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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5 Exposure Assessment Assessment of human exposure to four specific herbicides (2,4-dichloro- phenoxyacetic 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 environ- mental 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 Vet- erans 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 respec- tive sections on toxicokinetics in Chapter 3 of this report. EXPOSURE ASSESSMENT IN EPIDEMIOLOGIC STUDIES An ideal exposure assessment would provide quantification of the concentra- tion 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 concentra- tions. Instead, exposure assessments are based on questionnaires and interviews, occupational and public records, or measurements in environmental media and 214

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215 EXPOSURE ASSESSMENT 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 contami- nant provide estimates of the amount of the contaminant that contacts a body barrier over a defined period. Exposure can occur through inhalation, skin con- tact, 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 cal- culated 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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216 TABLE 5-1 Exposure Monitoring and Assessment 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) Ontario US Agri- New Seveso Army NIOSH Dow Farm cultural Zealand Seveso Women’s Air Force Chemical Australian Cohort Cohort Health Health Herbicide Area Health Health Corps Veteran Exposure Method Study Study Study Study Sprayers Study Study Study Study 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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217 EXPOSURE ASSESSMENT 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 con- taminant to classify exposure (Table 5-1). If an industrial facility emits a contami- nant, 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 Dis- ease 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) sug- gest 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 measure- ment 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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218 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 some- what 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, statisti- cal 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 re- mains 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 hydrocar- bons (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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219 EXPOSURE ASSESSMENT 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 dif- ficult 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 di- etary 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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220 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 dur- ing 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* Relevance to Specificity of Exposure Committee’s Reported in Study Additional Information Charge Pesticides Chemicals of interest were not used or no Not relevant additional information 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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221 EXPOSURE ASSESSMENT 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 un- specified 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 ex- posed 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 modi- fied 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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222 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 ex- posed 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 con- taminated 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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223 EXPOSURE ASSESSMENT 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 incom- plete 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 phar- macokinetic 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 stud- ies 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 elimina- tion 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 mea- surements of serum lipid TCDD concentrations from 36 adults from Seveso, Italy, and 3 adults from Vienna, Austria. They concluded that a large degree of uncer- tainty 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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224 VETERANS AND AGENT ORANGE: UPDATE 2006 and examined three birth outcomes of offspring: birth weight, preterm deliv- ery, 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 chlo- rophenoxy 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 work- ers 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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250 VETERANS AND AGENT ORANGE: UPDATE 2006 Burns CJ, Beard KK, Cartmill JB. 2001. Mortality in chemical workers potentially exposed to 2,4- dichlorophenoxyacetic acid (2,4-D) 1945–1994: An update. Occupational and Environmental Medicine 58:24–30. 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 Be- tween Exposure to 2,4-D and Spontaneous Abortions in Humans. SRI International. Prepared for the National Forest Products Association and the US Department of Agriculture, Forest Service. Carreon T, Butler MA, Ruder AM, Waters MA, Davis-King KE, Calvert GM, Schulte PA, Connally B, Ward EM, Sanderson WT, Heineman EF, Mandel JS, Morton RF, Reding DJ, Rosenman KD, Talaska G, Cancer B. 2005. Gliomas and farm pesticide exposure in women: The Upper Midwest Health Study. Environmental Health Perspectives 113(5):546–551. CDC (Centers for Disease Control). 1985. Agent Orange Projects Interim Report Number 2: Exposure Assessment for the Agent Orange Study. Atlanta, GA: CDC, Center for Environmental Health, Division of Chronic Disease Control, Agent Orange Projects. CDC. 1988a. Preliminary report: 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure in humans—Seveso, Italy. Morbidity and Mortality Weekly Report 37:733–736. CDC. 1988b. Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in US Army Vietnam era veterans. Journal of the American Medical Association 260:1249–1254. CDC. 1989. Health Status of Vietnam Veterans. Vietnam Experience Study. Atlanta: US Department of Health and Human Services. Vols. I–V, Supplements A–C. CDVA (Commonwealth Department of Veterans’ Affairs). 1998a. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community. Volume 1: Male Vietnam Veterans Survey and Community Comparison Outcomes. Canberra, Australia: Department of Veterans’ Affairs. CDVA. 1998b. Morbidity of Vietnam Veterans: A Study of the Health of Australia’s Vietnam Veteran Community. Volume 2: Female Vietnam Veterans Survey and Community Comparison Out- comes. Canberra, Australia: Department of Veterans’ Affairs. Checkoway H, Pearce NE, Kriebel D. 2004. Research Methods in Occupational Epidemiology. Sec- ond Edition. New York: Oxford University Press. Chiu BC, Weisenburger DD, Zahm SH, Cantor KP, Gapstur SM, Holmes F, Burmeister LF, Blair A. 2004. Agricultural pesticide use, familial cancer, and risk of non-Hodgkin lymphoma. Cancer Epidemiology, Biomarkers and Prevention 13(4):525–531. CIH (Commonwealth Institute of Health). 1984a. Australian Veterans Health Studies. Mortality Report. Part I. A Retrospective Cohort Study of Mortality Among Australian National Service- men of the Vietnam Conflict Era, and A Executive Summary of the Mortality Report. Canberra: Australian Government Publishing Service. CIH. 1984b. Australian Veterans Health Studies. The Mortality Report. Part II. Factors Influencing Mortality Rates of Australian National Servicemen of the Vietnam Conflict Era. Canberra: Aus- tralian Government Publishing Service. CIH. 1984c. Australian Veterans Health Studies. The Mortality Report. Part III. The Relationship Between Aspects of Vietnam Service and Subsequent Mortality Among Australian National Ser- vicemen of the Vietnam Conflict Era. Canberra: Australian Government Publishing Service. Ciolino H, Daschner P, Yeh G. 1999. Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. Biochemical Journal 340:715–722. 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.

