morison D, Magwood S, Mao Y. 1992. Brain cancer and farming in western Canada. Neuroepidemiology 11: 267-276. Moses M, Lilis R, Crow KD, Thornton J, Fischbein A, Anderson HA, Selikoff IJ. 1984. Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: comparison of findings with and without chloracne. American Journal of Industrial Medicine 5:161-182. Musicco M, Sant M, Molinari S, Filippini G, Gatta G, Berrino F. 1988. A case-control study of brain gliomas and occupational exposure to chemical carcinogens: the risks to farmers. American Journal of Epidemiology 128:778-785. Myers J, Ehrlich R. 1990. Does nondifferential misclassification of exposure always bias a true effect toward the null value? (letter). American Journal of Epidemiology 132:1429-1430. Needham LL, Burse VW, Head SL, Korver MP, McClure PC, Andrews JS Jr, Rowley DL, Sung J, Kahn SE. 1990. Adipose tissue/serum partitioning of chlorinated hydrocarbon pesticides in humans. Chemosphere 20:975-980. Ott MG, Holder BB, Olson RD. 1980. A mortality analysis of employees engaged in the manufacture of 2,4,5-trichlorophenoxyacetic acid. Journal of Occupational Medicine 22:47-50. Patterson DG Jr, Hoffman RE, Needham LL, Roberts DW, Bagby JR, Pirkle JL, Falk H, Sampson EJ, Houk VN. 1986. 2,3,7,8-Tetrachlorodibenzo-p-dioxin levels in adipose tissue of exposed and control persons in Missouri. An interim report. Journal of the American Medical Association 256:2683-2686. Patterson DG Jr, Hampton L, Lapeza CR Jr, Belser WT, Green V, Alexander L, Needham LL. 1987. High-resolution gas chromatographic/high-resolution mass spectrometric analysis of human serum on a whole-weight and lipid basis for 2,3,7,8-tetrachlorodibenzo-p-dioxin . Analytical Chemistry 59:2000-2005. Patterson DG Jr, Needham LL, Pirkle JL, Roberts DW, Bagby J, Garrett WA, Andrews JS Jr, Falk H, Bernert JT, Sampson EJ, Houk VN. 1988. Correlation between serum and adipose tissue levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin in 50 persons from Missouri. Archives of Environmental Contamination and Toxicology 17:139-143. Pirkle JL, Wolfe WH, Patterson DG, Needham LL, Michalek JE, Miner JC, Peterson MR, Phillips DL. 1989. Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam Veterans of Operation Ranch Hand. Journal of Toxicology and Environmental Health 27:165-171. Rappaport SM, Smith TJ, eds. 1991. Exposure Assessment for Epidemiology and Hazard Control. Chelsea, MI: Lewis Publishers. Rice C. 1991. Retrospective exposure assessment: a review of approaches and directions for the future. In: Rappaport SM, Smith TJ, eds. Exposure Assessment for Epidemiology and Hazard Control. Chelsea, MI: Lewis Publishers. 185-198. Rinsky RA, Smith AB, Hornung R, Filloon TG, Young RJ, Okun AH, Landrigan PJ. 1987. Benzene and leukemia: an epidemiologic risk assessment. New England Journal of Medicine 316:1044-1050.
