5
Exposure Assessment

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 worldwide for the control of weeds and unwanted vegetation, although the application



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Veterans and Agent Orange: Update 1998 5 Exposure Assessment 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 worldwide for the control of weeds and unwanted vegetation, although the application

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Veterans and Agent Orange: Update 1998 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 the plant's 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 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 TABLE 5-1 Major Herbicides Used in Operation Ranch Hand: 1962-1971 Herbicide 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 1998 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, 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, mine fields, 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

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Veterans and Agent Orange: Update 1998 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 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

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Veterans and Agent Orange: Update 1998 and application of chemicals, as well as in the cleaning and maintenance of the spray equipment (Thomas and Kang, 1990). Units and individuals other than the 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 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 troops' 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 four to six weeks after the mission, when defoliation was complete and the herbicide had been biodegraded or photo degraded (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

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Veterans and Agent Orange: Update 1998 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 with 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 one 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 four 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 one 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 lack sufficient information, so that estimates of the number of Army personnel close to sprayed areas could not be calculated. 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

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Veterans and Agent Orange: Update 1998 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 six-year period (Gough, 1986). OCCUPATIONAL AND ENVIRONMENTAL EXPOSURES TO HERBICIDES AND DIOXIN The Department of Agriculture, under the provisions of the Federal Insecticide, Fungicide, and Rodenticide Act, registered 2,4,5-T as an herbicide in 1948. Farmers recognized its usefulness for killing broadleaf plants and for controlling weeds in pasture lands to enable desirable grasses to grow. Foresters, including the U.S. Forest Service and other federal agencies having jurisdiction over national lands, forests, and parks, have used herbicides to keep clown brush and undergrowth and to eliminate unwanted hardwoods in pine forests. Railroads, utility companies, and certain government agencies have used 2,4,5-T to limit the growth of weeds along railroad tracks, next to power lines, and along highways. Because 2,4,5-T was inexpensive and easy to use, by the early 1970s it had become one of the most widely used herbicides in the United States (Gough, 1986). In investigating the possible health effects of exposure to herbicides in Vietnam, the committee also looked at available information on occupational and environmental exposures to dioxin, the contaminant found in 2,4,5-T. These studies included residents living in and around Seveso, Italy, who were exposed during industrial accidents; chemical plant workers who were occupationally 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 that contaminated wood preservatives; pulp and paper workers exposed to dioxin through the pulp bleaching process; and residents of China exposed to dioxin as a contaminant in a pesticide used to prevent schistosomiasis. 2,4-D, the other herbicide used in Agent Orange and a constituent of Agents Purple and White, has attracted less interest from researchers because published studies do not indicate it is contaminated with 2,3,7,8-TCDD. Rather little research has been conducted on exposures to the two other primary herbicides used in Vietnam, picloram and cacodylic acid. In Vietnam and in most of the occupational and environmental studies examined by the committee, subjects could have been exposed to a number of other chemicals besides herbicides or TCDD. In some cases the exposure mixture included a variety of dioxin and dibenzofuran congeners. Attempts to assess the

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Veterans and Agent Orange: Update 1998 toxicity of these mixtures are discussed later in this chapter as well as in Chapter 3. In other cases the exposure mixtures include a range of herbicides, fungicides, insecticides, wood preservatives, insect repellents, and other chemicals that might be used in the industry being studied. In such situations it is possible that these co-exposures could be confounding the association of herbicides or TCDD with the disease. Alternatively, these co-exposures may act synergistically with the herbicides, increasing the risk from exposure. EXPOSURE ASSESSMENT FOR EPIDEMIOLOGY The committee was asked to evaluate the scientific literature to determine, if possible, whether there is a statistical association between various health effects and herbicide use, taking into consideration the strength of the scientific evidence and the appropriateness of the methods used to detect the association. Estimation of health risks associated with herbicide exposure consists of two primary activities: (1) exposure assessment and (2) assessment of the health effects in exposed individuals. This and previous committees have all found that the weakest methodologic aspect complicating the interpretation of the available epidemiologic studies is the definition and quantification of exposure. When epidemiologists assess the potential health risks of exposure to a toxic chemical, they compare the disease experience of groups of people with different levels of exposure to that substance. Accurate estimation of any risk associated with exposure depends on the ability to identify those who are "exposed" and those who are not. When the concern is with low-level, possibly intermittent exposure to a chemical such as an herbicide, it becomes important not only to assess the presence or absence of exposure, but also to characterize the degree of exposure—its intensity and duration. Exposure assessment contributes to the epidemiologic study process in several ways. First, well-defined contrasts in the exposure of groups being studied increase the validity of individual and group risk assessments. A poorly defined contrast could result, for example, if a group of people assumed to be exposed to a particular agent contained many individuals who were not, in fact, truly exposed. Second, very large groups must be studied to identify the small risks associated with low levels of exposure, whereas a relatively small study may be able to detect the effect of heavy or sustained exposure to a toxic substance. In this way, a study's precision or statistical power is also linked to the extent of the exposure and the accuracy of its measurement. Exposure has been characterized in many different ways in epidemiologic studies, depending on the availability of data and the hypothesis being tested. One can usefully distinguish a few basic approaches to exposure assessment (Checkoway, 1986; Smith, 1987). The simplest approach compares the members of a class presumably exposed to an agent with the general population or with an "unexposed" group. Occupational studies are often of this type, comparing for example, herbicide production workers to the general population. Vietnam veter-