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251 EXPOSURE ASSESSMENT 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, Budinsky RA, Burns CJ, Lamparski LL, Carson ML, Martin GD, Wilken M. 2006. Serum dioxin levels in former chlorophenol workers. Journal of Exposure Science and Environmental Epidemiology 16(1):76–84. 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, Bond GG, Olson RA. 1986. Evaluation of the mortality experience of workers exposed to the chlorinated dioxins. Chemosphere 15:1769–1776. Costani G, Rabitti P, Mambrini A, Bai E, Berrino F. 2000. Soft tissue sarcomas in the general popula- tion living near a chemical plant in Northern Italy. Tumori 86(5):381–383. Crane PJ, Barnard DL, Horsley KW, Adena MA. 1997a. Mortality of Vietnam Veterans: The Veteran Cohort Study. A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans. Canberra, Australia: Department of Veterans’ Affairs. Crane PJ, Barnard DL, Horsley KW, Adena MA. 1997b. Mortality of National Service Vietnam Veter- ans: A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans. Canberra, Australia: Department of Veterans’ Affairs. Crump KS, Canady R, Kogevinas M. 2003. Meta-analysis of dioxin cancer dose response for three occupational cohorts. Environmental Health Perspectives 111(5):681–687. Curtis KM, Savitz DA, Weinberg CR, Arbuckle TE. 1999. The effect of pesticide exposure on time to pregnancy. Epidemiology 10:112–117. Curwin BD, Hein MJ, Sanderson WT, Barr DB, Heederik D, Reynolds SJ, Ward EM, Alavanja MC. 2005. Urinary and hand wipe pesticide levels among farmers and nonfarmers in Iowa. Journal of Exposure Analysis and Environmental Epidemiology 15(6):500–508. Dai LC, Phuong NTN, Thom LH, Thuy TT, Van NTT, Cam LH, Chi HTK, Thuy LB. 1990. A com- parison of infant mortality rates between two Vietnamese villages sprayed by defoliants in wartime and one unsprayed village. Chemosphere 20:1005–1012. Dankovic DA, Andersen ME, Salvan A, Stayner LT. 1995. A simplified PBPK model describing the kinetics of TCDD in humans (abstract). Toxicologist 15:272. Darrow RA, Irish KR, Minarik CD. 1969. Herbicides Used in Southeast Asia. Kelly AFB, TX. Techni- cal Report SAOQ-TR-69-11078. 60 pp. De Felip E, Porpora MG, di Domenico A, Ingelido AM, Cardelli M, Cosmi EV, Donnez J. 2004. Dioxin-like compounds and endometriosis: A study on Italian and Belgian women of reproduc- tive age. Toxicology Letters 150(2):203–209. De Roos AJ, Cooper GS, Alavanja MC, Sandler DP. 2005. Rheumatoid arthritis among women in the Agricultural Health Study: Risk associated with farming activities and exposures. Annals of Epidemiology 15(10):762–770. Dosemeci 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(4):746–748. Dosemeci M, Alavanja MCR, Rowland AS, Mage D, Zahm SH, Rothman N, Lubin JH, Hoppin JA, Sandler DP, Blair A. 2002. A quantitative approach for estimating exposure to pesticide in the Agricultural Health Study. Annals of Occupational Hygiene 46:245–260. Duell EJ, Millikan RC, Savitz DA, Schell MJ, Newman B, Tse CJ, Sandler DP. 2001. Reproducibility of reported farming activities and pesticide use among breast cancer cases and controls. A com- parison of two modes of data collection. Annals of Epidemiology 11(3):178–185. Dwernychuk LW. 2005. Dioxin hot spots in Vietnam. Chemosphere 60(7):998–999. Dwernychuk LW, Cau HD, Hatfield CT, Boivin TG, Hung TM, Dung PT, Thai ND. 2002. Dioxin reservoirs in southern Viet Nam—a legacy of Agent Orange. Chemosphere 47(2):117–137. Engel LS, Hill DA, Hoppin JA, Lubin JH, Lynch CF, Pierce J, Samanic C, Sandler DP, Blair A, Alavanja MC. 2005. Pesticide use and breast cancer risk among farmers’ wives in the Agricul- tural Health Study. American Journal of Epidemiology 161(2):121–135.

