Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
5 Exposure Assessment Assessment of human exposure to four speciï¬c 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 speciï¬c 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 militaryâs 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 quantiï¬cation 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
EXPOSURE ASSESSMENT 215 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 deï¬ned period. Exposure can occur through inhalation, skin con- tact, and ingestion. Exposure also can be assessed by measuring the compounds of interestâor their metabolitesâin 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 classiï¬cation offers simplicity and ease of interpretation. A more reï¬ned 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 doseâresponse 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 difï¬cult to deï¬ne 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 deï¬ned 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 âinternal exposureâ for years, even if exposure from the environment has ceased. Deï¬ning 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 jobâexposure 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.
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 Womenâs 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 Jobâexposure 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
EXPOSURE ASSESSMENT 217 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 difï¬cult to use this type of information to classify the exposures of individuals with conï¬dence. Such assessments can be reï¬ned 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 veteransâ 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 speciï¬c sources (Pless-Mulloli et al., 2005) sug- gest that the proï¬les are not sufï¬ciently distinct to permit discrimination from general urban background exposure. Exposure Misclassiï¬cation Exposure misclassiï¬cation in epidemiologic studies can affect estimates of risk. A typical situation is a caseâcontrol study in which the reported measure- ment of exposure can be misclassiï¬ed for either or both groups. The simplest situation to consider is classiï¬cation of exposure into just two levels, for example ever or never exposed. If the probability of exposure misclassiï¬cation 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 misclassiï¬cation
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 classiï¬ed into more than two levels is some- what more complicated. Dosemeci et al. (1990) have demonstrated that for this situation, the slope of a doseâresponse trend is not necessarily attenuated towards the null value, even if the probability of misclassiï¬cation 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 misclassiï¬cation typically are unknown at the start of the study. If one had perfect knowledge of the misclassiï¬cation probabilities, statisti- cal adjustment still will not necessarily lead to a result that is more signiï¬cant than the unadjusted analysis, even if the misclassiï¬cation probabilities are non- differential between the comparison groups. Analyses in which adjustments have been made for exposure misclassiï¬cation 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 misclassiï¬cation from the study data themselves. Finally, it is important to consider the effect of exposure misclassiï¬cation on the statistical signiï¬cance of the result. Greenland and Gustafson (2006) have shown that if one adjusts for exposure misclassiï¬cation when the exposure is represented as binary (e.g., ever and never exposed), the resulting association is not necessarily more signiï¬cant 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 identiï¬ed as an important component of the exposure. We took this approach for two reasons. First, exposure of Vietnam veterans to signiï¬cant amounts of these other compounds, as compared to exposure to TCDD, has not been documented. Second, the most important mechanism for TCDD toxicity
EXPOSURE ASSESSMENT 219 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 difï¬cult to attribute toxic effects from such exposures to TCDD. Exposure to mixtures of dioxin-like compounds presents a particularly dif- ï¬cult 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 speciï¬c 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 scientiï¬c 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 ï¬avonoids 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, 1997â1998). 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 difï¬culties of interpreting exposures to chemical mixtures relative to the exposure of veterans to Agent Orange and other herbicides in Vietnam, the committeeâs 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 inï¬uenced by local differences in speciï¬c sources.
220 VETERANS AND AGENT ORANGE: UPDATE 2006 Exposure Speciï¬city 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 scientiï¬c studies reviewed by the committee have reported exposures to broad categories of chemicals rather than to these speciï¬c compounds. These categories are presented in Table 5-2, along with their relevance to the committeeâs charge. The information in Table 5-2 represents the current committeeâs 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 speciï¬city. A large number of studies have examined the relationship between exposure to âpesticidesâ and adverse health outcomes, while others have used the category of âherbicidesâ without identifying speciï¬c compounds. A careful reading of a scientiï¬c 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 deï¬ne exposure in the broad category of âpesticidesâ with no further information have little relevance to the committeeâs charge to determine associations between exposures to herbicides used in Vietnam and adverse health outcomes. Reports TABLE 5-2 Current Committee Guidance for the Classiï¬cation of Exposure Information in Epidemiologic Studies That Focus on the Use of Pesticides or Herbicides, and Relevance of the Information to the Committeeâs Charge to Evaluate Exposures to 2,4-D, 2,4,5-T (phenoxy herbicides), Cacodylic Acid, and Picloram* Relevance to Speciï¬city of Exposure Committeeâs 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 speciï¬ed exposure to cacodylic acid or picloram.
EXPOSURE ASSESSMENT 221 that deï¬ne exposure in the more restricted category of âherbicidesâ 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) identiï¬ed in the study; the chemicals of interest are used commonly for a speciï¬c purpose, such as removal of weeds and shrubs along highways). Among the various chemical classes of herbicides that have been identiï¬ed 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- speciï¬ed pesticides for the neurologic health effects section of this report; their results have been entered in the corresponding outcome-speciï¬c tables. However, such studies tend to contribute little to the evidence considered by the committee. The many studies that provide chemical-speciï¬c exposure information are far more informative for the committeeâs 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 identiï¬ed do not possess the toxicity of TCDD (ATSDR, 1998; Huston, 1972; NorstrÃ¶m 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- ï¬ed to minimize contamination, but use of the products most subject to containing speciï¬cally 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
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 identiï¬ed 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 conï¬rmed by measuring serum TCDD in 253 cohort members. Duration of exposure was deï¬ned 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 efï¬cient 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 deï¬ned 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 reï¬ned exposure assessment was conducted. Workers whose records were inadequate to determine duration of exposure were excluded. The ï¬nal 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
EXPOSURE ASSESSMENT 223 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 speciï¬c process, and a qualitative contact value (0.01â1.5) 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 misclassiï¬cation (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 exposureâresponse analysis from data on workers at one of the original 12 companies in the cohort study. A group of 170 workers was identiï¬ed 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 deï¬ned in 1999. Crump et al. (2003) conducted a meta-analysis of dioxin doseâresponse 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 ï¬t to serum sampling data than ï¬rst-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,
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 classiï¬ed 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 classiï¬ed as âexposure unknown.â 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 classiï¬ed 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 cohortâyears since ï¬rst exposure, duration of exposure (in years), year of ï¬rst exposure, and job titleâbut 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
EXPOSURE ASSESSMENT 225 and furans (PCDD/Fs). The authors estimated maximum PCDD/F exposure for 190 workers using a ï¬rst-order kinetics model, half-lives from an elimination study in 48 workers from this cohort, and background concentrations for the German population. The authors then regressed the estimated maximum PCDD/F exposures of the workers against the length of time they worked in each produc- tion department in the plant. The working-time weights were then used with work histories for the remainder of the cohort to estimate PCDD/F exposure for each member at the end of that personâs exposure. These values were then used to estimate TCDD doses in the population. Becher et al. (1996) conducted an analysis of several German cohorts, in- cluding the BoehringerâIngelheim cohort described above (Kogevinas et al., 1997), a cohort from the BASF Ludwigshafen plant that did not include those involved in a 1953 accident, and cohorts from a Bayer plant in Uerdingen and a Bayer plant in Dormagen. All the plants were involved in production of phenoxy herbicides or chlorophenols. Exposure assessment involved estimates of dura- tion of employment from the start of work in a department where exposure was possible until the end of employment at the plant. Analysis was based on time since ï¬rst exposure. Hooiveld et al. (1998) updated the mortality experience of production work- ers from two chemical factories in the Netherlands with known exposure to dioxins: workers in herbicide production, non-exposed production workers, and workers known to have been exposed as a result of an accident that occurred in 1963. Assuming ï¬rst-order TCDD elimination with an estimated half-life of 7.1 years, measured TCDD levels were extrapolated to the time of maximum TCDD exposure for a group of 47 workers. A regression model then estimated the effect on estimated maximum TCDD exposure for each cohort member attributable to exposure as a result of the accident, duration of employment in the main produc- tion department, and time of ï¬rst exposure before (or after) 1970. Since Update 2004, a follow-up study on the mortality experience of the small subcohort of the IARC cohort from New Zealand has been published (ât Mannetje et al., 2005). No direct data on levels of exposure were available for either the production workers or the herbicide sprayers. Exposure categories for production workers were based on job codes, while estimates for sprayers were based on exposure history questionnaires. Dow Cohort Studies Workers at Dow Chemical Company facilities where 2,4-D was manufac- tured, formulated, or packaged have been the focus of a cohort analysis since the 1980s (Bond et al., 1988). Industrial hygienists developed a JEM that ranked employee exposures as low, moderate, or high on the basis of available air- monitoring data and professional judgment. That matrix was merged with em- ployee work histories to assign an estimate of exposure to each job assignment. A
226 VETERANS AND AGENT ORANGE: UPDATE 2006 cumulative dose was then developed for each of the 878 employees by multiply- ing the representative eight-hour time-weighted average (TWA) exposure value for each job assignment by the number of years in the job and then adding those products for all jobs. A 2,4-D TWA of 0.05 mg/m3 was used for low, 0.5 mg/m3 for moderate, and 5 mg/m3 for high exposure. The role of dermal exposure in the facilities does not appear to have been considered in the exposure estimates. It is not clear to what extent the use of air measurements alone can provide accurate classiï¬cation of workers into low-, moderate-, and high-exposure groups. Bio- logic monitoring of 2,4-D apparently was not included in this study. Follow-up reports were published in 1993 (Bloemen et al., 1993) and most recently in 2001 (Burns et al., 2001); neither of those studies modiï¬ed the exposure assessment procedures of the original study. Bodner et al. (2003) reported new risk estimates for cancer, using the same assessments. Dow also has conducted a cohort study of its manufacturing workers exposed to PCP (Ramlow et al., 1996). Assessment of exposure for this cohort was based on consideration of the available industrial-hygiene and process data, including process and job-description information obtained from employees, process and engineering-control change information, industrial-hygiene surface-wipe sample data, area exposure monitoring, and personal breathing-zone data. Jobs with higher estimated potential exposure involved primarily dermal exposure to air- borne PCP in the ï¬akingâprillingâpackaging area; the industrial-hygiene data suggested about a 3-fold difference between the areas of highest to lowest poten- tial exposure. All jobs were therefore assigned an estimated exposure intensity score on a scale of 1â3 (from lowest to highest potential exposure intensity). Reliable information concerning the use of personal protective equipment was not available. Cumulative PCP and TCDD exposure indices were calculated for each subject by multiplying the duration of each exposed job by its estimated exposure intensity and then summing across all exposed jobs. Since Update 2004, Dow researchers have published a study of serum dioxin levels measured in 2002 in former chlorophenol workers (Collins et al., 2006). Most of the workers in this study were included in the NIOSH and IARC cohorts. The authors used these data to estimate worker exposures at the time of exposure termination using several different pharmacokinetic models. They concluded that their ï¬ndings were consistent with other studies reporting high serum dioxin levels among chlorophenol workers after occupational exposures. Waste Incineration Worker Studies Four studies of waste incineration workers have been published recently. A study of infectious waste incineration plant workers in Japan used serum dioxin levels to document higher exposures of workers than of controls (Kumagai and Koda, 2005). A second study in Japan examined the association between serum dioxin levels and oxidative DNA-damage markers in municipal waste incinera- tion workers (Yoshida et al., 2006).
