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Veterans and Agent Orange: Update 2006 5 Exposure Assessment Assessment of human exposure to four specific herbicides (2,4-dichlorophenoxyacetic acid [2,4-D], 2,4,5-trichlorophenoxyacetic acid [2,4,5-T], 4-amino-3,5-trichloropicolinic acid [picloram], and cacodylic acid [dimethyl-arsinic acid or DMA]) and the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a key element in determining whether specific health outcomes are linked to these chemicals. In this chapter we review information on occupational and environmental exposures to these herbicides and TCDD, including exposure of Vietnam veterans. We discuss exposure assessments from selected epidemiologic studies introduced in Chapter 4 and provide background information for the health-outcome chapters that follow; health outcomes are not discussed here. Further discussion of exposure assessment and a detailed review of the US military’s wartime use of herbicides in Vietnam can be found in Chapters 3 and 6 of Veterans and Agent Orange (VAO; IOM, 1994); additional information concerning exposure assessment is located Chapter 5 of the updates (IOM, 1996, 1999, 2001, 2003a, 2005). Reviews of the most recent studies of the absorption, distribution, metabolism, and excretion of herbicides and TCDD can be found in their respective sections on toxicokinetics in Chapter 3 of this report. EXPOSURE ASSESSMENT IN EPIDEMIOLOGIC STUDIES An ideal exposure assessment would provide quantification of the concentration of a chemical at the site of toxic action in the tissue of an organism. In studies of human populations, however, it is rarely possible to measure those concentrations. Instead, exposure assessments are based on questionnaires and interviews, occupational and public records, or measurements in environmental media and
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Veterans and Agent Orange: Update 2006 in biologic specimens. Table 5-1 provides a guide to exposure monitoring and assessment methods used in selected epidemiologic studies of the health effects of the herbicides applied in Vietnam by US military forces and TCDD. Exposure assessments based on measurements of an environmental contaminant provide estimates of the amount of the contaminant that contacts a body barrier over a defined period. Exposure can occur through inhalation, skin contact, and ingestion. Exposure also can be assessed by measuring the compounds of interest—or their metabolites—in human tissues. Such biologic markers of exposure integrate absorption from all routes, and their interpretation is usually complex. Knowledge of pharmacokinetics is essential for linking measurements at the time of sampling with past exposures. Quantitative assessments based on environmental or biologic samples are not always available for epidemiologic studies, so investigators often rely on a mixture of qualitative and quantitative information to derive estimates (Armstrong et al., 1994; Checkoway et al., 2004). The most basic approach compares members of a presumably exposed group with the general population or with a non-exposed group. This method of classification offers simplicity and ease of interpretation. A more refined method assigns each study subject to an exposure category, such as high, medium, and low exposure. Disease risk for each group is calculated separately and compared with a reference or non-exposed group. This method can identify the presence or absence of a dose–response trend. In some cases, more detailed information is available for quantitative exposure estimates, and these can be used to construct what are sometimes called exposure metrics. These metrics integrate quantitative estimates of exposure intensity (such as chemical concentration in air or extent of skin contact) with exposure duration to produce an estimate of cumulative exposure. The temporal relationship between exposure and disease is complex and often difficult to define in epidemiologic investigations. Many diseases do not appear immediately following exposure. In the case of cancer, for example, the disease may not appear for many years after the exposure. The time between a defined exposure period and the occurrence of disease is often referred to as a latency period (IOM, 2004). Exposures can be brief (sometimes referred to as acute exposures) or protracted (sometimes referred to as chronic exposures). At one extreme the exposure can be the result of a single insult, as in an accidental poisoning. At the other extreme, an individual exposed to a chemical that is stored in the body may continue to experience “internal exposure” for years, even if exposure from the environment has ceased. Defining the proper time frame for duration of exposure represents a challenge in the assessment of exposure for epidemiologic studies. Occupational-exposure studies use work histories, job titles, and workplace measurements of contaminant concentration; this information is often combined to create a job–exposure matrix (JEM) wherein a quantitative exposure estimate is assigned to each job or task, and the time spent on each job or task is calculated.