OCR for page 214
252 VETERANS AND AGENT ORANGE: UPDATE 2006 Erickson JD, Mulinare J, Mcclain PW. 1984a. Vietnam veterans’ risks for fathering babies with birth defects. Journal of the American Medical Association 252:903–912. Erickson JD, Mulinare J, Mcclain PW, Fitch TG, James LM, McClearn AB, Adams MJ. 1984b. Viet- nam Veterans’ Risks for Fathering Babies with Birth Defects. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control. Eskenazi B, Mocarelli P, Warner M, Samuels S, Needham L, Patterson D, Brambilla P, Gerthoux PM, Turner W, Casalini S, Cazzaniga M, Chee WY. 2001. Seveso Women’s Health Study: Does zone of residence predict individual TCDD exposure? Chemosphere 43(4-7):937–942. Eskenazi B, Warner M, Mocarelli P, Samuels S, Needham LL, Patterson DG Jr, Lippman S, Vercellini P, Gerthoux PM, Brambilla P, Olive D. 2002a. Serum dioxin concentrations and menstrual cycle characteristics. American Journal of Epidemiology 156(4):383–392. Eskenazi B, Mocarelli P, Warner M, Samuels S, Vercellini P, Olive D, Needham LL, Patterson DG Jr, Brambilla P, Gavoni N, Casalini S, Panazza S, Turner W, Gerthoux PM. 2002b. Serum dioxin concentrations and endometriosis: A cohort study. Environmental Health Perspectives 110(7):629–634. Eskenazi B, Mocarelli P, Warner M, Chee W-Y, Gerthoux PM, Samuels S, Needham LL, Patterson DG Jr. 2003. Maternal serum dioxin levels and birth outcomes in women of Seveso, Italy. En- vironmental Health Perspectives 111(7):947–953. Eskenazi B, Mocarelli P, Warner M, Needham LL, Patterson DG Jr, Samuels S, Turner W, Gerthoux PM, Brambilla P. 2004. Relationship of serum TCDD concentrations and age at exposure of female residents of Seveso, Italy. Environmental Health Perspectives 112(1):22–27. Eskenazi B, Warner M, Marks AR, Samuels S, Gerthoux PM, Vercellini P, Olive DL, Needham L, Patterson D Jr, Mocarelli P. 2005. Serum dioxin concentrations and age at menopause. Environ- mental Health Perspectives 113(7):858–862. Evatt P. 1985. Royal Commission on the Use and Effect of Chemical Agents on Australian Personnel in Vietnam, Final Report. Canberra: Australian Government Publishing Service. Farr SL, Cooper GS, Cai J, Savitz DA, Sandler DP. 2004. Pesticide use and menstrual cycle charac- teristics among premenopausal women in the Agricultural Health Study. American Journal of Epidemiology 160(12):1194–1204. Farr SL, Cai J, Savitz DA, Sandler DP, Hoppin JA, Cooper GS. 2006. Pesticide exposure and tim- ing of menopause: The Agricultural Health Study. American Journal of Epidemiology 163(8): 731–742. Fattore E, Di Guardo A, Mariani G, Guzzi A, Benfenati E, Fanelli R. 2003. Polychlorinated dibenzo- p-dioxins and dibenzofurans in the air of Seveso, Italy, 26 years after the explosion. Environ- mental Science and Technology 37(8):1503–1508. 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. Fett MJ, Adena MA, Cobbin DM, Dunn M. 1987a. Mortality among Australian conscripts of the Viet- nam conflict era. I. Death from all causes. American Journal of Epidemiology 126:869–877. Fett MJ, Nairn JR, Cobbin DM, Adena MA. 1987b. Mortality among Australian conscripts of the Vietnam conflict era. II. Causes of death. American Journal of Epidemiology 125:878–884. Fierens S, Mairesse H, Hermans C, Bernard A, Eppe G, Focant JF, De Pauw E. 2003a. Dioxin ac- cumulation in residents around incinerators. Journal of Toxicology and Environmental Health, Part A 66(14):1287–1293. Fierens S, Mairesse H, Heilier JF, de Burbure C, Focant JF, Eppe G, de Pauw E, Bernard A. 2003b. Dioxin/polychlorinated biphenyl body burden, diabetes and endometriosis: Findings in a popula- tion-based study in Belgium. Biomarkers 8(6):529–534. 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-tetrachloro- dibenzo-p-dioxin. New England Journal of Medicine 324:212–218.

