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Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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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,

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

(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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

confounders in these studies, and the lack of information needed to extrapolate from the level of exposure in the studies reviewed to that of 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 PCT becomes evident shortly after exposure, there is no risk of new cases occurring long after service in Vietnam.

OTHER METABOLIC AND DIGESTIVE DISORDERS

Several other metabolic and digestive disorders (diabetes mellitus, hepatic enzymes, lipid abnormalities, and gastrointestinal ulcers) have been reported in the scientific literature as possibly associated with TCDD or herbicide exposure. Assessment of these disorders in association with exposure to herbicides and TCDD involves the medical evaluation of a wide array of clinical signs and symptoms, laboratory parameters, and other diagnostic tools. These diagnostic criteria and their use in the clinical evaluation of these four health parameters are described below.

Diabetes Mellitus

Diabetes mellitus is a syndrome of disordered metabolism and hyperglycemia due to an absolute or relative deficiency of insulin secretion, a reduction in its biologic effectiveness, or both. There are two major types of diabetes: type I (insulin-dependent) and type II (non-insulin dependent). Type I diabetes occurs most commonly among juveniles but occasionally among adults, whereas type II diabetes occurs predominantly in adults and only occasionally in juveniles. More than 90 percent of the estimated 7 million diabetics in the United States are classified as type II diabetics (Karam, 1992). Many of these patients initially exhibit few or no symptoms, although polyuria (increased urination) and polydipsia (excessive thirst) may be present.

Diabetes is associated with high levels of serum glucose. Plasma glucose levels in excess of 140 mg/dl after an overnight fast are generally suggestive of an abnormal glucose tolerance, a prerequisite for the diagnosis of diabetes. The presence of obesity or a strongly positive family history for mild diabetes suggests a high risk for the development of type II diabetes.

A 1981 study suggesting a potential association between exposure to TCDD and the risk of diabetes in humans has prompted further investigation (Pazderova-Vejlupkova et al., 1981). There have been no reported animal studies suggesting that TCDD or other herbicides are associated with changes resembling human diabetes. There is also no biological reason to suspect these agents as a cause of diabetes.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

Epidemiologic Studies of Diabetes Mellitus

Occupational and Environmental Studies

Pazderova-Vejlupkova and colleagues (1981) reported an increased number of abnormal glucose tolerance tests in a 10 year follow-up of 55 workers involved in the production of TCP between 1965 and 1968 who were also exposed to TCDD. Two-fifths of the workers exhibited a pathological change in glucose tolerance tests; one-fifth exhibited a diabetic glucose tolerance test, and another one-fifth had a flat glucose tolerance test.

Sweeney and colleagues (in press) reported briefly on serum glucose and TCDD levels in 281 exposed workers at a TCP production plant and 260 nonexposed neighborhood referents at the Twelfth International Symposium on Chlorinated Dioxins. These findings suggest that serum TCDD levels may be positively and significantly related to fasting serum glucose levels and to an increased risk of diabetes; however the authors also note the strong confounding effects of age and body mass index in interpreting these data.

Two other studies have not found evidence of an increased risk of diabetes or glucose intolerance with TCDD exposure (Moses et al., 1984; Suskind and Hertzberg, 1984). Other studies that have examined mortality among individuals occupationally and environmentally exposed to TCDD have not found a significantly increased risk of death from diabetes (Bertazzi et al., 1989a; Cook et al., 1987; Henneberger et al., 1989).

Vietnam Veterans Studies

In recent studies of Air Force Ranch Hand veterans, fasting glucose and two-hour postprandial glucose levels were measured in 930 Ranch Hands and 1,198 controls (AFHS, 1991b). A significant relationship between elevated levels of blood glucose and TCDD serum levels was observed. Although the correlation was statistically significant, the glucose values were not outside the normal range.

An increased risk of diabetes was noted among Ranch Hands with the highest serum TCDD levels in reference to the comparison group. Among Ranch Hand veterans who developed diabetes, the data suggest an earlier onset of the disease compared to controls and a possible greater severity of the disease in the Ranch Hand group. The problem of interpreting the observed association in epidemiologic studies between serum TCDD and glucose levels is complicated by the role of body fat/obesity as both a risk factor for diabetes and a major determinant of the storage and metabolism of TCDD in the body (see Chapter 6, and the example below in the section on lipid abnormalities). Therefore, this confounding possibility would need

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

to be excluded before the data are accepted as indicating an association between serum TCDD levels and diabetes. In the absence of reliable data and statistical models for the metabolism of TCDD in humans, however, even if current measurements of body fat or other measures of obesity are available, considerable uncertainty will remain in the interpretation of associations seen in epidemiologic studies carried out many years after exposure.

Summary for Diabetes Mellitus

Limited information suggests the possibility of increased glucose intolerance and diabetes in chemical production workers and Ranch Hand veterans exposed to TCDD, but the data are inconclusive. Additional information on the pharmacokinetics of dioxin metabolism, particularly with regard to total body fat, is necessary in order to interpret epidemiologic studies indicating an association between TCDD exposure and serum glucose levels.

Hepatic Enzymes

Increases in the serum activity of certain hepatic enzymes, including aspartate aminotransferase (AST or SGOT), and alanine aminotransferase (ALT or SGPT), as well as gamma-glutamyltransferase (GGT), d-glucaric acid, and others, are commonly noted in many kinds of liver disorders. The relative sensitivity and specificity of these enzymes for liver disease vary, and several different tests may be required to suggest a diagnosis. The only regularly reported abnormality in liver function associated with TCDD exposure in humans is elevation in GGT. Estimates of the serum activity of this enzyme provide a sensitive indicator of alcohol and drug hepatotoxicity, infiltrative lesions of the liver, parenchymal liver disease, and biliary tract obstruction (Berkow and Fletcher, 1987). Elevations are noted with many chemical and drug exposures without evidence of liver injury. The confounding effects of alcohol ingestion (frequently associated with increased GGT) make interpretation of changes in GGT in exposed individuals difficult (Calvert et al., 1992a). Moreover, elevation in GGT may be considered a normal biologic adaptation to chemical, drug, or hormone exposure.

In animal species that exhibit sensitivity to TCDD, the liver represents one of the primary metabolic organs; studies show that TCDD is transported to the liver where it is stored and metabolized (Piper et al., 1973; Lakshman et al., 1986). TCDD is metabolized by enzymes in the liver to form derivatives that can dissolve in water and therefore be more easily eliminated from the body than TCDD itself, which is water insoluble. Changes in hepatic enzyme levels after TCDD exposure in animals have been observed although there is considerable variation among species (see Chapter 4).

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Epidemiologic Studies of Hepatic Enzymes

Occupational and Environmental Studies

There are several reports of changes in liver enzymes among workers occupationally exposed to TCDD and in residents of Seveso, Italy. Elevated levels of GGT have been reported in industrial accidents and in studies of chemical workers. May (1982) observed increased GGT levels in 41 workers with chloracne examined 10 years after exposure as a result of a TCP accident in comparison to a group of 31 unexposed workers. Elevated GGT levels were also reported among 105 workers with chloracne exposed to TCDD in a factory explosion in Nitro, West Virginia, compared to 101 workers without chloracne (Moses et al., 1984).

