5
Exposure Assessment

Assessment of individual exposure to herbicides and dioxin is a key element in determining whether specific health outcomes are linked to these compounds. This chapter briefly reviews information on occupational and environmental dioxin exposures, and herbicide spraying in Vietnam and exposure of veterans. More complete discussions of the occupational and environmental exposures, and the U.S. military’s wartime use of herbicides in Vietnam and of herbicide and dioxin exposure assessment in epidemiologic studies may be found in Chapters 3 and 6 of Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994) and in Chapter 5 of Veterans and Agent Orange: Update 1996 (IOM, 1996) and Update 1998 (IOM, 1999). Reviews of the most recent studies of the absorption, distribution, and passage of herbicides and dioxin through the body may be found under the discussions of toxicokinetics in Chapter 3 of this report.

OCCUPATIONAL AND ENVIRONMENTAL EXPOSURES TO HERBICIDES AND DIOXIN

The committee reviewed a large number of epidemiologic studies of occupationally or environmentally exposed groups for evidence of an association between health risks and exposure to TCDD and herbicides used in Vietnam, especially the phenoxy herbicides 2,4-D and 2,4,5-T, chlorophenols, and other compounds. In reviewing these studies, two types of exposure were explicitly considered: exposure to TCDD per se and exposure to the various herbicides used, particularly 2,4-D and 2,4,5-T. This separate consideration is necessary



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Veterans and Agent Orange: Update 2000 5 Exposure Assessment Assessment of individual exposure to herbicides and dioxin is a key element in determining whether specific health outcomes are linked to these compounds. This chapter briefly reviews information on occupational and environmental dioxin exposures, and herbicide spraying in Vietnam and exposure of veterans. More complete discussions of the occupational and environmental exposures, and the U.S. military’s wartime use of herbicides in Vietnam and of herbicide and dioxin exposure assessment in epidemiologic studies may be found in Chapters 3 and 6 of Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (IOM, 1994) and in Chapter 5 of Veterans and Agent Orange: Update 1996 (IOM, 1996) and Update 1998 (IOM, 1999). Reviews of the most recent studies of the absorption, distribution, and passage of herbicides and dioxin through the body may be found under the discussions of toxicokinetics in Chapter 3 of this report. OCCUPATIONAL AND ENVIRONMENTAL EXPOSURES TO HERBICIDES AND DIOXIN The committee reviewed a large number of epidemiologic studies of occupationally or environmentally exposed groups for evidence of an association between health risks and exposure to TCDD and herbicides used in Vietnam, especially the phenoxy herbicides 2,4-D and 2,4,5-T, chlorophenols, and other compounds. In reviewing these studies, two types of exposure were explicitly considered: exposure to TCDD per se and exposure to the various herbicides used, particularly 2,4-D and 2,4,5-T. This separate consideration is necessary

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Veterans and Agent Orange: Update 2000 because of the possibility that, for example, some health effects may be associated with exposure to 2,4-D in agriculture and forestry. The herbicide 2,4-D does not contain TCDD, although small quantities of other dioxins are present. For TCDD-exposed populations, serum measures of TCDD concentrations can be collected from a representative sample of those exposed. Serum biomarkers of TCDD exposure are sometimes used to estimate the degree of prior exposure of individuals; however, there are limitations to their use. The available information on occupational and environmental exposures to dioxin, the contaminant found in 2,4,5-T includes studies of residents living in and around Seveso, Italy, who were exposed during industrial accidents; chemical plant workers who were occupationally or accidentally exposed to TCDD during the production of 2,4,5-T or other phenoxy herbicides or chlorophenols such as hexachlorophene or trichlorophenol; sawmill workers exposed to higher chlorinated dioxins from contaminated wood preservatives; and pulp and paper workers exposed to dioxin through the pulp bleaching process. Occupational Studies Production Workers One of the most extensive sets of data on workers engaged in the production of chemicals potentially contaminated with TCDD has been compiled by NIOSH. From 12 chemical companies, more than 5,000 workers were identified from personnel and payroll records indicating whether the worker had been involved in production or maintenance processes associated with TCDD contamination (Fingerhut et al., 1991). In an update, Steenland (1999) constructed an exposure matrix for a subcohort of the workers, and attempted to evaluate the relationship between estimated TCDD exposures and mortality. A multisite study by the International Agency for Research on Cancer (IARC) involved 18,390 production workers and herbicide sprayers from 10 countries (Saracci et al., 1991). Exposure was estimated from a combination of factory records, work histories, spraying data, and questionnaires. Several other occupational studies of workers involved in chemical production plants have relied upon job titles as recorded on individual work histories and company personnel records to classify exposure (Ott et al., 1980; Zack and Gaffey, 1983; Coggon et al., 1986, 1991; Cook et al., 1986; Zober et al., 1990). Similarly, exposure in chemical plant workers has been characterized by worker involvement in various production processes such as synthesis, packaging, waste removal, shipping, and plant supervision (Manz et al., 1991; Bueno de Mesquita et al., 1993). Flesch-Janys et al. (1995) did an update of this 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 levels for the Ger-

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Veterans and Agent Orange: Update 2000 man population, the authors estimated PCDD/F levels for the 190 workers with serum or adipose measurements of PCDD/F. Then regressing the estimated PCDD/F level of these workers at the end of their exposure against the time they worked in each production department in the plant, the authors estimated the contribution of the working time in each production department to the PCDD/F level at the end of exposure. These production department working time “weights” were then used, along with the work histories of the remainder of the cohort, to estimate the PCDD/F level for each cohort member at the end of the person’s exposure. The epidemiologic analysis used these estimated TCDD doses. Becher et al. (1996) report an analysis of several German cohorts including the Boehringer-Ingelheim cohort described above, a cohort from the BASF Ludwigshafen plant that did not include those involved in the 1953 accident, and a cohort from a Bayer plant in Uerdingen and a Bayer plant in Dormagen. All of the plants were involved in the production of phenoxy herbicides or chlorophenols. Exposure assessment involved the estimation of duration of employment from the start of work in a department with suspected exposure until the end of employment at the plant. This may include some periods without exposure. Analysis was based upon time since first exposure. Hooiveld et al. (1998) reported on an update of a mortality study of workers at two chemical factories in the Netherlands. This study included analysis by estimated maximum TCDD serum level. This was estimated for each member of the cohort by measuring serum TCDD levels for 144 subjects, including production workers known to be exposed to dioxins, workers in herbicide production, nonexposed production workers, and workers known to be exposed as a result of an accident that occurred in 1963. Assuming first-order TCDD elimination with an estimated half-life of 7.1 years, TCDDmax was extrapolated for a group of 47 workers, then a regression model was constructed to estimate the effect of exposure as a result of the accident, duration of employment in main production department, time of first exposure before (or after) 1970 on the estimated TCDDmax for each cohort member. Agricultural/Forestry/Outdoor Workers Occupational studies of agricultural workers have estimated exposure to herbicides or TCDD using a variety of methods. In the simplest method, data on an individual’s occupation are derived from death certificates, cancer registries, or hospital records (Burmeister, 1981). Although this information is relatively easy to obtain, it is not possible to estimate duration or intensity of exposure, or to determine the specific type of herbicide or chemical a worker was exposed to. Some studies of agricultural workers have attempted to investigate differences in occupational practices to identify subsets of workers who were likely to have had higher levels of herbicide exposure (Vineis et al., 1986; Wiklund and Holm, 1986; Musicco et al., 1988; Wiklund et al., 1988a; Hansen et al., 1992; Ronco et al., 1992). Other studies have used county of residence as a surrogate of expo-