OCR for page 214
253 EXPOSURE ASSESSMENT Flesch-Janys D, Berger J, Gurn P, Manz A, Nagel S, Waltsgott H, Dwyer JH. 1995. Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany. American Journal of Epidemiology 142:1165–1175. Flesch-Janys D, Steindorf K, Gurn P, Becher H. 1998. Estimation of the cumulated exposure to polychlorinated dibenzo-p-dioxins/furans and standardized mortality ratio analysis of cancer mortality by dose in an occupationally exposed cohort. Environmental Health Perspectives 106 (Suppl 2):655–662. Forcier L, Hudson HM, Cobbin DM, Jones MP, Adena MA, Fett MJ. 1987. Mortality of Australian veterans of the Vietnam conflict and the period and location of their Vietnam service. Military Medicine 152:9–15. 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. Fritschi L, Benke G, Hughes AM, Kricker A, Turner J, Vajdic CM, Grulich A, Milliken S, Kaldor J, Armstrong BK. 2005. Occupational exposure to pesticides and risk of non-Hodgkin’s lym- phoma. American Journal of Epidemiology 162(9):849–857. Garaj-Vrhovac V, Zeljezic D. 2002. Assessment of genome damage in a population of Croatian work- ers employed in pesticide production by chromosomal aberration analysis, micronucleus assay and comet assay. Journal of Applied Toxicology 22:249–255. Garry VF, Holland SE, Erickson LL, Burroughs BL. 2003. Male reproductive hormones and thyroid function in pesticide applicators in the Red River Valley of Minnesota. Journal of Toxicology and Environmental Health, Part A 66(11):965–986. Gonzales J. 1992. List of Chemicals Used in Vietnam. Presented to the Institute of Medicine Commit- tee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. Illinois Agent Orange Committee, Vietnam Veterans of America. Gordon JE, Shy CM. 1981. Agricultural chemical use and congenital cleft lip and/or palate. Archives of Environmental Health 36:213–221. Gorell JM, Peterson EL, Rybicki BA, Johnson CC. 2004. Multiple risk factors for Parkinson’s disease. Journal of Neurological Sciences 217(2):169–174. Gough M. 1986. Dioxin, Agent Orange: The Facts. New York: Plenum Press. Greenland P, Gustafson S. 2006. The performance of random coefficient regression in accounting for residual confounding. Biometrics 62(3):760–768. Hanke W, Romitti P, Fuortes L, Sobala W, Mikulski M. 2003. The use of pesticides in a Polish rural population and its effect on birth weight. International Archives of Occupational Environmental Health 76(8):614–620. Hansen ES, Hasle H, Lander F. 1992. A cohort study on cancer incidence among Danish gardeners. American Journal of Industrial Medicine 21:651–660. Harris SA, Corey PN, Sass-Kortsak AM, Purdham JT. 2001. The development of a new method to estimate total daily dose of pesticides in professional turf applicators following multiple and varied exposures in occupational settings. International Archives of Occupational Environmental Health 74(5):345–358. 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. Hertzman C, Teschke K, Ostry A, Hershler R, Dimich-Ward H, Kelly S, Spinelli JJ, Gallagher RP, McBride M, Marion SA. 1997. Mortality and cancer incidence among sawmill workers exposed to chlorophenate wood preservatives. American Journal of Public Health 87(1):71–79. 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.

OCR for page 214
254 VETERANS AND AGENT ORANGE: UPDATE 2006 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. Hooiveld M, Heederik DJ, Kogevinas M, Boffetta P, Needham LL, Patterson DG Jr, Bueno de Mesquita HB. 1998. Second follow-up of a Dutch cohort occupationally exposed to phenoxy herbicides, chlorophenols, and contaminants. American Journal of Epidemiology 147(9):891–901. Hoppin JA. 2005. Integrating exposure measurements into epidemiologic studies in agriculture. Scan- dinavian Journal of Work, Environment and Health 31(Suppl 1):115–117. Hoppin JA, Adgate JL, Eberhart M, Nishioka M, Ryan PB. 2006. Environmental exposure assessment of pesticides in farmworker homes. Environmental Health Perspectives 114(6):929–935. Huston BL. 1972. Identification of three neutral contaminants in production grade 2,4-D. Journal of Agriculture and Food Chemistry. 20(3):724–727. IOM (Institute of Medicine). 1994. Veterans and Agent Orange Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1997. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research. Washing- ton, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2003a. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. IOM. 2003b. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Interim Findings and Recommendations. Washington, DC: The National Academies Press. IOM. 2003c. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Final Report. Washington, DC: The National Academies Press. IOM. 2004. Veterans and Agent Orange: Veterans and Agent Orange: Length of Presumptive Period for Association Between Exposure and Respiratory Cancer. Washington, DC: The National Academies Press. IOM. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. IOM. 2006. Disposition of the Air Force Health Study. Washington, DC: The National Academies Press. 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. Kang HK, Dalager NA, Needham LL, Patterson DG, Matanoski GM, Kanchanaraksa S, Lees PSJ. 2001. US army chemical corps Vietnam veterans health study: Preliminary results. Chemosphere 43:943–949. Kang HK, Dalager NA, Needham LL, Patterson DG, Lees PSJ, Yates K, Matanoski GM. 2006. Health status of Army Chemical Corps Vietnam veterans who sprayed defoliant in Vietnam. American Journal of Industrial Medicine 49(11):875–884. Kang MJ, Lee DY, Joo WA, Kim CW. 2005. Plasma protein level changes in waste incineration workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Proteome Research 4(4): 1248–1255. Kern PA, Said S, Jackson WG Jr, Michalek JE. 2004. Insulin sensitivity following agent orange expo- sure in Vietnam veterans with high blood levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of Clinical Endocrinology and Metabolism 89(9):4665–4672.