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Veterans and Agent Orange: Update 2006 TABLE 5-1 Exposure Monitoring andAssessment Methods Used in Selected Epidemiologic Studies of the Health Effects of Herbicides Applied in Vietnam by US Military Forces and 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Exposure Method NIOSH Cohort Study Dow Cohort Study Ontario Farm Health Study US Agricultural Health Study New Zealand Herbicide Sprayers Seveso Area Study Seveso Women’s Health Study Air Force Health Study Army Chemical Corps Study Australian Veteran Study Job title x x x x x x x x Self-reported chemical use x x x x Exposure duration x x x x x x x Exposure categories x x x x x x Review of records x x x Job–exposure matrix x x Proximity to source x x x Soil sampling x Air sampling x 2,4-D concentration in urine x TCDD concentration in serum x x x x x
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Veterans and Agent Orange: Update 2006 This approach may also incorporate exposure-mitigating factors, such as process changes, engineering controls, and the use of protective clothing. The production-worker cohort analysis conducted by the US National Institute for Occupational Safety and Health (NIOSH) included these methods (Table 5-1). Many environmental-exposure studies use proximity to the source of a contaminant to classify exposure (Table 5-1). If an industrial facility emits a contaminant, investigators might identify geographic zones around the facility and assign exposure categories to people on the basis of residence. That approach was used to analyze data from the industrial accident in Seveso, Italy, that contaminated nearby areas with TCDD; the zones established were calibrated by the collection of soil samples. In general, it is difficult to use this type of information to classify the exposures of individuals with confidence. Such assessments can be refined to include analyses of exposure pathways (how chemicals move from the source through the environment) and personal behaviors (how individuals interact with their environment). Biologic markers of exposure can provide important information for use in occupational and environmental studies, permitting assignment of a quantitative exposure estimate to each person in a study group. The most important marker in the context of Vietnam veterans’ exposure to Agent Orange is the measurement of TCDD in serum, although it should be noted that TCDD and Agent Orange are not synonymous. The absorption, distribution, and metabolism of TCDD have been studied over the last 20 years. In the late 1980s, the Centers for Disease Control and Prevention (CDC) developed a highly sensitive assay to detect TCDD in serum and demonstrated a high correlation between serum TCDD and TCDD in adipose tissue (Patterson et al., 1986, 1987). The serum TCDD assay is now used extensively to evaluate exposure in Vietnam veterans and other people (Table 5-1). Studies of the patterns of individual chlorinated hydrocarbons observed in the tissues of people exposed to specific sources (Pless-Mulloli et al., 2005) suggest that the profiles are not sufficiently distinct to permit discrimination from general urban background exposure. Exposure Misclassification Exposure misclassification in epidemiologic studies can affect estimates of risk. A typical situation is a case–control study in which the reported measurement of exposure can be misclassified for either or both groups. The simplest situation to consider is classification of exposure into just two levels, for example ever or never exposed. If the probability of exposure misclassification is the same (i.e., non-differential) between cases and controls, then it can be shown that the estimated association between disease and exposure is biased towards the null value. In other words, one would expect the true association to be stronger than the association actually observed. However, if the probability of misclassification
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Veterans and Agent Orange: Update 2006 is different for cases and controls, then bias in the estimated association can occur in either direction. In this case, the true association might be stronger or weaker than the association observed. The situation when exposure is classified into more than two levels is somewhat more complicated. Dosemeci et al. (1990) have demonstrated that for this situation, the slope of a dose–response trend is not necessarily attenuated towards the null value, even if the probability of misclassification is the same for the two groups of subjects being compared, so the observed trend in disease risk across the several levels of exposure may be either an over-estimate or an under-estimate of the true trend in risk. The probabilities of misclassification typically are unknown at the start of the study. If one had perfect knowledge of the misclassification probabilities, statistical adjustment still will not necessarily lead to a result that is more significant than the unadjusted analysis, even if the misclassification