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Veterans and Agent Orange: Update 2000 sure, relying upon agricultural censuses of farm production and chemical use to characterize exposure in individual counties (Gordon and Shy, 1981; Cantor, 1982; Blair and White, 1985). Still other studies attempted to refine exposure estimates by categorizing the exposure based on the number of years employed in a specific occupation as a surrogate for exposure duration, obtaining supplier records on the amount of herbicides purchased to estimate the level of exposure, or estimating acres sprayed to quantify the amount used (Wigle et al., 1990; Morrison et al., 1992). In some cases, self-reported information on exposure was obtained, including direct handling of the herbicide, whether it was applied by tractor or hand-held spray, and what type of protective equipment was worn or what safety precautions were exercised, if any (Hoar et al., 1986; Zahm et al., 1990). Some studies attempted to validate self-reported information, based on verification using written records, signed statements, or telephone contacts with coworkers or former employers (Carmelli et al., 1981; Woods and Polissar, 1989). Forestry workers and other outdoor workers, such as highway maintenance workers, are likely to have been exposed to herbicides and other chemicals to varying degrees. Exposure has been classified in a manner similar to other studies, for example, by number of years employed, job category, and occupational title. Herbicide/Pesticide Sprayers Studies of herbicide sprayers are relevant because it can be presumed that applicators had more sustained exposure to herbicides; however, applicators were also likely to be exposed to a multiplicity of chemicals, complicating the assessment of any individual or group exposure to specifically phenoxy herbicides or TCDD. Some studies have attempted to quantify exposure of applicators based on information from work records on the number of acres sprayed or the number of days of herbicide spraying. Employment records can also be used to extract information on the type of chemicals sprayed. One surrogate indicator of herbicide exposure is receipt of a license to perform spraying. Several studies have specifically identified licensed or registered pesticide and herbicide applicators (Smith et al., 1981, 1982; Blair et al., 1983; Wiklund et al., 1988b, 1989; Swaen et al., 1992). Individual estimates of the intensity and frequency of exposure were rarely quantified in the studies the committee examined, however, and often applicators were known to have applied many different kinds of herbicides, pesticides, and other chemicals. In addition, herbicide spraying is generally a seasonal occupation, and information may not be available on possible exposure-related activities during the rest of the year. One study provided information on serum TCDD concentrations in herbicide sprayers, that of Smith et al. (1992). Blood from nine professional spray applicators in New Zealand, who first sprayed before 1960 and were also spraying in 1984, was analyzed. The duration of actual spray work varied from 80 to 370

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Veterans and Agent Orange: Update 2000 months. The serum levels ranged from 3 to 131 ppt TCDD on a lipid basis, with a mean of 53 ppt. The corresponding values for age-matched controls ranged from 2 to 11 ppt; the mean was 6 ppt. Serum TCDD levels were positively correlated with the number of months of professional spray application. Several studies have evaluated various herbicide exposures during spraying in terms of type of exposure, routes of entry, and routes of excretion: Kolmodin-Hedman and Erne (1980); Kolmodin-Hedman et al. (1983), Lavy et al. (1980a, b), Ferry et al. (1982), Libich et al. (1984), Frank et al. (1985). Based on these studies, it would appear that the major route of exposure is through dermal absorption, with 2 to 4 percent of that on the skin being absorbed into the body during a normal work day. Air concentrations were usually less than 0.2 mg/m3. The absorbed phenoxy acid herbicides are virtually cleared within one day, primarily through urinary excretion. Typical measured excretion levels for ground crews ranged from 0.1 to 5 mg/day and less for air crews. Paper and Pulp Mill Workers Another occupational group likely to be exposed to TCDD and chlorinated phenols consists of paper and pulp mill workers. These workers are likely to have received varying degrees of exposure as part of the bleaching process in the production of paper and paper products. Pulp and paper production workers are also likely to be exposed to other chemicals in the workplace, which vary, for example, according to the type of paper mill or pulping operation, and the final product manufactured (Robinson et al., 1986; Henneberger et al., 1989; Solet et al., 1989; Jappinen and Pukkala, 1991) In a study of a cohort of Danish paper mill workers, Rix et al. (1998), there were no direct measures of exposure for these workers, and a qualitative assessment of chemicals used in paper manufacture by department does not include chlorinated organic compounds although chlorine, chlorine dioxide, and hypochlorite were used. Sawmill Workers Workers in sawmills may be exposed to pentachlorophenates, which are contaminated with higher chlorinated PCDDs (C16–C18) or tetrachlorophenates, which are less contaminated with higher chlorinated PCDDs. The wood is dipped in these chemicals and then cut and planed in the mills. Most exposure is dermal, although some exposure can occur via inhalation (Teschke et al., 1994; Hertzman et al., 1997). Environmental Studies Studies of environmental exposures related primarily to unintentional releases of TCDD into the environment at Seveso, Italy, and Times Beach, Mis-