OCR for page 214
255 EXPOSURE ASSESSMENT Ketchum NS, Michalek JE. 2005. Postservice mortality of Air Force veterans occupationally ex- posed to herbicides during the Vietnam War: 20-Year follow-up results. Military Medicine 170(5):406–413. Kim JS, Kang HK, Lim HS, Cheong HK, Lim MK. 2001. A study on the correlation between catego- rizations of the individual exposure levels to Agent Orange and serum dioxin levels among the Korean Vietnam veterans. Korean Journal of Preventive Medicine 34(1):80–88. Kim J-S, Lim H-S, Cho S-I, Cheong H-K, Lim M-K. 2003. Impact of Agent Orange exposure among Korean Vietnam veterans. Industrial Health 41:149–157. Kirrane EF, Hoppin JA, Umbach DM, Samanic C, Sandler DP. 2004. Patterns of pesticide use and their determinants among wives of farmer pesticide applicators in the Agricultural Health Study. Journal of Occupational and Environmental Medicine 46(8):856–865. Kirrane EF, Hoppin JA, Kamel F, Umbach DM, Boyes WK, DeRoos AJ, Alavanja M, Sandler DP. 2005. Retinal degeneration and other eye disorders in wives of farmer pesticide applicators enrolled in the Agricultural Health Study. American Journal of Epidemiology 161(11):1020–1029. Kogevinas M, Becher H, Benn T, Bertazzi PA, Boffetta P, Bueno de Mesquita HB, Coggon D, Colin D, Flesch-Janys D, Fingerhut M, Green L, Kauppinen T, Littorin M, Lynge E, Mathews JD, Neuberger M, Pearce N, Saracci R. 1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study. American Journal of Epidemiology 145(12):1061–1075. 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. Kumagai S, Koda S. 2005. Polychlorinated dibenzo-p-dioxin and dibenzofuran concentrations in serum samples of workers at an infectious waste incineration plant in Japan. Journal of Oc- cupational and Environmental Hygiene 2(2):120–125. Landi MT, Bertazzi PA, Baccarelli A, Consonni D, Masten S, Lucier G, Mocarelli P, Needham L, Caporaso N, Grassman J. 2003. TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident. Carcinogenesis 24(4):673–680. 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. Lawson CC, Schnorr TM, Whelan EA, Deddens JA, Dankovic DA, Piacitelli LA, Sweeney MH, Connally LB. 2004. Paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and birth outcomes of offspring: Birth weight, preterm delivery, and birth defects. Environmental Health Perspectives 112(14):1403–1408. Lee WJ, Lijinsky W, Heineman EF, Markin RS, Weisenburger DD, Ward MH. 2004. Agricultural pesticide use and adenocarcinomas of the stomach and oesophagus. Occupational and Envi- ronmental Medicine 61(9):743–749. Libich S, To JC, Frank R, Sirons GJ. 1984. Occupational exposure of herbicide applicators to her- bicides used along electric power transmission line right-of-way. American Industrial Hygiene Association Journal 45:56–62. Mandel JS, Alexander BH, Baker BA, Acquavella JF, Chapman P, Honeycutt R. 2005. Biomonitoring for farm families in the Farm Family Exposure Study. Scandinavian Journal of Work, Environ- ment and Health 31(Suppl 1):98–104. 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.