In an assessment of hepatic and gastrointestinal effects among the National Institute for Occupational Safety and Health (NIOSH) cohort of 281 workers involved in the manufacture of TCP and 260 unexposed comparisons, Calvert and colleagues (1992a) noted significantly higher mean GGT levels for workers compared to the unexposed referent group (p = .03, means not provided). In addition, workers had a significantly elevated risk for out-of-range GGT levels compared to the referents (OR = 2.3, CI 1.2-4.4).

Mocarelli and colleagues (1986) observed alterations in serum GGT in a series of laboratory tests conducted from 1976 to 1982 among children who were aged 6 to 10 years at the time of the industrial accident in Seveso, Italy. A slight increase in GGT levels in exposed boys who lived in the area of highest TCDD contamination (zone A) compared to those who lived in the control area was noted after the accident, although the values were within reference limits and declined over time. Caramaschi and colleagues (1981) reported more abnormal GGT levels among children with chloracne in Seveso who presented themselves to clinics before July 1977, compared to children without chloracne. The degree of severity of chloracne was positively correlated with soil concentrations of TCDD at the sampling point of each child's residence.

A medical evaluation of 41 individuals exposed to TCDD-contaminated waste oils in Times Beach, Missouri, who had participated in a study of TCDD levels in adipose tissue found no association between adipose tissue TCDD levels and GGT levels or alterations in any other liver enzymes (Webb et al., 1989).

Slightly abnormal levels of alanine aminotransferase (ALT) were observed by Mocarelli and colleagues (1986) among male children in Seveso compared to nonexposed male children, although there was no clinical evidence of liver disease and the observed abnormalities disappeared over time. No abnormal findings in ALT levels were observed among the NIOSH cohort

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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of TCP production workers (Calvert et al., 1992a). Also, Hoffman and colleagues (1986) found no difference in ALT levels between exposed residents at Quail Run mobile home park and individuals not exposed, although when duration of residence in the mobile home park was used as a surrogate of TCDD exposure, it was found to be positively and significantly associated with serum ALT levels.

The increase in urinary d-glucaric acid observed in animal studies may be another manifestation of biochemical induction of liver enzymes (Lucier et al., 1986), although reports of changes in d-glucaric acid excretion after human exposure to TCDD are inconsistent. Elevated levels have been observed among chemical production workers and among residents of Seveso (May, 1982; Martin, 1984; Ideo et al., 1985). In 1978, two years after the Seveso accident, d-glucaric acid excretion was higher among Seveso residents than those from a neighboring community. At all ages, exposed subjects showed higher urinary d-glucaric acid levels than controls. Until 1979, Seveso area adults and children showed higher levels of d-glucaric acid than controls (Ideo et al, 1985). Among children with chloracne, Ideo and colleagues (1982) found significantly higher levels of d-glucaric acid as compared to children without chloracne from the same exposure zone. Elevations in urinary d-glucaric acid were not associated with TCDD exposure among residents of Quail Run mobile home park (Hoffman et al., 1986) or workers involved in TCP production (Calvert et al., 1992a).

Vietnam Veterans Studies

Serum TCDD levels were found to be positively and significantly associated with elevated GGT levels in the 1991 Ranch Hand serum TCDD analysis (AFHS, 1991b). Increased levels of ALT were also reported in association with higher TCDD levels, although there was no reported association between serum TCDD and elevations in urinary d-glucaric acid. Because of the confounding effect of obesity or alcohol ingestion on these measurements, a specific association with dioxin exposure is difficult to determine.

Summary for Hepatic Enzymes

Among these studies, changes in liver function in humans exposed to TCDD are limited to an increase in GGT, whereas results are inconsistent regarding ALT and d-glucaric acid excretion. These metabolic ''adaptations" to chemical exposure have been seen in industrial workers as well as Ranch Hand veterans. Any study suggesting an association between TCDD exposure and changes in hepatic enzymes or occurrence of liver disease must consider known associations with alcohol, hepatitis, or other known

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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toxic chemical exposures. Given the long observation period since TCDD exposure occurred in most studies and consideration of other known risk factors, it seems very unlikely that there is any association between TCDD or herbicide exposure, at levels seen to date in humans, and liver dysfunction.

Lipid Abnormalities

Hyperlipidemia, or elevation in cholesterol, triglycerides, or the lipoprotein carriers of these lipids [very low-density lipoproteins (VDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL)] has been described in relation to hereditary and dietary factors. The clinical manifestations of these changes relate primarily to the incidence of ischemic cardiovascular disease and other forms of atherosclerosis. Measurement of lipid and lipoprotein levels is essential to the diagnostic evaluation of hyperlipidemia; however, the measurements should be adjusted for diet and gender, because the concentration of lipids varies with nutritional, endocrine, and gender differences. There is frequently a substantial delay time between onset of lipid changes and clinical manifestations of disease, often 20 to 40 years (Stanbury et al., 1978).

Recent studies comparing the hepatotoxic effects of TCDD in Ah-responsive and nonresponsive mice have demonstrated a mild to moderate hepatic lipid accumulation in some mice strains. Fatty liver induction following exposure to TCDD and related compounds has also been demonstrated in a number of other animal species including the rat, chicken, and man. Sublethal doses of TCDD in rats have been reported to produce an increase in total hepatic lipid content. Specifically, triglycerides and free fatty acids were increased while sterol esters were decreased.

In light of the results from animal studies that indicated hepatic lipid accumulation following TCDD treatment and the frequent association of increased serum lipids with elevated hepatic fat, measurements of serum lipids have been made in individuals exposed to TCDD.

Epidemiologic Studies of Lipid Abnormalities

Occupational and Environmental Studies

Among Czechoslovakian TCP workers studied by Jirasek and colleagues (1974), lipid metabolism was altered in more than 50 percent of the 55 individuals tested; the majority of individuals with altered lipid levels showed elevated serum triglyceride and cholesterol levels. There was mixed chemical exposure in these individuals. In a 10 year follow-up study of this same group, Pazderova-Vejlupkova and colleagues (1981)

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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reported that all workers tested had a return of lipid levels to normal after removal from the environment.

Moses and colleagues (1984) reported a modest increase in serum triglycerides in workers who had also displayed chloracne versus those who had not exhibited chloracne from a Nitro, West Virginia, chemical plant. The last occupational exposure to TCDD for these individuals had been at least 10 years prior to the study, and for the majority more than 20 years had passed. No significant changes were observed in serum cholesterol levels that could be attributed to TCDD exposure.

Similarly, a study of British TCP workers 10 years after exposure to TCDD showed a slight elevation in triglycerides and a modest decrease in serum cholesterol compared to unexposed controls (May, 1982). In a separate study of workers from this same plant, Martin (1984) reported a slight increase in triglycerides among those individuals that had exhibited chloracne as an indicator of exposure to TCDD, compared to unexposed controls, but also found serum cholesterol to be slightly decreased among this same group. Although the mean values for serum triglycerides and cholesterol in TCDD-exposed individuals were higher than in nonexposed controls, these values were still within the normal laboratory range.

No effect on either serum triglycerides or cholesterol was observed in children who resided in highly contaminated areas of Seveso, Italy, compared to children living in uncontaminated areas (Mocarelli et al., 1986). Furthermore, no changes were noted after they were moved to uncontaminated areas. In a follow-up study, Assennato and colleagues (1989a) compared serum cholesterol and triglycerides among a subgroup of subjects who developed chloracne between 1976 and 1985. Mean cholesterol and triglyceride values were significantly higher in 1976 compared to the 1982-1983 data.

