Assessment of human exposure to herbicides and the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a key element in determining whether specific health outcomes are linked to them. This chapter reviews information on occupational and environmental exposures to herbicides and TCDD, including exposure of Vietnam veterans. It discusses exposure assessments from selected epidemiologic studies introduced in Chapter 4 and provides background information for the health-outcome chapters that follow; health outcomes are not discussed here. Further discussion of exposure assessment, and a detailed review of the US military’s wartime use of herbicides in Vietnam can be found in Chapters 3 and 6 of Veterans and Agent Orange (VAO; IOM, 1994); additional information is in Chapter 5 of Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), and Update 2002 (IOM, 2003a). Reviews of the most recent studies of the absorption, distribution, metabolism, and excretion of herbicides and TCDD can be found in the discussion of toxicokinetics in Chapter 3 of this report.
EXPOSURE ASSESSMENT FOR EPIDEMIOLOGY
Exposure to contaminants can be defined as the amount of the contaminant that contacts a body barrier and is available for absorption over a defined period. Ideally, exposure assessment would quantify the amount of a compound at the site of toxic action in the tissue of an organism. In studies of human populations, however, it generally is not possible to measure those concentrations. Instead, exposure assessments are based on measurements in environmental media or in
biologic specimens. In either case, exposure serves as a surrogate for dose. Exposure assessments based on measurements of environmental contaminants attempt to quantify the amount of the contaminant that contacts a body barrier over a defined period. Exposure can occur through inhalation, skin contact, and ingestion. Exposure also can be assessed by measuring the compounds of interest—or their metabolites—in human tissues. Such biologic markers of exposure integrate absorption from all routes. The evaluation of those markers can be complex, because most are not stable for long periods. Knowledge of pharmacokinetics is essential to the linkage of measurements at the time of sampling with past exposures. Similarly, the assessment of markers that could be markers of effect—such as DNA adducts—shows promise, but does not necessarily provide accurate measurements of past exposure; that is, there is little evidence that currently measured DNA adducts are related to occupational or environmental exposures experienced years before.
Because quantitative assessments based on environmental or biologic samples are not always available for epidemiologic studies, investigators rely on a mixture of qualitative and quantitative information to derive estimates. There are a few basic approaches to exposure assessment for epidemiology (Armstrong et al., 1994; Checkoway et al., 1989). The simplest compares the members of a presumably exposed group with the general population or with a non-exposed group. That approach offers simplicity and ease of interpretation. If, however, only a small fraction of the group is exposed to the agent, the increased risk posed by exposure might not be detectable when the risk of the entire group is assessed.
A more refined method assigns each study subject to an exposure category, typically high, medium, low, or no exposure. Disease risk for each group is calculated separately and compared with a reference or non-exposed group. That method can identify the presence or absence of a dose–response trend. In some cases, more-detailed information is available for use in quantitative exposure estimates, which are sometimes called exposure metrics. They integrate quantitative estimates of exposure intensity (such as air concentration or extent of skin contact) with exposure duration to produce an estimate of cumulative exposure. Ideally, these refined estimates reduce errors associated with misclassification and thereby increase the power of statistical analysis to identify true associations between exposure and disease.
The temporal relationship between exposure and disease is complex and often difficult to define in epidemiologic investigations. Many diseases do not appear immediately following exposure. In the case of cancer, for example, the disease may not appear for many years after the exposure. The time between an exposure 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, an individual exposed to a chemical that is stored in the body may continue
to experience “internal exposure” for years, even if exposure from the environment has ceased. The definition of the proper time frame for exposure duration represents a challenging aspect of exposure assessment and epidemiology.
Occupational–exposure studies use work histories, job titles, and workplace measurements of contaminant concentration; those data are combined to create a job–exposure matrix that assigns a quantitative exposure estimate to each job or task, and the time spent on each job or task is calculated. Those metrics incorporate exposure mitigation factors, such as process changes, engineering controls, or the use of protective clothing. The production worker cohort analysis conducted by the US National Institute for Occupational Safety and Health (NIOSH) used those methods.
Many environmental-exposure studies use proximity to the source of a contaminant to classify exposure. If an industrial facility emits a contaminant, investigators might identify geographic zones around the facility and assign exposure categories to people on the basis of residence. That approach was used to analyze data from the industrial accident in Seveso, Italy, that contaminated nearby areas with TCDD. Assessments often are refined to include exposure pathways (how chemicals move from the source through the environment) and personal behavior; they sometimes include measurements of contaminants in environmental samples, such as soil.
Biologic markers of exposure can provide important information for use in occupational and environmental studies; a quantitative exposure estimates can be assigned to each person in the study group. The most important marker in the context of Vietnam veterans’ exposure to Agent Orange is the measurement of TCDD in serum. Studies of the absorption, distribution, and metabolism of TCDD have been conducted over the past 20 years. In the late 1980s, the Centers for Disease Control and Prevention (CDC) developed a highly sensitive assay to detect TCDD in serum and demonstrated a high correlation between serum TCDD and TCDD in adipose tissue (Patterson et al., 1986, 1987). The serum TCDD assay is now used extensively to evaluate exposure in Vietnam veterans and other people.