EXPOSURE ASSESSMENT 227 Researchers in South Korea compared plasma protein levels for 31 waste incineration workers with those of 33 unexposed subjects (Kang et al., 2005). A second Korean study evaluated immunologic and reproductive toxicities in 31 waste-incinerator workers in comparison to 84 control subjects (Oh et al., 2005). Rather than measuring serum dioxin levels, both studies inferred dioxin exposure levels for individual workers on the basis of dioxin concentrations in air and also estimated exposures to PAHs by analyzing two urinary metabolites: 1-hydroxypyrene and 2-napthol. Other Production-Worker Studies Several other studies of chemical production workers have relied on job titles as recorded in individual work histories and company personnel records to clas- sify exposure to TCDD (Coggon et al., 1986, 1991; Cook et al., 1986; Ott et al., 1980; Zack and Gaffey, 1983; Zober et al., 1990). Similarly, TCDD exposure of chemical-plant workers has been characterized by worker involvement in various production processes, such as synthesis, packaging, waste removal, shipping, and plant supervision (Bueno de Mesquita et al., 1993; Garaj-Vrhovac and Zeljezic, 2002; Manz et al., 1991). Since Update 2004, no additional studies of other cohorts of production workers have been published. Agriculture, Forestry, and Other Outdoor Work In occupational studies of agricultural workers various methods have been used to estimate exposure to herbicides or TCDD. The simplest method derives data from death certiï¬cates, cancer registries, or hospital records (Burmeister, 1981). Although such information is relatively easy to obtain, it cannot be used to estimate duration or intensity of exposure or to determine whether a worker was exposed to a speciï¬c agent. In some studies of agricultural workers, examina- tion of differences in occupational practices has allowed identiï¬cation of subsets of workers who were likely to have had higher exposures (Hansen et al., 1992; Musicco et al., 1988; Ronco et al., 1992; Vineis et al., 1986; Wiklund and Holm, 1986; Wilklund et al., 1988a). In other studies, county of residence was used as a surrogate for exposure, relying on agricultural censuses of farm production and chemical use to characterize exposure in individual counties (Blair and White, 1985; Cantor, 1982; Gordon and Shy, 1981). In other studies, exposure was estimated according to the number of years employed in a speciï¬c occupation as a surrogate for exposure duration, using supplier records of pesticide sales to estimate exposure or estimating acreage sprayed to determine the amount used (Morrison et al., 1992; Wigle et al., 1990). Other studies used self-reported infor- mation on exposure that recounted direct handling of an herbicide, whether it was applied by tractor or hand-held sprayer, and what type of protective equipment or safety precautions were used (Hoar et al., 1986; Zahm et al., 1990). Another set
228 VETERANS AND AGENT ORANGE: UPDATE 2006 of studies validated self-reported information with written records, signed state- ments, or telephone interviews with co-workers or former employers (Carmelli et al., 1981; Woods and Polissar, 1989). Forestry and other outdoor workers, such as highway-maintenance work- ers, are likely to have been exposed to herbicides and other compounds (see Table C-1 in Appendix C for a summary of studies). Exposure of those groups has been classiï¬ed by approaches similar to those noted above for agricultural workers, for example, by using the number of years employed, job category, and occupational title. Ontario Farm Family Health Study The Ontario Farm Family Health Study has produced several reports on exposure to phenoxyacetic acid herbicides, including 2,4-D. A study of male pesticide exposure and pregnancy outcome (Savitz et al., 1997) developed an exposure metric based on self-reports of mixing or application of crop herbicides, crop insecticides, and fungicides; livestock chemicals; yard herbicides; and build- ing pesticides. Subjects were asked whether they participated in those activities during each month, and their exposure classiï¬cations were based on activities in 3-month periods. The exposure classiï¬cation was reï¬ned with answers to ques- tions regarding use of protective equipment and speciï¬city of pesticide use. A related study included analysis of 2,4-D residues in semen as a biologic marker of exposure (Arbuckle et al., 1999a). The study began with 773 potential participants, but only 215 eventually consented to the study. Of the 215, 97 pro- vided semen and urine samples for 2,4-D analysis. The Ontario Farm Family Health Study also examined the effect of exposure to pesticides, including 2,4-D, on time to pregnancy (Curtis et al., 1999) and on the risk of spontaneous abortion (Arbuckle et al., 1999b, 2001). About 2,000 farm couples participated in the study. Exposure information was pooled from inter- views with husbands and wives to construct a history of monthly agricultural and residential pesticide use. Exposure classiï¬cation was based on a yesâno response for each month. Data on such variables as acreage sprayed and use of protective equipment were collected but were not available in all cases. More recent studies have used herbicide biomonitoring in a subset of the population to evaluate the validity of self-reported predictors of exposure (Arbuckle et al., 2002). Assum- ing that the presence of 2,4-D in urine was an accurate measure of exposure and that the results of the questionnaire indicating 2,4-D use were more likely to be subject to exposure classiï¬cation error (that is, the questionnaire results were less accurate than was the urine analysis), the questionnaireâs prediction of exposure, when compared with the urine 2,4-D concentrations, had a sensitivity of 57 per- cent and a speciï¬city of 86 percent. In multivariate models, the variables for pes- ticide formulation, protective clothing and gear, application equipment, handling practice, and personal-hygiene practice were valuable as predictors of urinary herbicide concentrations in the ï¬rst 24 hours after application was initiated.
EXPOSURE ASSESSMENT 229 Since Update 2004, three additional publications have reported results from the Ontario Farm Family Health Study. Urinary concentrations of 2,4-D and 2-methyl-4-chlorophenoxyacetic acid (MCPA) were measured in samples from farm applicators (Arbuckle et al., 2005) and for women living on Ontario farms (Arbuckle and Ritter, 2005). Indirect sources of herbicide exposure for farm families were evaluated through wipe sampling of surfaces and drinking water samples (Arbuckle et al., 2006). The Agricultural Health Study The Agricultural Health Study (AHS) in the United States enrolled approxi- mately 58,000 commercial and private pesticide applicators in two states (Iowa and North Carolina) between 1993 and 1997 (Alavanja et al., 1994). Exposure assessment in this study has been based primarily on questionnaire data collected at the time of enrollment and in periodic follow-ups. Dosemeci et al. (2002) pub- lished an algorithm designed to better characterize personal exposures for that population. Weighting factors for key exposure variables were developed from the literature on pesticide exposure. This quantitative approach has potential to improve the accuracy of exposure classiï¬cation for the cohort, but has not yet been used in published epidemiologic studies. Since Update 2004, eight epidemiologic studies have been published on the AHS cohort. All have developed pesticide exposure estimates or exposure categories from self-administered questionnaires (Alavanja et al., 2004, 2005; Blair et al., 2005; De Roos et al., 2005; Engel et al., 2005; Farr et al., 2004, 2006; Kirrane et al., 2005). Three additional publications discuss pesticide use patterns in this population (Hoppin, 2005; Kirrane et al., 2004; Samanic et al., 2005). The AHS questionnaire collected detailed information regarding herbicide use, with 2,4-D being the most commonly reported herbicide. United Farm Workers of America (UFW) Population Studies California researchers evaluated breast cancer risk (Mills and Yang, 2005) and lymphohematopoietic cancer risk (Mills et al., 2005) in members of the United Farm Workers of America (UFW). The exposed populations were deï¬ned as those who had ever been a UFW member. Exposure estimates to speciï¬c pesti- cides, including 2,4-D, were developed through linkage of job histories with the California Pesticide Use Reporting Database. Other Agricultural Worker Studies A study of Canadian farmers examined pesticide exposures of men (McDufï¬e et al., 2001). Data were collected by questionnaires that included information on speciï¬c chemicals (including 2,4-D), frequency of application, and dura- tion of exposure. A small validation study (n 27) was performed to test the
230 VETERANS AND AGENT ORANGE: UPDATE 2006 self-reported pesticide-use data against records of purchases. The investigators reported an âexcellent concordanceâ between the two sources, but they did not provide a statistical analysis. Ruder et al. (2004) and Carreon et al. (2005) evaluated farm pesticide ex- posure in men and women, respectively, in relation to the incidence of gilomas as part of the Upper Midwest Health Study. Self-reported lifetime agricultural pesticide exposures were collected by telephone interview, including speciï¬c questions on phenoxy herbicides and 2,4-D. Mandel et al. (2005) reported urinary biomonitoring results for farm families in Minnesota and South Carolina as a part of the CropLife Americaâs Farm Fam- ily Pesticide Exposure Study. The peak geometric mean concentration of 2,4-D was 64 ppb. Lee et al. (2004) used a telephone interview of cases and control or their next-of-kin in a Nebraska study to determine the extent of agricultural use of pesticides, including 2,4,5-T and 2,4-D. Fritschi et al. (2005) used a computer- assisted telephone interview and occupational histories reviewed by an industrial hygienist to estimate exposures to phenoxy herbicides in an Australian study. Cur- win et al. (2005) measured 2,4-D concentrations in urine and hand-wipe samples to characterize exposures among farmers and non-farmers in Iowa. Other studies of the agricultural use of pesticides do not provide speciï¬c information on exposure to 2,4-D, TCDD, or other compounds relevant to Viet- nam veteransâ exposure (Bell et al., 2001a,b; Chiu et al., 2004; Duell et al., 2001; Garry et al., 2003; Gorell et al., 2004; Hanke et al., 2003; Van Wijngaarden et al., 2003). A series of papers from a recent workshop focused on methods of assessing pesticide exposure in farmworker populations (Arcury et al., 2006; Barr et al., 2006a,b; Hoppin et al., 2006; Quandt et al., 2006). These publications provide a helpful review of current methodological issues in exposure science for these populations, but do not address directly the VAO compounds of interest. Commercial Herbicide Sprayers Studies of commercial herbicide applicators are relevant because they can be presumed to have had sustained exposure to herbicides. However, because they also are likely to be exposed to a variety of compounds, assessment of individual or group exposure to speciï¬c phenoxy herbicides or TCDD is complicated. Some studies have attempted to measure applicatorsâ exposure on the basis of information from work records on acreage sprayed or on the number of days of spraying. Employment records also can be used to extract information on which compounds are sprayed. One surrogate indicator of herbicide exposure is the receipt of a license to spray. Several studies have speciï¬cally identiï¬ed licensed or registered pesticide and herbicide applicators (Blair et al., 1983; Smith et al., 1981, 1982; Swaen