OCR for page 297
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Robinson CF, Waxweiler RJ, Fowler DP. 1986. Mortality among production workers in pulp and paper mills. Scandinavian Journal of Work, Environment, and Health 12:552-560. Ronco G, Costa G, Lynge E. 1992. Cancer risk among Danish and Italian farmers. British Journal of Industrial Medicine 49:220-225. Rosner B, Spiegelman D, Willett WC. 1990. Corrections of logistic regression relative risk estimates and confidence intervals for measurement error: the case of multiple covariates measured with error. American Journal of Epidemiology 132:734-745. Ryan JJ, Schecter A, Sun W-F, Lizotte R. 1986. Distribution of chlorinated dibenzo-p-dioxins and chlorinated dibenzofurans in human tissues from the general population. In: Rappe C, Choudhary G, Keith L, eds. Chlorinated Dioxins and Dibenzofurans in Perspective. Chelsea, MI: Lewis Publishers. 3-16. Saracci R, Kogevinas M, Bertazzi PA, Bueno De Mesquita BH, Coggon D, Green LM, Kauppinen T, L'Abbe KA, Littorin M, Lynge E, Mathews JD, Neuberger M, Osman J, Pearce N, Winkelmann R. 1991. Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols. Lancet 338:1027-1032. Schecter A, Ryan JJ, Constable JD. 1986. Chlorinated dibenzo-p-dioxin and dibenzofuran levels in human adipose tissue and milk samples from the North and South of Vietnam. Chemosphere 15:1613-1620. Schecter A, Constable JD, Arghestani S, Tong H, Gross ML. 1987. Elevated levels 2,3,7,8-tetrachlorodibenzodioxin in adipose tissue of certain U.S. veterans of the Vietnam war. Chemosphere 16:1997-2002. Schlatter C. 1991. Data on kinetics of PCDDs and PCDFs as a prerequisite for human risk assessment . In: Gallo MA, Scheuplein RJ, van der Heijden KA, eds. Biological Basis for Risk Assessment of Dioxins and Related Compounds. Plainview, NY: Cold Spring Harbor Laboratory Press. Banbury Report 35. 215-227. Schneider T, Olsen I, Lauersen B. 1991. Evaluation of other sources of exposure information. Applied Occupational and Environmental Hygiene 6:475-481. Sielken RL Jr. 1987. Statistical evaluations reflecting the skewness in the distribution of TCDD levels in human adipose tissue. Chemosphere 16:2135-2140. Seixas NS. 1990. Estimation of cumulative exposure for a cohort of coal miners with ''post-MSHA" exposures. Presented at the American Industrial Hygiene Conference, 17 May, 1990, Orlando, FL. Sexton K, Selevan SG, Wagener DK, Lybarger JA. 1992. Estimating human exposures to environmental pollutants: availability and utility of existing databases. Archives of Environmental Health 47:398-407. Smith AH, Matheson DP, Fisher DO, Chapman CJ. 1981. Preliminary report of reproductive outcomes among pesticide applicators using 2,4,5-T. New Zealand Medical Journal 93:177-179. Smith AH, Fisher DO, Pearce N, Chapman CJ. 1982. Congenital defects and miscarriages among New Zealand 2,4,5-T sprayers. Archives of Environmental Health 37:197-200. Smith AH, Patterson DG Jr, Warner ML, Mackenzie R, Needham LL. 1992. Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels of New Zealand pesticide applicators and their implication for cancer hypotheses. Journal of the National Cancer Institute 84:104-108. Smith TJ. 1987. Exposure assessment for occupational epidemiology. American Journal of Industrial Medicine 126:249-268. Smith TJ, Hammond SK, Hallock M, Woskie SR. 1991. Exposure assessment for epidemiology: characteristics of exposure. Applied Occupational and Environmental Hygiene 6:441-447. Solet D, Zoloth SR, Sullivan C, Jewett J, Michaels DM. 1989. Patterns of mortality in pulp and paper workers. Journal of Occupational Medicine 31:627-630. Stanton SL. 1989. Area-scoring methodology for estimating Agent Orange exposure status of
OCR for page 298
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam U.S. Army personnel in the Republic of Vietnam. In: Centers for Disease Control, Veterans Health Study. Comparison of Serum Levels of 2,3,7,8-Tetrachlorodibenzo-p-dioxin with Indirect Estimates of Agent Orange Exposure Among Vietnam Veterans. Atlanta: CDC. Appendix A. Stellman SD, Stellman JM. 1986. Estimation of exposure to Agent Orange and other defoliants among American troops in Vietnam: a methodological approach. American Journal of Industrial Medicine 9:305-321. Stellman JM, Stellman SD. 1993. An Appraisal of Military Records Available for Research on the Health Effects of Herbicides Used During the Vietnam War. Prepared for the Institute of Medicine Committee to Survey the Health Effects in Vietnam Veterans of Exposure to Herbicides. February 4, 1993. Stellman