Exposure to Dioxin-like Compounds
A major focus of the work of the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fifth Biennial Update) has been the analysis of studies involving exposure to a single compound: 2,3,7,8-tetrachlorodibenzo-p-dioxin, or TCDD. The committee recognizes that there are hundreds of similar compounds to which humans might be exposed, among them the polychlorinated biphenyls (PCBs), other polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and polycyclic aromatic hydrocarbons. The literature on those compounds was often not considered in this evaluation, for several reasons. The exposure of Vietnam veterans to significant amounts (relative to TCDD) was considered unlikely or had not been docu-
mented. Several of them might act by different mechanisms in addition to their ability to bind to and activate the aryl hydrocarbon receptor (AhR). Those mechanisms are sometimes related to the ability of the compounds to be metabolized to chemicals that might induce greater biologic activity. In addition, the exposure of human populations, for example occupationally, to those compounds occurs most often along with exposures to other compounds. It is difficult to determine whether the toxic effects should be attributed to the dioxin-like compound or to some other compound that has a different mechanism of action.
The toxic equivalency factor (TEF) method of comparing the relative toxicity of dioxin-like compounds has come into common use by agencies of governments around the world. Although it is considered among the best of the approaches for assessing the relative risk posed by exposure to complex mixtures of the contaminants, it presents several uncertainties. TEFs are determined through inspection of the available congener-specific biologic and biochemical data on a compound and then assignment of a relative toxicity for that compound in comparison with TCDD. TEF values are by no means precise; they are the result of scientific judgment and expert opinion considering all available data. The quantity and quality of those data might vary considerably, and the values might differ by several orders of magnitude, depending on the different biologic endpoints chosen for a particular compound. Thus, there is considerable unquantifiable, uncertainty about their use. Although the World Health Organization values (Van den Berg et al., 1998) are most often cited and generally accepted, the values used can differ slightly among states, countries, and health organizations. Nevertheless, most agencies in the United States, including the Environmental Protection Agency, support the basic approach as providing a “reasonable estimate” of relative toxicity. Many countries and international organizations have adopted it although, again, the accepted values might differ.
The TEF concept is based on the premise that the toxic and biologic responses of a particular group of compounds are mediated through the AhR. Although all the available data support that idea, the set of data on individual compounds within the group considered to be dioxin-like is incomplete. One limitation is that use of TEF values does not consider synergistic or antagonistic interactions among the compounds. It also does not consider possible actions or interactions of compounds that are not mediated by the AhR. Indeed, little research has been done on this. For some mixtures, another limitation is that the risk posed by non-dioxin-like chemicals (non-coplanar PCBs) is not assessed, and some non-coplanar PCBs can act as AhR antagonists (Safe, 1997–1998). The kinetics and metabolism of each dioxin-like compound might differ considerably from the others, and complete data on tissue concentrations often are unavailable.
Extrapolation to a meaningful dose might add considerable uncertainty to calculation of the TCDD toxicity equivalent (TEQ) to which a person was exposed. There also is exposure to dietary flavonoids and other phytochemicals that bind the AhR that is not considered by the TEQ method (Ashida et al., 2000; Ciolino
et al., 1999; Quadri et al., 2000). Considering the many difficulties of interpretation relative to the exposure of veterans to Agent Orange and other herbicides in Vietnam, some published literature on humans exposed either occupationally or environmentally to several other dioxin-like compounds was not evaluated. However, when such exposures were considered relevant to Vietnam veterans, the data were critically evaluated.
OCCUPATIONAL EXPOSURE TO HERBICIDES AND TCDD
The committee reviewed many epidemiologic studies of occupationally exposed groups for evidence of an association between health risks and exposure to TCDD and the herbicides used in Vietnam, primarily the phenoxy herbicides 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and chlorophenols. In reviewing the studies, the committee explicitly considered two types of exposure: exposure to TCDD itself and exposure to the various herbicides, particularly 2,4-D and 2,4,5-T. Separate consideration was necessary because of the possibility that, for example, some health effects could be associated with exposure to 2,4-D in agriculture and forestry. TCDD is an unwanted byproduct of 2,4,5-T production, but not of 2,4-D, although small quantities of other dioxins can be found in 2,4-D.
Studies of occupational exposure to dioxins focus primarily on workers in chemical plants that produce phenoxy herbicides or chlorophenols. Other occupationally exposed groups include workers in agriculture and forestry who spray herbicides, sawmill workers exposed to chlorinated dioxins from contaminated wood preservatives, and pulp-and-paper workers exposed to dioxins through the pulp-bleaching process.
US National Institute for Occupational Safety and Health Cohort Study
One extensive set of data on chemical production workers potentially contaminated with TCDD has been compiled by NIOSH. More than 5,000 TCDD-exposed workers in 12 companies were identified from personnel and payroll records. Exposure status was determined initially through a review of process operating conditions; employee duties; and analytical records of TCDD in industrial-hygiene samples, process streams, products, and waste (Fingerhut et al., 1991). Occupational exposure to TCDD-contaminated processes was confirmed by measuring serum TCDD in 253 cohort members. Duration of exposure was defined as the number of years worked in processes contaminated with TCDD and was used as the primary exposure metric in the study. The use of duration of exposure as a surrogate for cumulative exposure was based on the high correlation (Pearson correlation efficient = 0.72) between log-transformed
serum TCDD and years worked in TCDD-contaminated processes. Duration of exposure for individual workers was calculated from work records, and exposure duration categories were created: <1 year, 1 to <5 years, 5 to <15 years, and 15+ years. In some cases, information was not available for duration of exposure, so a separate metric, called duration of employment, was defined as the total time each worker was employed at the study plant.
