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Veterans and Agent Orange: Update 1998 (1999)

Chapter: 11 Other Health Effects

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Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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11
Other Health Effects

INTRODUCTION

A variety of health outcomes are evaluated in this chapter, including chloracne, porphyria cutanea tarda, respiratory disorders, immune system disorders (immune suppression, autoimmunity), diabetes mellitus, lipid abnormalities, gastrointestinal and digestive disease (including liver toxicity), and circulatory disorders. Many of these outcomes have not been addressed as thoroughly in the epidemiologic literature as the health outcomes described in Chapters 7, 9, and 10.

For most of the health outcomes discussed in this chapter, a brief summary of the scientific evidence described in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (henceforth called VAO) (IOM, 1994) and Veterans and Agent Orange: Update 1996 (henceforth called Update 1996) (IOM, 1996) is presented, followed by an update of the recent scientific literature. Because of special interest expressed by the Department of Veterans Affairs, a complete discussion of the evidence, including the studies cited in VAO and Update 1996, is presented for diabetes and for lipid and lipoprotein disorders.

CHLORACNE

Background

Skin disorders are among the most common health problems encountered in combat, aside from traumatic injuries. Because of the tropical environment and

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

living conditions in Vietnam, veterans developed 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 and other herbicides, including the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD, TCDD, or dioxin), is chloracne. Therefore, this discussion focuses on chloracne and its link to TCDD.

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 manifest the condition.

Chloracne has a variable natural history. 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). Like 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, a number of precautionary steps should be taken 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 and that there be careful comparison with an appropriate control group. Definitive diagnosis may require histologic confirmation from a biopsy specimen.

Chloracne can be viewed as both a toxic outcome of exposure to TCDD and a potential clinical marker of TCDD exposure. It is the latter that has generated the most controversy. In this section, the primary focus is on 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 exposure are discussed in more detail in Chapter 5. A major unresolved issue is whether TCDD exposure below the level required to cause chloracne may have other adverse health consequences such as cancer.

Summary of VAO and Update 1996

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.

From the studies reviewed in VAO and Update 1996, it is apparent that higher levels of exposure to TCDD, as reflected by increased serum levels, are

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

associated in a general way with increased risk of developing chloracne. However, the great degree of variability in TCDD levels among subjects with a history of chloracne and among those with no evidence of the condition suggests a complex dose-response relationship, with highly variable individual susceptibility. In addition, in many subjects the serum TCDD levels were measured many years after first exposure or onset of chloracne. Based on current data, it is not possible to assign a "threshold" TCDD level associated with chloracne.

Update of the Scientific Literature

No new informative publications were identified that related chloracne to exposure to herbicides or dioxin in humans. Because TCDD-associated chloracne becomes evident shortly after exposure, there is no risk that new cases will occur in veterans due to Vietnam service-related exposures.

Conclusions

Strength of Evidence in Epidemiologic Studies

Evidence is sufficient to conclude that there is a positive association between exposure to the herbicides considered in this report and chloracne. The evidence regarding association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.

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. A more thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and chloracne is contained in Chapter 3; a summary is presented in the conclusion to this chapter.

PORPHYRIA CUTANEA TARDA

Background

Porphyria cutanea tarda (PCT) is an uncommon disorder of porphyrin metabolism manifest in patients by thinning and blistering of the skin in sun-exposed areas, as well as by 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 of uroporphyrinogen decarboxylase (UROD), a cytoplasmic enzyme in the pathway of hemoglobin synthesis (Sweeney, 1986). In the hereditary form, no precipitat-

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

ing exposure is necessary for the appearance of excess uroporphyrin and coproporphyrin in the urine and the development of clinical symptoms.

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).

Summary of VAO and Update 1996

The occurrence of clinical PCT is rare and may be influenced by genetic predisposition of individuals with low enzyme levels of UROD. The cases reported have occurred relatively shortly after exposure to specific chemicals, including TCDD, and have improved 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 and may represent a preclinical stage of PCT.

There is no suggestion of an increase in PCT in studies of Vietnam veterans or Ranch Hands, possibly because of comparatively low dioxin exposure even for Ranch Hand veterans or a fortuitous absence of genetically predisposed individuals who could develop PCT after exposure to TCDD. Further studies of PCT incidence in Vietnam veterans would not be called for, since the biologic and clinical evidence indicates 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 exposure and PCT that do not simultaneously assess alcohol consumption.

Jung et al. (1994) presented porphyrin data on former workers in a German pesticide plant that had manufactured 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). The study found no difference in porphyrin levels or abnormal liver function tests between subjects with and without chloracne. There was also no relationship between porphyrin levels in urine, red blood cells, or plasma and TCDD levels in adipose tissue. Three cases of chronic hepatic porphyria (none with overt PCT and none with chloracne) were identified, which did not exceed the expected prevalence in this population.