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Veterans and Agent Orange: Update 1998 ans have also been compared to veterans who served during the Vietnam era but did not serve in Vietnam. The advantages of this approach are its simplicity and the ease of interpretation of the results. Studies of this type can effectively identify the increased morbidity or mortality in the group. If, however, only a small fraction of class members are actually substantially exposed to a toxic agent (in all likelihood, only a fraction of the estimated 2.6 million to 3.8 million veterans who served in Vietnam were substantially exposed to herbicides), then any increased risk from exposure in this subgroup may be lost entirely when the disease risk of the full class (all Vietnam veterans) is assessed. A somewhat more refined method of exposure assessment assigns to each cohort member a qualitative degree or level of exposure. This may be done in several different ways. For example, a cohort of herbicide production workers could be divided into subgroups in such a way that those who were likely to have been heavily exposed through their job assignments are placed in one group (e.g., "high exposure"); a second group might be identified who had sustained exposures, but not in those jobs or departments in direct contact with the toxin ("moderate exposure"); and finally, a residual group might contain those with little or no exposure who were nonetheless employed at the production facility ("low exposure"). The disease risk may then be calculated separately for each of these groups compared to a referent or "unexposed" group. This method, as opposed to the simple exposed/unexposed comparison described above, should (if the classification of exposure is done without serious errors) yield less diluted risk estimates and provide support for a dose-response trend. This method also does not necessarily require expensive and time-consuming measurements of the actual exposure of each cohort member. Ideally, quantitative estimates should be available on the total exposure history of each subject in the study. When such data are available, it is possible to estimate quantitatively the relationship between a given level of exposure and the degree of risk that is expected to accrue. In occupational epidemiologic studies, quantitative exposure data are sometimes developed through a process called historic exposure reconstruction. In occupational cohort studies, work records and industrial hygiene data may be available that cover the entire history of the factory being studied. In this way it is often possible to know with considerable accuracy the length of time that each cohort member has spent in the industry. Somewhat more precise assessments may be possible if the cohort can be subdivided into those who were employed in one or more areas of the plant where the exposure of interest was heaviest. A variety of approaches have been used to estimate the intensity of exposure in each job or department in an industry, including the use of expert judgment, development of physical process models, and the extrapolation of sampling or production data. An analogous approach for Vietnam veterans might, for example, distinguish individuals by dates of service, proximity to herbicide spraying, and job responsibilities relative to herbicides.