EXPOSURE ASSESSMENT 231 et al., 1992; Wiklund et al., 1988b, 1989). Individual estimates of the intensity and frequency of exposure were rarely quantiï¬ed in the studies that the commit- tee examined, however, and many applicators were known to have applied many kinds of herbicides, pesticides, and other substances. In addition, herbicide spray- ing is generally a seasonal occupation, and information is not always available on possible exposure-related activities during the rest of the year. Several studies have evaluated various herbicide exposures: type of exposure, routes of entry, and routes of excretion (Ferry et al., 1982; Frank et al., 1985; Kolmodin-Hedman and Erne, 1980; Kolmodin-Hedman et al., 1983; Lavy et al., 1980a,b; Libich et al., 1984). Those studies appear to show that the major route of exposure is dermal absorption, with 2â4 percent of the chemical that contacts the skin being absorbed into the body during a normal workday. Air concentra- tions of the herbicides were usually less than 0.2 mg/m3. Absorbed phenoxy acid herbicides are virtually cleared within 1 day, primarily through urinary excretion. Typical measured excretion in ground crews was 0.1â5 mg/day; for air crews the value was lower. A study of 98 professional turf sprayers in Canada developed new models to predict 2,4-D dose (Harris et al., 2001). Exposure information was gathered from self-administered questionnaires. Urine samples were collected throughout the spraying season (24-hour samples on 2 consecutive days). Estimated 2,4-D doses were developed from the data and used to evaluate the effect of protective clothing and other exposure variables. Only one study has provided information on serum TCDD concentrations in herbicide applicators. Smith et al. (1992) analyzed blood from nine professional spray applicators in New Zealand who ï¬rst sprayed before 1960 and were also spraying in 1984. The duration of spraying varied from 80 to 370 months. Serum TCDD was 3â131 ppt on a lipid basis (mean 53 ppt). The corresponding val- ues for age-matched controls were 2â11 ppt (mean 6 ppt). Serum TCDD was positively correlated with the number of months of professional spraying. Since Update 2004, another study of New Zealand herbicide sprayers was published (ât Mannetje et al., 2005). This study population also included herbicide production workers and is a subcohort of the IARC cohort, which was discussed earlier in the section on production workers. Pulp, Paper, and Sawmill Work Pulp, paper, and sawmill workers are likely to be exposed to TCDD and chlo- rinated phenols occurring during the bleaching process. Depending on the type of paper mill or pulping operation and the product manufactured, pulp and paper production workers are also likely to be exposed to toxic compounds in addition to those of concern for the VAO series (Henneberger et al., 1989; Jappinen and Pukkala, 1991; Robinson et al., 1986; Solet et al., 1989). One study of a cohort of Danish paper mill workers (Rix et al., 1998) presented no direct measures of oc-
232 VETERANS AND AGENT ORANGE: UPDATE 2006 cupational exposure, and the qualitative assessment of compounds used by each department did not include chlorinated organic compounds, although chlorine, chlorine dioxide, and hypochlorite were used. In the past, workers in sawmills might have been exposed to pentachloro- phenates, which are contaminated with higher-chlorinated PCDDs (Cl6âCl8), or to tetrachlorophenates, which are less contaminated with higher-chlorinated PCDDs. Wood is dipped into those chemical preservatives and then cut and planed in the mills. Most exposure is dermal, although some exposure can occur by inhalation (Hertzmann et al., 1997; Teschke et al., 1994). No new studies in those populations have been reported since Update 2000. ENVIRONMENTAL EXPOSURES TO HERBICIDES AND TCDD The committee reviewed several new studies of TCDD-exposed populations associated with industrial facilities, including recent investigations at Seveso, Italy. The committee also reviewed exposure studies related to Agent Orange use in Vietnam. Industrial Sources Seveso, Italy A large industrial accident involving environmental exposure to TCDD oc- curred in Seveso in July 1976 as the result of an uncontrolled reaction during trichlorophenol production. Various indicators, including TCDD measurements in soil, have been used as indicators of individual exposure. Three areas were deï¬ned around the release point on the basis of soil sampling for TCDD (Bertazzi et al., 1989). Zone A was the most heavily contaminated; all residents were evacuated within 20 days. Zone B was less contaminated; women in the ï¬rst tri- mester and all children were urged to avoid it during daytime. Zone R had some contamination; consumption of crops grown there was prohibited. Data on serum TCDD concentrations in Zone A residents have been pre- sented by Mocarelli et al. (1990, 1991) and by CDC (1988a). In those with severe chloracne (n 10), TCDD was 828â56,000 ppt of lipid weight. Those without chloracne (n 10) had TCDD 1,770â10,400 ppt. TCDD was undetectable in all control subjects but one. The highest of those concentrations exceeded any that had been estimated at the time for TCDD-exposed workers on the basis of back- ward extrapolation and a half-life of 7 years. Data on nearby soil concentrations, number of days a person stayed in Zone A, and whether local food was consumed were considered in evaluating TCDD. That none of those data correlated with serum TCDD suggested strongly that the exposure of importance was from fallout on the day of the accident. The presence and degree of chloracne did correlate with TCDD. Adults seemed much less likely than children to develop chloracne after acute exposure, but surveillance bias could have affected that ï¬nding. Recent
EXPOSURE ASSESSMENT 233 updates (Bertazzi et al., 1998, 2001) have not changed the exposure-assessment approach. As part of the Seveso Womenâs Health Study (SWHS), Eskenazi et al. (2001) tested the validity of exposure classiï¬cation by zone. Investigators measured se- rum TCDD in samples collected between 1976 and 1980 from 601 residents (97 from Zone A; 504 from Zone B). A questionnaire the women completed between 1996 and 1998 included age, chloracne history, animal mortality, consumption of homegrown food, and location at the time of the explosion. Participants did not know their TCDD concentrations at the time of the interview, although most knew their zone of residence. Interviewers and TCDD analysts were blinded to participantsâ zone of residence. Zone of residence explained 24 percent of the variability in serum TCDD. Addition of the questionnaire data improved the regression model, explaining 42 percent of the variance. Those ï¬ndings dem- onstrate a signiï¬cant association between zone of residence and serum TCDD, but much of the variability in TCDD concentrations is still unexplained by the models. A number of studies of the Seveso population have used lipid-adjusted serum TCDD concentrations as the primary exposure metric (Baccarelli et al., 2002; Eskenazi et al., 2002a,b, 2003, 2004; Landi et al., 2003). Fattore et al. (2003) measured current air concentrations of PCDDs in Zones A and B, and compared them with measurements from a control area near Milan. The authors concluded that release from PCDD-contaminated soil does not add appreciably to air con- centrations in the Seveso study area. Finally, Weiss et al. (2003) collected breast milk from 12 mothers in Seveso to compare TCDD concentrations with those from a control population near Milan. The investigators reported that the TCDD concentrations in human milk from mothers in Seveso were two times higher than were those in controls. The authors concluded that breastfed children in the Seveso area are likely to have higher body burdens of TCDD than are children from other areas. Since Update 2004, ï¬ve reports have been published on dioxin exposure in the Seveso population. Baccarelli et al. (2005a) used serum TCDD concentrations to evaluate chloracne cases. Bacarelli et al. (2005b) reviewed statistical strate- gies for handing non-detectable readings in dioxin measurement datasets. They recommended that a distribution-based multiple imputation method be used to analyze environmental data when substantial proportions of observations have non-detectable readings. In the SWHS, Warner et al. (2004) used serum dioxin concentrations to evaluate effects on age at menarche, while Eskanazi et al. (2005) used serum dioxin concentrations to evaluate effects on age at the onset of menopause. Warner et al. (2005) compared a chemical-activated luciferase-gene expression bioassay to an isotope dilution high-resolution gas chromatography/ high-resolution mass spectrometry assay to measure dioxin-like toxicity equiva- lents for 78 women residing near Seveso, and found similar results from the two methods.
234 VETERANS AND AGENT ORANGE: UPDATE 2006 Chapaevsk, Russia Researchers in the Samara region of Russia have identiï¬ed a chemical plant in Chapaevsk as a major source of TCDD pollution (Revich et al., 2001). From 1967 to 1987 the plant produced -hexachlorocyclohexane (lindane) and its derivatives. Since then, the plant has produced various crop-protection products. Dioxins have been detected in air, soil, drinking water, and cowsâ milk. However, the researchers do not describe air-, soil-, or water-sampling methods. The num- ber of samples analyzed was small for some media (2 drinking-water samples, 7 breast-milk samples pooled from 40 women, and 14 blood samples) and unre- ported for others (air, soil, and vegetables). Results from the samples suggested higher concentrations of dioxin around the center of Chapaevsk compared with those from outlying areas. That conclusion was based primarily on concentrations measured in soil: 141 ng TEQ/kg soil less than 2 km from the plant, compared with 37 ng TEQ/kg soil 2â7 km from the plant, and 4 ng TEQ/kg soil 7â10 km from the plant. Concentrations outside the city (10â15 km from the plant) were approximately 1 ng TEQ/kg soil. The authors also compared measurements from Chapaevsk with those from other Russian cities with industrial facilities. The data presented do not allow direct comparison of dioxin concentrations in soil as a function of distance from the industrial facilities. However, the highest TCDD concentrations in the Chapaevsk study (those nearest the plant) were higher than were the maximum concentrations reported by four other studies referenced in the article. Residence in the city of Chapaevsk was used as a surrogate for exposure in the epidemiologic analyses presented in the report. No attempt was made to create exposure categories based on residential location within the city or with occupational or lifestyle factors that might have inï¬uenced TCDD exposure. Akhmedkhanov et al. (2002) sampled 24 volunteers from this same popula- tion for lipid-adjusted serum dioxin concentrations. Residents living near the plant ( 5 km) had higher concentrations than did those who lived farther from the plant. It was not clear whether the analysis included adjustments for age, body-mass index, or education, all of which are signiï¬cant predictors of dioxin concentrations. No new studies have been published since Update 2004. Other Studies Several reports have provided information on environmental exposure to TCDD in the Times Beach area of Missouri (Andrews et al., 1989; Patterson et al., 1986). In 1971, TCDD-contaminated sludge from a hexachlorophene pro- duction facility was mixed with waste oil and sprayed in various community areas for dust control. Soil contamination in some samples exceeded 100 ppb. Among the Missouri sites with the highest TCDD soil concentrations was the Quail Run mobile-home park. Residents were considered exposed if they had lived in the park for at least 6 months during the time that contamination occurred (Hoffman
EXPOSURE ASSESSMENT 235 et al., 1986). Other investigations of Times Beach have estimated exposure risk on the basis of residentsâ reported occupational and recreational activities in the sprayed area. Exposure estimates have been based on duration of residence and TCDD soil concentrations. Andrews et al. (1989) provided the most extensive data on human adipose- tissue TCDD in 128 non-exposed control subjects compared to concentrations in 51 exposed persons who had ridden or cared for horses at arenas sprayed with TCDD-contaminated oil, who lived in areas where the oil had been sprayed, who were involved in trichlorophenol (TCP) production, or who were involved in TCP non-production activities, such as laboratory or maintenance work. Persons were considered exposed if they lived near, worked with, or had other contact for at least 2 years with soil contaminated with TCDD at 20â100 parts per billion (ppb) or for 6 months or more with soil contaminated with TCDD above 100 ppb. Of the exposed-population samples, 87 percent had adipose tissue TCDD concentra- tions below 200 ppt; however, TCDD concentrations in seven of the 51 exposed persons were 250â750 ppt. In non-exposed persons, adipose-tissue TCDD ranged from undetectable to 20 ppt, with a median of 6 ppt. On the basis of a 7-year half-life, it is calculated that two study participants would have had adipose-tissue TCDD near 3,000 ppt at the time of the last date of exposure. Several epidemiologic studies have been conducted in association with industrial-facility emissions, or in regions with documented variation in dioxin exposures. Viel et al. (2000) reported on an investigation of apparent clusters of cases of soft-tissue sarcoma and non-Hodgkinâs lymphoma in the vicinity of a municipal solid-waste incinerator in Doubs, France. The presumptive source of TCDD in the region is a municipal solid-waste incinerator in the BesanÃ§on elec- toral ward in western Doubs. Dioxin emissions from the incinerator were mea- sured in international toxicity equivalent (I-TEQ) units at 16.3 nanograms (ng) I-TEQ per cubic meter (m3), far in excess of the European Union (EU) standard of 0.1 ng I-TEQ/m3. TCDD concentrations in cowsâ milk measured at three farms near the incinerator were well below the EU guideline of 6 ng I-TEQ/kg of fat, but the concentrations were highest at the farm closest to the incinerator. Combustion records for the Zeeburg area of Amsterdam in the Netherlands were used as a surrogate for exposure to dioxins in a study of orofacial clefts (ten Tusscher et al., 2000). Location downwind or upwind of an incineration source was used to deï¬ne exposed and reference groups for the study. A study of soft- tissue sarcomas in the general population was conducted in northern Italy around the city of Mantua (Costani et al., 2000). Several industrial facilities are in Man- tua, and residential proximity to them was presumed to result in increased TCDD exposure, but TCDD was not measured in the environment or in human tissues. A study of dioxin exposure pathways in Belgium focused on long-time resi- dents in the vicinity of two municipal-waste incinerators (Fierens et al., 2003a). Residents near a rural incinerator had signiï¬cantly higher serum dioxin concen- trations than did a control group (38 vs 24 pg TEQ/g of fat). Concentrations in