probabilities are non-differential between the comparison groups. Analyses in which adjustments have been made for exposure misclassification should not be assumed to increase the certainty that an association is present. The situation is even more complicated when one has to estimate the probabilities of misclassification from the study data themselves. Finally, it is important to consider the effect of exposure misclassification on the statistical significance of the result. Greenland and Gustafson (2006) have shown that if one adjusts for exposure misclassification when the exposure is represented as binary (e.g., ever and never exposed), the resulting association is not necessarily more significant than in the unadjusted estimate. This result remains true even though the observed magnitude of the association (for example, the relative risk) might be increased, as indicated previously. Exposure to Dioxin-like Compounds A major focus of the work of the current VAO update has been the analysis of studies concerning exposure to a single compound: TCDD, which is one of several of tetrachlorodibenzo dioxins. The committee recognizes that under real-world conditions exposure to TCDD virtually never occurs in isolation and that there are hundreds of similar compounds to which humans might be exposed, among them other polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs). Exposure to TCDD is almost always accompanied by exposure to one or more of these other compounds. The literature on these other compounds, particularly PCBs and PAHs, was not reviewed systematically by the committee, unless TCDD was identified as an important component of the exposure. We took this approach for two reasons. First, exposure of Vietnam veterans to significant amounts of these other compounds, as compared to exposure to TCDD, has not been documented. Second, the most important mechanism for TCDD toxicity
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Veterans and Agent Orange: Update 2006 involves its ability to bind to and activate the aryl hydrocarbon receptor (AhR). Many of these other compounds act by different or multiple mechanisms, so it is difficult to attribute toxic effects from such exposures to TCDD. Exposure to mixtures of dioxin-like compounds presents a particularly difficult challenge for toxicology and risk assessment. The total toxicity equivalency quotient (TEQ) method uses the sum of the relative toxicities of dioxin-like compounds in a mixture to express the overall toxicity of the mixture as a single TCDD-toxic equivalent value. This approach has come into common use by regulatory agencies around the world, and most agencies in the United States, including the Environmental Protection Agency, support its use as providing a reasonable estimate of toxicity for complex mixtures. World Health Organization values (Van den Berg et al., 2006) are most often cited and generally accepted. Calculation of a TEQ value for a mixture of dioxin-like compounds requires that each specific dioxin-like compound in the mixture be assigned a toxicity equivalency factor (TEF) relative to the toxicity of TCDD. This determination is based on an evaluation of existing biologic and biochemical data. These data are of variable quality, and their evaluation includes scientific judgment and expert opinion, so the resulting TEFs are by no means precise. Furthermore, the TEQ method is based on the premise that the toxic and biologic responses of dioxin-like compounds are mediated through the AhR mechanism. Available data support this premise, but data on some compounds are incomplete. The TEQ method also has several important limitations. It is not able to account for possible synergistic or antagonistic interactions among compounds, possible actions or interactions of compounds that are not mediated by the AhR mechanism, and exposures to dietary flavonoids and other phytochemicals that bind the AhR (Ashida et al., 2000; Ciolino et al., 1999; Quadri et al., 2000). For some mixtures the risk posed by non-dioxin-like compounds that can act as AhR antagonists (e.g., non-coplanar PCBs) is not assessed (Safe, 1997–1998). It should also be noted that the kinetics and metabolism of each dioxin-like compound might differ considerably from the others, and complete data on tissue concentrations often are unavailable. Finally, extrapolation of TEF values derived from blood or adipose tissue samples to a meaningful target dose can carry considerable uncertainty. Considering the many difficulties of interpreting exposures to chemical mixtures relative to the exposure of veterans to Agent Orange and other herbicides in Vietnam, the committee’s analyses have focused primarily on TCDD exposures. Background levels of TEQ overall are thought to have declined along with a decline in PCB levels in the environment (e.g., Schneider et al., 2001). There have also been apparent declines in the background levels of TCDD itself (Aylward and Hays, 2002). However, such declines may be influenced by local differences in specific sources.