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Veterans and Agent Orange: Update 1998 When quantitative estimates of the intensity of exposure are not available, it is sometimes possible to know the duration of exposure for each cohort member. Although less satisfactory, one may nevertheless assume that the intensity of exposure was relatively constant among exposure subgroups of the cohort, so that the total exposure (sometimes called cumulative exposure) is proportional to its duration. Based on these assumptions, one would hypothesize that a true risk would increase with the duration of exposure. Another form of quantitative exposure assessment involves the use of bio-markers for the agent of interest. TCDD and other chlorinated dibenzo-p-dioxins and dibenzofurans are found in blood and tissues of nonoccupationally exposed humans at part-per-trillion (nanogram-per-kilogram) levels. After absorption, TCDD is distributed to tissues with high lipid content. Adipose tissue appears to be the main site of accumulation, although TCDD has been found in all tissue samples that have been examined from autopsy (Ryan et al., 1986). Although exposure to TCDD from environmental sources occurs on a continuing basis (Geyer et al., 1986; Byard, 1987), both serum and fat biopsy samples taken from individuals with unusually high exposures indicate that TCDD may remain in the body for many years after exposure. This means that, in theory, TCDD levels in the body long after exposure could be used to estimate TCDD levels at the end of exposure using a pharmacokinetic model and the clearance rate (half-life) of TCDD in the body. Several epidemiologic studies have tried this approach to estimating exposures in the cohort under study (Flesch-Janys et al., 1995; Ott and Zober, 1996; Ramlow et al., 1996; and others). However, various authors have reported different estimates of TCDD half-life (Pirkle et al., 1989; Needham et al., 1994; Michalek et al., 1996a; Flesch-Janys et al., 1996; Michalek et al., 1997), and TCDD half-life is likely to change as a persons weight and percentage of body fat change when the person ages (Flesch-Janys et al., 1996). In addition, serum TCDD levels have been shown to vary with several other personal characteristics, including age, race, body mass, region of residence, and smoking status (Devine et al., 1990; Flesch-Janys et al., 1996). Although quantitative measures of exposure are highly desirable, a biomarker, especially one gathered years after exposure, is not necessarily better than qualitative exposure measures. For example, Fingerhut et al. (1989) reported that "years exposed" was correlated with both current TCDD level (r = .82) and estimated TCDD level at the end of exposure (r = .80). Group differences in serum TCDD levels can be useful in confirming that occupational exposure measures reflect true differences in exposure; this has been done in studies by the National Institute for Occupational Safety and Health (NIOSH) (Fingerhut et al., 1989, 1991; Sweeney et al., 1990) and others. To summarize, epidemiologists generally think of the various exposure assessment strategies described above in a hierarchy of increasing accuracy: the exposed/unexposed approach is the least accurate, followed by the qualitative

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Veterans and Agent Orange: Update 1998 classification of level of exposure, and best of all, quantitative estimates of both the intensity and the duration of exposure. It is important to stress that all of these strategies may be valid, but they vary in their precision and in the degree to which they can contribute to the evidence for or against a particular exposure-disease association. The strength of association between an exposure and a disease is only one of the criteria used in evaluating epidemiologic evidence. Another criterion often used in evaluating an association is whether or not there is evidence that as exposure increases, the risk of the disease also increases (Hill, 1971). This dose-response pattern can be detected only if the degree of exposure among different cohorts or subcohorts of the study can be determined. Inaccurate assessment of exposure can obscure the existence of such a trend and thus make it less likely that a true risk will be identified. Once an exposure-disease association has been established, it is often desirable to consider the implications for some exposed population other than the population in which the study was performed. In making this inference, it is important to have exposure assessments that allow valid comparisons of exposure of the different study populations. For example, if an increased risk of a particular disease has been demonstrated in workers occupationally exposed to an herbicide for a long period, what would the risk be for a Vietnam veteran who was exposed only occasionally or for just a short period? The proper scale on which to compare these risks is the scale of quantitative exposure (integrating both level and duration), with risk assessed per unit of exposure. If the exposure levels are unknown or poorly characterized, then extrapolating from one population to another may be difficult. The types of occupational and environmental exposure situations studied, and the likely intensity and duration of the exposures to herbicides and TCDD, are diverse. In principle, this provides an opportunity to compare results between studies to determine whether certain diseases are more common in populations likely to have higher exposures. However, because of the complex pattern of exposures to various herbicides and TCDD in the available epidemiologic studies, the committee was generally not able to differentiate among multiple chemical exposures to determine whether specific health effects were associated with a particular herbicide or with TCDD in the mixed exposure setting. Attempts to assess the toxicity of mixtures of dioxin and dibenzofuran congeners are discussed later in this chapter as well as in Chapter 3. In August of 1997, the committee hosted a workshop for many of the researchers involved in studies of Vietnam veterans and individuals exposed to herbicides or dioxin. The goal of the workshop was to discuss the feasibility of using current data combination techniques (such as meta-analysis and data pooling) with existing data bases to further investigate the health effects of herbicide and dioxin exposures. The question of which analysis techniques, which data sets, and which health outcomes might be best suited for such an approach was

