Veterans and Agent Orange Health Effects of Herbicides Used in Vietnam (1994) / Chapter Skim
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6 Exposure Assessment
6 Exposure Assessment
Pages 250-299
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From page 250... ...
Estimation of health risks associated with herbicide exposure consists of two primary activities: (1) exposure assessment and (2)
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From page 251... ...
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.
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From page 252... ...
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?
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From page 253... ...
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.
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From page 254... ...
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.
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From page 255... ...
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 sim
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From page 256... ...
, 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.
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From page 257... ...
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)
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From page 258... ...
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)
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From page 259... ...
By comparison, veterans with no unusual herbicide exposure had TCDD levels
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From page 260... ...
, 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.
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From page 261... ...
Based on these data, the committee concludes that serum TCDD measures are helpful in epidemiologic studies, but should not be taken as a "gold standard" of exposure. If there are group differences in serum TCDD levels, that probably does indicate a difference in exposure to TCDD between the two groups.
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From page 262... ...
Group differences in serum TCDD levels can be useful in confirming that occupational exposure measures reflect true differences in exposure, as has been done in the NIOSH study (Fingerhut et al., 1989, 1991; Sweeney et al., 1990) and other studies (see below)
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From page 263... ...
For TCDD-exposed populations, serum measures of TCDD concentrations can be made of a representative sample of those exposed. Serum biomarkers of TCDD exposure are sometimes used to estimate the degree of prior exposure of individuals; however, there are limitations to their use, as described in the previous section.
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From page 264... ...
At each chemical plant, a review of operating conditions, job duties, and records of TCDD levels in industrial hygiene samples, intermediate reactants, products, and wastes was conducted. Exposure was estimated from job records according to duration of exposure in processes involving TCDD contamination and total length of employment at the plant; serum TCDD levels were measured in a sample of 253 workers.
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From page 265... ...
Chloracne has been observed in some chemical plant workers and used as an indicator of prior TCDD exposure (Cook et al., 1980; Moses et al., 1984; Bond et al., 1987, 1989; Collins et al., 1993~. Chloracne, however, is neither a sensitive nor an exclusive indicator of prior TCDD exposure.
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From page 266... ...
One study provided information on serum TCDD concentrations in herbicide sprayers, that of Smith et al.
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From page 267... ...
The corresponding values for age-matched controls ranged from 2 to 11 ppt; the mean was 6 ppt. Serum TCDD levels were positively correlated with the number of months of professional spray application.
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From page 268... ...
None of these data correlated with serum TCDD levels, strongly suggesting that the exposure of importance was fallout on the day of the accident. The presence and degree of chloracne did correlate with TCDD levels; however, it appears that adults are much less likely to develop chloracne than children following an acute exposure, but surveillance bias may have played some role in this finding.
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From page 269... ...
For nonexposed persons, adipose tissue TCDD concentrations ranged from nondetectable to 20 ppt, with a median of 6 ppt. Based on a seven-year half-life it is calculated that two of the study participants would have had adipose tissue TCDD levels near 3,000 ppt at the time of the last date of exposure.
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From page 270... ...
Because of the complex pattern of exposures to the various herbicides and TCDD in the available epidemiologic studies, the committee was generally not able to differentiate among multiple chemical exposures to determine whether specific health effects were associated with any particular herbicide or TCDD. EXPOSURE ASSESSMENT IN STUDIES OF VIETNAM VETERANS Different approaches have been used in estimating exposure to herbicides in studies of Vietnam veterans.
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From page 271... ...
Records-Based Measures Records-based classifications of the exposure of Vietnam veterans have been estimated by using information from military personnel records and historical documents on Vietnam service, branch of service, and military occupation. Levels of combat exposure have also been used as a surrogate measure of herbicide exposure.
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From page 272... ...
Military Occupation Military occupation has been shown to be a valid exposure classification for two specific occupations that involved the direct handling and distribution of herbicides: first, the Air Force Ranch Hands, who were responsible for aerial spraying of herbicides and, second, the Army Chemical Corps, which performed ground and helicopter chemical operations. Biomarker
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From page 273... ...
Other classifications of general Vietnam veterans by military occupations are unlikely to improve the ability to predict exposure above what might be obtained from a category such as combat experience. Reconstructing Estimated Exposure from Troop Location and Herbicide Spray Data Another approach, the most detailed records-based classification scheme, matches troop location data with information on herbicide spray data from the HERBS and Services HERBS tapes to assign exposure categories based on the number of times a unit was within a defined time and distance from a documented herbicide spray.
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From page 274... ...
The potential for an individual Vietnam veteran's exposure to Agent Orange ("exposure opportunity") was estimated by military records specialists of the Army Agent Orange Task Force without knowledge of case or control status.
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From page 275... ...
1. Service in selected locations at specific times (any job description except handling Agent Orange)
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From page 276... ...