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Veterans and Agent Orange: Update 2006 Exposure Specificity for the Herbicides Used in Vietnam Only a limited number of herbicidal compounds were used as defoliants during the Vietnam War: esters and salts of 2,4-D and 2,4,5-T, cacodylic acid, and picloram, as combined in various formulations. Many scientific studies reviewed by the committee have reported exposures to broad categories of chemicals rather than to these specific compounds. These categories are presented in Table 5-2, along with their relevance to the committee’s charge. The information in Table 5-2 represents the current committee’s thinking, and has helped to guide our evaluation of studies. Because the body of evidence available for consideration was substantially more limited, previous committees cast a somewhat wider net by having slightly less stringent criteria for exposure specificity. A large number of studies have examined the relationship between exposure to “pesticides” and adverse health outcomes, while others have used the category of “herbicides” without identifying specific compounds. A careful reading of a scientific report often reveals that none of the compounds of interest (those used in Vietnam as mentioned above) contributed to the exposures of the study population, so such studies can be excluded from consideration. But in many cases the situation will be more ambiguous. For example, reports that define exposure in the broad category of “pesticides” with no further information have little relevance to the committee’s charge to determine associations between exposures to herbicides used in Vietnam and adverse health outcomes. Reports TABLE 5-2 Current Committee Guidance for the Classification of Exposure Information in Epidemiologic Studies That Focus on the Use of Pesticides or Herbicides, and Relevance of the Information to the Committee’s Charge to Evaluate Exposures to 2,4-D, 2,4,5-T (phenoxy herbicides), Cacodylic Acid, and Picloram* Specificity of Exposure Reported in Study Additional Information Relevance to Committee’s Charge Pesticides Chemicals of interest were not used or no additional information Not relevant Chemicals of interest were used Relevant Herbicides Chemicals of interest were not used Not relevant No additional information Limited relevance Chemicals of interest were used Relevant Phenoxy herbicides Highly relevant 2,4-D or 2,4,5-T Highly relevant * None of the epidemiologic studies reviewed by the committee to date have specified exposure to cacodylic acid or picloram.
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Veterans and Agent Orange: Update 2006 that define exposure in the more restricted category of “herbicides” are of greater relevance, but are of limited value unless it is clear from additional information that exposure to one or more of the herbicides used in Vietnam occurred within the study population (e.g., the published report indicates that the chemicals of interest were among the pesticide or herbicides used by the study population; the lead investigator of a published report has been contacted and has indicated that the chemicals of interest were among the chemicals used; the chemicals of interest are used commonly for the crop(s) identified in the study; the chemicals of interest are used commonly for a specific purpose, such as removal of weeds and shrubs along highways). Among the various chemical classes of herbicides that have been identified in published studies reviewed by the committee, only phenoxy herbicides, and particularly 2,4-D and 2,4,5-T, are directly relevant to the exposures experienced by US military forces in Vietnam. The committee retained some studies on unspecified pesticides for the neurologic health effects section of this report; their results have been entered in the corresponding outcome-specific tables. However, such studies tend to contribute little to the evidence considered by the committee. The many studies that provide chemical-specific exposure information are far more informative for the committee’s purposes. OCCUPATIONAL EXPOSURE TO HERBICIDES AND TCDD The committee reviewed many epidemiologic studies of occupationally exposed groups for evidence of an association between health risks and exposure to TCDD or to the herbicides used in Vietnam, primarily the phenoxy herbicides 2,4-D and 2,4,5-T. TCDD is an unwanted byproduct of 2,4,5-T production, but not of 2,4-D production. Other contaminants including other dioxins (e.g., 1,3,6,8-tetrachlorodibenzo-p-dioxin) have been reported at low levels in 2,4-D, however those identified do not possess the toxicity of TCDD (ATSDR, 1998; Huston, 1972; Norström et al., 1979). In reviewing these studies, the committee considered two types of exposure separately: exposure to 2,4-D or 2,4,5-T and exposure to TCDD from 2,4,5-T or other sources. This separation is necessary because some health effects could be associated with exposure to 2,4-D or 2,4,5-T in the absence of substantial TCDD exposure. After recognition of the problem of dioxin contamination in phenoxy herbicides, production conditions were modified to minimize contamination, but use of the products most subject to containing specifically TCDD (2,4,5-T and Silvex) were banned. As a result, study subjects exposed to phenoxy herbicides only after the late 1970s would not be assumed to have been at elevated risk for exposure to TCDD. This distinction is particularly important for workers in agriculture and forestry, where exposure is primarily the result of mixing, loading, and applying herbicides. In addition to these occupational groups the committee considered studies of occupational exposure to dioxins, focusing primarily on workers in