The NIOSH cohort study was updated in 1999 (Steenland et al., 1999), and a more refined exposure assessment was conducted. Workers whose records were inadequate to determine duration of exposure were excluded. The final analysis was restricted to 8 plants because 4 plants (with 591 workers) had no records on the degree of TCDD contamination of work processes or lacked the detailed work histories required to estimate TCDD exposure by job. Another 38 workers at the remaining 8 plants were eliminated because they worked in processes in which TCDD contamination could not be estimated. Finally, 727 workers with exposure to both pentachlorophenol (PCP) and TCDD were eliminated to avoid possible confounding of any TCDD effects by PCP effects. Those restrictions led to a subcohort of 3,538 workers (69% of the overall cohort).
The exposure assessment for the subcohort was based on a job–exposure matrix (Piacitelli and Marlow, 1997) that assigned each worker a quantitative exposure score for each year of work. The score was based on three factors: concentration of TCDD in micrograms per gram of process materials, fraction of the day when the worker worked in the specific process, and a qualitative contact value (0.01–1.5) based on the estimated TCDD contamination reaching exposed skin or the potential for inhalation of TCDD-contaminated dust. The scores for each year of work were combined to yield a cumulative exposure score for each worker. The new exposure analysis presumably reduced misclassification (through exclusion of non-exposed workers) and uncertainty (through exclusion of workers with incomplete information) and improved accuracy (through more detailed information on daily exposure).
Steenland et al. (2001) conducted a detailed exposure–response analysis from data on workers at one of the original 12 companies in the cohort study. A group of 170 workers was identified with serum TCDD greater than 10 parts per trillion (ppt), as measured in 1988. The investigators conducted a regression by using the following information: the work history of each worker, the exposure scores for each job held by each worker over time, a simple pharmacokinetic model for the storage and excretion of TCDD, and an estimated TCDD half-life of 8.7 years. That pharmacokinetic model allowed calculation of the estimated serum TCDD concentration at the time of last exposure for each worker. Results of the analysis were used to estimate serum TCDD over time that was attributable to occupational exposure for all 3,538 workers in the subcohort defined in 1999.
Crump et al. (2003) conducted a meta-analysis of dioxin–cancer, dose–response studies for three occupational cohorts: the NIOSH cohort (Fingerhut et al., 1991); the Hamburg cohort (Flesch-Janys et al., 1998); and the BASF cohort
(Ott and Zober, 1996). That analysis incorporated recent exposure data for the NIOSH cohort generated by Steenland et al. (2001). No other reports on the cohort have been published since Update 2002. An update of the Dow Chemical Company worker cohort (Bodner et al., 2003), which is part of the NIOSH cohort, is discussed below.
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 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 manufacturers of chlorophenoxy herbicides or chlorinated phenols and for spraying cohorts. Surveys were completed with the assistance of industrial hygienists, workers, and factory personnel. Industry and production records also were used. Job histories were examined when available. Workers were classified as exposed, probably exposed, exposure unknown, or non-exposed. The exposed-workers group (N = 13,482) consisted of all known to have sprayed chlorophenoxy herbicides and all who worked in particular aspects of chemical production. Two cohorts (N = 416) had no job titles available but were deemed probably exposed. Workers with no exposure information (N = 541) were classified as “exposure unknown.” Non-exposed workers (N = 3,951) were those who had never been employed in parts of factories that produced chlorophenoxy herbicides or chlorinated phenols and those who had never sprayed chlorophenoxy herbicides. Review of the later analysis indicated that the lack of detailed occupational exposure information prevented meaningful classification beyond exposed and non-exposed.
An expanded and updated version of that cohort study was published in 1997 (Kogevinas et al., 1997). The researchers added herbicide production workers from 12 plants in the United States (the NIOSH cohort) and from 4 plants in Germany. Exposure was reconstructed from individual job records, company exposure questionnaires developed specifically for the study, and, in some cohorts, measurements of TCDD and other dioxin and furan congeners in serum and adipose tissue and in the workplace. The 21,863 workers exposed to phenoxy herbicides or chlorophenols were classified in three categories of exposure to TCDD or higher-chlorinated dioxins: those exposed (N = 13,831), those not exposed (N = 7,553), and those with unknown exposure (N = 479). Several exposure metrics were constructed for the cohort—years since first exposure, duration of exposure (in years), year of first exposure, and job title—but detailed
methods were not described. No new studies of the full cohort have been reported since Update 2000.
Researchers have studied various subgroups of the IARC cohort. Flesch-Janys et al. (1995) updated the cohort and added quantitative exposure assessment based on blood or adipose measurements of polychlorinated dibenzo-p-dioxin and furan (PCDD/F). Using a first-order kinetics model, half-lives from an elimination study in 48 workers from this cohort, and background concentrations for the German population, the authors estimated PCDD/F exposure of the 190 workers by mean of measurements of serum or adipose concentrations of PCDD/F. The authors regressed the estimated PCDD/F exposure of those workers at the end of their exposure against the length of time they worked in each production department in the plant. The authors estimated the contribution of the time worked in each production department to PCDD/F exposure. 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 person’s exposure. The epidemiologic analysis used the estimated TCDD doses.