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Veterans and Agent Orange: Update 1998 three repeated blood serum measurements from 1982, 1987, and 1992, Michalek et al. (1996a) estimated a half-life of 8.7 years. An erratum published for this study changed that estimate to 8.5 years (Michalek et al., 1997). A study of 27 persons exposed during the 1976 TCDD release in Seveso, Italy, and followed for 15.9 years, yielded a mean half-life estimate of 8.2 years and a median half-life estimate of 7.8 years (Needham et al., 1994). A recently published study of 48 German workers exposed to TCDD in a plant producing herbicides showed a median half-life of 7.2 years (Flesch-Janys et al., 1996). The time between the first and last analysis was 6.3 years. Increasing age and percentage of body fat were associated with increasing half-life for most congeners. Smokers in general had a faster decay rate than non-or ex-smokers. Also during this review a study investigating the reliability of serum TCDD measurements using paired samples from 46 Ranch Hands veterans was reported. The coefficient of reliability for these repeated measurements was 0.87 when the measurement was made at 50 ppt dioxin or less. When it was more than 50 ppt dioxin, the coefficient of reliability was 0.93, but only if the measurements were analyzed after logarithmic transformation (Michalek et al., 1996b). Other Dioxin Congeners In addition to 2,3,7,8-TCDD, other congeners of dioxin and dibenzofuran contaminated the herbicides sprayed in Vietnam, as well as the products used and manufactured by the occupational cohorts whose health experience forms the basis for many of the committee's conclusions. Because these may contribute to cancer risk, dioxin "toxic equivalent factors" (Teq factors) have been estimated for the various other congeners of dioxin and dibenzofuran (U.S. EPA, 1989). A Teq factor for each dioxin or furan congener is estimated by comparing its toxicity to that of 2,3,7,8-TCDD, which is arbitrarily assigned a Teq factor of 1.0. Other congeners have lower Teq factors, some as much as 1,000 times lower. In principle, it is possible to measure each congener and calculate a toxic equivalent for the entire mixture, but this is costly. Most studies of dioxin-exposed individuals have related health effects to TCDD levels only and have not considered other associated dioxins or furans. The use of 2,3,7,8-TCDD alone as a measure of risk when exposure includes many congeners must be considered cautiously. Different sources of dioxin contamination may have different distributions of congeners. Also, the stability of the different congeners in the environment differs, so that human exposures occurring long after spraying may differ from those at the time of spraying. Finally, the half-lives of different congeners in the body differ, so that an exposed individual will have varying patterns of exposure to each congener over time. Therefore, although it is probably not feasible to conduct a total congener analysis in every study, the use of TCDD measurements alone may represent an over-simplification of the full exposure picture.

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Veterans and Agent Orange: Update 1998 Since Update 1996, Flesch-Janys et al. (1996) have published a study reporting the half-lives for various dioxin congeners. These ranged from 3.7 years for heptachlorinated dibenzodixoin (1,2,3,4,6,7,8-HpCDD) to 15.7 years for pentachlorinated dibenzodioxin (1,2,3,7,8-PCDD). For the furans, the median half-lives were between 3.0 and 19.6 years. Schecter et al. (1996a) measured TCDD and its congeners among 50 Vietnam veterans from the state of Michigan, chosen on the basis of their likely exposure to Agent Orange in Vietnam. They measured the levels of dioxin and dibenzofuran congeners in blood samples. They found average 1,2,3,4,6,7,8-HpCDD levels 13 times higher than the average TCDD levels and average 1,2,3,4,6,7,8,9-OCDD levels 88 times higher than average TCDD levels. The dioxin total Teq level averaged 24.7 for these veterans, with an average total Teq level of 31.8 when dibenzofuran congeners were also included. This report described semen sample levels for a subset of this population (N = 17) as well; these were pooled into 3 sets of samples for analysis. Average 1,2,3,4,6,7,8-HpCDD levels 30 times higher than average TCDD levels were found, along with average 1,2,3,4,6,7,8,9-OCDD levels that were more than 260 times higher than average TCDD levels. The dioxin total Teq level for these semen samples averaged 0.010, with an average total Teq level of 0.013 when dibenzofuran congeners were also included. DeVito et al. (1995) report that background Teq blood levels of dibenzodioxins and dibenzofurans vary from 28 to 41 ng/kg (lipid adjusted). Sodium pentachlorophenol (NaPCP) has been widely used in the control of schistosomiasis. Dioxin is a contaminant in NaPCP. During 1972, 1973, and 1978 more than 1,300 tons of 5-ppm NaPCP were sprayed in problem areas in central China. Samples were collected from sprayers or handlers of NaPCP, from persons living for more than 30 years (or their whole lives, if younger) in areas where NaPCP was sprayed, and persons living in unsprayed area (Schecter et al., 1996b). Samples were pooled for analysis, so that for each category there is only one sample result. The dioxin total Teq levels in blood and breast milk samples from residents who lived and/or worked in the sprayed areas were about two times the levels of those from nonsprayed areas. Those living in the area when spraying was done had a total Teq level of 16.3, which is 2.6 times higher than that in nonsprayed areas (6.4 Teq). Analysis for dioxin congeners was done for a bulk sample of the NaPCP product that was sprayed, four sediment samples from a lake where NaPCP was sprayed, and personal blood and breast milk samples. A similar pattern of dioxin congener levels was found in all samples, suggesting a "fingerprint" that may represent NaPCP exposures in this area of China. TCDD Exposure Levels for Selected Studies Flesch-Janys et al. (1995) reported updated results for a cohort of workers (N = 1,184) in a German plant where herbicides and insecticides were produced (2,4,5-T, trichlorophenol, bromophos, and lindane). The original study (Manz et