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Veterans and Agent Orange: Update 2006 chemical plants that produced phenoxy herbicides or chlorophenols, which tend to be contaminated with PCDDs. Waste-incineration workers were also included in the occupation category, because they can come into contact with dioxin-like compounds while handling byproducts of incineration. Other occupationally exposed groups include pulp-and-paper workers exposed to dioxins through bleaching processes that use chlorinated compounds, and sawmill workers exposed to chlorinated dioxins that can be contaminants of chlorophenates used as wood preservatives. Production Work US National Institute for Occupational Safety and Health Cohort Study One extensive set of data on chemical production workers potentially contaminated with TCDD has been compiled by NIOSH. More than 5,000 TCDD-exposed workers in 12 companies were identified from personnel and payroll records. Exposure status was determined initially through a review of process operating conditions; employee duties; and analytical records of TCDD in in-dustrial-hygiene samples, process streams, products, and waste (Fingerhut et al., 1991). Occupational exposure to TCDD-contaminated processes was confirmed by measuring serum TCDD in 253 cohort members. Duration of exposure was defined as the number of years worked in processes contaminated with TCDD and was used as the primary exposure metric in the study. The use of duration of exposure as a surrogate for cumulative exposure was based on a correlation (Pearson correlation efficient = 0.72) between log-transformed serum TCDD and years worked in TCDD-contaminated processes. Duration of exposure for individual workers was calculated from work records, and exposure duration categories were created: <1 year, 1 to <5 years, 5 to <15 years, and 15+ years. In some cases, information on duration of exposure was not available, so a separate metric, called duration of employment, was defined as the total time each worker was employed at the study plant. The NIOSH cohort study was updated in 1999 (Steenland et al., 1999), and a more refined exposure assessment was conducted. Workers whose records were inadequate to determine duration of exposure were excluded. The final analysis was restricted to 8 plants because 4 plants (with 591 workers) had no records on the degree of TCDD contamination of work processes or lacked the detailed work histories required to estimate TCDD exposure by job. Another 38 workers at the remaining 8 plants were eliminated because they worked in processes in which TCDD contamination could not be estimated. Finally, 727 workers with exposure to both pentachlorophenol (PCP) and TCDD were eliminated to avoid possible confounding of any TCDD effects by PCP effects. Those restrictions led to a subcohort of 3,538 workers (69 percent of the overall cohort). The exposure assessment for the subcohort was based on a JEM (Piacitelli
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Veterans and Agent Orange: Update 2006 and Marlow, 1997) that assigned each worker a quantitative exposure score for each year of work. The score was based on three factors: concentration of TCDD in micrograms per gram of process materials, fraction of the day when the worker worked in the specific process, and a qualitative contact value (0.01–1.5) based on the estimated TCDD contamination reaching exposed skin or the potential for inhalation of TCDD-contaminated dust. The scores for each year of work were combined to yield a cumulative exposure score for each worker. The new exposure analysis presumably reduced misclassification (through exclusion of non-exposed workers) and uncertainty (through exclusion of workers with incomplete information) and improved accuracy (through more detailed information on daily exposure). Steenland et al. (2001) conducted a detailed exposure–response analysis from data on workers at one of the original 12 companies in the cohort study. A group of 170 workers was identified with serum TCDD greater than 10 ppt (parts per trillion), as measured in 1988. The investigators conducted a regression analysis by using the following information: the work history of each worker, the exposure scores for each job held by each worker over time, a simple pharmacokinetic model for the