Vietnam Veterans Studies

In the follow-up of the Ranch Hand cohort reported in 1984 and 1987, no alterations in lipid values were recognized in the total group (AFHS, 1984; Wolfe et al., 1990). However, the serum dioxin analyses of the 1987 follow-up examination data found that the ratios of cholesterol to HDL cholesterol and to triglycerides were both positively correlated with serum TCDD levels in the Ranch Hands (AFHS, 1991b).

Flanders and colleagues (1992), however, suggest that this particular pattern of results, observed in this case when serum TCDD levels and triglycerides are measured concurrently, could have been the result of "reverse causation." That is, the outcome (triglyceride levels) may have affected the measured exposure level (serum TCDD), rather than the exposure to TCDD (as measured by serum TCDD levels) exerting an effect on triglycerides.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Summary for Lipid Abnormalities

The variable results do not allow clear-cut attribution of lipid abnormalities to TCDD exposure. It is possible that levels of TCDD were increased in those with hypercholesterolemia (elevated levels of serum cholesterol) because of the concentration of the agent in lipids or because of obesity. In industrial exposures, increases have been modest and variable. A positive association was noted between serum TCDD levels and triglycerides among Ranch Hands. Further research on the pharmacokinetics of TCDD and its relation to percentage body fat will be important in understanding the significance of these associations.

The problem of interpreting the observed association in epidemiologic studies between serum TCDD and lipid levels is complicated by the role of body fat/obesity as both a risk factor for lipid abnormalities and a major determinant of the storage and metabolism of TCDD in the body (see Chapter 6, and the example above in the section on lipid abnormalities). Body fat must be taken into account in analyses of this kind to ensure the validity of the results. In the absence of reliable data and statistical models for the metabolism of TCDD in humans, however, even if current measurements of body fat or other measures of obesity are available, considerable uncertainty will remain in the interpretation of associations seen in epidemiologic studies carried out many years after exposure.

Gastrointestinal Ulcers

There are usually no specific physical signs in-patients with gastrointestinal ulcers. The symptoms of gastric ulcer are often nonspecific; the typical pattern of epigastric pain is variable, and many patients with this symptom may not have an ulcer when examined endoscopically, whereas patients with ulcers demonstrated by endoscopy may report no pain. Endoscopy is generally recommended only in-patients whose symptoms persist despite treatment. Acid secretory values are of relatively little clinical value in diagnosis of ulcer disease (Samiy et al., 1987). The onset of symptomatic ulcer disease may be initiated by nonsteroidal anti-inflammatory drugs (NSAIDs) or alcoholism. In many patients, the disease is associated with the presence of Helicobacter pylori (H. pylori).

Several investigators, in their review of the scientific literature on the health effects of herbicide exposure, have reported a positive association between herbicides and/or TCDD exposure and gastrointestinal ulcer (Agent Orange Scientific Task Force, 1990; Jenkins, 1991). Based on their conclusions, the human epidemiologic studies investigating the relationship between exposure and ulcers were reviewed.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Epidemiologic Studies of Ulcers

Occupational and Environmental Studies

A greater frequency of upper gastrointestinal tract ulcers was reported in Nitro, West Virginia, 2,4,5-T production and maintenance workers exposed to TCDD, as compared to a group of unexposed workers (Suskind and Hertzberg, 1984). Additional studies have not confirmed this finding in chemical plant workers exposed to TCDD (Bond et al., 1983; Calvert et al., 1992a). In Seveso, among children with chloracne, gastrointestinal tract symptoms were reported more frequently than among children from that area who did not have chloracne (Caramaschi et al., 1981).

Vietnam Veterans Studies

The serum TCDD analysis of the Ranch Hand Study did not find an increase in the risk of upper gastrointestinal ulcer in Vietnam veterans with elevated TCDD levels (AFHS, 1991b).

Summary for Ulcers

The risk of ulcers in exposed populations has not been sufficiently studied to exclude an association with TCDD or herbicides. However, detection of a specific association is unlikely, given the frequency of ulcer disease and the varied factors (e.g., alcoholism, NSAIDs, H. pylori infection) that are known to be related to the onset of symptomatic ulcer disease. Furthermore, given the length of time that has elapsed since veterans last exposure to TCDD in Vietnam, it is unlikely that new cases of ulcer disease would occur.

Conclusions for Other Metabolic and Digestive 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 diabetes mellitus, changes in hepatic enzymes, lipid abnormalities, or gastrointestinal ulcers.

Biologic Plausibility

The liver is the site of TCDD storage and metabolism in laboratory animals. Some of the herbicides have also induced liver toxicity in laboratory

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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animals. There have been no reports of an association between TCDD or herbicide exposure and diabetes in laboratory animals. Hyperlipidemia has been reported in laboratory animals following exposure to TCDD, but not following exposure to the herbicides. Specific digestive disorders have not been reported.

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 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.

IMMUNE SYSTEM DISORDERS

Immunotoxicology is the study of the effects of xenobiotics (chemical compounds that are foreign to the human body) on the immune system. The consequences of alterations of the immune response to a foreign antigen are outlined more fully below. Following a method recently outlined by the CDC for categorizing effects on the immune system, immune suppression, immune enhancement (reviewed collectively here as immune modulation), and autoimmunity are discussed. The evidence for alterations of immunity in humans by the herbicides of interest is also categorized. Although alterations in the immune system can be related to increases in the incidence of infection and neoplasm (immune suppression) and immune-mediated diseases (immune enhancement and autoimmunity), there is no observed increase in infectious (perhaps an increase in the incidence of some types of neoplasms) or immune-mediated disease in the populations examined. Instead, alterations are observed in measures of immune function or populations of immune cells. Efforts are under way in animal studies to correlate such parameters with increased susceptibility to disease, but these analyses have not yet been completed.

Immune Modulation

The immune system is involved with the defense of the host (the body) against foreign invaders. It confers resistance to infection by bacteria, viruses, and parasites; functions in the rejection of allografts (tissue transplants); and may eliminate spontaneously occurring tumors (Katz and Benacerraf,

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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1972). Proper function of the immune system is exquisitely sensitive to disruptions in physiologic homeostasis. The immune response is highly complementary, and several different mechanisms may be employed to eliminate an antigen (Jerne, 1974). Therefore, a toxicant can affect one facet of the immune system without altering the ability of the host to survive challenge by an infectious agent.

In most circumstances, the protection of the host against infection and neoplasms is accomplished in the absence of extensive destruction of the surrounding tissues due to tolerance of self-antigens through mechanisms currently not understood. However, a number of diseases involve hyperresponsiveness of the immune system to either foreign allergens (e.g., allergy) or self-antigens (autoimmunity). Allergic responses have been noted to numerous environmental components including ragweed and domesticated animals. Allergy is the result of formation of allergen-specific immunoglobulin E (IgE) antibodies, which bind to the surface of mast cells and lead to mast cell degranulation upon subsequent exposure to antigen, and allergen-specific T cell activation. The alterations discussed below are only in immune parameters and not in disease incidence. In fact, there was no observed increase in hypersensitivity disease in any of the studies reviewed.