OCR for page 214
256 VETERANS AND AGENT ORANGE: UPDATE 2006 McDuffie HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, Robson D, Skinnider LF, Choi NW. 2001. Non-Hodgkin’s lymphoma and specific pesticide exposures in men: Cross-Canada study of pesticides and health. Cancer Epidemiology, Biomarkers and Prevention 10(11):1153–1163. Michalek JE, Wolfe WH, Miner JC, Papa TM, Pirkle JL. 1995. Indices of TCDD exposure and TCDD body burden in veterans of Operation Ranch Hand. Journal of Exposure Analysis and Environ- mental Epidemiology 5(2):209–223. Michalek JE, Ketchum N, Longnecker MP. 2001a. Serum dioxin and hepatic abnormalities in veterans of Operation Ranch Hand. Annals of Epidemiology 11(5):304–311. Michalek JE, Akhtar FZ, Arezzo JC, Garabrant DH, Albers JW. 2001b. Serum dioxin and peripheral neuropathy in veterans of Operation Ranch Hand. Neurotoxicology 22:479–490. Michalek JE, Akhtar FZ, Longnecker MP, Burton JE. 2001c. Relation of serum 2,3,7,8-tetrachloro- dibenzo-p-dioxin (TCDD) level to hematological examination results in veterans of Operation Ranch Hand. Archives of Environmental Health 56(5):396–405. Michalek JE, Ketchum NS, Tripathi RC. 2003. Diabetes mellitus and 2,3,7,8-tetrachlorodibenzo-p- dioxin elimination in veterans of Operation Ranch Hand. Journal of Toxicology and Environ- mental Health, Part A 66(3):211–221. Mills PK, Yang R. 2005. Breast cancer risk in Hispanic agricultural workers in California. Interna- tional Journal of Occupational and Environmental Health 11(2):123–131. Mills PK, Yang R, Riordan D. 2005. Lymphohematopoietic cancers in the United Farm Workers of America (UFW), 1988–2001. Cancer Causes and Control 16(7):823–830. 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. MRI (Midwest Research Institute). 1967. Assessment of Ecological Effects of Extensive or Repeated Use of Herbicides. MRI Project No. 3103-B. Kansas City, MO: MRI. NTIS AD-824-314. 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. NAS (National Academy of Sciences). 1974. The Effects of Herbicides in South Vietnam. Washington, DC: National Academy Press. Norström A, Rappe C, Lindahl R, Buser HR. 1979. Analysis of some older Scandinavian formulations of 2,4-dichlorophenoxy acetic acid for contents of chlorinated dibenzo-p-dioxins and dibenzo- furans. Scandanavian Journal of Work, Environment and Health 5:375–378. Oh E, Lee E, Im H, Kang HS, Jung WW, Won NH, Kim EM, Sul D. 2005. Evaluation of immuno- and reproductive toxicities and association between immunotoxicological and genotoxicological parameters in waste incineration workers. Toxicology 210(1):65–80. Ott MG, Zober A. 1996. Cause specific mortality and cancer incidence among employees exposure to 2,3,7,8-TCDD after a 1953 reactor accident. Occupational and Environmental Medicine 53:606–612. 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.

OCR for page 214
257 EXPOSURE ASSESSMENT 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 chromatography/high-resolution mass spectrometric analysis of human serum on a whole-weight and lipid basis for 2,3,7,8-TCDD. Analytical Chemistry 59:2000–2005. Pavuk M, Schecter AJ, Akhtar FZ, Michalek JE. 2003. Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) levels and thyroid function in Air Force veterans of the Vietnam War. Annals of Epi- demiology 13(5):335–343. Pavuk M, Michalek JE, Schecter A, Ketchum NS, Akhtar FZ, Fox KA. 2005. Did TCDD exposure or service in Southeast Asia increase the risk of cancer in Air Force Vietnam veterans who did not spray Agent Orange? Journal of Occupational and Environmental Medicine 47(4):335–342. Pavuk M, Michalek JE, Ketchum NS. 2006. Prostate cancer in US Air Force veterans of the Vietnam War. Journal of Exposure Science and Environmental Epidemiology 16(2):184–190. Petreas M, Smith D, Hurley S, Jeffrey SS, Gilliss D, Reynolds P. 2004. Distribution of persistent, lipid-soluble chemicals in breast and abdominal adipose tissues: Lessons learned from a breast cancer study. Cancer Epidemiology, Biomarkers and Prevention 13(3):416–424. Piacitelli LA, Marlow DA. 1997. NIOSH 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure matrix. Or- ganohalogen Compounds 33:510–514. Pless-Mulloli T, Edwards R, Howel D, Wood R, Paepke O, Herrmann T. 2005. Does long term resi- dency near industry have an impact on the body burden of polychlorinated dibenzo-p-dioxins, furans, and polychlorinated biphenyls in older women? Occupational and Environmental Medi- cine 62(12):895–901. Quadri SA, Qadri AN, Hahn ME, Mann KK, Sherr DH. 2000. The bioflavonoid galangin blocks aryl hydrocarbon receptor activation and polycyclic aromatic hydrocarbon-induced pre-B cell apoptosis. Molecular Pharmacology 58:515–525. Quandt SA, Hernandez-Valero MA, Grzywacz JG, Hovey JD, Gonzales M, Arcury TA. 2006. Work- place, household, and personal predictors of pesticide exposure for farmworkers. Environmental Health Perspectives 114(6):943–952. Ramlow JM, Spadacene NW, Hoag SR, Stafford BA, Cartmill JB, Lerner PJ. 1996. Mortality in a cohort of pentachlorophenol manufacturing workers, 1940–1989. American Journal of Indus- trial Medicine 30(2):180–194. Revich B, Aksel E, Ushakova T, Ivanova I, Zhuchenko N, Klyuev N, Brodsky B, Sotskov Y. 2001. Dioxin exposure and public health in Chapaevsk, Russia. Chemosphere 43:951–966. Rix BA, Villadsen E, Engholm G, Lynge E. 1998. Hodgkin’s disease, pharyngeal cancer, and soft tissue sarcomas in Danish paper mill workers. Journal of Occupational and Environmental Medicine 40(1):55–62. 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. Ruder AM, Waters MA, Butler MA, Carreon T, Calvert GM, Davis-King KE, Schulte PA, Sanderson WT, Ward EM, Connally LB, Heineman EF, Mandel JS, Morton RF, Reding DJ, Rosenman KD, Talaska G. 2004. Gliomas and farm pesticide exposure in men: The Upper Midwest Health Study. Archives of Environmental Health 59(12):650–657. Safe S. 1997–1998. Limitations of the toxic equivalency factor approach for risk assessment of TCDD and related compounds. Teratogenesis, Carcinogenesis, and Mutagenesis 17(4-5):285–304.