storage and excretion of TCDD, and an estimated TCDD half-life of 8.7 years. That pharmacokinetic model allowed calculation of the estimated serum TCDD concentration at the time of last exposure for each worker. Results of the analysis were used to estimate serum TCDD concentration over time that was attributable to occupational exposure for all 3,538 workers in the subcohort defined in 1999. Crump et al. (2003) conducted a meta-analysis of dioxin dose–response studies for three occupational cohorts: the NIOSH cohort (Fingerhut et al., 1991), the Hamburg cohort (Flesch-Janys et al., 1998), and the BASF cohort (Ott and Zober, 1996). That analysis incorporated recent exposure data for the NIOSH cohort generated by Steenland et al. (2001). Aylward et al. (2005a) applied a concentration- and age-dependent elimination model to the NIOSH cohort data to determine the impact of these factors on estimates of serum TCDD concentrations. The authors found that their model produced a better fit to serum sampling data than first-order models did. Dose rates varied by a factor of 50 among different combinations of input parameters, elimination models, and regression models. The authors concluded that earlier dose reconstruction efforts may have under-estimated peak exposure levels in these populations. Aylward et al. (2005b) also applied this model to serial measurements of serum lipid TCDD concentrations from 36 adults from Seveso, Italy, and 3 adults from Vienna, Austria. They concluded that a large degree of uncertainty is characteristic of back-calculated dose estimates of peak TCDD exposure, and recommended that further analyses explicitly recognize this uncertainty. Lawson et al. (2004) continued the NIOSH cross-sectional medical study reported by Sweeney et al. (1989, 1993). They compared serum lipid TCDD concentrations from the NIOSH cohort with those in a reference population,
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Veterans and Agent Orange: Update 2006 and examined three birth outcomes of offspring: birth weight, preterm delivery, and birth defects. TCDD exposures at conception were estimated using physiologically-based pharmacokinetic modeling approaches (Dankovic et al., 1995; Thomaseth and Salvan, 1998). No other reports on the cohort have been published since Update 2004. International Agency for Research on Cancer Cohort Studies A multisite study by the International Agency for Research on Cancer (IARC) involved 18,390 production workers and herbicide sprayers working in 10 countries (Saracci et al., 1991). The full cohort was established by using the International Register of Workers Exposed to Phenoxy Herbicides and Their Contaminants. Twenty cohorts were combined for this analysis: one each from Canada, Finland, and Sweden; two each from Australia, Denmark, Italy, the Netherlands, and New Zealand; and seven from the United Kingdom. There were 12,492 production workers and 5,898 sprayers in the full cohort. Questionnaires were constructed for workers manufacturing chlorophenoxy herbicides or chlorinated phenols and for herbicide sprayers, and were completed with the assistance of industrial hygienists. Information from production records and job histories were examined when available. Workers were classified as exposed, probably exposed, exposure unknown, or non-exposed. The exposed-workers group (n = 13,482) consisted of all individuals known to have sprayed chlorophenoxy herbicides and all who worked in particular aspects of chemical production. Two subcohorts (n = 416) had no job titles available, but worked in chemical production facilities that were likely to produce TCDD exposure, so they were deemed probably exposed. Workers with no exposure information (n = 541) were classified as “exposure unknown.” Non-exposed workers (n = 3,951) were those who had never been employed in parts of factories that produced chlorophenoxy herbicides or chlorinated phenols and those who had never sprayed chlorophenoxy herbicides. An expanded and updated analysis of the IARC cohort was published in 1997 (Kogevinas et al., 1997). The researchers added herbicide production workers from 12 plants in the United States (the NIOSH cohort) and from four plants in Germany. The 21,863 workers exposed to phenoxy herbicides or chlorophenols were classified in three categories of exposure to TCDD or higher-chlorinated dioxins: those exposed (n = 13,831), those not exposed (n = 7,553), and those with unknown exposure (n = 479). Several exposure metrics were constructed for the cohort—years since first exposure, duration of exposure (in years), year of first exposure, and job title—but detailed methods were not described. No new studies of the full cohort have been reported since Update 2000. Researchers have studied various subgroups of the IARC cohort. Flesch-Janys et al. (1995) updated the cohort and added a quantitative exposure assessment based on blood or adipose measurements of polychlorinated dibenzo-p-dioxins
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