Becher et al. (1996) reported on analysis of several German cohorts, including the Boehringer–Ingelheim 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 a cohort from a Bayer plant in Uerdingen and a Bayer plant in Dormagen. All of the plants were involved in production of phenoxy herbicides or chlorophenols. Exposure assessment involved estimation of duration of employment from the start of work in a department where exposure was possible until the end of employment at the plant; a period that could include some time without exposure. Analysis was based on time since first exposure.
Hooiveld et al. (1998) reported on an update of a mortality study of workers (production workers who had known exposure to dioxins, workers in herbicide production, non-exposed production workers, and workers known to be exposed as a result of an accident that occurred in 1963) from two chemical factories in the Netherlands. Assuming first-order TCDD elimination with an estimated half-life of 7.1 years, measured TCDD levels were extrapolated to the time of maximum exposure (TCDDmax) for a group of 47 workers. A regression model then estimated the effect on estimated TCDDmax for each cohort member attributable to exposure as a result of the accident, duration of employment in the main production department, and time of first exposure before (or after) 1970.
No new report for that cohort has been published since Update 2002. An update of the Dow Chemical Company worker cohort (Bodner et al., 2003), which is part of the IARC cohort, is discussed below.
Dow Cohort Studies
Workers at Dow Chemical Company facilities where 2,4-D was manufactured, formulated, or packaged have been the subject of a cohort analysis since
the 1980s (Bond et al., 1988). Industrial hygienists developed a job–exposure matrix 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 employee work histories to assign an exposure magnitude to each job assignment. A cumulative dose was then developed for each of the 878 employees by multiplying the representative 8-h 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. The 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 classification of workers into low-, moderate-, and high-exposure groups. Biologic monitoring of 2,4-D in a subset of workers could provide a straightforward evaluation of the validity of the job–exposure matrix but apparently it was not undertaken 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 modified the exposure assessment procedures of the original study. Since Update 2002, new cancer risk estimates for that cohort have been reported (Bodner et al., 2003). The exposure assessment procedures were unchanged from previous studies.
Dow also has conducted a cohort study of manufacturing workers exposed to PCP (Ramlow et al., 1996). Exposure assessment for that 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 controls 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 airborne PCP in the flaking–prilling–packaging area; the industrial-hygiene data suggest about a 3-fold difference between the areas of highest to lowest potential exposure. All jobs were therefore assigned an estimated exposure intensity score on a scale of 1–3 (from lowest to highest potential exposure intensity). Reliable information concerning the use of personal protective equipment was not available for modification of estimated exposure intensity.
Cumulative PCP and TCDD exposure indexes were calculated for each subject by multiplying the duration of each exposed job by its estimated exposure intensity and then adding the products across all exposed jobs.
Other Production Worker Studies
Several other occupational studies for chemical production plants have relied on job titles as recorded on individual work histories and company personnel records to classify exposure (Coggon et al., 1986, 1991; Cook et al., 1986; Ott et al., 1980; Zack and Gaffey, 1983; Zober et al., 1990). Similarly, 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).
Agriculture, Forestry, and Other Outdoor Work
Occupational studies for agricultural workers have had various methods to estimate exposure to herbicides or TCDD. The simplest method derives occupational data from death certificates, 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 the specific exposure. Some studies of agricultural workers have attempted to investigate differences in occupational practices, allowing identification 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). Other studies have used county of residence as a surrogate for exposure, relying on agricultural censuses of farm production and chemical use to characterize exposure in individual countries (Blair and White, 1985; Cantor, 1982; Gordon and Shy, 1981). Still others have attempted to refine exposure estimates by categorizing exposure on the basis of the number of years employed in a specific 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). Some studies used self-reported information on exposure that recounted direct handling of a 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). Other studies have validated self-reported information through written records, signed statements, 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 workers, are likely to have been exposed to herbicides and other compounds (see Table A-1 in Appendix A for a summary of studies). Exposure for those groups has been classified by approaches similar to those noted above for agricultural workers, for example, by the number of years employed, job category, and occupational title.
The Ontario Farm Family Health Study has produced several reports that are relevant to phenoxyacetic acid herbicide exposures, 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 building pesticides. Subjects were asked whether they participated in those activities during each month, and their exposure classifications were based on activities in 3-month segments of time. The exposure classification was refined
through answers to questions regarding use of protective equipment and specificity 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 provided semen and urine samples for 2,4-D analysis.
The Ontario Farm Family Health Study also examined the effect of pesticide exposure, including 2,4-D, on time to pregnancy (Curtis et al., 1999) and the risk of spontaneous abortion (Arbuckle et al., 1999b, 2001). About 2,000 farm couples participated in the study. Exposure information was pooled from interviews with husbands and wives to construct a history of monthly agricultural and residential pesticide use. Exposure classification was based on a yes/no 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). Assuming 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 classification error (that is, the questionnaire results were less accurate than was the urine analysis), the questionnaire’s prediction of exposure, when compared with the urine 2,4-D concentrations, had a sensitivity of 57% and a specificity of 86%. In multivariate models, the variables for pesticide formulation, protective clothing and gear, application equipment, handling practice, and personal-hygiene practice were significant as predictors of urinary herbicide concentrations in the first 24-h after application was initiated.