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Veterans and Agent Orange: Update 1998 al., 1991) used exposure surrogates such as duration of employment, time of entry into the plant, and qualitative exposure groups in the mortality analysis. The update increased the follow-up period of this cohort and added quantitative exposure assessment based on blood or adipose measurements of PCDD/F. Using a first-order kinetic model, half-lives from an elimination study in 48 workers from this cohort, and background levels for the German 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 contribution of the working time in each production department to the PCDD/F level at the end of exposure was estimated. 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 his or her exposure. This yielded a mean estimated TCDD level at last exposure of 141.4 ng/kg (median, 38.2 ng/kg) for the cohort. The estimated TCDD level at last exposure ranged from 0 to 3890.2 ng/kg for the cohort. A total toxic equivalency was also computed for all dioxins and furans combined by summing the levels of all congeners weighted by their toxic equivalency factor relative to TCDD. The mean of toxic equivalencies for the cohort (without TCDD) was 155 ng/kg (median, 69.2 ng/kg). The mean of the total toxic equivalencies for the cohort (with TCDD) was 296.5 ng/kg (median, 118.3 ng/kg; range 1.2-4361.9 ng/kg). Schecter et al. (1996a) measured TCDD and its congeners among 50 Vietnam veterans from the state of Michigan who were selected for having a high likelihood of exposure to Agent Orange based on self-report or history of cancer or on children with birth defects. They found TCDD levels greater than 5 ppt in 16 (32 percent) of these Vietnam veterans. Six (12 percent) had TCDD levels higher than 20 ppt 23-24 years after their potential Agent Orange exposure. The authors report the mean of the U.S. population TCDD level in blood or adipose tissue as 3.5 ppt (median, 3.1; range 1.0-7.7 ppt). Needham et al. (1997) report TCDD levels from serum samples taken at Seveso in 1976 after the accident there. In zone A, presumed to be the area of highest exposure, serum TCDD levels for 296 residents were determined. Seven percent (N = 22) of these samples were below the limit of detection of the method. Using one-half of the limit of detection for these values resulted in a median TCDD level of 447 ppt (129-1860 ppt) for the 25th and 75th percentiles. For zone B the median value for 80 samples, with 45 percent (N = 36) below the limit of detection, was 94 ppt (51-153 ppt) for the 25th and 75th percentiles. For zone R the median value for 48 samples, with 23 percent (N = 11) below the limit of detection, was 48 ppt (22-118 ppt for the 25th and 75th percentiles). Almost 20 years later, plasma TCDD levels were assayed among 62 individuals living in the region of Seveso, Italy, at the time of the industrial accident there (Landi et al., 1997). Among the seven from the highly exposed zone A, the

