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Veterans and Agent Orange: Update 1998 (1999)

Chapter: 5 Exposure Assessment

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Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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.

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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-

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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.

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

also discussed. A review of that workshop will be released as a National Academy of Sciences report.

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 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.

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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 exposures, 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.

More recently, 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., 1984 a,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., 1984 a,b).

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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., 1984 a,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 opportunities 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 scores of 4 or 5 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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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, 1988). 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, 1988).

The median TCDD level in Vietnam veterans was 4 ppt, with a range from 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, 1988). 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,

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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 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.

EXPOSURE ASSESSMENT IN OCCUPATIONAL AND ENVIRONMENTAL STUDIES

Problems exist in the estimation of exposures among nonveteran groups studied for health outcomes. In many of the studies reviewed, exposure to herbicides or TCDD was inferred simply by using occupation as a surrogate measure. Types of occupations involving potential exposure include workers in herbicide or other chemical production plants, agricultural and forestry workers, herbicide and pesticide applicators, sawmill workers, and paper and pulp mill workers. As noted in the beginning of this chapter, the problem with characterizing exposure based on occupation only is that misclassification can occur if those classified as exposed were actually unexposed, or vice versa. Any actual increased risk from exposure might not be detected in the entire group when exposure is classified simply by occupation.

Studies of environmental exposures are related primarily to unintentional releases of TCDD into the environment at Seveso, Italy, or in an area where herbicides or antiparasitic pesticides were applied. 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.

The studies described below are also addressed in detail in Chapter 6 of this report, in Chapter 6 of Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (henceforth called VAO) (IOM, 1994), and Chapter 5 of Veterans and Agent Orange: Update 1996 (henceforth called Update 1996) (IOM, 1996).

Production Workers

The Netherlands

Two plants in the Netherlands that manufactured phenoxy herbicides and chlorophenols between 1955 and 1986 were studied by Bueno de Mesquita et al.

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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(1993). In one of the plants an accident in 1963 resulted in the release of polychlorinated dibenzo-p-dioxins (PCDDs). Cohort exposure was based on employment records and interviews. Workers were considered "exposed" if they worked in any of several departments, had been exposed as a result of the 1963 accident, or entered an exposed department at least once a week on a regular basis. This initial study was part of the first International Agency for Research on Cancer (IARC) analysis (Saracci et al., 1991). A follow-up of the cohort included a more detailed exposure assessment using serum TCDD levels of a subset of workers to model historical exposure levels (Hooiveld et al., 1996). This expanded follow-up cohort was included in the second follow up IARC analysis (Kogevinas et al., 1997).

United Kingdom

Workers from four factories that manufactured phenoxy herbicides and chlorophenols between 1963 and 1985 were studied by Coggon et al. (1991) and Kauppinen et al. (1994). No air or biological sampling was done. Subjects were classified according to their potential exposure to phenoxy herbicides and chlorophenols based on job histories. These cohorts were included in the first IARC analysis (Saracci et al., 1991) and the second follow-up IARC analysis (Kogevinas et al., 1997).

First IARC Study

A multisite study by IARC involved 18,390 production workers and herbicide sprayers from 20 cohorts in 10 countries (Saracci et al., 1991). Included in this analysis are the cohorts from the Netherlands and the United Kingdom described above. Four of the cohorts included workers who sprayed 2,4,5-T, 2,4-D, or 2-methyl-4-chlorophenoxyacetic acid (MCPA). Exposure for this study was estimated from a combination of factory records, work histories, and questionnaires. The cohort was subdivided according to whether individuals were exposed by spraying or during production and by the type of chemical used or produced. Workers who sprayed chlorophenoxy herbicides or worked in factory departments in contact with these chemicals were considered "exposed" (N = 13,482); workers "probably exposed" had no job title but were judged to have been exposed (N = 416). Workers with no exposure status information were treated as having "unknown" exposure (N = 541), and those who never worked in factory departments with exposure to chlorophenoxy herbicides, or who never sprayed these chemicals, were considered "nonexposed'' (N = 3,951). Exposure to TCDD was assumed to be possible for those who worked producing or spraying 2,4,5-trichlorophenol and 2,4,5-T or related products. The degree of exposure to TCDD, however, is more uncertain than that of the NIOSH study since some of the cohorts of individuals either sprayed or produced compounds such as MCPA

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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or mecoprop (MCPP), which were unlikely to contain significant quantities of TCDD.

Two nested case-control studies were conducted using this cohort (Kogevinas et al., 1995). For the case-control studies, exposures to 21 chemicals were estimated on a relative scale by three industrial hygienists. A cumulative exposure score was calculated for each subject for each chemical, based on the individual's work history and knowledge of the determinants of exposure such as department or job, use of personal protective equipment, contact with chemicals and other factors (Kauppinen et al., 1994). In the case-control analysis, the cumulative exposure scores for each chemical were divided into low-, medium-, and high-exposure categories (Kogevinas et al., 1995).