The Agricultural Health Study in the United States enrolled approximately 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 is based primarily on questionnaire data collected at the time of enrollment and in periodic follow-up. Recently, Dosemeci et al. (2002) published 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. That new quantitative approach is likely to improve the accuracy of exposure classification for the cohort.
Studies of herbicide applicators are relevant because they can be presumed to have had more 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 specific phenoxy herbicides or TCDD is complicated. Some studies have attempted to measure applicators’ exposure on the basis of information from work records on acreage sprayed or on the number of days of spraying. Employ-
ment 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 specifically identified licensed or registered pesticide and herbicide applicators (Blair et al., 1983; Smith et al., 1981, 1982; Swaen et al., 1992; Wiklund et al., 1988b, 1989). Individual estimates of the intensity and frequency of exposure were rarely quantified in the studies that the committee examined, however, and many applicators were known to have applied many kinds of herbicides, pesticides, and other substances. In addition, herbicide spraying is generally a seasonal occupation, and information is not always available on possible exposure-related activities during the rest of the year.
One study provided information on serum TCDD concentrations in herbicide applicators. Smith et al. (1992) analyzed blood from nine professional spray applicators in New Zealand who first sprayed before 1960 and were also spraying in 1984. The duration of actual spray work varied from 80 to 370 months. Serum TCDD was 3–131 ppt on a lipid basis (mean = 53 ppt). The corresponding values for age-matched controls were 2–11 ppt (mean = 6 ppt). Serum TCDD was positively correlated with the number of months of professional spray application.
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 2–4% of the chemical that contacts the skin being absorbed into the body during a normal workday. Air concentrations 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 0.1–5 mg/day; for air crews the value was lower.
A study of Canadian farmers examined pesticide exposures of men (McDuffie et al., 2001). Data were collected by questionnaires that included information on specific chemicals (including 2,4-D), frequency of application, and duration of exposure. A small validation study (N = 27) was performed to test the self-reported pesticide use data against records of purchases. Investigators reported an “excellent concordance” between the two sources, but they did not provide a statistical analysis. 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-h 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.
Other studies of the agricultural use of pesticides published recently do not provide specific information on exposure to 2,4-D, TCDD, or other compounds relevant to Vietnam veterans’ 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).
Pulp and Paper Mill Work
Pulp and paper mill workers are likely to be exposed to TCDD and chlorinated phenols during the bleaching process. Pulp and paper production workers also are likely to be exposed to other compounds, depending on the type of paper mill or pulping operation and the product manufactured (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 occupational exposure, and the qualitative assessment of compounds used by each department does not include chlorinated organic compounds, although chlorine, chlorine dioxide, and hypochlorite were used. No new studies of those populations have been reported since Update 2000.
In the past, workers in sawmills might have been exposed to pentachlorophenates, which are contaminated with higher-chlorinated PCDDs (Cl6–Cl8), or to tetrachlorophenates, which are less contaminated with higher-chlorinated PCDDs. Wood is dipped in those chemicals 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 EXPOSURE 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.
A large industrial accident involving environmental exposure to TCDD occurred 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 defined 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 first trimester 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 presented by Mocarelli et al. (1990, 1991) and by CDC (1988a). In those with severe chloracne (N = 10), TCDD was 828–56,000 ppt of lipid weight. Those without chloracne (N = 10) had TCDD 1,770–10,400 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 backward 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 seem much less likely than children to develop chloracne after acute exposure, but surveillance bias could have affected that finding. Recent updates (Bertazzi et al., 1998, 2001) have not changed the exposure assessment approach.
The validity of exposure classification by zone was tested recently as a part of the Seveso Women’s Health Study (Eskenazi et al., 2001). Investigators measured serum 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 participants’ zone of residence. Zone of residence explained 24% of the variability in serum TCDD. Addition of the questionnaire data improved the regression model, explaining 42% of the variance. Those findings demonstrate a significant association between zone of residence and serum TCDD, but much of the variability in TCDD concentrations is still unexplained by the models.
Several new studies of the Seveso population have been published since Update 2002 (Baccarelli et al., 2002; Eskenazi et al., 2002a,b, 2003, 2004; Landi et al., 2003). All of the studies used lipid-adjusted serum TCDD concentrations as the primary exposure metric. 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 concentrations in the Seveso study zone. 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 breast-fed children in the Seveso area are likely to have higher body burdens of TCDD than are children from other areas.
Times Beach, Missouri
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 production 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 et al., 1986). Other investigations of Times Beach have estimated exposure risk on the basis of residents’ reported occupational and recreational activities in the sprayed area. Exposure has been estimated from 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 with comparison concentrations from 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 20–100 parts per billion (ppb) or for 6 months or more with soil contaminated with TCDD above 100 ppb. Of the exposed-population samples, 87% had adipose tissue TCDD concentrations below 200 ppt; however, TCDD concentrations in 7 of the 51 exposed persons were 250–750 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 2 study participants would have had adipose tissue TCDD near 3,000 ppt at the time of the last date of exposure. No new studies have been published since Update 2000.