Calvert et al. (1994) analyzed porphyrin levels and TCDD serum levels in a cross-sectional medical study of the National Institute for Occupational Safety and Health (NIOSH) cohort of workers who had been previously exposed to TCDD through manufacture of sodium trichlorophenol, 2,4,5-T, or hexachlorophene. There were no cases of overt PCT, and three exposed and three unexposed subjects had subclinical PCT. Porphyrin levels did not differ between exposed and unexposed workers, and there was no significant relationship between urinary porphyrin levels and serum TCDD levels.

Taken together, the studies reviewed did not support the hypothesis that TCDD caused disturbances in heme metabolism in humans, even at the relatively

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

high exposure levels experienced by these cohorts. Reports that some persons employed in herbicide production have evidence of increased porphyrins in urine warrant further investigation.

Update of the Scientific Literature

No informative publications were identified relating PCT to exposure to herbicides or dioxin in humans. Because TCDD-associated PCT becomes evident shortly after exposure, there is no risk that new cases will occur in veterans due to Vietnam service-related exposures.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is limited/suggestive evidence of an association between exposure to the herbicides considered in this report and porphyria cutanea tarda. Evidence regarding the association is drawn from occupational and other studies in which subjects were exposed to a variety of herbicides and herbicide components.

Biologic Plausibility

There is some evidence that TCDD 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. A more thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and PCT is contained in Chapter 3; a summary is presented in the conclusion to this chapter.

RESPIRATORY DISORDERS

Background

The studies reviewed in this section cover a wide range of respiratory conditions encompassed by International Classification of Diseases, Ninth Edition (ICD·9) codes 460-519, including acute respiratory infections, other diseases of the upper respiratory tract, pneumonia, influenza, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, asthma, pleurisy, and pneumoconiosis. In the morbidity studies, a variety of methods were used to assess the respiratory system, including assessment of symptoms, physical examination of the chest, lung function tests, and chest radiographs. Lung function (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

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

restriction or decrease in lung volume (which can occur because of lung scarring or inflammation). Tests that measure airflow obstruction include FEV1 (forced expirating volume, the amount of air that can be exhaled forcefully in one second); the ratio FEV1/FVC (forced vital capacity, the total amount of air that can be forcefully exhaled); FEF25-75 (forced expiratory flow, the rate of airflow in the middle range of total volume); and FEFmax (rate of airflow at highest lung volume). The test that measures restriction is FVC, which determines the total amount of air that can be exhaled with sustained effort. Chest radiographs, which were used in several studies, can assess whether inhaled agents have damaged the lungs; damage is usually apparent as opacities such as scarring, inflammation, or both.

Summary of VAO and Update 1996

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 involved in herbicide spraying, the respiratory tract could be viewed as a target organ for aerosol or other particulate deposition. In general, the lack of working hypotheses about respiratory disease outcomes associated with herbicides, the nonuniformity in methods and reported results, and the variable ability to adjust for the effects of cigarette smoking make it difficult to interpret much of the morbidity data, especially reports of symptoms and radiographic data.

Interpretation of many of the mortality studies was generally limited by the small number of deaths observed. These studies also tended to use the ICD·9 codes for all respiratory diseases. The wide range of diverse conditions and small number of total deaths make it difficult to assess any particular respiratory outcome using mortality studies. In some studies, the specific ICD·9 codes used were not stated, thus making comparisons with other studies difficult. Overall, there was little evidence of any associations with herbicide or dioxin exposure.

Update of the Scientific Literature

Occupational Studies

Becher et al. (1996) examined mortality among workers in four German facilities that produced phenoxy herbicides and chlorophenols. The population included workers who had a least one month of employment, and resulted in a cohort consisting of 2,479 male workers. Standardized mortality ratios (SMRs) and 95 percent confidence intervals (95% CIs) were calculated using West German mortality rates by five-year age and calendar intervals. SMRs for respiratory system disease among the four plants ranged from 0.5 to 0.8.

Svensson et al. (1995) studied mortality and disease incidence in two cohorts

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

of Swedish fishermen. One group (2,896 men) resided on the east coast of Sweden and consumed fish from the Baltic Sea. These fatty fish (particularly salmon and herring) are reported to contain elevated levels of polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs). The other group of fishermen (8,477 men) resided on the west coast of Sweden and were presumed to have a higher intake of lean (and less contaminated) fish, including cod and flat fish. Bronchitis and emphysema rates (ICD·9 codes 490-493), were reported, and no significant increase was found among east coast fishermen (SMR 0.5, 95% CI 0.1-1.2).

Ott and Zober (1996) updated the experience of workers exposed to TCDD during the cleanup of a trichlorophenol (TCP) reactor that exploded in 1953 at a BASF plant in Ludwigshafen, Germany. They studied disease incidence and mortality up to 1992 for a group of 243 men and developed TCDD dose estimates based on work activity information, blood TCDD determinations on a subset of the population, and estimates of TCDD elimination rates. Expected numbers of incident cases and cause-specific deaths were obtained from German sources by five-year age and calendar intervals. The overall SMR (95% CI) for respiratory system diseases was 0.1 (0.0-0.8); in the highest TCDD dose group, the SMR (95% CI) was 0.4 (0.0-2.0).