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Veterans and Agent Orange: Update 2000 souri. In these cases, the simplest measure of exposure was classification according to place of residence. Intensity of exposure has been estimated by years of residence in a contaminated area; this measure does not take into account the concentration of TCDD or herbicide, or the frequency of individual contact with contaminated soil or water. One of the largest industrial accidents involving environmental exposures to TCDD occurred in Seveso, in July 1976, as a result of an uncontrolled reaction during trichlorophenol production. A variety of indicators were used to estimate individual exposure; soil contamination by TCDD has been the most extensively used. On the basis of soil sampling, three areas were defined about the release point. They were zone A, the most heavily contaminated, from which all residents were evacuated within 20 days; zone B, an area of lesser contamination that children and pregnant women in their first trimester were urged to avoid during daytime; and zone R, a region with some contamination, in which consumption of local crops was prohibited (Bertazzi et al., 1989). The samples so obtained are virtually unique in that they were numerous and were obtained prior to elimination and degradation of TCDD in the sample media. Data on serum concentrations of zone A residents have been presented by Mocarelli et al. (1990, 1991) and earlier by the CDC (1988a). For those with severe chloracne (N=10) the TCDD levels ranged from 828 to 56,000 ppt lipid weight. Those without chloracne (N=10) had levels from 1,770 to 10,400 ppt. The levels in all controls but one were not detectable. The highest of these levels exceeded any that had been estimated at the time for TCDD-exposed workers, based on backward extrapolation with a half-life of seven years. Data on nearby soil levels, number of days an individual stayed in zone A, and whether local food was consumed were considered in evaluating TCDD levels. None of these data correlated with serum TCDD levels, strongly suggesting that the exposure of importance was fallout on the day of the accident. The presence and degree of chloracne did correlate with TCDD levels; however, it appears that adults are much less likely to develop chloracne than children following an acute exposure, but surveillance bias may have played some role in this finding. Recent updates (Bertazzi et al., 1998, 2001) have not changed the exposure assessment approach in any way. A number of reports have provided information on exposure to TCDD from environmental contamination in Missouri (Patterson et al., 1986; Andrews et al., 1989). 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 parts per billion (ppb). One of 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 six months during the time the contamination occurred (Hoffman et al., 1986). Other investigations of Times Beach have estimated exposure risk based on residents’ reported occupational and recreational

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Veterans and Agent Orange: Update 2000 activities in the sprayed area. Levels of exposure have been estimated from duration of residence and TCDD soil concentrations. Andrews et al. (1989) provided the most extensive data on human adipose tissue levels for 51 persons who had ridden or cared for horses at arenas sprayed with TCDD-contaminated oil; persons exposed in residential areas where such oil had been sprayed; individuals involved in TCP production; persons exposed in TCP nonproduction activities, such as lab and maintenance workers; and 128 controls. Persons were considered exposed if they lived, worked, or had other contact for two years or more with TCDD-contaminated soil at levels of 20–100 ppb or for six months or more with soil contaminated with TCDD at levels greater than 100 ppb. Of the exposed population samples, 87 percent of adipose tissue TCDD levels were less than 200 ppt; however TCDD concentrations in 7 of the 51 exposed ranged from 250 to 750 ppt. For nonexposed persons, adipose tissue TCDD concentrations ranged from nondetectable to 20 ppt, with a median of 6 ppt. Based on a seven-year half-life it is calculated that two of the study participants would have had adipose tissue TCDD levels near 3,000 ppt at the time of the last date of exposure. Viel et al. (2000) reported on an investigation of apparent clusters of soft-tissue sarcoma and non-Hodgkin’s lymphoma cases in the vicinity of a municipal solid waste incinerator in Doubs, France. The presumptive source of dioxin in this region is a municipal solid waste incinerator in the Besançon electoral ward in the west of Doubs. A measurement of dioxin emissions from the incinerator showed a level of 16.3 ng I-TEQ/m3, far in excess of the EU standard of 0.1 ng I-TEQ/m3. In addition, measurements of dioxin in cow’s milk from three farms near the incinerators suggested that dioxin content of the milk was highest at the farm closest to the incinerator. These measurements were all well below the guideline of 6 ng I-TEQ/kg of fat, however. Vietnamese Studies Several studies have investigated exposure to herbicides among the residents of southern Vietnam (Constable and Hatch, 1985), comparing unexposed residents of the South to residents of the North. Other studies have attempted to identify veterans of northern Vietnam who served in the South during the Vietnam era. 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, residents of villages were considered exposed if a recorded herbicide mission 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 number of times the area had reportedly been sprayed. A small number of studies provide information on TCDD concentrations in Vietnamese civilians exposed during the war. Schecter et al. (1986) detected

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Veterans and Agent Orange: Update 2000 TCDD in 12 of 15 samples of adipose tissue taken at surgery or autopsy in southern Vietnam during 1984. The concentrations in the positive samples were from 3 to 103 ppt. No detectable levels of TCDD were found in nine samples from residents of northern Vietnam who had never been in the South. The detection sensitivity was 2–3 ppt. Analysis of three breast milk samples collected in 1973 from Vietnamese women thought to have been exposed to Agent Orange varied from 77 to 230 ppt on a lipid basis. MILITARY USE OF HERBICIDES IN VIETNAM Background The military use of herbicides in Vietnam began in 1962, was expanded during 1965 and 1966, and reached a peak from 1967 to 1969. Herbicides were used extensively in Vietnam by the U.S. Air Force’s Operation Ranch Hand to defoliate inland hardwood forests, coastal mangrove forests, and to a lesser extent, cultivated land, by aerial spraying from C-123 aircraft and helicopters. According to military records of Operation Ranch Hand, from August 1965 to February 1971 a total of 17.6 million gallons of herbicide was sprayed over approximately 3.6 million acres in Vietnam (NAS, 1974). Soldiers also sprayed herbicides on the ground to defoliate the perimeters of base camps and fire bases; this spraying was executed from the rear of trucks and from spray units mounted on the backs of soldiers on foot. Navy river boats also sprayed herbicides along riverbanks. The purpose of spraying herbicides was to improve the ability to detect enemy base camps and enemy forces along lines of communication and infiltration routes and around U.S. base camps and fire bases. Spraying was also used to destroy the crops of the Vietcong and North Vietnamese (Dux and Young, 1980). Four major compounds were used in the Ranch Hand herbicide formulations—2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), picloram, and cacodylic acid. These compounds have been used world-wide for the control of weeds and unwanted vegetation, although the application of 2,4,5-T is no longer permitted in the United States following a series of Environmental Protection Agency directives in the 1970s. Which of these four major chemicals (2,4-D, 2,4,5-T, picloram, or cacodylic acid) was chosen for a specific application depended on the desired effects. 2,4-D and 2,4,5-T are chlorinated phenoxy acids, and each is effective against a wide array of broadleaf plant species (Irish et al., 1969). They persist in soil only a few weeks (Buckingham, 1982). Picloram, like 2,4-D and 2,4,5-T, regulates plant growth. Compared to 2,4-D, picloram is more mobile and therefore better able to penetrate the plant’s roots and be transported throughout plant tissues. Unlike the phenoxy herbicides, picloram is extremely persistent in soils. The fourth compound, cacodylic acid, contains an organic form of arsenic. Cacodylic acid is a