Suppression of the immune system leads to increased susceptibility to infection and neoplasia. However, the degree of immune suppression necessary to result in increased disease is unknown at this time and is the subject of intense scientific interest. Immune deficiency may result from genetic abnormalities (e.g., a deficiency in the enzyme adenosine deaminase, leading to severe combined immune deficiency), congenital malformations, surgical accidents, pregnancy, stress, disease [e.g., human immunodeficiency virus (HIV-I) can lead to AIDS], and exposure to immunosuppressive agents (Purtilo et al., 1972; Jose and Good, 1973; Folch and Waksman, 1974; Heise et al., 1976; Monjan and Collector, 1977; Cohen, 1978; Cohen et al., 1978; Heise and Palmer, 1978). Immune suppression can also occur in-patients with autoimmune disease (discussed further below); for example, in systemic lupus erythematosus, the suppression of complement levels and leukocyte function has been noted. Impaired host defenses can result in severe and recurrent infections with opportunistic microorganisms. As noted above, the immune system may prevent or limit tumor growth, and a high incidence of tumors may follow immune suppression (Penn and Starzl, 1972; Penn, 1985).

Epidemiologic Studies of Immune Modulation

Occupational and Environmental Studies

Pilot studies of Missouri residents living in the Times Beach area were

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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conducted by Knutsen (1984) and by Webb and colleagues (1987). In the Knutsen study, trends toward immune suppression were noted, but the changes did not reach statistical significance. In the Webb study, there was no difference in (1) the prevalence of immune disorders, (2) the total duration of the response to delayed hypersensitivity skin test (DTH), or (3) lymphocyte proliferative response. The pilot study indicated that living in an area with TCDD-contaminated soil had no effect on immune function (Stehr et al., 1986; Webb et al., 1987).

A larger study involving the examination of persons in the Quail Run mobile home park, who were potentially exposed to TCDD through contaminated oil in the soil, indicated a decrease in T cell numbers; suppressed cell-mediated immunity as measured by the generation of a cutaneous DTH response to recall antigens; and an increase in the percentage of persons in the exposed population with decreased T4/T8 ratios (Hoffman et al., 1986; Knutsen et al., 1987; Stehr-Green et al., 1987; Andrews et al. 1986). Of note, T cell subset changes were in a different pattern from those of Webb and colleagues (1987), and very small changes were observed. There was a greater than expected number of anergic persons in the control population. Further examination of these results indicated that the amount of antigen used in the test was suboptimal, and the data from two out of four of the readers (i.e., assessors of the immunologic response) were eliminated, thereby calling into question the data from the remaining two readers. On retesting, anergic subjects failed to confirm this anergy (Evans et al., 1988). This may be due to (1) an increase in immunity resulting from exposure to the antigen in the initial test, (2) recovery from immune suppression related to TCDD exposure, or (3) the gathering of incorrect information in the initial test (Allison and Lewis, 1986). A decrease in the level of the thymic peptide thymosin was also measured in persons thought to be exposed to TCDD (as determined by length of residence in a TCDD-contaminated area) after controlling for age, sex, and socioeconomic status (Stehr-Green et al., 1989).

An immunologic assessment of 41 persons from Missouri with documented levels of TCDD in adipose tissue was conducted by Webb and colleagues (1989). The data were analyzed by multiple regression based on adipose tissue TCDD level and clinical dependent variables. Increased TCDD levels were correlated with increased numbers of T cells, primarily increases in CD8+ and T11+ cells, with no change in CD4+ cells. There was an increase in serum IgG but not IgA. No change in proliferative responses to mitogen was noted. No adverse clinical disease was associated with TCDD levels in these subjects. In this study, no anergy or alterations in proliferative responses to mitogens were found despite a clustering of decreased T4/T8 ratios in persons with the highest adipose TCDD level. On the other hand, some immune parameters were increased (as discussed below).

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Pocchiari and colleagues (1979) reported studies on the immune status of 45 children that were exposed to TCDD following an explosion at a chemical factory in Seveso, Italy. No abnormalities were found in many of the immune parameters tested, including serum immunoglobulin levels, levels of circulating complement, and mitogenic responses. A study of the immune function of persons involved in cleanup operations after this accident showed no alterations in immune function (Ghezzi et al., 1982). A study conducted six years after the explosion in a different cohort of TCDD-exposed children reported an increase in complement protein levels, which correlated with chloracne; an increased number of peripheral blood lymphocytes; and increased lymphocyte proliferative responses to mitogens (Sirchia, 1980; Tognoni and Bonaccorsi, 1982).

No association with TCDD exposure and Kaposi's sarcoma in AIDS patients has been found (Hardell et al., 1987).

Vietnam Veterans Studies

Only one study that was conducted suggested that exposure to herbicides, specifically Agent Orange, in Vietnam resulted in immune suppression. This study was conducted by Stellman and colleagues (1988) and showed that a cluster of nonspecific self-reported symptoms, including faint aches, fatigue, and colds, was associated with combat exposure and herbicide handling in Vietnam. This study, however, indirectly measured herbicide exposure (i.e., self-reported location of the person at a particular place and time) and did not specifically measure immune responsiveness. In addition, self-reported disease data are subject to recall bias that may confound these results.

Another study was conducted by the New Jersey Agent Orange Commission (Kahn et al., 1992). Three study groups were included in this study: herbicide handlers in Vietnam (N = 10), "nonexposed" Vietnam veterans (N = 10), and Vietnam era veterans (N = 7). The groupings of individuals were confirmed by measurements of serum TCDD levels, although the authors indicate that some outliers in the nonexposed group may have been exposed to base perimeter spraying. The skin response to recall antigens was uninterpretable due to anergy in 4 of 17 controls and 0 of 10 exposed veterans. There were some alterations in the lymphocyte subpopulations, but the inconsistency of control values with expected laboratory control levels, and the lack of differences between the exposed and the nonexposed Vietnam veterans, reduced the relevance of these data to the present report.

A co-twin control study of veterans from the Vietnam war involving self-reported physical problems was also conducted (Eisen et al., 1991). No significant effect on the immune system was observed in this study. Problems

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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with interpreting the data from this study include the potential for misclassification of exposure due to the indirect measures of TCDD and the self-reporting of medical problems.

In a study of immune system parameters of Vietnam veterans conducted by the Agent Orange Advisory Committee of Texas, out of 12 immune parameters examined, an increase in the percentage of cells in a subset of T cells (called "rosette-forming cells") that were active was increased (Newell, 1984). The physiologic relevance of this parameter is unknown. The study did not control for confounders such as smoking.

Studies to date of individuals involved in Operation Ranch Hand, which include a records-based and serum TCDD measure of exposure, and specific tests for immune function, have not revealed any indication of overt immune suppression (Wolfe et al., 1985, 1990). In fact, most studies have indicated no effect on the immune parameters examined. The few parameters that were altered indicated an increase and are discussed further below. Studies of Vietnam veterans in the CDC Vietnam Experience Study (VES) also suggested that there was no effect on immune parameters in the cohorts studied (CDC, 1988).

A recent reanalysis of the 1987 results (AFHS, 1991b, vol. 6) from follow-up of the Ranch Hands using serum dioxin levels as a measure of exposure, indicated that there is a dose-dependent increase in the maximum proliferative response of peripheral blood lymphocytes to the mitogen phytohemagglutinin. The authors of the report do not feel that this is indicative of an overall alteration in the cell-mediated immune responsiveness of these individuals due to the fact that (1) the enhancement was slight, (2) the enhancement may be due to confounders not assessed by the investigators, and (3) an enhancement of the proliferation of lymphocytes in response to allogeneic lymphocytes (a mixed leukocyte reaction) was not observed in these patients. However, this increase was dose-dependent and significant, and therefore should not be dismissed. Significant dose-dependent associations between increasing concentrations of TCDD in the serum and increasing IgA concentrations were also found. The authors suggest that these increased IgA levels may represent a chronic inflammatory response as a result of TCDD exposure, but the concentrations of IgA in the serum were also found to increase with the amount of alcohol consumption reported, which confounded the results. In other sections of the 1991 reanalysis, it was shown that there was a dose-dependent increase in the erythrocyte sedimentation rate (also observed in the 1982 baseline study AFHS, 1984), white blood cell count, and platelet count. Increases in these parameters confirm the possibility that there is an ongoing chronic inflammatory response occurring in these individuals as a result of TCDD exposure.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Autoimmunity

In general, the immune response is directed to foreign antigens. However, in some instances, antibodies can be demonstrated that react with endogenous antigens i.e., autoantibodies. These ''natural autoantibodies" are usually of the IgM class, are not associated with any disease, and may actually have beneficial or regulatory function(s).