236 VETERANS AND AGENT ORANGE: UPDATE 2006 residents living near the incinerators increased proportionately with intake of local-animal fat. A second study (Fierens et al., 2003b) measured dioxin body burden in 257 people who had been environmentally exposed, with the object of determining whether dioxin and PCB exposures were associated with type 2 diabetes and endometriosis. No difference in body burden was found between women with endometriosis and women in a control group, but the risk of type 2 diabetes was signiï¬cantly higher for those with higher body burdens of dioxin- like compounds and PCBs. Another study of the correlation between dioxin-like compounds in Italian and Belgian women and the risk of endometriosis used measurements of TCDD and other dioxins in blood (De Felip et al., 2004). There was no difference in body burden among women with endometriosis and a control group, but dioxin concentrations were substantially higher in the control groups of women from Belgium than in a similar group from Italy (45 vs. 18 pg TEQ/g, lipid-adjusted, respectively). Since Update 2004, Bloom et al. (2006) measured serum dioxin levels in New York sports ï¬shermen as part of a study of thyroid function. Also, a methodological study by Petreas et al. (2004) found generally quite high cor- relations between concentrations of dioxins and related compounds in breast and abdominal fat within the same woman, which suggested that they could be used interchangeably in epidemiological studies. The same study, however, also found that adjusting concentrations according to lipid content rather than weight of the fat samples is important because of the presence of non-lipid components in these samples. Studies in Vietnam Studies of exposure to herbicides among the residents of Vietnam have com- pared unexposed residents of the South with residents of the North (Constable and Hatch, 1985). Other studies have attempted to identify wives of North Viet- namese veterans who served in South Vietnam. Records of herbicide spraying have been used to reï¬ne exposure measurements, comparing individuals who lived in sprayed villages in the South with those living in unsprayed villages. In some studies, village residents were considered exposed if an herbicide mission had passed within 10 km of the village center (Dai et al., 1990). Other criteria for classifying exposure included length of residence in a sprayed area and the number of times the area reportedly had been sprayed. A small number of studies provide information on TCDD concentrations in Vietnamese civilians exposed during the war. Schecter et al. (1986) detected TCDD in 12 of 15 samples of adipose tissue taken during surgery or autopsy in South Vietnam during 1984. The concentrations in the positive samples were 3â103 ppt. TCDD was not detected in nine samples from residents of North Vietnam who had never been to South Vietnam; detection sensitivity was 2â3 ppt. Analysis of three breast-milk samples collected in 1973 from Vietnamese women
EXPOSURE ASSESSMENT 237 thought to have been exposed to Agent Orange yielded TCDD concentrations of 77â230 ppt on a lipid basis. Blood samples from 43 residents of Bien Hoa City were analyzed for TCDD (Schecter et al., 2002). Bien Hoa City is in the southern part of South Vietnam, and the surrounding area was treated heavily with Agent Orange. The median lipid-normalized TCDD concentration was 67 ppt in those residents, compared with an average of 2 ppt in residents of Hanoi. The study also indicated that TCDD exposure of the population was continuing, presumably through consump- tion of ï¬sh and other foods. Schechter et al. (2006) recently reported additional sampling of residents in areas believed to have ongoing TCDD contamination. Blood samples from residents at eight sites were analyzed for TCDD and related compounds. Elevated TCDD concentrations were found in residents from one of these sites; data from a second site were suggestive of elevated exposures; results from the other six sites were similar to those found in the general population in the south of Vietnam. Dwernychuk et al. (2002) collected environmental and food samples, human blood, and breast milk from residents of the Aluoi Valley of central Vietnam. The investigators identiï¬ed locations where relatively high dioxin concentrations remain in soil or water systems. Dioxin concentrations in soil were particularly high around former air ï¬elds and military bases where herbicides were handled. Fish harvested from ponds in these areas were found to contain elevated dioxin concentrations. More recently Dwernychuk (2005) elaborated on the importance of âhot spotsâ as important locations for future studies and argued that herbicide use at former US military installations was the most likely cause of these hot spots. These studies are not directly relevant to this committeeâs task, but they may prove useful in future epidemiologic studies of the Vietnamese population and in the development of risk mitigation policies. MILITARY USE OF HERBICIDES IN VIETNAM Military use of herbicides in Vietnam began in 1962, expanded in 1965 and 1966, and reached a peak between 1967 and 1969. The herbicides were used primarily to defoliate inland hardwood forests, coastal mangrove forests, culti- vated land, and zones around military bases. Using records concerning herbicides sprayed from helicopters and other aircraft from August 1965 to February 1971, a National Academy of Sciences committee (NAS, 1974) calculated that about 17.6 million gallons (66.5 million liters) of herbicide were sprayed over about 3.6 million acres (1.5 million hectares) in Vietnam. It was more difï¬cult to quantify the amounts of herbicides sprayed on the ground to defoliate the perimeters of base camps and ï¬re bases and by Navy boats along river banks. In 1997, a committee convened by IOM issued a request for proposals (RFP) seeking individuals and organizations to develop historical exposure reconstruc- tion approaches suitable for epidemiologic studies of herbicide exposure among
238 VETERANS AND AGENT ORANGE: UPDATE 2006 US veterans during the Vietnam War (IOM, 1997). The RFP resulted in the project, Characterizing Exposure of Veterans to Agent Orange and Other Herbi- cides in Vietnam, which was carried out under contract by a team of researchers from Columbia Universityâs Mailman School of Public Health. The project yielded new estimates of the use of military herbicides in Viet- nam from 1961 to 1971 (IOM, 2003b,c; Stellman et al., 2003a). Investigators reviewed the original data used in the 1970s to make estimates and identiï¬ed in- consistencies, data gaps, and typographical errors. They determined the amounts of herbicide applied but not recorded on the data tapes (the so-called HERBS tapes) compiled in the 1970s and clariï¬ed data on missions that presumably âdumpedâ herbicide loads over very short periods before returning to base. The new analyses led to a revision in estimates of the amounts of the agents applied, as indicated in Table 5-3. Previous VAO reports estimated that a total of 67.8 million liters of military herbicides were applied from 1961 to 1971. The new research effort estimated that ~77 million liters was applied; a difference of more than 9 million liters. Four compounds were used in the herbicide formulations: 2,4-D, 2,4,5-T, picloram, and cacodylic acid. The chlorinated phenoxy acids (2,4-D and 2,4,5-T) persist in soil only for a few weeks (Buckingham, 1982). Picloram is more mobile than 2,4-D and 2,4,5-T and is extremely persistent in soils. Cacodylic acid, or dimethylarsinic acid, is an organic form of arsenic. Herbicides were identiï¬ed by the color of a band on 55-gal containers and called Agents Pink, Green, Purple, Orange, White, and Blue (Table 5-3). Agent Green and Agent Pink were used in 1961 and 1965; Agent Purple was used from 1962 through 1965. Agent Orange was used from 1965 through 1970, and a slightly different formulation (Agent Orange II) probably was used after 1968. Agent White was used from 1966 through 1971. Agent Blue was used in powder form from 1962 through 1964 and as a liquid from 1964 through 1971. Agents Pink, Green, Purple, Orange, and Orange II all contained 2,4,5-T, and were contaminated to some extent with TCDD. Agent White contained 2,4-D and picloram. Agent Blue (powder and liquid) contained cacodylic acid. More details on the herbicides used are presented in the earlier reports (IOM, 1994, 1996, 1999, 2001, 2003a). In addition to the four major compounds, diquat was applied to native grasses and bamboo (Brown, 1962). Soil-applied herbicides also were reportedly used around base camp perimeters, mineï¬elds, ammunition storage areas, and other sites where it was necessary to control grasses and woody vegetation (Darrow et al., 1969). Other accounts discuss the use of other herbicides, fungicides, in- secticides, insect repellents, wetting agents, and wood preservatives (Gonzales, 1992). There are no data on the number of military personnel potentially exposed to those substances. TCDD was formed as an unwanted by-product of 2,4,5-T production, but was not formed during 2,4-D production. The concentration of TCDD in any
TABLE 5-3 Military Use of Herbicides in Vietnam (1961â1971) Amount Sprayed Concentration of Active Code Name Chemical Constituentsa Ingredienta Years Useda VAO Estimateb Revised Estimatea Pink 60%â40% n-butyl, 961â1,081 g/L acid 1961, 1965 464,817 L 50,312 L sprayed; isobutyl ester of 2,4,5-T equivalent (122,792 gal) 413,852 L additional on procurement records Green n-butyl ester 2,4,5-T â â 31,071 L 31,026 L shown on (8,208 gal) procurement records Purple 50% n-butyl ester 2,4-D, 1,033 g/L acid equivalent 1962â1965 548,883 L 1,892,733 L 30% n-butyl ester 2,4,5-T, (145,000 gal) 20% isobutyl ester 2,4,5-T Orange 50% n-butyl ester 2,4-D, 1,033 g/L acid equivalent 1965â1970 42,629,013 L 45,677,937 L (could 50% n-butyl ester 2,4,5-T (11,261,429 gal) include Agent Orange II) Orange II 50% n-butyl ester 2,4-D, 910 g/L acid equivalent Postâ1968 (?) â Unknown, but at least 50% isooctyl ester 2,4,5-T 3,591,000 L shipped White Acid weight basis: 21.2% triisopropanolamine By acid weight: 240 g/L 1966â1971 19,860,108 L 20,556,525 L salts of 2,4-D and 5.7% picloram 2,4-D and 65 g/L picloram (5,246,502 gal) Blue powder Cacodylic acid (dimethylarsinic acid) and Acid: 65% active ingredient; 1962â1964 â 25,650 L sodium cacodylate salt: 70% active ingredient Blue aqueous 21% sodium cacodylate cacodylic acid to Acid weight: 360 g/L 1964â1971 4,255,952 L 4,715,731 L solution yield at least 26% total acid equivalent by (1,124,307 gal) weight Total, all 67,789,844 L 76,954,766 L (including formulations (17,908,238 gal) procured) a Based on Stellman et al. (2003a). b Based on data from MRI (1967), NAS (1974), and Young and Reggiani (1988). 239
240 VETERANS AND AGENT ORANGE: UPDATE 2006 given lot of 2,4,5-T depended on the manufacturing process (Young et al., 1976), and different manufacturers produced 2,4,5-T with different concentrations of TCDD. Of all the herbicides used in South Vietnam, only Agent Orange was formu- lated differently from the materials for commercial application that were readily available in the United States (Young et al., 1978). TCDD concentrations in in- dividual shipments were not recorded, and they varied in sampled inventories of herbicides containing 2,4,5-T. Analysis of the TCDD concentration in stocks of Agent Orange remaining after the conï¬ict, which either had been returned from South Vietnam or had been procured but not shipped, ranged from less than 0.05 ppm to almost 50 ppm and averaged 1.98 and 2.99 ppm in two sets of samples (NAS, 1974; Young et al., 1978). Comparable manufacturing standards for the domestic use of 2,4,5-T in 1974 required that TCDD be present at less than 0.05 ppm (NAS, 1974). Until recently, data from Young and Gough and coworkers have been used to estimate the amount of TCDD in the various herbicide formulations (Gough, 1986; Young, 1992; Young et al., 1978). Young et al. (1978) estimated that Agents Green, Pink, and Purple used early in the program (through 1965) contained 16 times the mean TCDD content of formulations used between 1965 and 1970. The mean concentration of TCDD in Agent Purple was estimated at 32.8 ppm; in Agents Pink and Green, it was estimated at 65.6 ppm (Young et al., 1978). Gough (1986) estimated that about 167 kg of TCDD was sprayed in Vietnam over a 6-year period. Analysis of archive samples of Agent Purple reported TCDD as high as 45 ppm (Young, 1992). New analyses produced by the Columbia University team have proposed 366 kg of TCDD as a plausible estimate of the total amount of TCDD applied in Vietnam between 1961 and 1971, and the authors argue that the true amount may be higher (Stellman et al., 2003a). EXPOSURE ASSESSMENT IN STUDIES OF VIETNAM VETERANS Different approaches have been used to estimate the exposure of Vietnam veterans, including self-reporting, record-based exposure estimation, and assess- ment of biologic markers of TCDD exposure. Each approach has a limited ability to ascribe individual exposure. Some studies rely on such gross markers as ser- vice in Vietnamâperhaps reï¬ned by branch of service, military region, military specialty, or combat experienceâas a proxy for exposure to herbicides. Studies of that type include CDCâs Vietnam Experience Study and Selected Cancers Study, VAâs mortality studies, and most studies of veterans conducted by the states. This approach has the potential to miss associations between exposures and health ef- fects, if they exist, because many members of the cohorts presumed to have been exposed to herbicides might not have been exposed. The number of US military personnel who directly handled (mixed, loaded,