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Veterans and Agent Orange: Update 2000 desiccant, causing a plant’s tissues to lose their moisture and eventually killing the plant. The different types of herbicide used by U.S. forces in Vietnam were identified by a code name referring to the color of the band around the 55-gallon drum that contained the chemical. These included Agents Orange, White, Blue, Purple, Pink, and Green (see Table 5–1). From 1962 to 1965, small quantities of Agents Purple, Blue, Pink, and Green were used. From 1965 to 1970, Agents Orange, White, and Blue were employed; from 1970 to 1971, only Agents White and Blue were used in the defoliation program (Young and Reggiani, 1988). Agent Purple was a 5:3:2 mixture of the n-butyl ester of 2,4-D and the n-butyl and isobutyl esters of 2,4,5-T that was used on broadleaf plants. Because of its volatility, Agent Purple was replaced by Agent Orange in 1965. Blue was the code designation for a liquid formulation of cacodylic acid and its sodium salt. The term Blue was first applied to cacodylic acid in a powder form that was mixed in the field with water. It was later replaced by the liquid formulation Phytar 560-G. Cacodylic acid is a highly soluble organic arsenic compound that is readily broken down in soil. Approximately one-half of all Agent Blue was used for crop destruction missions; it was the agent of choice for destruction of rice crops. The remainder was used in defoliation or sprayed around base perimeters, being delivered by helicopters or ground vehicles with sprayers attached to them (Young et al., 1978). Agents Pink and Green were used in small quantities; however, official records of herbicide sprays during the early years of the program (1962–1964), when these two herbicides were used, are incomplete. Agent Green was a single-component formulation of the n-butyl ester of 2,4,5-T, used primarily in defoliation missions (Young et al., 1978). In January 1965, two additional herbicides, code named Orange and White, TABLE 5–1 Major Herbicides Used in Operation Ranch Hand: 1962–1971 Code Name Formulation Purpose No. of Gallons Sprayed Period of Use Purple 2,4-D; 2,4,5-T General defoliation 145,000 1962–1964 Blue (Phytar 560-G) Cacodylic acid Rapid defoliation, grassy plant control, rice destruction 1,124,307 1962–1971 Pink 2,4,5-T Defoliation 122,792 1962–1964 Green 2,4,5-T Crop destruction 8,208 1962–1964 Orange, Orange II 2,4-D; 2,4,5-T General defoliation 11,261,429 1965–1970 White (Tordon 101) 2,4-D; picloram Forest defoliation, long-term control 5,246,502 1965–1971   SOURCES: MRI, 1967; NAS, 1974; Young and Reggiani, 1988.

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Veterans and Agent Orange: Update 2000 were introduced into the herbicide program. Agent Orange, a 1:1 mixture of 2,4-D and the n-butyl ester of 2,4,5-T, accounted for approximately 61 percent of the recorded herbicide use. Orange was the general-purpose herbicide for defoliation and crop destruction. According to military estimates of herbicide use, 90 percent of Agent Orange was used in Ranch Hand forest defoliation missions; 8 percent was used in Ranch Hand crop destruction missions; and 2 percent was sprayed from the ground around base perimeters and cache sites, waterways, and communication lines (NAS, 1974). Orange II was introduced later in the program. It differed from the original Agent Orange in that the n-butyl ester of 2,4,5-T was replaced by the isooctyl ester; however, their herbicidal effects were similar. According to procurement records, less than 10 percent of the total Agent Orange used was Orange II (Craig, 1975). White was the code name for Tordon 101, a liquid mixture of 2,4-D and picloram. More than 95 percent of Agent White was applied in defoliation missions (NAS, 1974; Young and Reggiani, 1988). Because of the persistence of Agent White in soil, it was not recommended for use on crops but was most often used in areas where longer persistence rather than immediate defoliation was desired, such as inland forests. In addition to these four major compounds, Dinoxol, Trinoxol, and diquat were applied on native grasses and bamboo (Brown, 1962). Soil-applied herbicides were also reportedly used around base camp perimeters, minefields, ammunition storage areas, and other specialized sites requiring control of grasses and woody vegetation (Darrow et al., 1969). Additional accounts include the use of fungicides, insecticides, wetting agents, wood preservatives, insect repellents, and other herbicides (Gonzales, 1992). The number of military personnel potentially exposed to these chemicals is not available. An undetermined amount of herbicides and insecticides was procured and distributed by Australian forces in Vietnam during 1966–1971. The use of these chemicals was confined largely to defoliation around base camps, improving security, and controlling mosquito-borne diseases. It appears that the chemicals were largely dispersed by use of ground delivery techniques, although low-volume aerial applications of insecticides, usually by helicopter, have been reported. The chemicals tested and used included 2,4-D, chlordane, DDT, diazinon, lindane, malathion, and picloram (Australian Senate Standing Committee, 1982). The military use of 2,4,5-T, and thus Agent Orange, was suspended by the U.S. Department of Defense in April 1970 (Young and Reggiani, 1988). On February 12, 1971, U.S. Military Assistance Command, Vietnam, announced that herbicides would no longer be used for crop destruction in Vietnam, and the last Ranch Hand fixed-wing aircraft (C-123) was flown. Subsequent spraying of herbicides was limited to controlled use around U.S. fire bases by helicopter or ground troops (MACV, 1972). On October 31, 1971, nearly 10 years after the