Autoimmune disease is the pathological consequence of autoimmunization, either inadvertent or deliberate. Among the effector mechanisms of autoimmune disease are autoantibodies that activate the complement cascade or interact with "killer" mononuclear cells to induce antibody-dependent cell-mediated cytotoxicity. Other autoimmune diseases are caused by cytotoxic T cells acting directly on their targets or by injurious cytokines released by activated T cells.

It is important to distinguish the mere presence of autoimmunity from autoimmune disease. Autoimmunity, as indicated by the presence of autoantibodies, is relatively common, whereas autoimmune disease is a relatively rare occurrence. Yet the presence of autoantibodies, particularly in high titers and with high affinity, is the first step in diagnosing autoimmune disease in humans. A definite diagnosis of autoimmune disease, however, depends on careful correlation of history and clinical findings with detailed immunologic investigations.

It is convenient to consider two major categories of autoimmune disease, although the distinction between the two groups is often blurred. So-called systemic autoimmune disease is directed to antigens that are widely distributed throughout the body; the disease correspondingly affects multiple organ systems. The prototype of a systemic autoimmune disease is systemic lupus erythematosus (SLE). The other group of autoimmune diseases targets antigen unique for particular organs of the body, and the pathological phenomenon is confined to that organ. The prototype of an organ-specific autoimmune disease is autoimmune thyroiditis. The evidence associating TCDD with systemic autoimmune disease is considered next, and in the following section its possible role in organ-specific autoimmune disease is discussed.

Epidemiologic Studies of Autoimmunity

Occupational and Environmental Studies

An assessment of immunological abnormalities among 18 workers involved in the manufacture of 2,4,5-T and exposed to TCDD during an industrial accident 17 years earlier, found no change in many of the immune parameters examined (Jennings et al., 1988). However, an increase was

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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noted in the number of persons with immune complexes (low titer), the number of antinuclear antibodies (in one assay but not in another), and the number of Leu 7+ cells (natural killer cells) along with decreased T4/T8 ratios. In this study, exposure was defined by being in the vicinity during the explosion or cleanup, and there was no measure of the body burden of TCDD. The findings from this study are compatible with, but not necessarily diagnostic of SLE or a related connective tissue disorder.

Vietnam Veterans Studies

Early results of the Ranch Hand study do not show any evidence of an increase in the signs and symptoms associated with connective tissue diseases. Changes in the immune profiles of Ranch Hand veterans were also not observed (Wolfe et al., 1990). The CDC Vietnam Experience Study failed to show evidence of connective tissue diseases or of abnormal immune responses (CDC, 1988).

In a more limited study of Vietnam veterans reported by Newell (1984), no medical problems associated with connective tissue disease were found, but as stated, a small decrease in the total number of T cells and an increase in the number of so-called active T cells were observed in exposed veterans. The deviations from normality were not of sufficient magnitude to be biologically significant.

Two autoimmune diseases, chronic thyroiditis and insulin-dependent diabetes, are suspected in connection with exposed Vietnam veterans. An extensive assessment of endocrine function including a series of thyroid function tests, was carried out in connection with the Ranch Hand study (AFHS, 1991b). These studies failed to show any difference in thyroid function between exposed and control veterans. Diabetes was increased in a population of the Ranch Hands (as discussed in the earlier section on diabetes); however it is unclear at this time if this is an autoimmune disease or adult-onset diabetes related to increased body fat.

Summary for Immune Disorders

The effects of herbicide exposure on the level of several immune parameters have been presented. The data are divided into the categories: immune modulation and autoimmunity. Parameters of cellular function or number were measured, not incidence of disease. Currently, the level of alteration in immune parameters necessary to increase the incidence of disease is unknown.

These data correlate with some of the data observed in animal studies, but much more information is required to determine the mechanism and clinical significance of this increase in immune parameters. Furthermore,

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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since so many immune parameters have been assessed in these studies, there is a high probability that at least a few positive results would be noted based on chance alone, which would undermine the interpretation of the few positive results.

Conclusions for Immune 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 immune modulation or autoimmunity.

Biologic Plausibility

Experiments in laboratory animals have demonstrated a variety of effects of TCDD on immunologic parameters. Similar effects have not been demonstrated for the herbicides.

Increased Risk in 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 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.

CIRCULATORY DISORDERS

The studies to be reviewed in the following section on circulatory diseases cover a wide variety of diverse circulatory conditions. Cerebrovascular diseases, including stroke, are not included in the following section but are covered in Chapter 10. The studies that are reviewed here are divided into two categories—morbidity studies and mortality studies. In the morbidity studies, a variety of methods were used to assess the circulatory system, including assessing symptoms or history, performing physical examination of the heart and peripheral arteries, and assessing Doppler measurement of peripheral pulses, electrocardiogram results, and chest radiographs. Doppler measurements and physical examination of the pulses in

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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the arms and legs are used to detect decreased strength of the pulses, which can be caused by conditions such as atherosclerosis, a thickening and hardenin g of the arteries (blood vessels that carry oxygenated blood from the heart to the rest of the body). The electrocardiogram can be used to detect heart conditions and abnormalities such as arrhythmias (abnormal heart rhythms), heart enlargement, and previous heart attacks. Chest radiographs can be used to assess whether the heart is enlarged, which can result from heart failure and other heart conditions.

Very limited information is available on the cardiovascular toxicity of TCDD and herbicides in animals. The available studies are described in Chapter 4.

Epidemiologic Studies of Circulatory Disorders

Occupational Studies

The occupational studies assessing circulatory outcomes can be divided into mortality and morbidity studies. Zack and Suskind (1980) observed no excess mortality for diseases of the circulatory system including heart disease in a study of 121 male workers who developed chloracne following the accident at the TCP production plant in Nitro, West Virginia. In a larger Monsanto cohort, Zack and Gaffey (1983) observed an SMR = 1.3 for excess of arteriosclerotic heart disease, including chronic heart disease, and significantly decreased SMR = 0.6 for all other diseases of the circulatory system. Other occupational mortality studies used different diagnostic codes (or did not specify the International Classification of Disease [ICD] code) to report on various circulatory outcomes, none of which was significantly elevated in the exposed group. These included the following: overall circulatory deaths among pesticide applicators (Blair, 1983); ischemic heart disease among soil/forest conservation workers (Alavanja et al., 1989); hypertensive and ischemic heart disease deaths among 2-methyl-4-chlorophenoxyacetic acid (MCPA) manufacturers/sprayers (Coggon et al., 1986); and circulatory diseases among production workers of phenoxy herbicides and chlorophenols (Coggon et al., 1991).