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Veterans and Agent Orange: Update 1998 geometric mean level was 53 ppt. In zone B, 55 persons were measured and the geometric mean level was 11 ppt, with women having significantly higher TCDD levels than men. Neither presence in the contaminated area at the time of the accident, number of years spent in the zone, occupation, nor distance from the accident site within the zone, explained the gender difference. When zone B measurements were pooled, gender, distance from the accident site, and meat consumption were significantly associated with TCDD concentration. In the noncontaminated area zone non-ABR, the geometric mean TCDD levels were 4.9 ppt. Although this represents a typical background level of TCDD, the authors found that women had a significantly higher TCDD concentrations than men. Development of Exposure Indices In an epidemiologic study, it would be ideal to have a measure of the dose at the target organ to use in the dose-response analysis. This would necessitate the development of a pharmacokinetic model for the estimation of tissue dose over the period of interest. In a number of studies the authors have attempted to estimate dose of tetrachlorinated dibenzo-p-dioxin and furan (TCDD/F) at the time of last exposure by extrapolating back from more current serum TCDD measurements (Fingerhut et al., 1989; Ott et al., 1993; Flesch-Janys et al., 1995). In each case the authors chose a half-life estimate for TCDD that applied to all members of the cohort and assumed a one-compartment first-order kinetics model of TCDD levels. As stated earlier, the caveats with the pharmacokinetic modeling done to date are several: (1) it is assumed that among all potential toxic agents in Agent Orange, TCDD is the agent responsible for the health effects of interest; (2) the congeners of TCDD are not accounted for; (3) it is assumed that a single-compartment model is sufficient for dose estimation; (4) to date, no parameters for the effects of age, smoking, percentage of body fat, or weight on clearance have been included in these models; and (5) it is also assumed that the dose received prior to the end of exposure (the ''peak") was accumulated at a constant rate. Despite these caveats, developments in this area of exposure assessment may prove fruitful in attempts to pool diverse data sets relevant to evaluating the risks of exposures to Agent Orange and other herbicides in Vietnam. When the issues of toxicokinetic modeling of dose have been addressed, a question will still remain regarding what dose metric should be used. It could be the peak dose, the average dose over a lifetime or the period of exposure, or the cumulative dose over either the individual's lifetime or the period of exposure. Many of these dose metrics will be highly correlated and will also be correlated with more simple metrics such as duration of exposure. Nevertheless, if such dose metrics could be developed, they might provide a means to pool data across studies where exposures have been measured simply in categorical terms or in terms of duration of exposure.

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Veterans and Agent Orange: Update 1998 Scheuplein and Bowers (1995) and Aylward et al. (1996) have modeled exposure to TCDD as a simple single-compartment constant infusion process with exponential decline post-exposure. They estimate the peak concentration of TCDD—assumed to be at the end of exposure—as well as the area under the curve (AUC)—which is the cumulative dose of TCDD in parts-per-trillion-years—and the average concentration—which divides the AUC by the number of years. Aylward and colleagues used this model with the NIOSH worker cohort (Fingerhut et al., 1989) and found a great overlap in the exposures estimated for the four NIOSH exposure duration categories, regardless of the exposure metric used. It should be pointed out that in the NIOSH study, blood samples were available on only about 5 percent of those in the study cohort so that estimation of dose using blood TCDD was not possible for the whole cohort. However, because the NIOSH analysis did find a high correlation between measured TCDD levels and duration (years) of exposure (r = .72) and between estimated TCDD levels at the end of exposure (peak) and duration (years) of exposure (r = .80), exposure duration was assumed to be a good surrogate for TCDD level. Aylward has estimated the peak, average, and AUC TCDD levels of the Ranch Hand (Aylward et al., 1997) and Seveso (Hays et al., 1997) populations as well. Again, regardless of the dose metric used, there is great overlap in the estimated exposure levels for all the analysis categories used in these studies (zones in Seveso and exposure groups in Ranch Hands). REFERENCES Air Force Health Study (AFHS). 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. Australian Senate Standing Committee on Science and the Environment. 1982. Pesticides and the Health of Australian Vietnam Veterans. First report. 240 pp. Aylward LL, Hays SM, Karch NJ, Paustenbach DJ. 1996. Relative susceptibility of animals and humans to the cancer hazard posed by 2,3,7,8-tetrachlorodibenzop-dioxin using internal measures of dose. Environmental Science and Technology 30: 3534-3543. (Erratum published in Environmental Science and Technology 1997; 31:1252.) Aylward LL, Hays SM, Czernec J, Brien B, Paustenbach DJ, Karch NJ. 1997. Relative doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using alternate dosimetrics: comparison of the NIOSH and Ranch Hand Populations. Organohalogen Compounds 34:6-9. 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):312-21. 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, Zochetti C, Guercilena S, Consonni D, Tironi A, Landi MT, Pesatori AC. 1997. Dioxin exposure and cancer risk: a 15-year mortality study after the "Seveso Accident," Epidemiology 8(6):646-652. Blair A, White DW. 1985. Leukemia cell types and agricultural practices in Nebraska. Archives of Environmental Health 40:211-214.