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Veterans and Agent Orange: Update 2000 herbicide program began in Vietnam, the last U.S. helicopter herbicide operation was flown (NAS, 1974). Ground Spraying of Herbicides Although the number of U.S. military personnel exposed to herbicides is impossible to determine precisely, the majority of those assigned to Operation Ranch Hand can be presumed to have been exposed to Agent Orange and other herbicides. During the entire operation, approximately 1,250 military personnel served in Ranch Hand units. Although the Air Force maintained complete records of its Operation Ranch Hand fixed-wing herbicide missions, documentation of spraying conducted on the ground by boat, truck, or backpack and authorized at the unit level was less systematic. Authorization for herbicide missions by helicopter or surface spraying from river boats, trucks, and hand-operated backpacks was delegated to the Republic of Vietnam and U.S. authorities at the Corps level; these operations required only the approval of the unit commanders or senior advisors. “Free-spraying” areas, including the Demilitarized Zone (DMZ) at the seventeenth parallel and the first 100 meters outside base camps, were also exempt from Ranch Hand regulations (NAS, 1974). This delegation of authority for spraying to the Corps level reduced the lag time that existed from proposal to completion of small defoliation projects, for example, around depots, airfields, and outposts (Collins, 1967). However, because these helicopter and ground sprays were less rigidly controlled than fixed-wing aerial spraying, the recording of such sprays was not as systematic as those of Operation Ranch Hand. The U.S. Army Chemical Corps, using hand equipment and H-34-type helicopters, conducted smaller spray operations, such as defoliation around Special Forces camps; clearance of perimeters surrounding airfields, depots, and other bases; and small-scale crop destruction (Warren, 1968; Thomas and Kang, 1990). Twenty-two Army Chemical Corps units were assigned to South Vietnam between 1966 and 1971. Approximately 950 veterans who served in the Army Chemical Corps in Vietnam between 1966 and 1971 have been identified from unit morning reports. Men serving in these units were trained in the preparation and application of chemicals, as well as in the cleaning and maintenance of spray equipment (Thomas and Kang, 1990). Units and individuals other than members of the Air Force Ranch Hand and Army Chemical Corps were also likely to have handled or sprayed herbicides around bases or lines of communication. For example, Navy river patrols were reported to have used herbicides for clearance of inland waterways. Engineering personnel required the use of herbicides for removal of underbrush and dense growth in constructing fire support bases. It is estimated that 10 to 12 percent of the total volume of herbicides was dispensed from the ground by spraying from backpacks, boats, trucks, and buffalo turbines (NAS, 1974). The buffalo turbine was a trailer-mounted spray system used for roadside spraying and perimeter

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Veterans and Agent Orange: Update 2000 applications, which essentially “shot” the herbicide with a velocity up to 240 km/ hour and a volume of 280 m3/min (Young and Reggiani, 1988). Hand spray units consisted of a backpack type of dispenser with a capacity of 3 gallons (Collins, 1967). Although some information is documented in military records, it is impossible to determine accurately from military records alone the extent of spraying conducted on the ground or the number of personnel involved in these operations with potential herbicide exposure. An unknown number of non-Ranch Hand personnel likely received various degrees of exposure to herbicides. Young and Reggiani (1988) report that the actual number “may be in the thousands since at least 100 helicopter spray equipment units were used in South Vietnam, and most military bases had vehicle-mounted and backpack spray units available for use in routine vegetation control programs.” According to official documents, the “small-scale use of herbicides, for example around friendly base perimeters, were at the discretion of area commanders. Such uses seemed so obvious and so uncontroversial at the time that little thought was given to any detailed or permanent record of the uses or results” (U.S. Army, 1972). The Department of Defense (DoD) took few precautions to prevent troop exposure to herbicides since they were considered to be a low health hazard. Precautions prescribed were consistent with those applied in the domestic use of herbicides existing before the Vietnam conflict (U.S. GAO, 1979). The Army added that exposure of ground troops was very unlikely since DoD personnel did not enter a Ranch Hand-sprayed area until approximately 4 to 6 weeks after the mission, when defoliation was complete and the herbicide had been biodegraded or photodegraded (U.S. Army, 1972). The restriction placed on troops entering a previously sprayed area was primarily for operational reasons, to prevent troops from being injured by the fighter aircraft that often accompanied the herbicide spraying aircraft (U.S. GAO, 1979). A very different picture arose when the U.S. General Accounting Office (U.S. GAO, 1979) examined the military defoliation operation in the Con Thieu province of I Corps between January 1966 and December 1969. During this period, more than 2 million gallons of herbicides were sprayed in I Corps. By using average troop strength and turnover figures, an estimated 218,000 Marine infantry personnel were determined to have been assigned to I Corps during this period. By randomly selecting 276 of 976 Marine monthly battalion reports, the GAO tracked troop movement and compared troop locations to herbicide mission data. Nearly 26,000 U.S. Marines and Navy medical personnel were identified who entered within a radius of 2.5 km of the defoliated target areas within 1 day of spraying; 4,300 troops were identified as being within 0.5 km of the flight path; 11,700 were within 2.5 km within 4 weeks. In the Khe Sanh-Thon Son Lam area, an estimated 4,300–8,000 troops were within 0.5 km of the sprayed area within 1 day of spraying; within 28 days, 33,600–45,300 troops were determined to have been within 2.5 km of the defoliation target. Army records were found to

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Veterans and Agent Orange: Update 2000 lack sufficient information, so that the number of Army personnel close to sprayed areas could not be estimated. The GAO report concluded that “the chances that ground troops were exposed to herbicide Orange are higher than the DoD previously acknowledged…the group of personnel most likely to have been exposed could include ground troops as well as herbicide handlers and aircraft crew members” (U.S. GAO, 1979). Level of Dioxin (TCDD) in Herbicides Used in Vietnam 2,3,7,8-Tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD, TCDD, or dioxin) is a contaminant of 2,4,5-T. Small quantities of other dioxins are present in 2,4-D. The levels of TCDD found in any given lot of 2,4,5-T depend on the manufacturing process (Young et al., 1976), and different manufacturers produced 2,4,5-T with various concentrations of TCDD. The primary source of 2,4,5-T in the herbicides used in Vietnam was Agent Orange. 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 levels of TCDD 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 to almost 50 parts per million (ppm), averaging 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 levels be less than 0.05 ppm (NAS, 1974). Therefore, depending on which stocks were sampled, the level of dioxin contamination in Agent Orange could have been up to 1,000 times higher than the level of dioxin found in phenoxy herbicides domestically available at the time. Agents Green, Pink, and Purple, also contained 2,4,5-T and were used from 1962 through mid-1965. These 2,4,5-T formulations used early in the program (prior to 1965) contained 16 times the mean dioxin content of formulations used during 1965–1970 (Young et al., 1978). Analysis of archive samples of Agent Purple reported levels of TCDD as high as 45 ppm (Young, 1992). The mean concentration of TCDD in Agent Purple was estimated to be 32.8 ppm; the estimate for Agents Pink and Green was 65.6 ppm (Young et al., 1978). As a result of TCDD contamination in the herbicides, it has been estimated that about 368 pounds of dioxin was sprayed in Vietnam over a 6-year period (Gough, 1986). EXPOSURE ASSESSMENT IN STUDIES OF VIETNAM VETERANS Different approaches have been used to estimate the exposure of Vietnam veterans, including self-reported exposures, records-based exposure estimates, or