In occupational studies that assessed circulatory morbidity (Moses et al., 1984; Suskind and Hertzberg, 1984), no significant differences were found in the circulatory variables examined between exposed and unexposed groups. Suskind and Hertzberg (1984) compared 204 workers involved in 2,4,5-T production with 163 nonexposed workers from the same plant. No exposure-related differences were observed in self-reports of hypertension, coronary artery disease, or angina, or in measured blood pressure, plasma lipids, electrocardiogram (EKG), or chest radiographic results. Additionally, in Dow workers included in a medical surveillance no differences

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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in reports of high blood pressure occurred between those exposed to TCP or TCDD and those unexposed (Bond et al., 1983).

Moses and colleagues (1984) evaluated circulatory morbidity in 226 workers exposed to TCDD in a 2,4,5-T production plant. Workers were categorized based on current evidence or past history of chloracne (N = 117) versus no current or past chloracne (N = 109). There were no differences between the two groups with regard to age-adjusted angina or reported myocardial infarction, or physical examination of the cardiovascular system. Limitations in interpretation of these studies arise from possible misclassification due to the inaccuracy of chloracne history as a means of assessing exposure.

Environmental Studies

The major environmental studies that address circulatory mortality are those describing mortality among residents in the area of Seveso, Italy, following the 1976 accident that released TCDD (Bertazzi et al., 1989a,b). The highest soil levels of TCDD were generally found in zone A, followed by lower levels in zone B, and the lowest levels in zone R. In one study that defined the population groups by zone of exposure and gender (Bertazzi et al., 1989b), the authors reported significantly increased mortality for several cardiovascular outcomes (comparing exposed groups with the reference population) as follows: chronic ischemic disease for the first five year follow-up period 1976-1981 in males in zones A (RR = 5.2, CI 1.3-21) and R (RR = 1.7, CI 1.2-2.5); cerebrovascular disease among males in zone A for the second five year period 1982-1986 (RR = 4.8, CI 1.5-15), hypertensive vascular disease among females in zone R for the first five year period 1976-1981 (RR = 4.8, CI 1.3-4.4); and all circulatory disease among females in zone A in the second five year period 1982-1986 (RR = 2.9 CI 1.1-7.8). No statistically significant increase in cardiovascular mortality was reported when comparing subjects (males or females) from zone B with the reference population.

In the other study (Bertazzi et al., 1989a), which was not stratified by zone of exposure, results showed significant increases in relative risk for mortality due to chronic ischemic heart disease in males in the first five year follow-up (RR = 1.8, CI 1.2-2.5) from 1976 to 1981 and in the full ten year follow-up period, 1976-1986, (RR = 1.6, CI 1.2-2.1) and an increase in hypertensive vascular disease deaths among females in the first five year period (RR = 2.4, CI 1.4-4.3).

These studies are limited for the purpose of assessing relationships between circulatory deaths and TCDD exposure. Because increases in chronic ischemic disease and hypertensive vascular disease mortality were observed in the first five years following the accident, stressors related to the accident

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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itself could not be eliminated as a cause. The second study (Bertazzi et al., 1989a) was performed in part because of criticisms raised about possible inaccuracies in defining zones of exposure, but itself was limited because of dilution of the exposed cohort in combining all three exposed groups. Variability in diagnosis of specific circulatory cause of mortality, which varied across gender and zones, also limits this study.

Vietnam Veterans Studies

Several studies have examined morbidity or mortality due to circulatory diseases among Vietnam veterans. The studies that addressed circulatory mortality reported on various outcomes using different ICD codes. None showed significant increases in circulatory mortality, with the exception of cerebrovascular disease mortality in one study (Kogan and Clapp, 1985). The Australian Vietnam veteran study (Fett et al., 1987) found no significant differences in circulatory disease mortality. In a study that compared U.S. Army Vietnam veterans with U.S. Army Vietnam era veterans or all Vietnam era veterans, and compared U.S. Marine Vietnam veterans with U.S. Marine Vietnam era veterans or all Vietnam era veterans (Watanabe et al., 1991), there were no significant differences in proportionate mortality ratios for circulatory diseases. A proportionate mortality study comparing Wisconsin Vietnam veterans with Wisconsin Vietnam era veterans (Anderson et al., 1986) reported no differences in all circulatory system disease mortality or arteriosclerotic disease mortality.

The Centers for Disease Control VES study (CDC, 1987, 1988) showed significantly reduced mortality due to circulatory diseases. In a study comparing Massachusetts Vietnam veterans with Vietnam era veterans who did not serve in Vietnam (Kogan and Clapp, 1985), the authors reported a significantly decreased proportionate mortality ratio (PMR) for circulatory diseases (PMR = 0.8, p = .03), excluding cerebrovascular diseases. Cerebrovascular diseases were significantly increased among Vietnam veterans (see Chapter 10). In a mortality study comparing women Vietnam veterans to women Vietnam era veterans, the authors reported no increases in deaths from circulatory diseases (Thomas et al., 1991).

Other studies have examined morbidity due to circulatory diseases among Vietnam veterans. In the CDC VES study, Army Vietnam veterans were compared to Army Vietnam era veterans who had not served in Vietnam (CDC, 1988). A significant difference in self-reported hypertension between the groups was reported. However, there was no significant difference in hypertension measured as part of a physical examination in the study. At physical exam all cardiovascular tests showed no difference between Vietnam and Vietnam era veterans except for left ventricular hypertrophy

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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which was associated with an increased risk (OR = 1.8 CI 1.0-3.3) among Vietnam veterans (CDC, 1988).

A study of monozygotic twins who were in U.S. military service during the Vietnam era showed that service in Southeast Asia was not associated with increased self-report of heart trouble (Eisen et al., 1991). In another study, no differences were reported in the two chest x-ray abnormalities related to the heart, namely, cardiomegaly and prominent pulmonary vasculature in comparing 422 Vietnam veterans from the Agent Orange Registry at the Albuquerque Veterans Administration (VA) Medical Center with 105 Air Force flight staff who did not serve in Vietnam (Pollei et al., 1986).

Stellman and colleagues (1988) assessed the effects on self-reported health outcomes not only of the Vietnam experience, but also of herbicide handling and Agent Orange exposure among nonherbicide handlers. In that study, 2,858 American Legion veterans who had served in Southeast Asia from 1961 to 1975 and returned questionnaires were compared to veterans who had served elsewhere during the same period. The authors reported a significant increase among Vietnam veterans compared to those serving elsewhere in self-report of physician-diagnosed heart disease occurring no earlier than one year prior to discharge from military service (OR = 1.5, age-adjusted). Among those who served in Southeast Asia, herbicide handlers did not differ significantly from those who did not handle herbicides in frequency of age-adjusted heart disease. Among nonherbicide handlers, the level of Agent Orange exposure, based on a score derived from self-reported service locations and military records of spraying locations, and the level of combat experience, were not significantly associated with heart disease. For the self-reported variable of physician-diagnosed hypertension, Vietnam veterans did not differ from Vietnam era veterans. Among those who served in Southeast Asia, herbicide handlers reported significantly more hypertension than those who did not handle herbicides (OR = 1.7). Among nonherbicide handlers, the level of Agent Orange exposure was not significantly associated with hypertension, but the level of combat was. These results suggest that the Vietnam experience, but not herbicide handling in Vietnam, was associated with self-report of physician-diagnosed heart disease and that herbicide handling and level of combat experience among nonherbicide handlers were associated with self-report of physician-diagnosed hypertension. Conclusions to be drawn are limited by the potential for misclassification of exposure and the lack of validation of self-reported diagnoses. It is unclear if adequate adjustments were made for modifiers such as cigarette smoking and obesity.