EXPOSURE ASSESSMENT 241 or applied) herbicides is impossible to determine precisely, but two groups have been identiï¬ed as high-risk subpopulations among veterans: Air Force personnel involved in ï¬xed-wing aircraft spraying activities known commonly as Operation Ranch Hand, and members of the US Army Chemical Corps involved in using hand-operated equipment and helicopters to conduct smaller (but potentially high-exposure) operations: mixing; defoliation around special forces camps; clearing the perimeters of airï¬elds, depots, and other bases; and small-scale crop destruction (Thomas and Kang, 1990; Warren, 1968). Units and individuals other than members of the Air Force Ranch Hand and Army Chemical Corps also were likely to have handled or sprayed herbicides around bases or lines of communication. Navy river patrols were reported to have used herbicides to clear inland waterways, and engineering personnel used herbi- cides to remove underbrush and dense growth in constructing ï¬re support bases. Because the herbicides were not considered to present a health hazard, few precautions were taken to prevent troop exposure. The precautions that were prescribed were consistent with those applied in the domestic use of herbicides before the Vietnam conï¬ict (US GAO, 1979). Young et al. (2004a,b) now allege that care was taken in planning missions to avoid spraying friendly forces. Air Force Health Study Major defoliation activities in Vietnam were conducted by Air Force person- nel as part of Operation Ranch Hand. These veterans became the ï¬rst subpopu- lation among Vietnam veterans to receive special attention in regard to Agent Orange, and have become known as the Ranch Hand cohort within the Air Force Health Study (AFHS). The AFHS was initiated in 1979 by the Air Force. Results of biologic marker studies of Ranch Hand personnel have been consistent with their being exposed, as a group, to TCDD. When the Ranch Hand cohort was classiï¬ed by military occupation, a general increase in serum TCDD was detected for jobs that involved more-frequent handling of herbicides (AFHS, 1991). The exposure index initially proposed in the AFHS relied on military records of TCDD-containing herbicides (Agents Orange, Purple, Pink, Green) sprayed as reported in the HERBS tapes for the period starting in July 1965 and on military procurement records and dissemination information for the period before July 1965. In 1991, the exposure index was compared with the results of the Ranch Hand serum-TCDD analysis. The exposure index and the TCDD body burden correlated weakly. Michalek et al. (1995) developed several indexes of herbicide exposure for members of the Ranch Hand cohort and tried to relate them to the measurements of serum TCDD from 1987 to 1992. Self-administered questionnaires completed by veterans of Operation Ranch Hand were used to develop three indexes of herbicide or TCDD exposure: number of days of skin exposure; the percentage of skin area exposed; and the product of the number of days of skin exposure,
242 VETERANS AND AGENT ORANGE: UPDATE 2006 percentage of skin exposed, and a factor for the concentration of TCDD in the herbicide. A fourth index, which used no information gathered from individual subjects, was calculated by multiplying the volume of herbicide sprayed during a personâs tour of duty by the concentration of TCDD in herbicides sprayed in that period and then dividing the product by the number of crew members in each job specialty at the time. Each of these four models tested was signiï¬cantly related to serum TCDD, although the models explained only 19â27 percent of the variability in serum TCDD concentrations. Days of skin exposure had the highest correlation. Military job classiï¬cation (non-Ranch Hand combat troops, Ranch Hand administrators, Ranch Hand ï¬ight engineers, and Ranch Hand ground crew), which is separate from the four indexes, explained 60 percent of the variability in serum TCDD. When the questionnaire-derived indexes were applied within each job classiï¬ca- tion, days of skin exposure added statistical signiï¬cance, but not substantially, to the variability explained by job alone. Most recent AFHS publications have relied on serum dioxin concentration as the primary exposure metric for epidemiologic classiï¬cation (Akhtar et al., 2004; Barrett et al., 2001, 2003; Michalek et al., 2001a,b,c, 2003; Pavuk et al., 2003). Since Update 2004, four additional publications employing serum dioxin concentrations have examined insulin sensitivity (Kern et al., 2004), post-service mortality (Ketchum and Michalek, 2005), risk of prostate cancer (Pavuk et al., 2006), and cancer risk in Air Force personnel who did not spray Agent Orange (Pavuk et al., 2005). The National Academies of Science recently issued a comprehensive review of the AFHS, together with recommendations for the use of the extensive data and biologic samples collected in the course of this project (IOM, 2006). Army Chemical Corps Studies Members of the US Army Chemical Corps performed chemical operations on the ground and by helicopter and were thereby involved in the direct handling and distribution of herbicides in Vietnam. This population was belatedly identiï¬ed for detailed study of health effects related to herbicide exposure (Thomas and Kang, 1990). Results of an initial feasibility study were reported by Kang et al. (2001). That study recruited 565 veterans: 284 Vietnam veterans and 281 non-Vietnam- veteran control subjects. Blood samples were collected in 1996 from 50 Vietnam veterans and 50 control veterans, and 95 of the samples met CDC standards for quality assurance and quality. Comparison of the entire Vietnam cohort with the entire non-Vietnam cohort showed that the geometric mean TCDD concentrations did not differ signiï¬cantly (p 0.6). Of the 50 Vietnam veterans sampled, analysis of questionnaire responses indicated that those who reported spraying herbicides had higher TCDD concentrations than did those who reported no spraying ac-
EXPOSURE ASSESSMENT 243 tivities. The authors concluded that Agent Orange exposure was a likely contribu- tor to TCDD concentrations in Vietnam veterans who had a history of spraying herbicides. Since Update 2004, Kang et al. (2006) reported ï¬ndings from the main study. A health survey was administered by telephone to 1,499 Vietnam veterans and 1,428 non-Vietnam veterans. Exposure to herbicides was assessed by analyzing serum specimens from a sample of 897 veterans for dioxin. Those veterans who reported spraying herbicides had signiï¬cantly higher TCDD serum levels than did Vietnam veterans and other veterans who did not report herbicide spraying. The ï¬nal analysis compared Vietnam-veteran sprayers with Vietnam-veteran non- sprayers from the entire study population. Australian Vietnam Veterans Three recent reports update earlier investigations (AIHW, 1999, 2000; CDVA 1998a,b; CIH, 1984a,b,c; Crane et al., 1997a,b; Evatt, 1985; Fett et al., 1987a,b; Forcier et al., 1987) of the health experience of Australian Vietnam veterans. The ï¬rst two reports compared the incidences of all types of cancer (ADVA, 2005a) and the frequencies of various causes of death (ADVA, 2005b) in all male Aus- tralian Vietnam veterans with the general population. The third study (ADVA, 2005c) compared mortality and cancer incidence in male Army veterans deployed to Vietnam (âNational Serviceâ veterans) with their non-deployed counterparts (âNational Service non-veteransâ). Like previous studies of Australian Vietnam veterans, these reports did not characterize the veteransâ exposure to the herbicides sprayed in Vietnam in any way beyond the fact that they served on land or in Vietnamese waters during May 23, 1962âJuly 1, 1973. It is the convention of this committee to regard Vietnam veterans in general as being more likely to have received higher exposures to the chemicals of concern than the general public. Korean Vietnam Veterans Military personnel from the Republic of Korea served in Vietnam between 1964 and 1973. Kim et al. (2001) attempted to use serum dioxin concentrations for validating an index estimating group exposure. The study involved 720 veter- ans who served in Vietnam, and 25 veterans who did not serve in Vietnam. The exposure index was based on Agent Orange spray patterns across military regions in which Korean personnel served, time-location data on the military units sta- tioned in Vietnam, and an exposure score derived from self-reported activities during service. A total of 13 pooled samples were submitted to CDC for serum dioxin analysis. One analytic sample was prepared from the pooled blood of the 25 veterans who did not serve in Vietnam. The remaining 12 analytic samples
244 VETERANS AND AGENT ORANGE: UPDATE 2006 were intended to correspond to 12 exposure categories; each was created by pooling blood samples from 60 veterans. The 12 exposure categories ultimately were reduced to 4 exposure groups, each representing a quartile of 180 Vietnam veterans, but characterized by only three serum TCDD measurements. The paper by Kim et al. (2001) reported highly signiï¬cant Pearson correla- tion coefï¬cients and multiple regression analysis results. The statistical analyses apparently were based on the assignment of the pooled-serum-dioxin value to each individual in the exposure group, thereby inï¬ating the true sample size. The multiple regression analysis evaluated such variables as age, body-mass index, and consumption of tobacco or alcohol. In a subsequent report for the same exposure groups and serum dioxin data, the authors corrected their analysis (Kim et al., 2003). A correlation was observed between serum dioxin concentra- tions and ordinal exposure categories, but the correlation was not statistically signiï¬cant. The authors attributed the lack of statistical signiï¬cance to the small sample size, and they noted that the data exhibited a distinct monotone upward trend (average serum dioxin concentrations of 0.3, 0.6, 0.62, 0.78, and 0.87 pg/g [lipid adjusted] for exposure categories 0â4, respectively). The decision to pool blood samples from a large number of persons within each exposure set (Kim et al., 2001) greatly reduced the power of the validation study. Instead of 180 samples for each of the ï¬nal exposure categories, the pooled analysis produced only 3 samples for each category. The lipid-adjusted serum TCDD concentra- tions from the 12 pooled samples for Vietnam veterans ranged from 0.25 to 1.2 pg/g, whereas the single sample from the non-Vietnam veterans contained 0.3 pg/g. The narrow range of results puts into question the biologic relevance of any differences. Thus, it appears that there was not a clear separation between Korean Vietnam veterans and non-Vietnam veterans. Furthermore, the range of mean values for the four Vietnam-veteran exposure categories was narrow, and all concentrations were relatively low ( 1 pg/g). The relatively low serum dioxin concentrations observed in the 1990s in those individuals are the residual of substantially higher initial concentrations, as has been seen with other Vietnam-veteran groups. How- ever, the concentrations reported in the Korean veteransâ study are signiï¬cantly lower than those reported for American Vietnam veterans in the 1988 CDC Agent Orange Validation Study, which was nonetheless unable to distinguish Vietnam veterans from non-Vietnam veterans on the basis of serum dioxin assay (CDC, 1988b). The Korean authors were able to construct plausible exposure categories based on military records and self-report, but they were unable to validate those categories with serum dioxin measurements. No additional reports on this population have been published since Update 2004.