Viel et al. (2000) reported on an investigation of apparent clusters of cases of soft-tissue sarcoma and non-Hodgkin’s 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 Besançon electoral ward in western Doubs. Dioxin emissions from the incinerator were measured 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 cows’ 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. No new studies have been published since Update 2000.
Researchers in the Samara region of Russia have identified 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 cows’ milk. However, the researchers do not describe air-, soil-, or water-sampling methods. The number 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 unreported for others (air, soil, and vegetables). Results from the samples suggested elevated 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 2–7 km from the plant, and 4 ng TEQ/kg soil 7–10 km from the plant. Concentrations outside the city (10–15 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 influenced TCDD exposure.
One additional article has been published on the Chapaevsk population since Update 2002. Akhmedkhanov et al. (2002) sampled 24 volunteers 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 is not clear whether the analysis included adjustments for age, body mass index, or education, all of which are significant predictors of dioxin concentrations.
Several epidemiologic studies have been conducted in association with industrial-facility emissions, or in regions with documented differences in dioxin
exposures. 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 define 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 Mantua, 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 recent study of dioxin exposure pathways in Belgium focused on long-time residents in the vicinity of two municipal-waste incinerators (Fierens et al., 2003a). Residents near a rural incinerator had significantly higher serum dioxin concentrations than did a control group (38 vs. 24 picograms [pg] TEQ/g fat). Concentrations in 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. The object was to identify an association for dioxin and PCB exposures with diabetes and endometriosis (Fierens et al., 2003b). No difference in body burden was found between women with endometriosis and women in a control group, but the risk of diabetes was significantly 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).
Studies in Vietnam
Studies of exposure to herbicides among the residents of South Vietnam (Constable and Hatch, 1985) have compared unexposed residents of the South with residents of the North. Other studies have attempted to identify wives from veterans of North Vietnam who served in South Vietnam. Records of herbicide sprays have been used to refine 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 a 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 3–103 ppt. TCDD was not detected in 9 samples from residents of North Vietnam who had never been to South Vietnam; detection sensitivity was 2–3 ppt. Analysis of 3 breast-milk samples collected in 1973 from Vietnamese women thought to have been exposed to Agent Orange yielded concentrations of 77–230 ppt on a lipid basis.
In a more recent study, 43 residents of Bien Hoa City provided blood samples for TCDD analysis (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 consumption of fish and other foods.
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 identified locations where relatively high dioxin concentrations remain in soil or water systems. Dioxin soil concentrations were particularly high around former airfields and military bases where herbicides were handled. Fish harvested from ponds in these areas were found to contain elevated dioxin concentrations. The study is not directly relevant to this Institute of Medicine (IOM) committee’s task, but it could prove useful in future epidemiologic studies of the Vietnamese population.
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 primarily used by the US Air Force’s Operation Ranch Hand to defoliate inland hardwood forests; coastal mangrove forests; and, to a lesser extent, cultivated land. In 1974, a National Academy of Sciences committee estimated the amount of herbicides sprayed from helicopters and other aircraft using Operation Ranch Hand records gathered from August 1965 to February 1971 (NAS, 1974). The committee calculated that about 17.6 million gallons (~66.5 million liters [L]) of herbicide were sprayed over about 3.6 million acres (~1.5 million hectares) in Vietnam in that time period. Soldiers also sprayed herbicides on the ground to defoliate the perimeters of base camps and fire bases; that spraying was performed from the rear of trucks and from backpack spray units carried by soldiers. Navy boats also sprayed herbicides along river banks.
A new analysis of spray activities and exposure potential of troops emerged from a recent study overseen by a committee of the IOM (Stellman and Stellman, 2003). Location data for military units assigned to Vietnam were compiled into a database developed from five primary and secondary sources: the Unit Identification 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 Office 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 generally 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.
“Mobility factor” analysis, a new concept for studying troop movement, was developed for use in reconstructing herbicide exposure histories. The analysis is a three-part classification 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; ground—truck, tank, or armored personnel carrier; or water). A mobility factor was assigned to every unit that served in Vietnam.
The same work also yielded new estimates of the use of military herbicides in Vietnam from 1961 to 1971 (IOM, 2003b,c; Stellman et al., 2003a). Investigators reviewed the original data used in the 1970s to make estimates and identified inconsistencies, 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 clarified data on missions that presumably “dumped” 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 (Table 5-1). Previous VAO reports estimated that a total of ~67.8 million L of military herbicides were applied from 1961 to 1971. The new research effort estimated that ~77 million L was applied; a difference of more than 9 million L.
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 contains an organic form of arsenic.