Two major groups of U.S. Vietnam veterans were known to have handled herbicides during military service in Vietnam, the Air Force Ranch Hands and the Army Chemical Corps. The latest available mortality study comparing Ranch Hands with other U.S. Air Force veterans involved in cargo

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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missions in Southeast Asia but not exposed to herbicides presents cumulative mortality through December 31, 1989 (AFHS, 1991a). The authors report statistically increased mortality from circulatory deaths among nonflying enlisted personnel (19 deaths observed, 11.3 expected; SMR = 1.7, CI 1.0-2.6). They further state that this increase is of concern because Ranch Hand nonflying enlisted personnel have higher current TCDD levels than Ranch Hands in other categories. In addition, they state that current and extrapolated initial TCDD levels were shown to be significantly associated with diabetes and increased cholesterol, HDL cholesterol, and triglyceride abnormalities. To assess the possibility that the increase in circulatory deaths could be related to TCDD through an association with diabetes and serum lipids, a review of individual medical records of all the circulatory deaths in Ranch Hands is being carried out. Potential confounders such as cigarette smoking were not addressed in this report, although results among living participants in the Air Force Health Study show that Ranch Hands had a higher frequency of current smokers (36 percent) than the comparison group of other U.S. Air Force veterans involved in cargo missions in Southeast Asia but not exposed to herbicides (31 percent). In addition, the specific causes of circulatory deaths in the Ranch Hand and comparison group would be of interest because the category of circulatory diseases is broad and contains diagnoses that are unrelated to either diabetes, lipid abnormalities, or cigarette smoking.

The latest Ranch Hand cardiovascular assessment results have been reported (AFHS, 1990), comparing the health status of Ranch Hands with other U.S. Air Force veterans involved in cargo missions in Southeast Asia but not exposed to herbicides. The parameters examined were the following: questionnaire data on the presence of three cardiovascular conditions—essential hypertension, heart disease, and myocardial infarction; verification of those three conditions by review of medical records; physical examination data on systolic and diastolic blood pressure, heart sounds, funduscopic examination, carotid bruits, and pulses including radial, femoral, popliteal, dorsalis pedis, and posterior tibial; and eight EKG abnormalities.

The report indicated that the health of the Ranch Hands and comparison group was similar with regard to reported and verified heart disease and central cardiac function (i.e., systolic blood pressure, heart sounds, and EKG results). Ranch Hands had a marginally higher mean diastolic blood pressure, but the frequency of elevated diastolic blood pressures was not significantly different between the groups. Ranch Hands also had a marginally higher frequency of individuals with carotid bruits. There were significant or marginally significant differences in femoral pulses, dorsalis pedis pulses, and three aggregate pulse indices. Significantly more abnormal pulses had been found at the baseline examination in 1983 but not in 1985, when both manual and Doppler examinations were used.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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In addition to the 1987 Ranch Hand cardiovascular assessment summarized above, further analyses of the 1987 circulatory outcomes were performed to assess associations with serum TCDD levels (AFHS, 1991b, vol. 5). According to these analyses, there was no consistent evidence of an adverse TCDD effect among nondiabetics. There were significant increases in risk of essential hypertension and adjusted mean systolic and diastolic blood pressures in Ranch Hands with high current TCDD levels (> 33 ppt) compared to comparison subjects in the background category (≤10 ppt), when body fat effects were not considered. In addition, verified heart disease risk was significantly decreased for Ranch Hands in the high-TCDD category, and the frequency of elevated systolic or diastolic blood pressure was not associated with TCDD level. The authors also suggested that there were significant associations between TCDD and decreases in peripheral pulses.

Difficulties with interpreting the Ranch Hand data are summarized in Appendix C. A consistent pattern of cardiovascular abnormalities among Ranch Hands or consistent associations between TCDD levels and cardiovascular outcomes has not been reported. Effects of body fat are suggested as confounders for the blood pressure abnormalities. Peripheral pulse differences between baseline (1983) and first follow-up examination (1985) have been explained, in part, by the requirement for four-hour tobacco abstinence during the 1985 examination prior to the Doppler measurement. It is unclear whether this requirement was used before the examination of peripheral pulses in the 1987 examination.

A mortality study of 894 Army Chemical Corps personnel who served in Vietnam, compared with the U.S. male population, reported 6 observed deaths from circulatory disease, whereas 10.9 were expected (Thomas and Kang, 1990). That study is of limited use in evaluating circulatory mortality because of the small number of deaths and the wide range of unrelated diagnoses covered by the ICD codes in classifying the circulatory disease deaths.

Summary for Circulatory Disorders

The literature concerning the effects of herbicides on the human circulatory system can be divided into morbidity and mortality studies. The circulatory outcomes addressed in these studies include the following: mortality from circulatory diseases, including overall circulatory disease mortality and various subgroups of cardiovascular disease; symptoms or history of circulatory illnesses such as heart disease, hypertension, coronary artery disease, angina, or myocardial infarction; abnormalities on physical examination; electrocardiogram results; and chest radiographs.

Several factors limit the usefulness of the mortality studies. For the most part, those studies have presented no a priori hypotheses regarding

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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herbicides and any particular circulatory outcome. The result is that many of the studies (e.g., Blair, 1983; Boyle et al., 1987; CDC, 1987; Fett et al., 1987; Thomas and Kang, 1990; Thomas et al., 1991; and Watanabe et al., 1991;) use the ICD codes for all diseases of the circulatory system, 390 to 458 or 459, as the circulatory mortality outcome. Those ICD codes cover the following circulatory system diseases: acute rheumatic fever; chronic rheumatic heart disease; hypertensive disease; ischemic heart disease; cerebrovascular disease; diseases of the arteries, arterioles, capillaries, veins, and lymphatics; and other heart diseases. This wide range of diverse conditions makes it difficult to assess any particular circulatory outcome of interest by using mortality studies. In some studies, the ICD codes used were not stated, making comparisons with other studies difficult. Possible independent risk factors for coronary artery disease, including cigarette smoking, diabetes, lipid abnormalities, and hypertension were generally not assessed in the mortality studies. The AFHS mortality study (1991a) results are important and require further examination to assess the role of confounders such as cigarette smoking and the specific circulatory diseases accounting for the increase. In general, the lack of assessment of independent risk factors for circulatory disease limits the usefulness of the mortality studies.

Among the morbidity studies, strong rationales for examining circulatory outcomes were not given. However, the Air Force Health Study (1991b) has reported associations between serum TCDD and both diabetes and blood lipids. This suggests a rationale for examining a major circulatory disease, coronary artery disease, in those exposed to dioxins because of the possible association between risk factors for coronary artery disease and serum TCDD level.

Two occupational studies (Moses et al., 1984; Suskind and Hertzberg, 1984) showed no significant increases in symptoms or history of circulatory disease. Several studies of Vietnam veterans showed increases in self-reported hypertension. The CDC VES study (CDC, 1988) reported a significant increase in the self-report of hypertension, but physical examinations did not show any differences in increased blood pressure. In the Stellman et al. (1988) study, herbicide handlers had significantly more self-reports of physician-diagnosed hypertension. However, validation by medical record review or measurement of blood pressure was not done in this study. The Air Force Health Study (1991b) stated that there were significant increases in reported essential hypertension associated with high current TCDD levels. However, it further reported that this effect was observed after body fat and cholesterol were removed from the model (AFHS, 1991b). Further evaluation is needed to assess the appropriate choice and interpretation of models before conclusions can be drawn from this study (AFHS, 1991b).