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Veterans and Agent Orange: Update 2000 biomarkers of TCDD exposure. Each approach is limited in its ability to determine precisely the degree of individual exposure. Some studies rely on gross markers such as service in Vietnam—perhaps enhanced by branch of service, military region, military specialty, or combat experience—as proxies for exposure to herbicides. Studies of this type include the Centers for Disease Control and Prevention’s (CDC’s) Vietnam Experience Study and Selected Cancers Study, the Department of Veterans Affairs’ (DVA’s) mortality studies, and most studies of veterans conducted by states. This approach almost surely dilutes whatever health effects of herbicides exist, because many members of the cohort presumed to be exposed to herbicides may, in reality, not have been. Ranch Hands and Army Chemical Corps Military occupation has been shown to be a valid exposure classification for two specific occupations that involved the direct handling and distribution of herbicides: the Air Force Ranch Hands, who were responsible for aerial spraying of herbicides, and the Army Chemical Corps, which performed ground and helicopter chemical operations. Biomarker studies of the Ranch Hands 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 levels was detected for jobs that involved more frequent handling of herbicides. The median TCDD level for enlisted ground crew (24 parts per trillion [ppt], range 0–618 ppt) was higher than the median level for enlisted flyers (18 ppt, range 0–196 ppt), and three times greater than the median level for officers (8 ppt, range 0–43 ppt) (AFHS, 1991). The exposure index initially proposed in the Air Force Ranch Hand study relied upon military records of TCDD-containing herbicides (Agents Orange, Purple, Pink, and Green) sprayed as reported in the HERBS tapes for the period after July 1965 and on military procurement records and dissemination information for the period prior to July 1965. A TCDD weighting factor (based on the concentration of TCDD in the herbicide and the duration of spraying) was applied to the number of gallons of herbicides sprayed during each subject’s tour of duty in Vietnam. The dates of each subject’s tour(s) in Vietnam were determined by a manual review of military records. The HERBS tapes were used with quarterly operations reports to construct a table of gallons of TCDD-containing herbicides sprayed for each month during the Ranch Hand operation. The exposure index for a Ranch Hand was defined as the product of the TCDD weighting factor and the number of gallons of TCDD herbicides sprayed during an individual’s tour of duty, divided by the number of Ranch Hands sharing such duties during this individual’s tour. Each Ranch Hand was placed in an exposure category (high, medium, or low) based on the value of the individual’s exposure index. The index included exposure from recorded Ranch Hand sprays only—the measure did not allow for other unrecorded herbicide expo-

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Veterans and Agent Orange: Update 2000 sures, such as chemical dumps or perimeter sprays, or other non-Ranch Hand herbicide applications. In 1991, the exposure index was compared to the results of the Ranch Hand serum TCDD analysis. The exposure index and the TCDD body burden were weakly correlated. Michalek et al. (1995) developed several indices of herbicide exposure for members of the Ranch Hand cohort and tried to relate these to the levels of serum TCDD measured between 1987 and 1992. Self-administered questionnaires completed by veterans of Operation Ranch Hand were used to develop three indices for herbicide or TCDD exposure: (1) the number of days of skin exposure; (2) the percentage of skin area exposed; and (3) the number of days of skin exposure, times the percentage of skin exposed, times a factor for the concentration of TCDD in the herbicide. A fourth index used no information gathered from individual subjects. It was calculated as the volume of herbicide sprayed during a specific individual’s tour of duty, times the concentration of TCDD in herbicides sprayed in that period, divided by the number of crew members at that time in each job specialty. Each of the four models tested was significantly related to the serum TCDD level, although each explained only between 19 and 27 percent of the variability in serum TCDD. 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 indices, explained 60 percent of the variance in serum TCDD concentrations. When the questionnaire-derived indices were applied within each job classification, days of skin exposure added significantly, but not substantially, to the variability explained by job alone. Other Vietnam Veterans Surveys of Vietnam veterans who were not part of the Ranch Hands or Chemical Corps groups indicate that 25 to 55 percent believe they were exposed to herbicides (Erickson et al., 1984a, b; Stellman and Stellman, 1986; CDC, 1989). A few attempts have been made to estimate exposures of the Vietnam veterans who were not part of the Ranch Hand or Chemical Corps groups. The CDC was involved in two such studies: the CDC Agent Orange Study (CDC, 1985) and the CDC Birth Defects Study which developed an exposure opportunity index (EOI) to score Agent Orange exposures (Erickson et al., 1984a, b). As part of a case-control study to determine if there was an increased risk of birth defects among the offspring of Vietnam veterans, an Agent Orange exposure assessment was done (Erickson et al., 1984a, b). The potential for an individual Vietnam veteran’s exposure to Agent Orange (“exposure opportunity”) was estimated by military records specialists of the Army Agent Orange Task Force without knowledge of case or control status. The EOI scores ranged from a value of 1 (minimum opportunities for exposure) to a value of 5 (most numerous opportuni-

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Veterans and Agent Orange: Update 2000 ties for exposure). Higher values signify a greater likelihood of exposure but do not necessarily indicate a higher degree (duration or intensity) of exposure. All individual veterans were given two index scores: one was derived from self-reported information on dates and location of service, and military duties, obtained during the interview; the second was developed based on a review of military records. The records-based EOI used unit location data determined from the Operational Report Lessons Learned. The proximity of these general unit locations was compared to Agent Orange and other herbicide spray data by using the HERBS tapes and other data available on base perimeter sprays to construct the index scores. Approximately 25 percent of interviewed Vietnam veterans reported that they had been exposed to Agent Orange. Fifty-two percent received the same score in both the index score and the self-reported Agent Orange exposure. A higher proportion of subjects who thought they had been exposed received 4 or 5 on the military records index score than did subjects who thought they had not been exposed. In 1983, the CDC was assigned by the U.S. government to conduct a study of the possible long-term health effects of Vietnam veterans’ exposures to Agent Orange. The Agent Orange Study attempted to classify veterans’ exposure to herbicides that occurred during military service. This was to be accomplished by determining the proximity of troops to Agent Orange spraying using military records to track troop movement and the HERBS tapes to locate herbicide spraying patterns. The original study was to involve three cohorts, each containing approximately 8,500 men. The DoD Environmental Services Group assisted CDC in the abstraction of military records on troop locations. According to the CDC protocol, 65 battalions were to be selected from III Corps. Herbicide exposure “scores” were calculated at the company level (about 250 men), based on a reported unit location occurring within a specified time and distance from a known herbicide application. Three exposure scores were proposed—short, intermediate, and chronic—to estimate an individual’s likelihood of exposure. These scores attempted to account for variations in TCDD half-life, dispersion of herbicides, error in the calculated distances from spray lines, and uncertainties regarding the time between spraying and possible exposure, as well as whether the exposure could be viewed as acute, chronic, or intermediate. The CDC initially concluded that “many veterans were in close enough proximity to applications of Agent Orange to be classified as highly likely to have been exposed to the herbicide” and that there was substantial variability in exposure scores among units and among individual veterans (CDC, 1985). To test the validity of several indirect methods for estimating exposure of ground troops to Agent Orange in Vietnam, in 1987 the CDC Agent Orange Validation Study measured serum TCDD levels in a nonrandom sample of Vietnam veterans and Vietnam era veterans who did not serve in Vietnam (CDC,