OCR for page 214
258 VETERANS AND AGENT ORANGE: UPDATE 2006 Samanic C, Hoppin JA, Lubin JH, Blair A, Alavanja MC. 2005. Factor analysis of pesticide use pat- terns among pesticide applicators in the Agricultural Health Study. Journal of Exposure Analysis and Environmental Epidemiology 15(3):225–233. 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. Savitz DA, Arbuckle T, Kaczor D, Curtis KM. 1997. Male pesticide exposure and pregnancy outcome. American Journal of Epidemiology 146(12):1025–1036. 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, Pavuk M, Constable JD, Dai LC, Papke O. 2002. A follow-up: High level of dioxin con- tamination in Vietnamese from Agent Orange, three decades after the end of spraying [letter]. Journal of Occupational and Environmental Medicine 44(3):218–220. Schecter A, Quynh HT, Papke O, Tung KC, Constable JD. 2006. Agent Orange, dioxins, and other chemicals of concern in Vietnam: Update 2006. Journal of Occupational and Environmental Medicine 48(4):408–413. Schneider AR, Stapleton HM, Cornwell J, Baker JE. 2001. Recent declines in PAH, PCB, and toxa- phene levels in the northern Great Lakes as determined from high resolution sediment cores. Environmental Science and Technology 35:3809–3815. 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-tetrachlo- rodibenzo-p-dioxin levels of New Zealand pesticide applicators and their implication for cancer hypotheses. Journal of the National Cancer Institute 84:104–108. 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. Steenland K, Piacitelli L, Deddens J, Fingerhut M, Chang LI. 1999. Cancer, heart disease, and diabe- tes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of the National Cancer Institute 91(9):779–786. Steenland K, Deddens J, Piacitelli L. 2001. Risk assessment for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on an epidemiologic study. American Journal of Epidemiology 154:451–458. Stellman JM, Stellman SD. 2003. Contractor’s Final Report: Characterizing Exposure of Veterans to Agent Orange and Other Herbicides in Vietnam. Submitted to the National Academy of Sci- ences, Institute of Medicine in fulfillment of Subcontract VA-5124-98-0019, June 30, 2003. Stellman JM, Stellman SD, Christian R, Weber T, Tomasallo C. 2003a. The extent and patterns of usage of Agent Orange and other herbicides in Vietnam. Nature 422:681–687. Stellman JM, Stellman SD, Weber T, Tomasallo C, Stellman AB, Christian R. 2003b. A geographic information system for characterizing exposure to Agent Orange and other herbicides in Viet- nam. Environmental Health Perspectives 111:321–328. 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 SD, Stellman JM. 2004. Exposure opportunity models for Agent Orange, dioxin, and other military herbicides used in Vietnam, 1961–1971. Journal of Exposure Analysis and Environ- mental Epidemiology 14:354–362. Swaen GMH, van Vliet C, Slangen JJM, Sturmans F. 1992. Cancer mortality among licensed herbi- cide applicators. Scandinavian Journal of Work, Environment and Health 18:201–204.