This was to be accomplished by determining the proximity of troops to Agent Orange spray using military records to track troop movement and the HERBS tapes to locate herbicide spraying patterns. Veterans' daily locations were to be abstracted from military records of company-sized units.
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From page 277... ...
Based on these analyses, the CDC initially concluded that "many veterans were in close enough proximity to applications of Agent Orange to be classified as highly likely to have been exposed to the herbicide" (CDC, 19851. The CDC also proposed three exposure scores-E1 (short exposure)
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From page 278... ...
Self-reported Agent Orange exposure was also determined based on a number of questions regarding whether subjects had sprayed, loaded, or handled herbicides, or had entered a sprayed area. According to the Stellmans, these measures "are to be regarded as approximations to population exposures in the same sense that past exposures to dusts and chemicals are often estimated for workers in industries for which industrial hygiene measurements of past conditions are not available" (Stellman and Stellman, 1986~.
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From page 279... ...
The exposure index for a Ranch Hand was defined as the product of the TCDD weighting factor and the number of gallons of TCDD herbicides sprayed during his tour of duty, divided by the number of Ranch Hands sharing such duties during his tour. The weighting factor served to separate from the total those who served in Vietnam prior to July 1965, a period in which TCDD levels in herbicides were known to be higher.
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From page 280... ...
, conducted by the New Jersey Agent Orange Commission, 10 Vietnam veterans reported to be heavily exposed to Agent Orange were compared to matched controls in both blood and adipose tissue levels of TCDD. Nine of the ten veterans had handled herbicides regularly- five were members of Operation Ranch Hand, one was an Air Force freight handler, two were Army Chemical Corps specialists, and one was an Army helicopter crew chief who flew herbicide spray missions.
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From page 281... ...
CDC Agent Orange Validation Study (AOVS) To test the validity of several indirect methods for estimating exposure of ground troops to Agent Orange in Vietnam, in 1987 the CDC measured serum TCDD levels in a nonrandom sample of Vietnam veterans and Vietnam era veterans who did not serve in Vietnam (CDC, 1988b)
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reported a correlation between serum TCDD levels and military records-based scores. This finding results from one veteran whose serum TCDD concentration was 45 ppt.
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From page 283... ...
to o ~_ a) cn _ i\\ \ '\\ \\\\ 3 or \\ L °°~\ 4 0 = Exposure Group 000 ~~0 00 1 967 Year 1 987 FIGURE 6-3 Possible scenarios for describing the relationship between current and prior serum TCDD levels, 1967-1987.
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From page 284... ...
Without adequate knowledge of the decay rate and pharmacokinetics of TCDD in humans, it is not possible to distinguish among the alternative explanations. If initial concentrations of TCDD differed but then over the years fell to background, estimates based on reconstruction of troop locations and herbicide spraying activities might be more reliable indicators of exposure than current serum TCDD levels.
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From page 285... ...
The median TCDD levels for Vietnam veterans and Vietnam era veterans were both 4 ppt. Serum TCDD levels obtained from Ranch Hand veterans in 1987, however, were able to distinguish among groups of Ranch Hand veterans (based on their military duties)
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From page 286... ...
Oral and written testimony presented before the committee also suggests that substantial numbers of veterans were exposed to Agent Orange and other herbicides. Results from a survey of U.S.
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From page 287... ...
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. Development of the Exposure Reconstruction Model This new effort would model the conditions under which herbicides were used in Vietnam and should consider the following information: troop location based on all available military records, including morning reports, daily journals, situation reports, intelligence summaries, ORLL, and combat operations after action reports; 2.
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From page 288... ...
Once an exposure reconstruction model based on these data has been developed, it should be possible to estimate an exposure score for the large numbers of veterans needed for epidemiologic studies. Considerable research has also been conducted on the environmental fate and persistence of TCDD and this information could be incorporated into the exposure model.
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From page 289... ...
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.
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From page 290... ...
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.
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From page 291... ...
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.
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From page 292... ...
1985. Agent Orange Projects Interim Report Number 2: Exposure Assessment for the Agent Orange Study.
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From page 293... ...
Part II, Mortality. American Journal of Industrial Medicine 4:421-433.
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From page 294... ...
1987. Review of Comparison of Serum Levels of 2,3,7,8-TCDD with Indirect Estimates of Agent Orange Exposure in Vietnam Veterans.
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From page 295... ...
1988. Dioxins and dibenzofurans in blood and adipose tissue of Agent Orangeexposed Vietnam veterans and matched controls.
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From page 296... ...
1989. Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam Veterans of Operation Ranch Hand.
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From page 297... ...
1987. Statistical evaluations reflecting the skewness in the distribution of TCDD levels in human adipose tissue.
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From page 298... ...
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.
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From page 299... ...
1986. Report of the Agent Orange Working Group Science Subpanel on Exposure Assessment.
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