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Veterans and Agent Orange: Update 2000 1988b). Vietnam veterans were selected for further study based on their estimated number of Agent Orange hits, derived from the number of days for which at least one company location was within 2 km and 6 days of a recorded Agent Orange spray: the “low-” exposure group included 298 veterans, the “medium-” exposure group included 157 veterans, and the “high-” exposure group included 191 veterans. Blood samples were obtained from 66 percent of Vietnam veterans (N=646) and 49 percent of the eligible comparison group of veterans (N=97). More than 94 percent of those whose serum was obtained had served in one of five battalions. Five indirect exposure scores based on military records and two scores based on self-reports were used to rank veterans according to their likelihood of exposure to Agent Orange. The five indirect scores incorporated a variety of assumptions concerning possible sources of TCDD exposure, the estimated half-life of TCDD in the environment, and the completeness of data on troop and spray location. Two Agent Orange exposure scores were calculated based on proximity to recorded Agent Orange sprays. Two similar scores were computed for recorded sprays of “unknown” agents. The fifth score, an area score, depended less on precise military unit location data than the other four scores. It was computed based on the number of days a company was in one of five heavily sprayed areas in III Corps during 1967 and 1968. Two self-assessed exposure scores were determined based on the number of days an individual reported direct and indirect exposure to herbicides during military service (CDC, 1988b). The median TCDD level in Vietnam veterans was 4 ppt, with a range of less than 1 to 45 ppt and two veterans having levels greater than 20 ppt; the distributions of these measurements were nearly identical to those for the control group of 97 non-Vietnam veterans. In other words, the CDC’s Validation Study found that study subjects could not be distinguished from controls based on serum TCDD levels. In addition, none of the records-derived estimates of exposure and neither type of self-reported exposure to herbicides identified Vietnam veterans who were likely to have currently elevated serum TCDD levels (CDC, 1988b). The study concluded it is unlikely that military records can be used to identify a large number of U.S. Army veterans who might have been heavily exposed to TCDD in Vietnam. In addition, these serum TCDD levels in Vietnam veterans suggest that the exposure to TCDD in Vietnam was substantially less, on average, than that of occupationally exposed workers; of persons exposed as a result of the industrial explosion in Seveso, Italy; or of the heavily exposed occupational workers that are the focus of many of the studies evaluated by the committee. As noted above, this estimation of average exposure does not preclude the existence of a heavily exposed subgroup of Vietnam veterans. In 1997, a committee convened by the Institute of Medicine developed a Request for Proposals (RFP) seeking individuals and organizations capable of conducting research to develop one or more historic exposure reconstruction

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Veterans and Agent Orange: Update 2000 approaches suitable for epidemiologic studies of herbicide exposure among U.S. veterans during the Vietnam war (IOM, 1997). These approaches were to incorporate information from, for example, existing data bases, biomarker data, and supplemental material gathered from surveys of military personnel, governmental and nongovernmental organizations, and other sources. Work funded under this RFP began in 1998 and was still under way at the end of 2000. REFERENCES 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. 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 18:499–506. Australian Senate Standing Committee on Science and the Environment. 1982. Pesticides and the Health of Australian Vietnam Veterans. First report. 240 pp. 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):312–321. 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 Epidemiology 129:1187–1200. 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): 625–633. 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 Epidemiology 153(11):1031–1044. Blair A, White DW. 1985. Leukemia cell types and agricultural practices in Nebraska. Archives of Environmental Health 40:211–214. 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 71:31–37. Brown JW. 1962. Vegetational Spray Test in South Vietnam. Fort Detrick, MD: U.S. 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 1961–1971. Washington, DC: U.S. Air Force Office of Air Force History. Bueno de Mesquita HB, Doornbos G, van der Kuip DA, Kogevinas M, Winkelmann R. 1993. Occupational exposure to phenoxy herbicides and chlorophenols and cancer mortality in the Netherlands. American Journal of Industrial Medicine 23:289–300. Burmeister LF. 1981. Cancer mortality in Iowa farmers: 1971–1978. Journal of the National Cancer Institute 66:461–464. Cantor KP. 1982. Farming and mortality from non-Hodgkin’s lymphoma: a case-control study. International Journal of Cancer 29:239–247. Carmelli D, Hofherr L, Tomsic J, Morgan RW. 1981. A Case-Control Study of the Relationship Between Exposure to 2,4-D and Spontaneous Abortions in Humans. SRI International. Prepared for the National Forest Products Association and the U.S. Department of Agriculture, Forest Service.