United States

On March 8, 1949, at the Monsanto Company's chemical plant in Nitro, West Virginia, an accident occurred in the autoclave in which trichlorophenol was being manufactured. The pressure inside the autoclave increased to a level that exceeded safety limits, and the safety valve gave way, allowing the pressurized contents (trichlorophenol that contained TCDD) to vent out through the chimney and into the inside of the building (Gough, 1986). The workers have been studied since the 1980s to evaluate the health impact of their exposures to TCDD (Zack and Suskind, 1980; Zack and Gaffey, 1983; Collins et al., 1993). No exposure measurements were made of this cohort; exposure was determined by their having chloracne, by their presence in the plant during a 9-month period after the accident, or in one study, by their having worked in the 2,4,5-T production area.

The Dow Chemical Company plant in Midland, Michigan was another widely studied U.S. plant. This plant produced 2,4,5-T and its esters—trichlorophenol and pentachlorophenol—(Cook et al., 1986; Ott et al., 1987; Bond et al., 1989). By using wipe samples, process streams, and intermediate product information, jobs in the various departments during different time periods were ranked on a scale of 0 to 4 for intensity of exposure to TCDD, with each unit indicating an increase on a logarithmic scale. Cumulative exposure indices were calculated for each "exposed" job by multiplying the duration of each job by the estimated intensity of exposure and then summing across all exposed jobs. Recently, Ramlow et al. (1996) have done an update study of this cohort, using the cumulative exposure index as part of the analysis.

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. This study of 12 chemical companies, included the Nitro, West Virginia, and Midland, Michigan, plants described above as well as others. 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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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with TCDD contamination (Fingerhut et al., 1991). At each chemical plant, a review of operating conditions, job duties, and records of TCDD levels in industrial hygiene samples, intermediate reactants, products, and wastes was conducted. Exposure was estimated from job records according to the length of time working in processes involving TCDD contamination and the total length of employment at the plant; serum TCDD levels were measured in a sample of 253 workers. Data on current TCDD levels demonstrated a good correlation with the duration of employment. For the full cohort, the duration of exposure in a process involving TCDD contamination was used as the primary exposure metric. It should be noted that workers were exposed concurrently to other chlorophenols and phenoxy herbicides that were contaminated with TCDD, as well as to numerous other chemicals during their employment.

Germany

In 1953 the BASF production unit at Ludwigshafen, Germany, which produced trichlorophenol, had an accidental release. The primary exposure classification scheme used was to classify workers exposed during the accident or during subsequent cleanup and repair and those not exposed (Zober et al., 1990). Also analyzed were workers who developed chloracne and those who did not. Later studies of this cohort estimated the TCDD dose for the entire cohort using a statistical model describing the relationship between various exposure conditions and TCDD blood levels for a subset of 138 workers. Then, using work history information and TCDD half-life data the authors estimated the TCDD levels of each worker in the cohort at the time of exposure (Ott et al., 1993; Ott and Zober, 1996). There were subsets of this cohort that were also exposed to aromatic amines, such as ß-naphthylamine, and to asbestos; these data were collected during the exposure assessment. This cohort was not included in any of the IARC studies.

Another German cohort studied involved workers from a herbicide manufacturing plant of Boehringer-Ingelheim in Hamburg, Germany. Assessment of exposure to TCDD was based on samples of materials, products, waste, and soil from the plant. Based on this information, workers were classified as having high, medium, or low exposure according to the production departments in which they worked (Manz et al., 1991). 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 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 authors estimated the contribution of the working time in each

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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.

Second IARC Study

Kogevinas et al. (1997) updated and expanded the international cohort studied by Saracci et al. (1991) to include the data of Fingerhut et al. (1991) and Becher et al. (1996). The study population was classified as exposed to phenoxy herbicides or chlorophenols based primarily on individual job records and company exposure questionnaires. The great majority of workers were classified as exposed if they had ever worked in the production or spraying of phenoxy herbicides or chlorophenols (four cohorts were an exception with minimum employment periods of 1 to 12 months). The exposed workers were aggregated into five groups: main production, maintenance, other exposed jobs, unspecified tasks, and sprayers. Based on these categories and on information about production processes and the composition of the materials used, the exposed workers were further classified into three categories: (1) exposed to TCDD or higher chlorinated dioxins; (2) unexposed to TCDD or higher chlorinated dioxins; and (3) unknown exposure to TCDD or higher chlorinated dioxins.

Agricultural, Forestry, Outdoor Workers, and Environmental Exposures

Agricultural 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 the duration or intensity of exposure or to determine the specific type of herbicide or chemical to which a worker was

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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exposed. Because agricultural workers are often exposed to a wide variety of herbicides, pesticides, and other chemicals, it is difficult to associate diseases with any particular exposure in this setting.

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., 1988; Hansen et al., 1992; Ronco et al., 1992). Other studies have used county of residence as a surrogate of exposure, relying on 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 exposure according to 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).

Herbicide and 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 specifically to phenoxy herbicides or TCDD. Individual estimates of the intensity and frequency of exposure were rarely quantified in the studies the committee examined, however, and applicators often were known to have sprayed 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.

Paper and Pulp Mill Workers

An occupational group thought to be exposed to TCDD and chlorinated phenols consists of paper and pulp mill workers. When free chlorine gas is used to bleach pulp, TCDD can be produced. Although TCDD has been found in chlorine-bleached pulp, studies of pulp and paper mill workers have not, to date, shown elevated levels of dioxins in their biological tissues (Rosenberg et al.,

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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1994, 1995; Mouradian et al., 1995). 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).

Sawmill Workers

Workers in sawmills may be exposed to pentachlorophenates, which are contaminated with higher chlorinated PCDDs (Cl6-Cl8) 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; Hertzmann et al., 1997).

Seveso, Italy

One of the largest industrial accidents involving environmental exposures to TCDD occurred in Seveso, Italy, 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: 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 the 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. The Seveso cohort continues to be monitored, including a 15-year follow-up of mortality (Bertazzi et al., 1997) and a continuing examination of serum TCDD levels (Pesatori, 1995; Needham et al., 1997).

Vietnamese Studies

Several studies have investigated exposure to herbicides among the residents of southern Vietnam, comparing unexposed residents of the South to residents of the North (Constable and Hatch, 1985). Other studies have attempted to identify North Vietnam veterans 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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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(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).

REVIEW OF THE SCIENTIFIC LITERATURE

Several studies published since the release of Update 1996 provided useful information for the refinement of exposure assessment strategies. Although none of these studies led the committee to revise its basic view of the role of exposure assessment in the evaluation of epidemiologic studies, several recent reports warrant brief discussion here. The studies fall into three categories: (1) investigations of the clearance of TCDD from the human body, (2) evaluations of other types (congeners) of dioxins found in humans exposed to herbicides and related chemicals, and (3) the development of several exposure indices for epidemiologic studies.

TCDD Half-Life Investigations

The pharmacokinetics of TCDD in humans—its absorption, distribution, and passage through the body—are not fully understood, which makes individual serum TCDD levels difficult to interpret and also complicates the interpretation of epidemiologic studies that rely on these measures of exposure. A complex, poorly understood process distributes dioxins among body tissues and slowly clears them from the body. There is evidence that this process is quite variable among humans, so it is difficult to model its behavior and thereby extrapolate backwards to estimate the likely concentration of TCDD in fat or blood in the past. It is also often assumed that TCDD is removed from the body according to first-order kinetics—that is, for a given period of time, a constant fraction of the TCDD body burden is eliminated—but some evidence suggests the process may be more complicated and may vary as conditions in the body change. Furthermore, the metabolic processes governing this movement and disposition may not be relevant in the determination of the dose of TCDD to specific areas, such as the brain or reproductive organs. In the epidemiologist's view, the "causal pathway" linking exposure to the biomarker (serum or fat TCDD) may be different from that linking exposure to disease. This can also be complicated by the role of individual susceptibility factors, which may be polymorphic in humans and hence increase or decrease the risk of TCDD-related disease (Pesatori, 1995).

A number of studies have tried to estimate the half-life of TCDD in humans. These have been reported in VAO or Update 1996. For example, in a study of 36 Ranch Hand veterans, the median half-life of TCDD was estimated to be 7.1 years (Pirkle et al., 1989). An expanded study of 337 Ranch Hand veterans, including the 36 from the previous study, estimated a median half-life between 11.5 and 12 years (Wolfe et al., 1994). Using 213 Ranch Hands veterans with

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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.

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

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.

Suggested Citation:"5 Exposure Assessment." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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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).

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×

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Third in a series of six congressionally mandated studies occurring biennially, this book is an updated review and evaluation of the available scientific evidence regarding the statistical association between exposure to herbicides used in Vietnam and various adverse health outcomes suspected to be linked with such exposures. As part of the review, the committee convened a workshop at which issues surrounding the reanalysis and the combination of existing data on the health effects of herbicide and dioxin exposure were addressed.

This book builds upon the information developed by the IOM committees responsible for the 1994 original report, Veterans and Agent Orange, and Veterans and Agent Orange: Update 1996, but will focus on scientific studies and other information developed since the release of these reports. The two previous volumes have noted that sufficient evidence exists to link soft tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, and chloracne with exposure. The books also noted that there is "limited or suggestive" evidence to show an association with exposure and a neurological disorder in veterans and with the congenital birth defect spina bifida in veterans' children. This volume will be critically important to both policymakers and physicians in the federal government, Vietnam veterans and their families, veterans organizations, researchers, and health professionals.

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