Herbicides were identified by the color of a band on 55-gal containers and called Agents Pink, Green, Purple, Orange, White, and Blue (Table 5-1). 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
TABLE 5-1 Military Use of Herbicides in Vietnam (1961–1971)
Concentration of Active Ingredienta
60%–40% n -butyl, isobutyl ester of 2,4,5-T
961–1,081 g/L acid equivalent
464,817 L (122,792 gal)
50,312 L sprayed; 413,852 L additional on procurement records
n-butyl ester 2,4,5-T
31,071 L (8,208 gal)
31,026 L shown on procurement records
50% n-butyl ester 2,4-D, 30% n-butyl ester 2,4,5-T, 20% isobutyl ester 2,4,5-T
1,033 g/L acid equivalent
548,883 L (145,000 gal)
50% n-butyl ester 2,4-D, 50% n-butyl ester 2,4,5-T
1,033 g/L acid equivalent
42,629,013 L (11,261,429 gal)
45,677,937 L (could include Agent Orange II)
50% n-butyl ester 2,4-D, 50% isooctyl ester 2,4,5-T
910 g/L acid equivalent
Unknown, but at least 3,591,000 L shipped
Acid weight basis: 21.2% triisopropanolamine salts of 2,4-D and 5.7% picloram
By acid weight: 240 g/L 2,4-D and 65 g/L picloram
19,860,108 L (5,246,502 gal)
Cacodylic acid (dimethylarinic acid) and sodium cacodylate
Acid: 65% active ingredient; salt: 70% active ingredient
Blue Aqueous Solution
21% Sodium cacodylate + cacodylic acid to yield at least 26% total acid equivalent by weight
Acid weight: 360 g/L
4,255,952 L (1,124,307 gal)
Total, all formulations
67,789,844 L (17,908,238 gal)
76,954,766 L (including procured)
a Based on Stellman et al. (2003a).
b Based on data from MRI (1967), NAS (1974), and Young and Reggiani (1988).
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, Dinoxol, Trinoxol, and diquat were applied to native grasses and bamboo (Brown, 1962). Soil-applied herbicides also were reportedly used around base camp perimeters, minefields, 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, insecticides, insect repellents, wetting agents, and wood preservatives (Gonzales, 1992). There are no data on the number of military personnel potentially exposed to those substances.
Air and Ground Spraying of Herbicides
The number of US military personnel who directly handled (mixed, loaded, or applied) herbicides is impossible to determine precisely, but most of those assigned to Operation Ranch Hand can be presumed to have been exposed to Agent Orange and other herbicides. The US Army Chemical Corps, using hand-operated equipment and helicopters, conducted smaller operations, including defoliation around special forces camps; clearing the perimeters of airfields, 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 herbicides to remove underbrush and dense growth in constructing fire 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 conflict (US GAO, 1979).
Recent work conducted under contract with the IOM (IOM, 1997, 2003b,c) has produced a geographic information system for characterizing exposure of ground troops to Agent Orange and other herbicides used in Vietnam (Stellman and Stellman, 2003; Stellman et al., 2003b). The method integrated extensive data resources on the dispersal of herbicides, locations of military units and bases, dynamic movement of combat troops in Vietnam, and locations of civilian population centers. It has been used to generate exposure opportunity models for Agent Orange, dioxin, and other herbicides used in Vietnam (Stellman and Stellman, 2004).
TCDD in Herbicides Used in Vietnam
TCDD is a contaminant of 2,4,5-T. Small quantities of other dioxins are present in 2,4-D. The concentration of TCDD in any given lot of 2,4,5-T depends 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 formulated differently from the materials for commercial application that were readily available in the United States (Young et al., 1978). TCDD concentrations in individual 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 conflict, 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).
New analyses resulted from the Department of Veterans Affairs (VA)-sponsored exposure characterization have proposed 366 kg of TCDD as a plausible estimate of the total amount of TCDD applied in Vietnam between 1961 and 1971; the true amount is thought to be higher (Stellman et al., 2003a). Before those estimates, data from Young and Gough were 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. Analysis of archive samples of Agent Purple reported TCDD as high as 45 ppm (Young, 1992). 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 ~368 lb (~167 kg) of TCDD was sprayed in Vietnam over a 6-year period.
EXPOSURE ASSESSMENT IN STUDIES OF VIETNAM VETERANS
Different approaches have been used to estimate the exposure of Vietnam veterans, including self-reports, record-based exposure estimates, and assessments of biologic markers of TCDD exposure. Each approach has a limited ability to ascribe individual exposure. Some studies rely on such gross markers as service in Vietnam—perhaps enhanced by branch of service, military region, military specialty, or combat experience—as a proxy for exposure to herbicides. Studies of that type include the CDC Vietnam Experience Study and Selected Cancers Study, VA mortality studies, and most studies of veterans conducted by the states. The approach almost surely underestimates the health effects of expo-
sure to herbicides; many members of the cohorts presumed to have been exposed to herbicides might, in reality, not have been.
Ranch Hand Studies
Job title while in the military has been shown to be a valid exposure classification for Air Force Ranch Hand personnel responsible for the aerial spraying of herbicides. Biologic marker studies of Ranch Hand personnel are consistent with their exposure to TCDD as a group. When the Ranch Hand cohort was further classified 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 Air Force Ranch Hand study relied on military records of TCDD-containing herbicides (Agents Orange, Purple, Pink, Green) sprayed as reported in the HERBS tapes for the period starting 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 for herbicide or TCDD exposure: number of days of skin exposure; percentage of skin area exposed; and the product of the number of days of skin exposure, percentage of skin exposed, and a factor for the concentration of TCDD in the herbicide. A fourth index that used no information gathered from individual subjects was calculated by multiplying the volume of herbicide sprayed during a person’s tour of duty by the concentration of TCDD in herbicides sprayed in that period and then dividing that product by the number of crew members in each job specialty at that time.