SD, Mager-Stellman J, Sommer JF Jr. 1988. Combat and herbicide exposures in Vietnam among a sample of American Legionnaires. Environmental Research 47:112-128. Stewart PA, Herrick RF, eds. 1991. International workshop on retrospective exposure assessment for occupational epidemiologic studies. Applied Occupational and Environmental Hygiene 6:417-559. Stewart PA, Blair A, Cubit D, et al. 1986. Estimating historical exposures to formaldehyde in a retrospective mortality study. Applied Industrial Hygiene 1:34-41. Suskind RR, Hertzberg VS. 1984. Human health effects of 2,4,5-T and its toxic contaminants. Journal of the American Medical Association 251:2372-2380. Swaen GMH, van Vliet C, Slangen JJM, Sturmans F. 1992. Cancer mortality among licensed herbicide applicators. Scandinavian Journal of Work, Environment, and Health 18:201-204. Sweeney MH, Fingerhut MA, Patterson DG, Connally LB, Piacitelli L, Morris JA, Greife AL. 1990. Comparison of serum levels of 2,3,7,8-TCDD in TCP production workers and in an unexposed comparison group. Chemosphere 20:993-1000. Tankersley WG, Ingle J, West C, Watson J, Crawford-Brown D. 1991. Guidelines for systematic assessment of occupational exposures in absence of monitoring data. Presented at Eighth International Symposium on Epidemiology in Occupational Health, Paris. Thomas TL, Kang HK. 1990. Mortality and morbidity among Army Chemical Corps Vietnam veterans: a preliminary report. American Journal of Industrial Medicine 18:665-673. U.S. Army. 1972. Herbicides and Military Operations. Vols I and II. Department of the Army, Engineer Strategic Studies Group, Office, Chief of Engineers. Vineis P, Terracini B, Ciccone G, Cignetti A, Colombo E, Donna A, Maffi L, Pisa R, Ricci P, Zanini E, Comba P. 1986. Phenoxy herbicides and soft tissue sarcomas in female rice weeders. A population-based case-referent study. Scandinavian Journal of Work, Environment, and Health 13:9-17. Wacholder S, Dosemici M, Lubin JH. 1991. Blind assignment of exposure does not always prevent differential misclassification. American Journal of Epidemiology 134:433-437. Werler MM, Pober BR, Nelson K, Holmes LB. 1989. Reporting accuracy among mothers of malformed and nonmalformed infants. American Journal of Epidemiology 129:415-421. Wigle DT, Semenciw RB, Wilkins K, Riedel D, Ritter L, Morrison HI, Mao Y. 1990. Mortality study of Canadian male farm operators: non-Hodgkin's lymphoma mortality and agricultural practices in Saskatchewan. Journal of the National Cancer Institute 82:575-582. Wiklund K, Holm L-E. 1986. Soft tissue sarcoma risk in Swedish agricultural and forestry workers. Journal of the National Cancer Institute 76:229-234. Wiklund K, Lindefors BM, Holm L-E. 1988a. Risk of malignant lymphoma in Swedish agricultural and forestry workers. British Journal of Industrial Medicine 45:19-24. Wiklund K, Dich J, Holm L-E. 1988b. Soft tissue sarcoma risk in Swedish licensed pesticide applicators. Journal of Occupational Medicine 30:801-804.
OCR for page 299
Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Wiklund K, Dich J, Holm L-E. 1989. Risk of soft tissue sarcoma, Hodgkin's disease and non-Hodgkin lymphoma among Swedish licensed pesticide applicators. Chemosphere 18:395-400. Woods JS, Polissar L. 1989. Non-Hodgkin's lymphoma among phenoxy herbicide-exposed farm workers in western Washington State. Chemosphere 18:401-406. Young AL, Barnes DG, Blair A, Bricker JG, Christian RS, Fingerhut M, Kang H, Keller C, Muray JE, Shepard BM. 1986. Report of the Agent Orange Working Group Science Subpanel on Exposure Assessment. Submitted to the Chairman, Agent Orange Working Group. Washington, DC: Executive Office of the President, Office of Science and Technology Policy. Zack JA, Gaffey WR. 1983. A mortality study of workers employed at the Monsanto company plant in Nitro, West Virginia. Environmental Science Research 26:575-591. Zahm SH, Weisenburger DD, Babbitt PA, Saal RC, Vaught JB, Cantor KP, Blair A. 1990. A case-control study of non-Hodgkin's lymphoma and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in eastern Nebraska. Epidemiology 1:349-356. Zober A, Messerer P, Huber P. 1990. Thirty four year mortality follow-up of BASF employees exposed to 2,3,7,8-TCDD after the 1953 accident. International Archives of Occupational and Environmental Health 62:139-157. Zumwalt ER Jr. 1993. Letter to the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides regarding draft version of the IOM chapter on the U.S. military and the herbicide program in Vietnam. May 20, 1993.
Representative terms from entire chapter: