11
Other Health Effects

A variety of health outcomes are evaluated in separate sections in this chapter. Many of these health outcomes have not been addressed as thoroughly in the epidemiologic literature as the health outcomes previously described in Chapters 8-10. The sections in this chapter of other health outcomes include chloracne, porphyria cutanea tarda, other metabolic and digestive disorders (diabetes mellitus, alterations in hepatic enzymes, lipid abnormalities, and gastrointestinal ulcers), immune system disorders (immune modulation, autoimmunity), and a number of circulatory and respiratory disorders.

CHLORACNE

After traumatic injuries, skin disorders are among the most common health problems encountered in combat. The tropical environment and living conditions in Vietnam resulted in a variety of skin conditions ranging from bacterial and fungal infections to a condition known as ''tropical acne" (Odom, 1993). However, the only dermatologic disorder consistently reported to be associated with Agent Orange or its components, including the contaminant, TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), is chloracne. Therefore, this discussion will focus on chloracne and its link to TCDD.

Chloracne is characterized by persistent comedones, keratin cysts, and inflamed papules. Lesions are often associated with hyperpigmentation and may result in a characteristic scarring pattern. The maculopapular rash of chloracne characteristically occurs in a facial butterfly distribution,



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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam 11 Other Health Effects A variety of health outcomes are evaluated in separate sections in this chapter. Many of these health outcomes have not been addressed as thoroughly in the epidemiologic literature as the health outcomes previously described in Chapters 8-10. The sections in this chapter of other health outcomes include chloracne, porphyria cutanea tarda, other metabolic and digestive disorders (diabetes mellitus, alterations in hepatic enzymes, lipid abnormalities, and gastrointestinal ulcers), immune system disorders (immune modulation, autoimmunity), and a number of circulatory and respiratory disorders. CHLORACNE After traumatic injuries, skin disorders are among the most common health problems encountered in combat. The tropical environment and living conditions in Vietnam resulted in a variety of skin conditions ranging from bacterial and fungal infections to a condition known as ''tropical acne" (Odom, 1993). However, the only dermatologic disorder consistently reported to be associated with Agent Orange or its components, including the contaminant, TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), is chloracne. Therefore, this discussion will focus on chloracne and its link to TCDD. Chloracne is characterized by persistent comedones, keratin cysts, and inflamed papules. Lesions are often associated with hyperpigmentation and may result in a characteristic scarring pattern. The maculopapular rash of chloracne characteristically occurs in a facial butterfly distribution,

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam frequently associated with back, chest, or periorbital lesions (Crow and Puhvel, 1991). Although severe cases of juvenile acne may mimic adult chloracne in appearance and distribution, it is generally agreed that exposure to chlorinated aromatic compounds causes the overwhelming preponderance of chloracne cases in adults (Crow and Puhvel, 1991). Chloracne was first described in relation to occupational exposure among chemical industry workers by Von Vettman in 1887 (AFHS, 1991b) and was first linked to the specific chemical trichlorophenol in 1957 (Crow and Puhvel, 1991). A large number of chloracne cases have been reported in industrial workers throughout this century. Among the numerous industrial chemicals known to cause chloracne, the most potent appears to be TCDD. However, as noted later in this discussion, individual host factors appear to play an important role in determining disease expression. Even at relatively high doses, not all exposed individuals develop chloracne, whereas others with similar or lower exposure demonstrate the condition. The natural history of chloracne is quite variable. Longitudinal studies of exposed cohorts suggest that the lesions typically regress and heal over time. However, historical reports indicate that a chronic form of the disease can persist up to 30 years after an exposure (Suskind and Hertzberg, 1984). As with many dermatologic conditions, chloracne can reasonably be suspected on the basis of a careful medical history or appropriate questionnaire information. A key element in diagnosis is the characteristic anatomic distribution. Because acne is such a common dermatologic condition, in any analysis attempting to link acne or chloracne with an environmental or occupational exposure, it is critical that adequate attention be paid to the clinical characteristics, time of onset, and distribution of lesions, as well as careful comparison with an appropriate control group. Definitive diagnosis may require histologic confirmation from a biopsy specimen. The toxicology of TCDD in animals, animal models, and humans has been well described; the major issue of current concern is the precise dose-response relationship between TCDD exposure by various routes (dermal, inhalation, ingestion) and the occurrence of chloracne. Recent reports have suggested a genetic basis for susceptibility to chloracne in animals (see Chapter 4). If the genetic and biochemical basis for this susceptibility can be defined in humans, it may lead to new tests to detect susceptible sub-populations among exposed individuals. Chloracne can be viewed both as a toxic outcome from exposure to TCDD and as a potential clinical marker of TCDD exposure. It is the latter that has generated the most controversy. For the purposes of this section, the primary focus is the linkage of chloracne to TCDD exposure. Dose-response relationships between TCDD exposure and chloracne are addressed briefly. The inadequacies of chloracne as a human biomarker of dioxin

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam exposure are discussed in more detail in Chapter 6. A major unresolved issue is whether TCDD exposure below the level required to cause chloracne may cause other adverse health consequences such as cancer. Epidemiologic Studies of Chloracne Occupational Studies Several reports have detailed the mortality experience and incidence of chloracne among a group of 2,192 employees of Dow Chemical, Michigan Division, who were potentially exposed to TCDD through the manufacture of higher chlorinated phenols beginning in the 1930s (Cook et al., 1980; Bond et al., 1987; Bond et al., 1989a,b). Nearly 16 percent of 2,072 workers whose medical records were reviewed were identified as having chloracne based on clinical criteria (Bond et al., 1989a). Approximate historical exposure categories were reconstructed from employment records in production areas where TCDD exposure was considered most likely. Unfortunately, accurate quantitative industrial hygiene or other exposure measures for TCDD were not available. Even with this limitation, however, a plausible dose-response relationship was identified between probable exposure to TCDD and the relative risk (RR) for chloracne. Relative risk estimates were as high as 5.5, compared to a referent nonexposed worker population. Younger age at time of employment and duration of exposure were also significant risk factors. Another large occupational cohort reported from the United States involved workers at the Monsanto Company plant in Nitro, West Virginia (Moses et al., 1984; Suskind and Hertzberg, 1984). Exposures at this plant included both accidental exposures following a trichlorophenol (TCP) process accident in 1949 and exposures occurring during regular operations concerning the production of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) from 1948 to 1969 (Suskind and Hertzbert, 1984). Like the Dow cohort, quantitative exposure data were not reported. However, among 204 workers considered exposed based on proximity to an accident or work history, more than 53 percent had clinical evidence of persistent chloracne (Suskind and Hertzberg, 1984). Interestingly, a self-reported history of chloracne was recorded among 86 percent of the exposed workers versus none of the clearly nonexposed workers (Suskind and Hertzberg, 1984). Not all reports were substantiated by company or medical record review. Age at exposure did not appear to influence the rate of chloracne. No attempt was made to define a dose-response relationship. Poland and colleagues (1971) described a study of 73 male employees in a 2,4,5-T manufacturing facility with potential exposure to TCDD in a follow-up to an earlier report of Bleiberg and colleagues (1964) on the same

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam plant. Chloracne was identified in 18 percent of these workers (Poland et al., 1971). Although a series of clinical and laboratory evaluations was carried out on this small cohort, no exposure data or estimates were reported. Finally, Fitzgerald and colleagues (1989) reported a medical follow-up of 377 individuals potentially exposed to TCDD from an electrical transformer fire in a Binghamton, New York, office building. Although a variety of complaints were reported in this population, no individuals were diagnosed with chloracne. An industrial accident in Great Britain resulted in the development of chloracne in 79 workers (May, 1973). Exposure information was unavailable and the total population of potentially exposed was not identified. Individuals with documented chloracne served as a presumably highly exposed cohort for subsequent mortality analyses. A 10 year follow-up of these workers was reported by May (1982). Three subject groups were formed: group A, 31 employees with no dioxin exposure; group B, 54 employees with possible dioxin exposure; and group C, 41 dioxin-exposed workers with chloracne. Medical employment histories were obtained by self-report. In group C, 22 of 41 workers still had mild forms of chloracne at follow-up. Workers involved in the manufacture of 2,4,5-T were examined in a mortality study 20 to 30 years after the initial exposure (Suskind, 1985). Included in the study were 204 exposed workers, 163 nonexposed workers, and 51 workers of questionable exposure. Of the 204 exposed workers, 86 percent developed chloracne at some time after exposure and 53 percent still had chloracne on examination 20 to 30 years postexposure. No workers in the other groups developed chloracne. A number of reports of occupational exposure to TCDD have also come from sites in Europe. Pazderova-Vejlupkova and colleagues (1981) reported a 10 year follow-up of 55 individuals exposed to TCDD in a 2,4,5-T manufacturing facility in Czechoslovakia. Study subjects were those available from a cohort of 80 workers who became ill following the occupational exposure (total worker population was approximately 400). Of the 55 symptomatic workers studied, 95 percent were reported to have chloracne of varying severity. A number of other clinical and laboratory abnormalities were reported, but no useful exposure data or estimates were included. Zober and coworkers (1990) reported a mortality follow-up study of several cohorts of workers exposed to TCDD during an accident in a plant in Germany. Three cohorts were identified, each with differing probable exposures based on the amount and reliability of exposure information, but no quantitative exposure estimates were available. Chloracne was found in all 69 workers from one cohort, 17 of 84 workers in a second cohort, and 28 of 94 workers in a third cohort. The results of a surveillance program of 200 employees in Germany with high occupational exposure to TCDD were reported by Beck and colleagues

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (1989). Adipose tissue was obtained from 45 exposed workers and from 21 Hamburg residents in a referent group. In the referent group, TCDD levels ranged between 2 and 20 parts per trillion (ppt) in fat, while there were values in the exposed group reaching 2,252 ppt. When the association between TCDD concentration and the development of chloracne was examined, there were workers with extremely high concentrations who showed no evidence of chloracne, whereas other workers with very low concentrations had chloracne. The authors suggested that skin contact as the main route of absorption may explain the individual variability in the development of chloracne and the lack of a linear association between fat levels and risk of chloracne. Thus, the appearance of chloracne does not seem to be a sensitive indicator of systemic TCDD dose. Several other European studies reported low-level exposure from pesticide application or industrial exposures (Riihimaki et al., 1983; Van Houdt et al., 1983; Jennings et al., 1988). Accurate exposure information was unavailable for all studies, and chloracne was rarely observed. Environmental Studies The best-documented environmental exposure to TCDD occurred near a chemical factory in Seveso, Italy, in 1976. Numerous epidemiologic studies have analyzed population groups in the surrounding region to define the potential adverse health impact of this disaster. Potential exposure zones at Seveso were identified using TCDD levels in soil samples taken immediately after the accident (Bisanti et al., 1980). Three exposure zones were established: zone A was the closest to the factory and most polluted; zone B was located southeast of zone A and slightly contaminated; and zone R, which surrounded both zones A and B, was found to be the least contaminated. Within the first three months after the accident, 50 cases of chloracne (34 among children aged 0-14 years) were identified; 46 cases occurred in zone A residents, no cases were reported in zone B, one case was identified in zone R, and 3 cases occurred in nearby cities. A total of 187 cases of chloracne were ultimately identified, including 164 children under the age of 15 and 23 adults. As with any environmental or ecological study, precise exposure data for individual subjects were not available. Caramaschi and colleagues (1981) investigated the distribution of 164 cases of chloracne among children following the accident. Of 146 of the original 164 children identified with chloracne, the highest frequency of chloracne was in zone A. In the majority of cases, the disease resolved within seven years after the incident (Assennato et al., 1989a). In a follow-up study of the residents of Seveso nine years after the accident, levels in serum taken at the time of the accident were analyzed (Mocarelli et al., 1991). Of the 30 samples, 10 were taken from residents of

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam zone A with chloracne, and 10 with no evidence of chloracne, and 10 from residents of the least contaminated zone. TCDD levels as high as 56,000 ppt were observed—the highest level ever reported in humans. All participants who had TCDD levels greater than 12,000 ppt (N = 7) had chloracne, although some with lower levels also developed chloracne. Children developed chloracne more frequently than adults, but this was not related to serum TCDD levels. The authors concluded that there had been minimal, if any, adverse health effects of TCDD observed in this population to date, with the exception of chloracne; and that chloracne was an indicator, but neither a sensitive nor a dose related indicator of TCDD exposure. No evidence of chloracne was found among cleanup workers following the Seveso accident (Assennato et al., 1989b). Although high levels of soil contamination were identified in several residential areas in Times Beach, Missouri, no cases of chloracne were identified in any of the reported pilot studies or epidemiologic surveys (Webb, 1984; Stehr et al., 1986; Webb et al., 1987). Vietnam Veterans Studies As indicated in other sections of this report, the anticipated exposure level in Vietnam veterans was substantially lower than that observed in occupational studies and in environmental disasters such as Seveso. Therefore, chloracne might be expected to be a relatively uncommon outcome in these studies. The Iowa Agent Orange Survey of 10,846 Iowa veterans who responded to a questionnaire, concluded from preliminary data that no definitive evidence could be found to link Agent Orange exposure and long-term adverse health effects, including chloracne (Wendt, 1985). However, this study was performed long after the potential exposure occurred, and methodologic considerations seriously limited the ability, in many instances, to identify chloracne even if it had existed. Of note, other studies did identify an apparent excess of acne or chloracne potentially attributed to TCDD in Vietnam. In the Centers for Disease Control Vietnam Experience Study (CDC, 1988), chloracne was reported more often by Vietnam veterans compared to Vietnam era veterans who were interviewed (OR = 3.9). Chloracne was also more often reported by Vietnam veterans compared to Vietnam era veterans who were examined, 1.9 percent and 0.3 percent, respectively (OR = 7.3). Quantitative exposure indices to TCDD and dose-response characteristics were not identified. Using an innovative exposure estimation algorithm, Stellman and colleagues (1988) reported a potential dose-response relationship between Agent Orange exposure (low, medium, high) and "adult acne" among Vietnam veterans. All health information was determined by self-administered questionnaire, and no attempt was made to validate these conditions by medical history or physical examination.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam A significant excess in acne was reported among Air Force Ranch Hand personnel potentially exposed to Agent Orange, compared to a nonexposed group (Wolfe et al., 1990). The odds ratio for acne appearing after Vietnam experience was 1.6 (CI 1.1-2.1) when comparing Ranch Hands to the nonexposed group. Among the 84 percent of Ranch Hands and 75 percent of comparison subjects who underwent a medical physical evaluation nearly 20 years after the potential herbicide exposure, no individuals from a total of 995 Ranch Hands and 1,299 comparisons examined, were observed to have lesions of chloracne or postinflammatory scars suggesting prior chloracne. Attempts to document medical records or physical examination results more proximal to the Vietnam exposure period were not discussed. In a follow-up report on serum TCDD analysis of the 1987 examination results for the Air Force Ranch Hand study, no cases of chloracne were identified, and no dermatologic endpoints were consistently related to the current body burden of TCDD (AFHS, 1991b). Summary for Chloracne In summary, chloracne has been linked to TCDD exposure in numerous epidemiologic studies of occupationally and environmentally exposed populations. The data on Vietnam veterans potentially exposed to Agent Orange and other herbicides are less convincing. Conclusions for Chloracne Strength of Evidence in Epidemiologic Studies Evidence is sufficient to conclude that there is a positive association between exposure to herbicides* (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram) and chloracne. Biologic Plausibility The formation of chloracne lesions after administration of TCDD is observed in some species of laboratory animals. Similar observations have not been reported for the herbicides. Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. Because TCDD-associated chloracne becomes evident shortly after exposure, there is no risk of new cases occurring long after service in Vietnam. PORPHYRIA CUTANEA TARDA Porphyria cutanea tarda (PCT) is an uncommon disorder of porphyrin metabolism manifested in-patients by thinning and blistering of the skin in sun-exposed areas, in addition to hyperpigmentation (excess pigment in skin) and hypertrichosis (excess hair growth) (Muhlbauer and Pathak, 1979; Grossman and Poh-Fitzpatrick, 1986). The disease is caused by a hereditary or acquired deficiency in uroporphyrinogen decarboxylase (UROD), a cytoplasmic enzyme in the pathway of hemoglobin synthesis (Sweeney, 1986). In the hereditary form of the disease, no precipitating exposure is necessary for the appearance of excess uroporphyrin and coproporphyrin in the urine and the development of clinical symptoms. The acquired form of the disease appears in association with excessive iron intake, alcoholism, and exposure to hexachlorobenzene (Cam and Nigogosyan, 1963; Strik and Doss, 1978; Axelson, 1986). In evaluating associations between herbicides and PCT, the relationship to hereditary and acquired development of the disease should be considered. It is postulated that heterozygotes for the disease with depressed levels of UROD are at increased risk for PCT if external exposures to agents that lower UROD are encountered. For example, abnormalities in urinary porphyrin excretion may be found in predisposed heterozygotes who do not have clinical symptoms but are susceptible to induction upon exposure to specific agents (Goerz and Merk, 1985). This induced form of porphyria, regardless of cause, is not associated with neuropsychiatric manifestations or with abdominal pain. Both hereditary and acquired PCT can be treated successfully by phlebotomy or restriction of alcohol intake. In cell culture and in rodents (mice and rats), TCDD causes a toxic porphyria resembling PCT in humans (De Verneuil et al., 1983; Cantoni et al., 1984; Smith and De Matteis, 1990). TCDD inhibits UROD, which is universally deficient in the liver tissue of patients with human PCT. Immunoquantitation of hepatic UROD in animals when UROD catalytic activity is rendered deficient by TCDD, is normal, suggesting strongly that the compound binds the enzyme protein and inhibits rather than destroys the enzyme. TCDD induces heme biosynthesis by the liver, and the reduced UROD activity in this situation probably leads to the porphyria in animals. There are several case reports suggesting the appearance of PCT in

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam chemical workers exposed to TCDD. However, in most of the reported cases, multiple chemicals were involved in the workplace, complicating interpretation of an association between TCDD exposure and the occurrence of PCT (Bleiberg et al., 1964; Jirasek et al., 1974). Follow-up after removal of workers from the contaminated environment showed a resolution of abnormal urinary porphyrin excretion. Epidemiologic Studies of Porphyria Cutanea Tarda Occupational Studies Bleiberg and colleagues (1964) reported the appearance of increased urinary uroporphyrin excretion in 11 of 29 workers in a chemical factory manufacturing 2,4-D (2,4-dichlorophenoxyacetic acid) and 2,4,5-T. Three of these individuals had some clinical evidence of PCT. Chloracne was diagnosed in the same plant but did not correlate with porphyrin abnormalities. In a follow-up of this same manufacturing facility six years later, Poland and colleagues (1971) restudied 73 workers and found no abnormalities in urinary porphyrin excretion or in the appearance of clinical PCT. Moreover, restudy of some of the original workers from 1964 showed normal porphyrin excretion. Although Bleiberg's chemical analysis of porphyrin excretion has been questioned, it seems equally plausible that markedly reduced contamination of herbicides by TCDD in this manufacturing plant accounted for the disappearance of abnormal uroporphyrin and coproporphyrin excretion and of clinical PCT. It is noteworthy that PCT occurred in a different group of workers from those with chloracne, suggesting that these are separable clinical manifestations of chemical exposure, most likely in specifically predisposed individuals. In a report at the Twelfth International Symposium on Chlorinated Dioxins, Calvert and colleagues (1992b) reported no difference in porphyrinuria or the occurrence of PCT between 281 workers who were involved in the production of TCP and exposed to TCDD at least 15 years earlier, and 260 unexposed workers who resided in the same community as the workers. In addition, serum TCDD levels were not associated with uroporphyrin or coproporphyrin levels. However, careful urinary porphyrin studies were not conducted during the period of acute exposure. Environmental Studies PCT has not been reported in individuals exposed to TCDD as a result of the 1976 chemical plant explosion in Seveso, Italy, unless a hereditary UROD deficiency existed. Doss and colleagues (1984) reported that exposure to TCDD triggered the manifestation of clinical PCT in a brother and

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam sister with the underlying genetic UROD abnormality. During the 1976 Seveso accident, it was reported that coproporphyrinuria without clinical symptoms occurred in 16 of 30 individuals (Caputo, 1989). In 1977, 60 Seveso residents were tested for elevated porphyrins: none of the 60 residents developed PCT; however, 13 exhibited secondary coproporphyrinuria. In three of the 13 persons with secondary coproporphyrinuria, elevated porphyrin levels persisted upon retesting in 1980, but were attributed by the authors to liver damage and alcohol consumption; elevated levels returned to normal in the remaining 10 cases (Doss et al., 1984). In a study of the Quail Run mobile home park in Missouri, 154 residents who were exposed to dioxin as a result of the spraying of waste oil that was contaminated with TCDD were compared to 155 individuals who lived in an unexposed area with no detectable levels of TCDD in the soil (Hoffman et al., 1986; Stehr-Green et al., 1987). Mean levels of urinary uroporphyrins were elevated among the exposed group, although there were no cases of clinical PCT diagnosed in either exposed or unexposed individuals. Vietnam Veterans Studies The baseline study of the U.S. Air Force Ranch Hands (1984) showed no difference in uroporphyrin or coproporphyrin levels in the urine between Ranch Hands and a control group of Air Force personnel who were not occupationally exposed to herbicides. There were no indications of the clinical appearance of PCT in Ranch Hands. In the first follow-up study (AFHS, 1987), two porphyrin analyses were not consistent with findings from the earlier baseline survey. Mean uroporphyrin levels were greater for the comparisons (17.9 mg/24 hours) than for Ranch Hands (16.9 mg/24 hours), whereas mean coproporphyrin levels were higher for Ranch Hands (119.1 mg/24 hours) than the comparison group (115.6 mg/24 hours). The clinical significance of such small changes in these mean levels is uncertain. Summary for PCT The occurrence of clinical PCT is rare and may be influenced by genetic predisposition of individuals demonstrating low enzyme levels of protoporphyrinogen decarboxylase. The cases reported have occurred relatively shortly after exposure to specific chemicals, including TCDD, and improve after removal of the agent. Simultaneous exposure to alcohol and other chemicals, such as hexachlorobenzene, probably increases the risk and severity of PCT. Abnormal porphyrin excretion without clinical illness may occur more commonly than clinical evidence of PCT. There is no suggestion of an increase in PCT in studies of Vietnam

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam veterans or the Ranch Hand group, possibly because of comparatively low dioxin exposure even in Ranch Hand studies, or a fortuitous absence of genetically predisposed individuals who could develop PCT after TCDD exposure. Further studies of PCT incidence in Vietnam veterans would not be called for since the biologic and clinical evidence indicate that the rare appearance of PCT occurs soon after heavy TCDD exposure and improves with time. Moreover, the association of PCT with alcoholism makes it difficult to interpret studies of TCDD and PCT that do not simultaneously assess alcohol consumption. It is possible that a rare individual with asymptomatic hereditary PCT was not worsened by exposure to TCDD. Whether such individuals were present in the military cannot be determined, although patients with overt symptomatic disease would likely be excluded from military service. In any individual case, evaluation of potential exposure to chemicals other than TCDD, such as ethanol, estrogens, or hexachlorobenzene, would be necessary to attribute abnormalities to dioxin or herbicide exposure specifically. The epidemiologic evidence associating PCT and TCDD is sparse because PCT is rare and because of methodological problems. However, case studies and animal studies show that PCT may be associated with TCDD exposure in genetically predisposed individuals. Conclusions for PCT Strength of Evidence in Epidemiologic Studies Evidence is sufficient to conclude that there is a positive association between exposure to herbicides* (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram) and PCT in genetically susceptible individuals. Biologic Plausibility There is some evidence that TCDD administration can be associated with porphyrin abnormalities in laboratory animals, although PCT has not been reported. Porphyria has not been reported in animals exposed to herbicides. Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental, and veterans studies that have been reviewed, inadequate control for important

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam had higher serum TCDD levels, but there was no difference between exposed and control groups in chest/lung physical examination results, chronic bronchitis (as defined by the American Thoracic Society), chronic obstructive pulmonary disease defined by abnormal results for FEV1 and FEV1/FVC ratio, or in any pulmonary function result (FEV1, FVC, FEV1/FVC ratio). Environmental Studies The limited available data concerning respiratory effects of environmental exposure to herbicides come from two mortality studies following the accidental release in 1976 of TCDD in the area of Seveso, Italy (Bertazzi et al., 1989a,b). Neither study showed significant differences in respiratory outcomes attributable to TCDD exposure. Vietnam Veterans Studies Several studies have examined mortality due to nonmalignant respiratory diseases among Vietnam veterans. In the CDC Vietnam Experience Study (Boyle et al., 1987; CDC, 1987), five deaths from respiratory diseases (ICD codes 460-519) were observed among the U.S. Army veterans who had served in Vietnam, compared with four deaths among U.S. Army veterans who served in the United States, Korea, or Germany during the same period. Among Australian Army Vietnam veterans (Fett et al., 1987), the number of deaths from respiratory disease was very low; only 1 of 270 deaths was observed among the Vietnam veterans and 1 among the Vietnam era veterans who had served in Australia. In a study with larger numbers of observed deaths due to respiratory disease (531 among Army Vietnam veterans and 93 among Marine Vietnam veterans), Watanabe and colleagues (1991), reported no significant differences in PMRs for respiratory diseases when comparing U.S. Army Vietnam veterans with U.S. Army Vietnam era veterans and all Vietnam era veterans or when comparing U.S. Marine Vietnam veterans with U.S. Marine Vietnam era veterans and all Vietnam era veterans. In another proportionate mortality study comparing Wisconsin Vietnam veterans with Wisconsin Vietnam era veterans, the authors reported an increase in PMR among Vietnam veterans due to pneumonia (Anderson et al., 1986). Eight deaths were observed, compared with four expected, for a PMR of 2.0 (CI 1.1-4.0), but the authors warn that small numbers make the PMRs unstable. Since the observed deaths covered the period from 1964 through 1983, the authors raise the possibility that the pneumonia deaths may have been due to complications of combat-related wounds. The PMRs for all respiratory diseases taken together showed no significant differences

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam when Vietnam veterans and Vietnam era veterans were compared (PMR = 1.0, CI 0.5-1.8). Other studies have examined morbidity due to respiratory diseases among Vietnam veterans. In the VES study of U.S. Army veterans compared to U.S. Army Vietnam era veterans who had not served in Vietnam (CDC, 1988), there were no differences between the groups in pulmonary abnormalities found on chest x-rays or on pulmonary function tests, both unadjusted and adjusted for current smoking status. A study of monozygotic twins who served in the U.S. military during the Vietnam era showed that service in Southeast Asia was not associated with increased self-report of respiratory conditions (Eisen et al., 1991). Veterans who had served in Southeast Asia from 1961 to 1975 were compared to veterans who served elsewhere during the same period (Stellman et al., 1988). The authors reported no significant differences between the groups in self-report of physician-diagnosed chronic bronchitis occurring no earlier than one year prior to discharge from military service. Among those who served in Southeast Asia, herbicide handlers did not differ from those who did not handle herbicides in frequency of chronic bronchitis. Among nonherbicide handlers, the level of Agent Orange exposure, based on a score derived from self-reported service locations and Air Force and Army records of spraying locations, was not significantly associated with chronic bronchitis. In another study (Pollei et al., 1986) no differences were reported in six types of chest x-ray abnormalities between 422 Vietnam veterans from the Agent Orange Registry at the Albuquerque Veterans Administration medical center compared to 105 Air Force flight staff who did not serve in Vietnam. There were no obvious differences in distribution of chest x-ray abnormalities in a subset of 27 Vietnam veterans who recalled handling Agent Orange repeatedly, although the number of those with abnormalities was small. A mortality study of 894 Chemical Corps personnel who served in Vietnam compared to the U.S. male population (Thomas and Kang, 1990) reported one observed death from respiratory disease, whereas 1.5 were expected. That study is of limited use in evaluating respiratory mortality primarily because of the small number of observed deaths. The latest Ranch Hand pulmonary assessment, examined the following parameters: questionnaire data on the presence of five reported respiratory illnesses—asthma, bronchitis, pleurisy, pneumonia, and tuberculosis; physical examination data on asymmetric expansion, hyperresonance, dullness, wheezes, rales, and a composite including all the others; chest x-rays read as normal or abnormal; and pulmonary function test results including FVC, FEV1, FEV1/FVC ratio, and FEFmax (AFHS, 1990, 1991b). There was no suggestion of an herbicide effect on the five reported respiratory illnesses based on results from the 1987 follow-up exam. Regarding the pulmonary assessment, the investigators reported that the ''health of the two groups

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam was reasonably comparable based on the clinical and laboratory variables, although the Ranch Hands had a significantly higher percentage of thorax and lung abnormalities on examination than the comparisons, based on the unadjusted analysis, and a marginally higher percentage after adjustment for covariates" (AFHS, 1991b:22). In addition to the 1987 Ranch Hand pulmonary assessment (AFHS, 1990), further analysis of the 1987 pulmonary outcomes was performed to assess associations with serum TCDD levels (AFHS, 1991b, vol. 7). According to these analyses, there was no evidence of a TCDD effect on the five verified respiratory illnesses or on chest x-ray results. There were significantly increased risks or marginally significant increased risks for each of the physical examination variables in at least one adjusted analysis. Initial serum TCDD was significantly associated with decreases in FVC, FEV1, and FEFmax, and an increase in FEV1/FVC ratio. Models assessing current serum TCDD levels and adjusted for covariates also showed these significant associations. The authors suggested that differences in mean spirometric indices were not clinically significant and might be due in part to associations between body fat and serum TCDD levels. The most recent updated reports of Ranch Hand mortality data have included no information about nonmalignant respiratory disease mortality (AFHS, 1991b; Michalek et al., 1990). Summary for Respiratory Disorders Among the morbidity studies, strong rationales for examining respiratory outcomes were not given. However, in the case of occupational exposures or exposures of military personnel who performed spraying, the respiratory tract could be viewed as a target organ for aerosol or other particulate deposition. Several studies provided spirometry data including FEV 1, FVC, and FEV1/FVC ratio (Suskind and Hertzberg, 1984; CDC, 1988; AFHS, 1991b; Calvert et al., 1991). Results of chest physical examinations were reported in some studies (AFHS, 1991b; Calvert et al., 1991). Although chest radiograph results were provided in several studies, there was no uniform reporting system used, such as the International Labor Organization classification system. For example, in one study (AFHS, 1991b), chest films were classified as either normal or abnormal. In another (CDC, 1988), clinical descriptions were provided by radiologists. In another (Pollei et al., 1986), scoring for six specific abnormalities was performed by three radiologists. Questionnaires used to assess smoking histories and various respiratory symptoms, and the resultant symptoms reported from questionnaire data, also varied across studies. The lack of working hypotheses about respiratory disease outcomes associated with herbicides and the nonuniformity

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam in methods and reported results make it difficult to interpret much of the morbidity data, especially symptom report and radiographic data. Any study examining respiratory outcomes such as symptoms of chronic bronchitis, decrements in lung function, or radiographic abnormalities must take into account the effects of cigarette smoking. Smoking data were generally not available in the mortality studies, but smoking was taken into account to various degrees in most of the morbidity studies. Interpretation of many of the mortality studies is limited by the small number of deaths observed. These studies also tend to use the ICD codes for all respiratory diseases, codes 460 to 519, as the respiratory mortality outcome. These codes include all diseases of the respiratory tract. For example, the following are among the diseases covered by these codes: acute respiratory infections, other diseases of the upper respiratory tract, pneumonia, influenza, chronic bronchitis, emphysema, asthma, pleurisy and pneumoconiosis. The combination of this wide range of diverse conditions and the small number of total deaths makes it difficult to assess any particular respiratory outcome of interest using mortality studies. In some studies, the ICD codes used were not stated, making comparisons with other studies difficult. Conclusions for Respiratory Disorders Strength of Evidence in Epidemiologic Studies There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides* (2,4-D; 2,4,5-T and its contaminant TCDD; cacodylic acid; and picloram) and the following respiratory outcomes: mortality from respiratory diseases; symptoms or history of respiratory illnesses such as chronic bronchitis, bronchitis, asthma, pleurisy, pneumonia, tuberculosis, and respiratory conditions; abnormalities on lung or thorax physical examination; pulmonary function test results; and chest radiographs. Biologic Plausibility Limited information from animal studies is available on the potential association between respiratory diseases and exposure to TCDD or the herbicides. Increased Risk of Disease Among Vietnam Veterans Given the large uncertainties that remain about the magnitude of potential risk from exposure to herbicides in the occupational, environmental,

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam and veterans studies that have been reviewed, inadequate control for important confounders in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of individual Vietnam veterans, it is not possible for the committee to quantify the degree of risk likely to have been experienced by Vietnam veterans because of their exposure to herbicides in Vietnam. NOTE *   The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components. REFERENCES Agent Orange Scientific Task Force. 1990. Human Health Effects Associated with Exposure to Herbicides and/or Their Associated Contaminants—Chlorinated Dioxins: Agent Orange and the Vietnam Veteran. A Review of the Scientific Literature. Agent Orange Scientific Task Force Working with the American Legion, Vietnam Veterans of America, and the National Veterans Legal Services Project. Air Force Health Study (AFHS). 1984. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A138 340. 362 pp. Air Force Health Study. 1985. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update: 1985 . Brooks AFB, TX: USAF School of Aerospace Medicine. Air Force Health Study. 1987. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. First Follow-Up Examination Results. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-87-27. 2. vols. 629 pp. Air Force Health Study. 1990. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-90-2. 2 vols. Air Force Health Study. 1991a. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update: 1991. Brooks AFB, TX: Armstrong Laboratory. AL-TR-1991-0132. 33 pp. Air Force Health Study. 1991b. 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. Alavanja MC, Merkle S, Teske J, Eaton B, Reed B. 1989. Mortality among forest and soil conservationists. Archives of Environmental Health 44:94-101. Allison AC, Lewis RA. 1986. Lack of health effects of long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of the American Medical Association 256:1446. Anderson HA, Hanrahan LP, Jensen M, Laurin D, Yick W-Y, Wiegman P. 1986. Wisconsin Vietnam Veteran Mortality Study: Proportionate Mortality Ratio Study Results. Madison: Wisconsin Division of Health. Andrews JS, Stehr-Green PA, Hoffman RE, Needham LL, Patterson DG Jr, Bagby JR Jr, Roberts DW, Webb KB, Evans RG. 1986. Missouri dioxin studies: some thoughts on

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