EXPOSURE ASSESSMENT 245 Other Vietnam Veterans Surveys of US Vietnam veterans who were not part of the Ranch Hand or Army Chemical Corps groups indicate that 25â55 percent believe they were ex- posed to herbicides (CDC, 1989; Erickson et al., 1984a,b; Stellman and Stellman, 1986). Several attempts have been made to estimate exposure of Vietnam veter- ans who were not part of the Ranch Hand or Army Chemical Corps groups. In 1983, the US government asked the CDC to conduct a study of possible long- term health effects in Vietnam veterans exposed to Agent Orange. The CDC Agent Orange study (CDC, 1985) attempted to classify veteransâ service-related exposures to herbicides. That involved determining the proximity of troops to Agent Orange spraying by using military records to track troop movement and the HERBS tapes to locate herbicide-spraying patterns. The CDC Birth Defects Study developed an exposure opportunity index to score Agent Orange exposure (Erickson et al., 1984a,b). In 1987, CDC conducted the Agent Orange Validation Study to test the valid- ity of the various indirect methods used to estimate exposure of ground troops to Agent Orange in Vietnam. The study measured serum TCDD in a non-random sample of Vietnam veterans and in Vietnam-era veterans who did not serve in Vietnam (CDC, 1988b). Vietnam veterans were selected for study based on the number of Agent Orange hits they were thought to have experienced, as derived from the number of days on which their company was located within 2 km and 6 days of a recorded Agent Orange spraying event. Blood samples were obtained from 66% of Vietnam veterans (n = 646) and from 49% of the eligible comparison group of veterans (n = 97). More than 94% of those whose serum was obtained had served in one of ï¬ve battalions. The median serum TCDD in Vietnam veterans in 1987 was 4 ppt, with a range of <1â45 ppt. Only two veterans had concentrations above 20 ppt. The âlowâ exposure group consisted of 298 Vietnam veterans, the âmediumâ exposure group had 157 Vietnam veterans, and the âhighâ exposure group had 191 Vietnam veterans. The distribution of TCDD measurements was nearly identical for the control group of 97 non-Vietnam veterans. The CDC validation study concluded that study subjects could not be distinguished from controls on the basis of serum TCDD. In addition, neither record-derived estimates of exposure nor self-reported exposure to herbicides could predict Vietnam veterans with currently high serum TCDD (CDC, 1988b). The report concluded that it was unlikely that military records alone could be used to identify a large number of veterans who might have been heavily exposed to TCDD in Vietnam. The serum TCDD measurements for Vietnam veterans also suggested that exposure to TCDD in Vietnam was substantially less, on average, than was that of persons exposed as a result of the industrial explosion in Seveso or that of the heavily exposed occupational workers who are the focus of many of the studies
246 VETERANS AND AGENT ORANGE: UPDATE 2006 evaluated by the committee. This assessment of average exposure does not pre- clude the possibility of heavily exposed subgroups of Vietnam veterans. The aforementioned 1997 IOM RFP for historical exposure reconstruction has led to the development of new methods for estimating Vietnam veteransâ exposures to Agent Orange. The Columbia University project integrated various sources of information concerning spray activities to generate individualized estimates of the exposure potential of troops serving in Vietnam (Stellman and Stellman, 2003). Location data for military units assigned to Vietnam were com- piled into a database developed from ï¬ve primary and secondary sources: the Unit Identiï¬cation Code list (a reference list of units serving in Vietnam created and used by the Army); a command post list (data on division level of the command locations for army personnel); Army Post Ofï¬ce lists (compilations of locations down to and including battalion size and other selected units that were updated on a monthly basis); troop strength reports (data assembled by the US Military Assistance Command on troop allocations, updated on a monthly basis and gen- erally collected on the battalion level); and order of battle information (data on command post, arrival and departure dates, and authorized strength of many but not all units). For units that served in the III Corps Tactical Zone between 1966 and 1969, battalion-tracking data were also available. These are data on the grid coordinate locations of battalion-sized units derived from Daily Journals, which recorded the company locations over 24-hour periods. âMobility factorâ analysis, a new concept for studying troop movement, was developed for use in reconstructing herbicide-exposure histories. The analysis is a three-part classiï¬cation system for characterizing the location and movement of military units in Vietnam. It comprises a mobility designation (stable, mobile, or elements mobile), a distance designation (usually in a range of kilometers) to indicate how far the unit might travel in a day, and a notation of the modes of travel available to the unit (air; groundâtruck, tank, or armored personnel carrier; or water). A mobility factor was assigned to every unit that served in Vietnam. All of these data were combined into a geographic information system (GIS) for Vietnam with a grid resolution of 0.01Â° latitude and 0.01Â° longitude. Herbicide-spraying records were integrated into the GIS and linked with data on military unit locations to permit estimation of exposure opportunity scores for individuals. The results are the subject of reports by the contractor (Stellman and Stellman, 2003) and the committee (IOM, 2003b,c). A summary of the ï¬ndings regarding the extent and pattern of herbicide spraying (Stellman et al., 2003a), a description of the GIS for characterizing exposure to Agent Orange and other herbicides in Vietnam (Stellman et al., 2003b), and an explanation of the exposure opportunity models based on that work (Stellman and Stellman, 2004) have been published in peer-reviewed journals. Those publications argue that it is now fea- sible to conduct epidemiologic investigations of veterans who served as ground troops during the Vietnam War A different perspective has been put forth in a series of papers (Young and
EXPOSURE ASSESSMENT 247 Newton, 2004; Young et al., 2004a,b) arguing that ground troops had little direct contact with herbicide sprays and that TCDD residues in Vietnam had low bio- availability. These conclusions were based on analyses of previously unpublished military records and environmental fate studies. They also argue that ground- troop exposures were relatively low because herbicide-spraying missions were carefully planned and spraying only occurred when friendly forces were not in the target area. Finally, they note that the GIS-based exposure opportunity model has not yet been validated through measurement of serum dioxin levels in veterans (Young, 2004). REFERENCES1 ADVA (Australia, Department of Veteransâ Affairs). 2005a. Cancer Incidence in Australian Vietnam Veteran Study 2005. Canberra, Australia: Department of Veteransâ Affairs. ADVA. 2005b. The Third Australian Vietnam Veterans Mortality Study 2005. Canberra, Australia: Department of Veteransâ Affairs. ADVA. 2005c. Australian National Service Vietnam Veterans: Mortality and Cancer Incidence 2005. Canberra, Australia: Department of Veteransâ Affairs. AFHS (Air Force Health Study). 1991. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. 9 vols. AIHW (Australian Institute of Health and Welfare). 1999. Morbidity of Vietnam Veterans: A Study of the Health of Australiaâs Vietnam Veteran Community: Volume 3: Validation Study. Canberra: AIHW. AIHW. 2000. Morbidity of Vietnam veterans. Adrenal Gland Cancer, Leukaemia and Non-Hodgkinâs Lymphoma: Supplementary Report No. 2. (AIHW cat. No. PHE 28). Canberra: AIHW. Akhmedkhanov A, Revich B, Adibi JJ, Zeilert V, Masten SA, Patterson DG Jr, Needham LL, Toniolo P. 2002. Characterization of dioxin exposure in residents of Chapaevsk, Russia. Journal of Exposure Analysis and Environmental Epidemiology 12(6):409â417. Akhtar FZ, Garabrant DH, Ketchum NS, Michalek JE. 2004. Cancer in US Air Force veterans of the Vietnam War. Journal of Occupational and Environmental Medicine 46(2):123â136. Alavanja MC, Akland G, Baird D, Blair A, Bond A, Dosemeci M, Kamel F, Lewis R, Lubin J, Lynch C. 1994. Cancer and noncancer risk to women in agriculture and pest control: The Agricultural Health Study. Journal of Occupational Medicine 36(11):1247â1250. Alavanja MC, Hoppin JA, Kamel F. 2004. Health effects of chronic pesticide exposure: Cancer and neurotoxicity. Annual Review of Public Health 25:155â197. Alavanja MCR, Sandler DP, Lynch CF, Knott C, Lubin JH, Tarone R, Thomas K, Dosemeci M, Barker J, Hoppin JA, Blair A. 2005. Cancer incidence in the Agricultural Health Study. Scandinavian Journal of Work, Environment and Health 31(Suppl 1):39â45. Andrews JS Jr, Garrett WA Jr, Patterson DG Jr, Needham LL, Roberts DW, Bagby JR, Anderson JE, Hoffman RE, Schramm W. 1989. 2,3,7,8-Tetrachlorodibenzo-p-dioxin levels in adipose tissue of persons with no known exposure and in exposure persons. Chemosphere 18:499â506. Arbuckle TE, Ritter L. 2005. Phenoxyacetic acid herbicide exposure for women on Ontario farms. Journal of Toxicology and Environmental Health, Part A 68(15):1359â1370. 1Throughout the report the same alphabetic indicator following year of publication is used con- sistently for the same article when there were multiple citations by the same ï¬rst author in a given year. The convention of assigning the alphabetic indicator in order of citation in a given chapter is not followed.