Each of the four models tested was significantly related to serum TCDD, although each explained only 19–27% of the variability in serum TCDD concentrations. Days of skin exposure had the highest correlation. Military job classification (non-Ranch Hand combat troops, Ranch Hand administrators, Ranch Hand flight engineers, and Ranch Hand ground crew), which is separate from the four indexes, explained 60% of the variability in serum TCDD. When the questionnaire-derived indexes were applied within each job classification, days of skin exposure added statistically significantly, but not substantially, to the variability explained by job alone.
Recent studies of the same population have used serum TCDD as the primary exposure index to examine possible associations with hepatic abnormalities, peripheral neuropathies, hematologic disorders, and cognitive functioning (Barrett et al., 2001; Michalek et al., 2001a,b,c).
Four new articles on the Ranch Hand cohort have appeared since Update 2002: Akhtar et al. (2004), Barrett et al. (2003), Michalek et al. (2003), and Pavuk et al. (2003). All of those studies used serum dioxin concentrations as the primary exposure metric for epidemiologic classification.
Army Chemical Corps Studies
Members of the US Army Chemical Corps performed ground and helicopter chemical operations and were thereby involved in the direct handling and distribution of herbicides in Vietnam. That population has only recently been identified 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 significantly (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 activities. The authors concluded that Agent Orange exposure was a likely contributor to TCDD concentrations in Vietnam veterans who had a history of spraying herbicides. The main study of 5,000 Vietnam veterans, including analysis of an additional 900 blood specimens, continues.
No new studies have been published related to the Army Chemical Corps since Update 2002.
Korean Vietnam Veterans
Military personnel from the Republic of Korea served in Vietnam between 1964 and 1973. Kim et al. (2001) evaluated the validity of an exposure index by comparing group exposure estimates with pooled serum dioxin concentrations. The study involved 720 veterans 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 for the military units stationed in Vietnam, and an exposure score derived from self-reported activities during service. A total of 13 blood samples were submitted to CDC for serum dioxin analysis. One sample was prepared from the 25 veterans who did not serve in Vietnam; the remaining 12 blood samples were created by pooling blood samples from 60 veterans into 12 exposure categories. The 12 categories ultimately were reduced to 4 exposure groups, each group containing 3 exposure categories and representing quartiles of veterans with Vietnam service.
The paper by Kim et al. (2001) reported highly significant Pearson correlation coefficients 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 inflating 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 concentrations and ordinal exposure categories, but the correlation was not statistically significant. The authors attributed the lack of statistical significance 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 0–4, 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 final exposure categories, the pooled analysis produced only 3 samples for each category. The lipid-adjusted serum TCDD concentrations 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 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. However, the concentrations reported in the Korean veterans’ study are significantly 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 authors were able to construct plausible exposure categories based on military records and self-reports, but they were unable to validate those categories with serum dioxin measurements.
Other Vietnam Veterans
Surveys of Vietnam veterans who were not part of the Ranch Hand or Army Chemical Corps groups indicate that 25–55% believe they were exposed to herbicides (CDC, 1989; Erickson et al., 1984a,b; Stellman and Stellman, 1986). A few attempts have been made to estimate exposure of the Vietnam veterans who were not part of the Ranch Hand or Army Chemical Corps groups. In 1983, CDC was assigned by the US government to conduct a study of the possible long-term health effects of Vietnam veterans’ exposures to Agent Orange. The CDC Agent
Orange study (CDC, 1985) attempted to classify veterans’ 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 validity 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 further study on the basis of the estimated number of Agent Orange hits, derived from the number of days on which at least one company location was within 2 km and 6 days of a recorded Agent Orange spray. The “low” exposure group consisted of 298 veterans, the “medium” exposure group had 157 veterans, and the “high” exposure group had 191 veterans. 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 five battalions.
The median serum TCDD in Vietnam veterans in 1987 was 4 ppt, with a range of <1–45 ppt; 2 veterans had concentrations above 20 ppt. The distribution of the measurements was nearly identical to that for a control group of 97 non-Vietnam veterans. The CDC validation study reported that study subjects could not be distinguished from controls on the basis of serum TCDD. In addition, none of the record-derived estimates of exposure and neither type of self-reported exposure to herbicides identified Vietnam veterans who were likely to have currently high serum TCDD (CDC, 1988b). The report concluded that it is unlikely that military records alone can be used to identify a large number of US Army veterans who might have been heavily exposed to TCDD in Vietnam.
The serum TCDD measurements for Vietnam veterans also suggest that exposure to TCDD in Vietnam was substantially less, on the 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 evaluated by the committee. This assessment of average exposure does not deny the existence of a heavily exposed subgroup of Vietnam veterans.
In 1997, a committee convened by IOM issued a request for proposals (RFP) seeking individuals and organizations to develop historical exposure reconstruction approaches suitable for epidemiologic studies of herbicide exposure among US veterans during the Vietnam War (IOM, 1997). The RFP resulted in the project “Characterizing Exposure of Veterans to Agent Orange and Other Herbicides in Vietnam”, carried out under contract by a team of researchers from Columbia University’s Mailman School of Public Health. The project, which began in 1998, created a geographic information system (GIS) for Vietnam with
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