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Veterans and Agent Orange: Update 2000 CDC (Centers for Disease Control). 1985. Agent Orange Projects Interim Report Number 2: Exposure Assessment for the Agent Orange Study. Atlanta: CDC, Center for Environmental Health, Division of Chronic Disease Control, Agent Orange Projects. CDC. 1988a. Preliminary report: 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure in humans-Seveso, Italy. Morbidity and Mortality Weekly Report 37:733–736. CDC. 1988b. Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in U.S. Army Vietnam era veterans. Journal of the American Medical Association 260:1249–1254. CDC. 1989. Health Status of Vietnam Veterans. Vietnam Experience Study. Atlanta: U.S. Department of Health and Human Services. Vols. I–V, Supplements A–C. Coggon D, Pannett B, Winter PD, Acheson ED, Bonsall J. 1986. Mortality of workers exposed to 2 methyl-4 chlorophenoxyacetic acid. Scandinavian Journal of Work, Environment, and Health 12:448–454. Coggon D, Pannett B, Winter P. 1991. Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine 48:173–178. Collins CV. 1967. Herbicide Operations in Southeast Asia, July 1961-June 1967. San Francisco: Headquarters, Pacific Air Forces. NTIS AD-779–796. Constable JD, Hatch MC. 1985. Reproductive effects of herbicide exposure in Vietnam: recent studies by the Vietnamese and others. Teratogenesis, Carcinogenesis, and Mutagenesis 5:231– 250. Cook RR, Bond GG, Olson RA. 1986. Evaluation of the mortality experience of workers exposed to the chlorinated dioxins. Chemosphere 15:1769–1776. Craig DA. 1975. Use of Herbicides in Southeast Asia. Historical Report. Kelly AFB, TX: San Antonio Logistics Center, Directorate of Energy Management. 58 pp. Dai LC, Phuong NTN, Thom LH, Thuy TT, Van NTT, Cam LH, Chi HTK, Thuy LB. 1990. A comparison of infant mortality rates between two Vietnamese villages sprayed by defoliants in wartime and one unsprayed village. Chemosphere 20:1005–1012. Darrow RA, Irish KR, Minarik CD. 1969. Herbicides Used in Southeast Asia. Kelly AFB, TX. Technical Report SAOQ-TR-69–11078. 60 pp. Dux J, Young PJ. 1980. Agent Orange: The Bitter Harvest. Sydney: Hodder and Stoughton. Erickson JD, Mulinare J, Mcclain PW. 1984a. Vietnam veterans’ risks for fathering babies with birth defects. Journal of the American Medical Association 252:903–912. Erickson JD, Mulinare J, Mcclain PW, Fitch TG, James LM, McClearn AB, Adams MJ. 1984b. Vietnam Veterans’ Risks for Fathering Babies with Birth Defects. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control. Ferry DG, Gazeley LR, Edwards IR. 1982. 2,4,5-T absorption in chemical applicators. Proceedings of the University Otago Medical School 60:31–34. 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-tetrachlorodibenzo-p-dioxin. New England Journal of Medicine 324:212–218. Flesch-Janys D, Berger J, Gurn P, Manz A, Nagel S, Waltsgott H, Dwyer. 1995. Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany. American Journal of Epidemiology 142:1165–1175. Frank R, Campbell RA, Sirons GJ. 1985. Forestry workers involved in aerial application of 2,4-dichlorophenoxyacetic acid (2,4-D): exposure and urinary excretion. Archives of Environmental Contamination and Toxicology 14:427–435. Gonzales J. 1992. List of Chemicals Used in Vietnam. Presented to the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. Illinois Agent Orange Committee, Vietnam Veterans of America. Gordon JE, Shy CM. 1981. Agricultural chemical use and congenital cleft lip and/or palate. Archives of Environmental Health 36:213–221.

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Veterans and Agent Orange: Update 2000 Gough M. 1986. Dioxin, Agent Orange: The Facts. New York: Plenum Press. Hansen ES, Hasle H, Lander F. 1992. A cohort study on cancer incidence among Danish gardeners. American Journal of Industrial Medicine 21:651–660. Henneberger PK, Ferris BG Jr, Monson RR. 1989. Mortality among pulp and paper workers in Berlin, New Hampshire. British Journal of Industrial Medicine 46:658–664. Hertzman C, Teschke K, Ostry A, Hershler R, Dimich-Ward H, Kelly S, Spinelli JJ, Gallagher RP, McBride M, Marion SA. 1997. Mortality and cancer incidence among sawmill workers exposed to chlorophenate wood preservatives. American Journal of Public Health 87(1):71–79. Hoar SK, Blair A, Holmes FF, Boysen CD, Robel RJ, Hoover R, Fraumeni JF. 1986. Agricultural herbicide use and risk of lymphoma and soft-tissue sarcoma. Journal of the American Medical Association 256:1141–1147. Hoffman RE, Stehr-Green PA, Webb KB, Evans RG, Knutsen AP, Schramm WF, Staake JL, Gibson BB, Steinberg KK. 1986. Health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of the American Medical Association 255:2031–2038. Hooiveld M, Heederik DJ, Kogevinas M, Boffetta P, Needham LL, Patterson DG Jr, Bueno de Mesquita HB. 1998. Second follow-up of a Dutch cohort occupationally exposed to phenoxy herbicides, chlorophenols, and contaminants. American Journal of Epidemiology 147(9):891– 901. IOM (Institute of Medicine). 1994. Veterans and Agent Orange Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1997. Characterizing Exposure of Veterans to Agent Orange and Other Herbicides Used in Vietnam: Scientific Considerations Regarding a Request for Proposals for Research. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. Irish KR, Darrow RA, Minarik CE. 1969. Information Manual for Vegetation Control in Southeast Asia. Misc. Publication 33. Fort Detrick, MD: Department of the Army, Plant Sciences Laboratories, Plant Physiology Division. NTIS AD-864–443. Jappinen P, Pukkala E. 1991. Cancer incidence among pulp and paper workers exposed to organic chlorinated compounds formed during chlorine pulp bleaching. Scandinavian Journal of Work, Environment, and Health 17:356–359. Kolmodin-Hedman B, Erne K. 1980. Estimation of occupational exposure to phenoxy acids (2, 4-D and 2,4,5-T). Archives of Toxicology Supplement 4:318–321. Kolmodin-Hedman B, Hoglund S, Akerblom M. 1983. Studies on phenoxy acid herbicides. I. Field study. Occupational exposure to phenoxy acid herbicides (MCPA, dichlorprop, mecoprop and 2,4-D) in agriculture. Archives of Toxicology 54:257–265. Lavy TL, Shepard JS, Mattice JD. 1980a. Exposure measurements of applicators spraying (2,4,5-trichlorophenoxy)acetic acid in the forest. Journal of Agricultural and Food Chemistry 28: 626–630. Lavy TL, Shepard JS, Bouchard DC. 1980b. Field worker exposure and helicopter spray pattern of 2,4,5-T. Bulletin of Environmental Contamination and Toxicology 24:90–96. Libich S, To JC, Frank R, Sirons GJ. 1984. Occupational exposure of herbicide applicators to herbicides used along electric power transmission line right-of-way. American Industrial Hygiene Association Journal 45:56–62. MACV (Military Assistance Command, Vietnam), Military History Branch. 1972. Chronology of Events Pertaining to U.S. Involvement in the War in Vietnam and Southeast Asia. Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H. 1991. Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet 338:959–964. 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 Environmental Epidemiology 5(2):209–223.

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