248 VETERANS AND AGENT ORANGE: UPDATE 2006 Arbuckle TE, Schrader SM, Cole D, Hall JC, Bancej CM, Turner LA, Claman P. 1999a. 2,4- Dichlorophenoxyacetic acid (2,4-D) residues in semen of Ontario farmers. Reproductive Toxi- cology 13(6):421â429. Arbuckle TE, Savitz DA, Mery LS, Curtis KM. 1999b. Exposure to phenoxy herbicides and the risk of spontaneous abortion. Epidemiology 10:752â760. Arbuckle TE, Lin Z, Mery LS. 2001. An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population. Environmental Health Perspec- tives 109(8):851â857. Arbuckle TE, Burnett R, Cole D, Teschke K, Dosemecci M, Bancej C, Zhang J. 2002. Predictors of herbicide exposure in farm applicators. International Archives of Occupational and Environ- mental Health 75:406â414. Arbuckle TE, Cole DC, Ritter L, Ripley BD. 2005. Biomonitoring of herbicides in Ontario farm ap- plicators. Scandinavian Journal of Work, Environment and Health 31(Suppl 1):90â97. Arbuckle TE, Bruce D, Ritter L, Hall JC. 2006. Indirect sources of herbicide exposure for families on Ontario farms. Journal of Exposure Science and Environmental Epidemiology 16(1):98â104. Arcury TA, Quandt SA, Barr DB, Hoppin JA, McCauley L, Grzywacz JG, Robson MG. 2006. Farmworker exposure to pesticides: Methodologic issues for the collection of comparable data. Environmental Health Perspectives 114(6):923â928. Armstrong BK, White E, Saracci R. 1994. Principles of Exposure Assessment in Epidemiology. New York, Oxford University Press. Ashida H, Fakuka I, Yamashita T, Kanazawa K. 2000. Flavones and ï¬avonols at dietary levels inhibit a transformation of aryl hydrocarbon receptor induced by dioxin. FEBS Letters 476:213â217. ATSDR (Agency for Toxic Substances and Diesease Registry). 1998. Toxicological Proï¬le for Chlo- rinated Dibenzo-p-dioxins (CDDs). Atlanta, GA: Centers for Disease Control. Aylward LL, Hays SM. 2002. Temporal trends in human TCDD body burden: Decreases over three decades and implications for exposure levels. Journal of Exposure Analysis and Environmental Epidemiology 12:319â328. Aylward LL, Brunet RC, Starr TB, Carrier G, Delzell E, Cheng H, Beall C. 2005a. Exposure recon- struction for the TCDD-exposed NIOSH cohort using a concentration- and age-dependent model of elimination. Risk Analysis 25(4):945â956. Aylward LL, Brunet RC, Carrier G, Hays SM, Cushing CA, Needham LL, Patterson DG Jr, Gerthoux PM, Brambilla P, Mocarelli P. 2005b. Concentration-dependent TCDD elimination kinetics in humans: Toxicokinetic modeling for moderately to highly exposed adults from Seveso, Italy, and Vienna, Austria, and impact on dose estimates for the NIOSH cohort. Journal of Exposure Analysis and Environment Epidemiology 15(1):51â65. Baccarelli A, Mocarelli P, Patterson DG Jr, Bonzini M, Pesatori AC, Caporaso N, Landi MT. 2002. Immunologic effects of dioxin: New results from Seveso and comparison with other studies. Environmental Health Perspectives 110(12):1169â1173. Baccarelli A, Pesatori AC, Consonni D, Mocarelli P, Patterson DG Jr, Caporaso NE, Bertazzi PA, Landi MT. 2005a. Health status and plasma dioxin levels in chloracne cases 20 years after the Seveso, Italy accident. British Journal of Dermatology 152(3):459â465. Baccarelli A, Pfeiffer R, Consonni D, Pesatori AC, Bonzini M, Patterson DG Jr, Bertazzi PA, Landi MT. 2005b. Handling of dioxin measurement data in the presence of non-detectable values: Overview of available methods and their application in the Seveso chloracne study. Chemo- sphere 60(7):898â906. Barr DB, Landsittel D, Nishioka M, Thomas K, Curwin B, Raymer J, Donnelly KC, McCauley L, Ryan PB. 2006a. A survey of laboratory and statistical issues related to farmworker exposure studies. Environmental Health Perspectives 114(6):961â968. Barr DB, Thomas K, Curwin B, Landsittel D, Raymer J, Lu C, Donnelly KC, Acquavella J. 2006b. Biomonitoring of exposure in farmworker studies. Environmental Health Perspectives 114(6): 936â942.
EXPOSURE ASSESSMENT 249 Barrett DH, Morris RD, Akhtar FZ, Michalek JE. 2001. Serum dioxin and cognitive functioning among veterans of Operation Ranch Hand. Neurotoxicology 22:491â502. Barrett DH, Morris RD, Jackson WG Jr, Michalek JE. 2003. Serum dioxin and psychological func- tioning in US Air Force veterans of the Vietnam War. Military Medicine 168(2):153â159. Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindorf K, Manz A, Wahrendorf J. 1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes and Control 7(3):312â321. Bell EM, Hertz-Picciotto I, Beaumont JJ. 2001a. Caseâcohort analysis of agricultural pesticide applications near maternal residence and selected causes of fetal death. American Journal of Epidemiology 154(8):702â710. Bell EM, Hertz-Picciotto I, Beaumont JJ. 2001b. A caseâcontrol study of pesticides and fetal death due to congenital anomalies. Epidemiology 12(2):148â156. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989. Ten-year mortality study of the population involved in the Seveso incident in 1976. American Journal of Epidemiol- ogy 129:1187â1200. Bertazzi PA, Bernucci I, Brambilla G, Consonni D, Pesatori AC. 1998. The Seveso studies on early and long-term effects of dioxin exposure: A review. Environmental Health Perspectives 106(Suppl 2):625â633. Bertazzi PA, Consonni D, Bachetti S, Rubagotti M, Baccarelli A, Zocchetti C, Pesatori AC. 2001. Health effects of dioxin exposure: A 20-year mortality study. American Journal of Epidemiol- ogy 153(11):1031â1044. Blair A, White DW. 1985. Leukemia cell types and agricultural practices in Nebraska. Archives of Environmental Health 40:211â214. Blair A, Grauman DJ, Lubin JH, Fraumeni JF Jr. 1983. Lung cancer and other causes of death among licensed pesticide applicators. Journal of the National Cancer Institute 71:31â37. Blair A, Sandler D, Thomas K, Hoppin JA, Kamel F, Coble J, Lee WJ, Rusiecki J, Knott C, Dosemeci M, Lynch CF, Lubin J, Alavanja M. 2005. Disease and injury among participants in the Agricul- tural Health Study. Journal of Agricultural Safety and Health 11(2):141â150. Bloemen LJ, Mandel JS, Bond GG, Pollock AF, Vitek RP, Cook RR. 1993. An update of mortality among chemical workers potentially exposed to the herbicide 2,4-dichlorophenoxyacetic acid and its derivatives. Journal of Occupational Medicine 35:1208â1212. Bloom M, Vena J, Olson J, Moysich K. 2006. Chronic exposure to dioxin-like compounds and thy- roid function among New York anglers. Environmental Toxicology and Pharmacology 21(3): 260â267. Bodner KM, Collins JJ, Bloemen LJ, Carson ML. 2003. Cancer risk for chemical workers ex- posed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Occupational and Environmental Medicine 60(9): 672â675. Bond GG, Wetterstroem NH, Roush GJ, McLaren EA, Lipps TE, Cook RR. 1988. Cause speciï¬c mortality among employees engaged in the manufacture, formulation, or packaging of 2,4- dichlorophenoxyacetic acid and related salts. British Journal of Industrial Medicine 45:98â105. Brown JW. 1962. Vegetational Spray Test in South Vietnam. Fort Detrick, MD: US Army Chemical Corps Biological Laboratories. DDC Number AD 476961. 119 pp. Buckingham WA. 1982. Operation Ranch Hand: The Air Force and Herbicides in Southeast Asia 1961â1971. Washington, DC: US Air Force Ofï¬ce of Air Force History. Bueno de Mesquita HB, Doornbos G, van der Kuip DA, Kogevinas M, Winkelmann R. 1993. Oc- cupational exposure to phenoxy herbicides and chlorophenols and cancer mortality in the Netherlands. American Journal of Industrial Medicine 23:289â300. Burmeister LF. 1981. Cancer mortality in Iowa farmers: 1971â1978. Journal of the National Cancer Institute 66:461â464.
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) 1945â1994: An update. Occupational and Environmental Medicine 58:24â30. Cantor KP. 1982. Farming and mortality from non-Hodgkinâs lymphoma: A caseâcontrol study. International Journal of Cancer 29:239â247. Carmelli D, Hofherr L, Tomsic J, Morgan RW. 1981. A CaseâControl 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):546â551. 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 humansâSeveso, Italy. Morbidity and Mortality Weekly Report 37:733â736. CDC. 1988b. Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in US Army Vietnam era veterans. Journal of the American Medical Association 260:1249â1254. CDC. 1989. Health Status of Vietnam Veterans. Vietnam Experience Study. Atlanta: US Department of Health and Human Services. Vols. IâV, Supplements AâC. CDVA (Commonwealth Department of Veteransâ Affairs). 1998a. Morbidity of Vietnam Veterans: A Study of the Health of Australiaâs Vietnam Veteran Community. Volume 1: Male Vietnam Veterans Survey and Community Comparison Outcomes. Canberra, Australia: Department of Veteransâ Affairs. CDVA. 1998b. Morbidity of Vietnam Veterans: A Study of the Health of Australiaâs Vietnam Veteran Community. Volume 2: Female Vietnam Veterans Survey and Community Comparison Out- comes. Canberra, Australia: Department of Veteransâ 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):525â531. 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 Conï¬ict 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 Inï¬uencing Mortality Rates of Australian National Servicemen of the Vietnam Conï¬ict 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 Conï¬ict Era. Canberra: Australian Government Publishing Service. Ciolino H, Daschner P, Yeh G. 1999. Dietary ï¬avonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. Biochemical Journal 340:715â722. 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 12:448â454.
EXPOSURE ASSESSMENT 251 Coggon D, Pannett B, Winter P. 1991. Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine 48:173â178. 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):76â84. Constable JD, Hatch MC. 1985. Reproductive effects of herbicide exposure in Vietnam: recent studies by the Vietnamese and others. Teratogenesis, Carcinogenesis, and Mutagenesis 5:231â250. Cook RR, Bond GG, Olson RA. 1986. Evaluation of the mortality experience of workers exposed to the chlorinated dioxins. Chemosphere 15:1769â1776. 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):381â383. 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 Veteransâ 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 Veteransâ Affairs. Crump KS, Canady R, Kogevinas M. 2003. Meta-analysis of dioxin cancer dose response for three occupational cohorts. Environmental Health Perspectives 111(5):681â687. Curtis KM, Savitz DA, Weinberg CR, Arbuckle TE. 1999. The effect of pesticide exposure on time to pregnancy. Epidemiology 10:112â117. 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):500â508. 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 20:1005â1012. Dankovic DA, Andersen ME, Salvan A, Stayner LT. 1995. A simpliï¬ed 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):203â209. 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):762â770. Dosemeci M, Wacholder S, Lubin JH. 1990. Does nondifferential misclassiï¬cation of exposure always bias a true effect toward the null value? American Journal of Epidemiology 132(4):746â748. 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 46:245â260. 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):178â185. Dwernychuk LW. 2005. Dioxin hot spots in Vietnam. Chemosphere 60(7):998â999. Dwernychuk LW, Cau HD, Hatï¬eld CT, Boivin TG, Hung TM, Dung PT, Thai ND. 2002. Dioxin reservoirs in southern Viet Namâa legacy of Agent Orange. Chemosphere 47(2):117â137. 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 farmersâ wives in the Agricul- tural Health Study. American Journal of Epidemiology 161(2):121â135.