OCR for page 214
259 EXPOSURE ASSESSMENT Sweeney MH, Fingerhut MA, Connally LB, Halperin WE, Moody PL, Marlow DA. 1989. Progress of the NIOSH cross-sectional medical study of workers occupationally exposed to chemicals contaminated with 2,3,7,8-TCDD. Chemosphere 19:973–977. Sweeney MH, Fingerhut MA, Arezzo JC, Hornung RW, Connally LB. 1993. Peripheral neuropathy after occupational exposure to 2,3,7,8-tertachlorodibenzo-p-dioxin (TCDD). American Journal of Industrial Medicine 23:845–858. ’t Mannetje A, McLean D, Cheng S, Boffetta P, Colin D, Pearce N. 2005. Mortality in New Zealand workers exposed to phenoxy herbicides and dioxins. Occupational and Environmental Medicine 62(1):34–40. ten Tusscher GW, Stam GA, Koppe JG. 2000. Open chemical combustions resulting in a local in- creased incidence of orofacial clefts. Chemosphere 40(9-11):1263–1270. Teschke K, Hertzman C, Morrison B. 1994. Level and distribution of employee exposures to total and respirable wood dust in two Canadian sawmills. American Industrial Hygiene Association Journal 55(3):245–250. Thomas TL, Kang HK. 1990. Mortality and morbidity among Army Chemical Corps Vietnam veter- ans: A preliminary report. American Journal of Industrial Medicine 18:665–673. Thomaseth K, Salvan A. 1998. Estimation of occupational exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin using a minimal physiologic toxicokinetic model. Environmental Health Perspectives 106(Suppl 2):742–753. US GAO (US General Accounting Office). 1979. US Ground Troops in South Vietnam Were in Areas Sprayed with Herbicide Orange. Report by the Comptroller General of the United States, FPCD 80 23. Washington, DC: GAO. Van den Berg M, Birnbaum LS, Denison M, De Vito M, Farland W, Feeley M, Fiedler H, Hakansson H, Hanberg A, Haws L, Rose M, Safe S, Schrenk D, Tohyama C, Tritscher A, Tuomisto J, Tysklind M, Walker N, Peterson RE. 2006. The 2005 World Health Organization Reevaluation of human and mammalian toxic equivalency factors for dioxin and dioxin-like compounds. Toxicological Sciences 93(2):223–241. Van Wijngaarden E, Stewart PA, Olshan AF, Savitz DA, Bunin GR. 2003. Parental occupational exposure to pesticides and childhood brain cancer. American Journal of Epidemiology 157(11): 989–997. Viel JF, Arveux P, Baverel J, Cahn JY. 2000. Soft-tissue sarcoma and non-Hodgkin’s lymphoma clusters around a municipal solid waste incinerator with high dioxin emission levels. American Journal of Epidemiology 152(1):13–19. 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. Warner M, Samuels S, Mocarelli P, Gerthoux PM, Needham L, Patterson DG Jr, Eskenazi B. 2004. Serum dioxin concentrations and age at menarche. Environmental Health Perspectives 112(13):1289–1292. Warner M, Eskenazi B, Patterson DG Jr, Clark G, Turner WE, Bonsignore L, Mocarelli P, Gerthoux PM. 2005. Dioxin-like TEQ of women from the Seveso, Italy area by ID-HRGC/HRMS and CALUX. Journal of Exposure Analysis and Environmental Epidemiology 15(4):310–318. Warren WF. 1968. A Review of the Herbicide Program in South Vietnam. San Francisco, CA: Scien- tific Advisory Group. Working Paper No. 10-68. NTIS AD-779-797. Weiss J, Papke O, Bignert A, Jensen S, Greyerz E, Agostoni C, Besana R, Riva E, Giovannini M, Zetterstrom R. 2003. Concentrations of dioxins and other organochlorines (PCBs, DDTs, HCHs) in human milk from Seveso, Milan and a Lombardian rural area in Italy: A study performed 25 years after the heavy dioxin exposure in Seveso. Acta Paediatrica 92(4):467–472.

OCR for page 214
260 VETERANS AND AGENT ORANGE: UPDATE 2006 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 applica- tors. Journal of Occupational Medicine 30:801–804. 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. Yoshida J, Kumagai S, Tabuchi T, Kosaka H, Akasaka S, Kasai H, Oda H. 2006. Negative association between serum dioxin level and oxidative DNA damage markers in municipal waste incinerator workers. International Archives of Occupational and Environmental Health 79(2):115–122. Young AL. 1992. The Military Use of Herbicides in Vietnam. Presentation to the Institute of Medi- cine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. December 8, 1992. Washington, DC. Young AL. 2004. TCDD biomonitoring and exposure to Agent Orange: Still the gold standard. Envi- ronmental Science and Pollution Research 11(3):143–146. Young AL, Newton M. 2004. Long overlooked historical information on Agent Orange and TCDD following massive applications of 2,4,5-T-containing herbicides, Eglin Air Force Base, Florida. Environmental Science and Pollution Research 11(4):209–221. Young AL, Reggiani GM, eds. 1988. Agent Orange and Its Associated Dioxin: Assessment of a Con- troversy. Amsterdam, The Netherlands: Elsevier. Young AL, Thalken CE, Arnold EL, Cupello JM, Cockerham LG. 1976. Fate of 2,3,7,8 Tetrachloro- dibenzo-p-dioxin (TCDD) in the Environment: Summary and Decontamination Recommenda- tions. Colorado Springs: US Air Force Academy. USAFA TR 76 18. Young AL, Calcagni JA, Thalken CE, Tremblay JW. 1978. The Toxicology, Environmental Fate, and Human Risk of Herbicide Orange and Its Associated Dioxin. Brooks AFB, TX: Air Force Oc- cupational and Environmental Health Lab. USAF OEHL TR 78 92. Young AL, Cecil PF Sr, Guilmartin JF Jr. 2004a. Assessing possible exposures of ground troops to Agent Orange during the Vietnam War: The use of contemporary military records. Environ- mental Science and Pollution Research 11(6):349–358. Young AL, Giesy JP, Jones P, Newton M, Guilmartin JF Jr, Cecil PF Sr. 2004b. Assessment of poten- tial exposure to Agent Orange and its associated TCDD. Environmental Science and Pollution Research 11(6):347–348. 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 ex- posed to 2,3,7,8-TCDD after the 1953 accident. International Archives of Occupational and Environmental Health 62(2):139–157.