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Veterans and Agent Orange: Update 1998 Bond GG, McLaren EA, Lipps TE, Cook RR. 1989. Update of mortality among chemical workers with potential exposure to the higher chlorinated dioxins. Journal of Occupational Medicine 31:121-123. 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. Byard JL. 1987. The toxicological significance of 2,3,7,8-tetrachlorodibenzop-dioxin and related compounds in human adipose tissue. Journal of Toxicology and Environmental Health 22: 381-403. 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. Centers for Disease Control (CDC). 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. Centers for Disease Control (CDC). 1988. 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. Centers for Disease Control (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. Checkoway H. 1986. Methods of treatment of exposure data in occupational epidemiology. Medicina del Lavoro 77:48-73. Coggon D, Pannett B, Winter P. 1991. Mortality and incidence of cancer at four factories making phenoxy herbicides. British Journal of Industrial Medicine 48:173-78. Collins CV. 1967. Herbicide Operations in Southeast Asia, July 1961-June 1967. San Francisco: Headquarters, Pacific Air Forces. NTIS AD-779 796. Collins JJ, Strauss ME, Levinskas GJ, Conner PR. 1993. The mortality experience of workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a trichlorophenol process accident. Epidemiology 4:7-13. 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. Devine OJ, Karon JM, Flanders WD, Needham LL, Patterson DG Jr. 1990. Relationships between concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin serum and personal characteristics in U.S. Army Vietnam veterans. Chemosphere 20:681—691.

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Veterans and Agent Orange: Update 1998 DeVito MJ, Birnbaum LS, Farland WH, Gasiewicz TA. 1995. Comparisons of estimated human body burdens of dioxinlike chemicals and TCDD body burdens in experimentally exposed animals. Environmental Health Perspectives 103(9):820-831. 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. Dept. of Health and Human Services, Centers for Disease Control. Fingerhut MA, Sweeney MH, Patterson DG Jr, Piacitelli LA, Morris JA, Marlow DA, Hornung RW, Cameron LW, Connally LB, Needham LL, Halperin WE. 1989. Levels of 2,3,7,8-TCDD in the serum of U.S. chemical workers exposed to dioxin contaminated products: interim results. Chemosphere 19:835-840. 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. Gum P, Manz A, Nagel S, Waltsgott H, Dwyer JH. 1995. Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany. American Journal of Epidemiology 142:1165-1175. Flesch-Janys D, Becher H, Gurn P. Jung D, Konietzko J, Manz A, Papke O. 1996. Elimination of polychlorinated dibenzo-p-dioxins and dibenzofurans in occupationally exposed persons. Journal of Toxicology and Environmental Health 47(4):363-378. Geyer H, Scheunert I, Korte F. 1986. Bioconcentration potential of organic environmental chemicals in humans. Regulatory Toxicology and Pharmacology 6:313-347. 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. 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. Hays SM, Aylward LL, Mocarelli P, Needham LL, Brambilla P, Gerthoux P, Patterson DG, Czernec J, Paustenbach DJ, Karch NJ. 1997. Comparative dose-response of the NIOSH and Seveso populations to the carcinogenic hazard of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using alternate dosimetrics. Organohalogen Compounds 34:305-310. 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. Hill. AB. 1971. Principles of Medical Statistics, 9th ed. New York: Oxford University Press. 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. Hooiveld M, Heederik D, Bueno de Mesquita HB. 1996. Preliminary results of the second follow-up of a Dutch cohort of workers occupationally exposed to phenoxy herbicides, chlorophenols and contaminants. Organohalogen Compounds 30:185-189. Institute of Medicine (IOM). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press.

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