252 VETERANS AND AGENT ORANGE: UPDATE 2006 Erickson JD, Mulinare J, Mcclain PW. 1984a. Vietnam veteransâ risks for fathering babies with birth defects. Journal of the American Medical Association 252:903â912. Erickson JD, Mulinare J, Mcclain PW, Fitch TG, James LM, McClearn AB, Adams MJ. 1984b. Viet- nam Veteransâ 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 Womenâs Health Study: Does zone of residence predict individual TCDD exposure? Chemosphere 43(4-7):937â942. 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):383â392. 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):629â634. 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):947â953. 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):22â27. 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):858â862. 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):1194â1204. 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): 731â742. 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):1503â1508. Ferry DG, Gazeley LR, Edwards IR. 1982. 2,4,5-T absorption in chemical applicators. Proceedings of the University Otago Medical School 60:31â34. Fett MJ, Adena MA, Cobbin DM, Dunn M. 1987a. Mortality among Australian conscripts of the Viet- nam conï¬ict era. I. Death from all causes. American Journal of Epidemiology 126:869â877. Fett MJ, Nairn JR, Cobbin DM, Adena MA. 1987b. Mortality among Australian conscripts of the Vietnam conï¬ict era. II. Causes of death. American Journal of Epidemiology 125:878â884. 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):1287â1293. 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):529â534. 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 324:212â218.
EXPOSURE ASSESSMENT 253 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 142:1165â1175. 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):655â662. Forcier L, Hudson HM, Cobbin DM, Jones MP, Adena MA, Fett MJ. 1987. Mortality of Australian veterans of the Vietnam conï¬ict and the period and location of their Vietnam service. Military Medicine 152:9â15. 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 14:427â435. 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-Hodgkinâs lym- phoma. American Journal of Epidemiology 162(9):849â857. 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 22:249â255. 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):965â986. 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 36:213â221. Gorell JM, Peterson EL, Rybicki BA, Johnson CC. 2004. Multiple risk factors for Parkinsonâs disease. Journal of Neurological Sciences 217(2):169â174. Gough M. 1986. Dioxin, Agent Orange: The Facts. New York: Plenum Press. Greenland P, Gustafson S. 2006. The performance of random coefï¬cient regression in accounting for residual confounding. Biometrics 62(3):760â768. 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):614â620. Hansen ES, Hasle H, Lander F. 1992. A cohort study on cancer incidence among Danish gardeners. American Journal of Industrial Medicine 21:651â660. 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):345â358. Henneberger PK, Ferris BG Jr, Monson RR. 1989. Mortality among pulp and paper workers in Berlin, New Hampshire. British Journal of Industrial Medicine 46:658â664. 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):71â79. 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 256:1141â1147.
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 255:2031â2038. 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):891â901. Hoppin JA. 2005. Integrating exposure measurements into epidemiologic studies in agriculture. Scan- dinavian Journal of Work, Environment and Health 31(Suppl 1):115â117. Hoppin JA, Adgate JL, Eberhart M, Nishioka M, Ryan PB. 2006. Environmental exposure assessment of pesticides in farmworker homes. Environmental Health Perspectives 114(6):929â935. Huston BL. 1972. Identiï¬cation of three neutral contaminants in production grade 2,4-D. Journal of Agriculture and Food Chemistry. 20(3):724â727. 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: Scientiï¬c 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 17:356â359. 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 43:943â949. 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):875â884. 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): 1248â1255. 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):4665â4672.
EXPOSURE ASSESSMENT 255 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):406â413. 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):80â88. 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 41:149â157. 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):856â865. 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):1020â1029. 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):1061â1075. 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 4:318â321. 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 54:257â265. 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):120â125. 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):673â680. 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: 626â630. 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 24:90â96. 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):1403â1408. 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):743â749. 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 45:56â62. 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):98â104. 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 338:959â964.
256 VETERANS AND AGENT ORANGE: UPDATE 2006 McDufï¬e HH, Pahwa P, McLaughlin JR, Spinelli JJ, Fincham S, Dosman JA, Robson D, Skinnider LF, Choi NW. 2001. Non-Hodgkinâs lymphoma and speciï¬c pesticide exposures in men: Cross-Canada study of pesticides and health. Cancer Epidemiology, Biomarkers and Prevention 10(11):1153â1163. 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):209â223. Michalek JE, Ketchum N, Longnecker MP. 2001a. Serum dioxin and hepatic abnormalities in veterans of Operation Ranch Hand. Annals of Epidemiology 11(5):304â311. Michalek JE, Akhtar FZ, Arezzo JC, Garabrant DH, Albers JW. 2001b. Serum dioxin and peripheral neuropathy in veterans of Operation Ranch Hand. Neurotoxicology 22:479â490. 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):396â405. 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):211â221. Mills PK, Yang R. 2005. Breast cancer risk in Hispanic agricultural workers in California. Interna- tional Journal of Occupational and Environmental Health 11(2):123â131. Mills PK, Yang R, Riordan D. 2005. Lymphohematopoietic cancers in the United Farm Workers of America (UFW), 1988â2001. Cancer Causes and Control 16(7):823â830. 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 20:967â974. 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 32:357â366. Morrison HI, Semenci RM, Morison D, Magwood S, Mao Y. 1992. Brain cancer and farming in western Canada. Neuroepidemiology 11:267â276. 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 caseâcontrol study of brain gliomas and occupational exposure to chemical carcinogens: The risks to farmers. American Journal of Epidemiology 128:778â785. NAS (National Academy of Sciences). 1974. The Effects of Herbicides in South Vietnam. Washington, DC: National Academy Press. NorstrÃ¶m 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 5:375â378. 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):65â80. Ott MG, Zober A. 1996. Cause speciï¬c mortality and cancer incidence among employees exposure to 2,3,7,8-TCDD after a 1953 reactor accident. Occupational and Environmental Medicine 53:606â612. 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 22:47â50.
EXPOSURE ASSESSMENT 257 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 256:2683â2686. 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 59:2000â2005. 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):335â343. 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):335â342. 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):184â190. 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):416â424. Piacitelli LA, Marlow DA. 1997. NIOSH 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure matrix. Or- ganohalogen Compounds 33:510â514. 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):895â901. Quadri SA, Qadri AN, Hahn ME, Mann KK, Sherr DH. 2000. The bioï¬avonoid galangin blocks aryl hydrocarbon receptor activation and polycyclic aromatic hydrocarbon-induced pre-B cell apoptosis. Molecular Pharmacology 58:515â525. 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):943â952. Ramlow JM, Spadacene NW, Hoag SR, Stafford BA, Cartmill JB, Lerner PJ. 1996. Mortality in a cohort of pentachlorophenol manufacturing workers, 1940â1989. American Journal of Indus- trial Medicine 30(2):180â194. 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 43:951â966. Rix BA, Villadsen E, Engholm G, Lynge E. 1998. Hodgkinâs disease, pharyngeal cancer, and soft tissue sarcomas in Danish paper mill workers. Journal of Occupational and Environmental Medicine 40(1):55â62. Robinson CF, Waxweiler RJ, Fowler DP. 1986. Mortality among production workers in pulp and paper mills. Scandinavian Journal of Work, Environment and Health 12:552â560. Ronco G, Costa G, Lynge E. 1992. Cancer risk among Danish and Italian farmers. British Journal of Industrial Medicine 49:220â225. 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):650â657. Safe S. 1997â1998. Limitations of the toxic equivalency factor approach for risk assessment of TCDD and related compounds. Teratogenesis, Carcinogenesis, and Mutagenesis 17(4-5):285â304.
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):225â233. Saracci R, Kogevinas M, Bertazzi PA, Bueno de Mesquita BH, Coggon D, Green LM, Kauppinen T, LâAbbe 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 338:1027â1032. Savitz DA, Arbuckle T, Kaczor D, Curtis KM. 1997. Male pesticide exposure and pregnancy outcome. American Journal of Epidemiology 146(12):1025â1036. 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 15:1613â1620. 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):218â220. 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):408â413. 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 35:3809â3815. 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 93:177â179. 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 37:197â200. 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 84:104â108. Solet D, Zoloth SR, Sullivan C, Jewett J, Michaels DM. 1989. Patterns of mortality in pulp and paper workers. Journal of Occupational Medicine 31:627â630. 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):779â786. 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 154:451â458. Stellman JM, Stellman SD. 2003. Contractorâs 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 fulï¬llment 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 422:681â687. 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 111:321â328. 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 9:305â321. Stellman SD, Stellman JM. 2004. Exposure opportunity models for Agent Orange, dioxin, and other military herbicides used in Vietnam, 1961â1971. Journal of Exposure Analysis and Environ- mental Epidemiology 14:354â362. Swaen GMH, van Vliet C, Slangen JJM, Sturmans F. 1992. Cancer mortality among licensed herbi- cide applicators. Scandinavian Journal of Work, Environment and Health 18:201â204.
EXPOSURE ASSESSMENT 259 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 19:973â977. 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 23:845â858. ât 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):34â40. 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):1263â1270. 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):245â250. Thomas TL, Kang HK. 1990. Mortality and morbidity among Army Chemical Corps Vietnam veter- ans: A preliminary report. American Journal of Industrial Medicine 18:665â673. 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):742â753. US GAO (US General Accounting Ofï¬ce). 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):223â241. 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): 989â997. Viel JF, Arveux P, Baverel J, Cahn JY. 2000. Soft-tissue sarcoma and non-Hodgkinâs lymphoma clusters around a municipal solid waste incinerator with high dioxin emission levels. American Journal of Epidemiology 152(1):13â19. Vineis P, Terracini B, Ciccone G, Cignetti A, Colombo E, Donna A, Mafï¬ 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 13:9â17. 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):1289â1292. 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):310â318. Warren WF. 1968. A Review of the Herbicide Program in South Vietnam. San Francisco, CA: Scien- tiï¬c 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):467â472.
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-Hodgkinâs lymphoma mortality and agricultural practices in Saskatchewan. Journal of the National Cancer Institute 82:575â582. Wiklund K, Holm L-E. 1986. Soft tissue sarcoma risk in Swedish agricultural and forestry workers. Journal of the National Cancer Institute 76:229â234. Wiklund K, Lindefors BM, Holm L-E. 1988a. Risk of malignant lymphoma in Swedish agricultural and forestry workers. British Journal of Industrial Medicine 45:19â24. Wiklund K, Dich J, Holm L-E. 1988b. Soft tissue sarcoma risk in Swedish licensed pesticide applica- tors. Journal of Occupational Medicine 30:801â804. Wiklund K, Dich J, Holm L-E. 1989. Risk of soft tissue sarcoma, Hodgkinâs disease and non-Hodgkin lymphoma among Swedish licensed pesticide applicators. Chemosphere 18:395â400. Woods JS, Polissar L. 1989. Non-Hodgkinâs lymphoma among phenoxy herbicide-exposed farm workers in western Washington State. Chemosphere 18:401â406. 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):115â122. 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):143â146. 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):209â221. 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):349â358. 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):347â348. Zack JA, Gaffey WR. 1983. A mortality study of workers employed at the Monsanto company plant in Nitro, West Virginia. Environmental Science Research 26:575â591. Zahm SH, Weisenburger DD, Babbitt PA, Saal RC, Vaught JB, Cantor KP, Blair A. 1990. A caseâ control study of non-Hodgkinâs lymphoma and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in eastern Nebraska. Epidemiology 1:349â356. 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):139â157.