Several studies provided electrocardiogram results (CDC, 1988; AFHS, 1990; Suskind and Hertzberg, 1984), but comparisons were difficult because

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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of nonuniformity in classifying the EKGs. Results were negative or inconsistent. Nonuniformity in classifying EKG abnormalities across the studies limited useful comparisons.

Chest radiograph results were presented in three studies with inconsistent findings (Suskind and Hertzberg, 1984; Pollei et al., 1986; CDC, 1988). Although all three reports showed no differences in chest radiographs, the Suskind and CDC studies did not assess herbicide or contaminant exposures. In the one study that attempted to assess such exposure (Pollei et al., 1986), the numbers in the subgroup that recalled repeated handling of herbicides were too small for adequate analysis.

Doppler measurements showed no differences in the two studies reported (AFHS, 1987; CDC, 1988). However, other reports of peripheral pulse abnormalities were in contrast to these (AFHS, 1984, 1991b, vol. 5). The timing of cigarette smoking in relation to the examination is a possible explanation that requires further assessment.

One parameter that could be assessed across several studies was blood pressure measurement from physical examination (Suskind and Hertzberg, 1984; CDC, 1988; AFHS, 1990). Similar criteria were used to define an elevated blood pressure (greater than 140/90), although one study used a higher cutoff for those 60 years of age and older (Suskind and Hertzberg, 1984). An occupational study of 2,4,5-T production workers (Suskind and Hertzberg, 1984) and the Vietnam Experience Study (CDC, 1988) showed no significant differences in measured blood pressure between exposed and unexposed. The AFHS (1991b) reported increases in adjusted mean systolic and diastolic blood pressure in association with high current TCDD levels when body fat was not considered. However, it reported that the frequency of elevated systolic or diastolic blood pressure was not associated with TCDD level. Further evaluation is needed to assess appropriate modeling of variables and the interpretation of models before conclusions can be drawn from this study (AFHS, 1991b). With regard to other abnormalities on physical examination, the AFHS reported no significant differences between Ranch Hands and the comparison group in heart sounds, marginally higher frequencies of carotid bruits, and significant or marginally more significant differences in peripheral pulses (AFHS, 1990). It further reported significant associations between TCDD and decreases in peripheral pulses (AFHS, 1991b). Further evaluation is needed to assess appropriate choice and interpretation of models, and the timing of cigarette smoking in relation to the examination of peripheral pulses, before conclusions can be drawn from these studies (AFHS, 1990, 1991b). In the morbidity studies, a wide range of outcomes was assessed, and the presentation of results varied across studies. Symptoms or history of heart disease was difficult to assess across studies since each study gathered unique noncomparable data. Data derived from physical examination differed among the studies.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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Conclusions for Circulatory 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 circulatory outcomes: circulatory disease mortality and various subgroups of cardiovascular disease; symptoms or history of circulatory illnesses such as heart disease, hypertension, coronary artery disease, angina, or myocardial infarction; abnormalities on physical examination, electrocardiogram results, and chest radiographs.

Biologic Plausibility

Limited information from animal studies is available on the potential association between circulatory 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, 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.

RESPIRATORY DISORDERS

The studies to be reviewed in the following section on respiratory diseases covered a wide variety of diverse respiratory conditions. In the morbidity studies, a variety of methods were used to assess the respiratory system, including assessing symptoms, performing physical examination of the chest, and assessing lung function tests and chest radiographs. Lung function tests, also called pulmonary function tests, included tests commonly used to detect airflow obstruction (which can occur in conditions such as asthma, chronic bronchitis, and emphysema) and restriction or decrease in lung volumes (which can occur in lung scarring and inflammation). The tests that measure reduced in airflow obstruction include FEV1 (amount of air which can be forcefully exhaled in one second), FEV1/FVC

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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ratio (ratio of the amount of air that can be forcefully exhaled in 1 second to the total amount of air that can be forcefully exhaled), FEF25-75 (rate of airflow in the middle range of total volume), and FEFmax (rate of airflow at the highest lung volume). The test that measures restriction is the FVC, or forced vital capacity, the total amount of air that can be forcefully exhaled. Chest radiographs, which were used in several studies, can assess whether inhaled agents have damaged the lungs, usually seen as opacities in the lungs indicating scarring, or inflammation, or a combination of the two.

Little research has been conducted on the possible effects of herbicides and TCDD on the respiratory tract in animals. Studies that are available have focused on enzyme induction, primarily cytochrome P450 in lung tissue (see Chapter 4).

Epidemiologic Studies of Respiratory Disorders

Occupational Studies

The occupational studies assessing respiratory outcomes can also be divided into mortality and morbidity studies. Mortality from respiratory disease was not elevated in studies of production workers of phenoxy herbicides and chlorophenols (Coggon et al., 1991), pesticide application (Blair, 1983), soil/forest conservationists (Alavanja et al., 1989), and MCPA manufacturing/spraying (Coggon et al., 1986).

In one study examining health outcomes among 204 workers involved in 2,4,5-T production as compared to 163 nonexposed workers from the same plant, results showed that the exposed group was older, had more retirees and terminated employees, and differed in education (Suskind and Hertzberg, 1984). Exposed and unexposed workers had similar frequencies of smokers, but for both smokers and ex-smokers, the pack-years were greater among those exposed, possibly reflecting age differences between the groups. There were also more reported and observed cases of chloracne among the exposed. No exposure-related differences were seen in chest radiograph findings. Among current smokers, the frequencies of abnormal forced expiratory volume (FEV 1), forced vital capacity (FVC), FEV1/FVC ratio, and forced mid-expiratory flow rate (FEF25-75) were significantly higher among those exposed than those unexposed. After adjustment for the number of pack-years smoked, the number of abnormal pulmonary function values were increased among the exposed group. Means predicted for FEV1, FEV1/FVC, and FVC, adjusted for smoking, were significantly lower among the exposed. For FEV1, the mean was significantly lower in smokers.

In another respiratory morbidity study (Calvert et al., 1991), 281 workers involved in the manufacture of TCDD-contaminated products at two plants were compared with 260 neighborhood controls. Exposed workers

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
×

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,

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: The National Academies Press. doi: 10.17226/2141.
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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.

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Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam Get This Book
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Have U.S. military personnel experienced health problems from being exposed to Agent Orange, its dioxin contaminants, and other herbicides used in Vietnam? This definitive volume summarizes the strength of the evidence associating exposure during Vietnam service with cancer and other health effects and presents conclusions from an expert panel.

Veterans and Agent Orange provides a historical review of the issue, examines studies of populations, in addition to Vietnam veterans, environmentally and occupationally exposed to herbicides and dioxin, and discusses problems in study methodology. The core of the book presents

  • What is known about the toxicology of the herbicides used in greatest quantities in Vietnam.
  • What is known about assessing exposure to herbicides and dioxin.
  • What can be determined from the wide range of epidemiological studies conducted by different authorities.
  • What is known about the relationship between exposure to herbicides and dioxin, and cancer, reproductive effects, neurobehavioral disorders, and other health effects.

The book describes research areas of continuing concern and offers recommendations for further research on the health effects of Agent Orange exposure among Vietnam veterans.

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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