Ramlow et al. (1996) examined mortality in a cohort of workers exposed to pentachlorophenol (PCP), as part of a larger study of Dow chemical manufacturing workers exposed to the higher chlorinated dioxins. The study cohort was assembled from company records, starting with a cohort of 2,192 workers ever employed in a department with potential PCDD exposure between 1937 and 1980. From this cohort, 770 workers were identified who were considered to have potential PCP exposure based on work history records. Cumulative exposure indices for PCP and dioxin were calculated using scores described by Ott et al. (1987). In the study analysis, the U.S. white male death rates (five-year age and calendar time specific) and the death rates of non-PCP and non-PCDD male Dow Michigan employees for 1940 to 1989 were both used as reference values to calculate expected deaths. The overall SMR (95% CI) for respiratory system disease was 0.9 (0.5-1.5), with no significant effect of latency or estimated exposure level.

In an update and expansion of the International Agency for Research on Cancer (IARC) cohort study, Kogevinas et al. (1997) examined mortality in a cohort of 26,615 male and female workers engaged in the production or application of phenoxy herbicides. Exposure information varied between cohorts, but in general exposures were reconstructed from job records. Based on job categories and information on production processes and the composition of the materials used, exposed workers were classified into three categories: exposed to TCDD or higher chlorinated dioxins, unexposed to the same, and unknown exposure to the same. Analysis was performed by calculating SMRs and 95% CI, using the World Health Organization (WHO) mortality data bank to calculate national

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

mortality rates by sex, age (five-year intervals), and calendar period (five years). Overall, a decrease in respiratory system disease was observed in exposed workers compared to unexposed workers for males (SMR 0.8, 95% CI 0.7-0.9), with no significant differences observed for women (SMR 1.1, 95% CI 0.4-2.2).

Studies of Vietnam Veterans

In a study of postservice suicide among Vietnam veterans, Bullman and Kang (1996) reported subsequent cause-specific mortality for 34,534 veterans who had been hospitalized for wounds suffered in Vietnam, compared to U.S. men overall. They observed no significant difference in respiratory system disease deaths (SMR 0.9, 95% CI 0.7-1.2) compared to U.S. men.

O'Toole et al. (1996) described the results of a simple random sample of Australian Army Vietnam veterans on self-reported health status. Data were obtained on 641 veterans from the Australian Bureau of Statistics Health Interview Survey 1989-90, and illness rates were compared to the age-and sex-matched Australian population. They observed no significant increase in overall respiratory system disease among veterans; the relative risk (RR) was 2.0 (99% CI 0.0-7.1). Hay fever (RR 1.6, [CI, 1.3-1.9]), bronchitis or emphysema (4.1 [CI 2.8-5.5]), and other respiratory disease (4.0 [CI 2.2-5.9]) were significantly elevated compared to the general population, although none of these conditions were related to an index of combat exposure. The veterans were significantly less likely to have never smoked than the general population (0.7 [CI 0.5-0.8]), a finding similar to data reported by McKinney et al. (1997) on U.S. Vietnam veterans. No information was available on other potential confounding factors such as occupational exposures.

Watanabe and Kang (1996) reported on the mortality of 33,833 U.S. Army and Marine Corps Vietnam veterans who died during 1965-1988, compared to mortality among 36,797 deceased non-Vietnam veterans, using proportionate mortality ratios (PMRs). They observed no increase in respiratory system disease mortality among Army Vietnam veterans (PMR 0.9) or among Marine Vietnam veterans (PMR 1.1).

Dalager and Kang (1997) reported a study comparing 2,872 Vietnam veterans with 2,737 non-Vietnam veterans (all of whom served in Chemical Corps specialties). All study subjects served at least 18 months' active duty between 1965 and 1973, and vital status ascertainment was complete for both groups. They reported no significant increase in respiratory system disease mortality among Vietnam veterans, with an RR (95% CI) of 2.6 (0.6-12.2).

A report on Australian Vietnam veterans (Crane et al., 1997a) compared cause-specific mortality rates of 59,036 male Vietnam veterans with those of other Australian males. They found a significant decrease in respiratory system disease (SMR [95% CI] for deaths in 1964-1979 (0.1 [0.0-0.3]) and no significance from expected rates for 1980-1994:0.9 (0.7-1.1).

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

A second cohort study of Australian veterans compared the mortality for 1982-1994 for 18,949 national servicemen who had served in Vietnam (veterans) with 24,646 national servicemen who had not served in Vietnam (nonveterans) (Crane et al., 1997b). They observed an RR (95% CI) for veterans compared to nonveterans of 0.9 (0.3-2.7) for all respiratory diseases and 0.3 (0.0-3.2) for chronic obstructive airways disease.

The ongoing study of Ranch Hand veterans (AFHS, 1996) reported cause-specific mortality among 1,261 Ranch Hand personnel compared to 19,080 Air Force veterans from the same era who did not handle herbicides. No increase was observed in respiratory system disease deaths (SMR 0.5).

Synthesis

Although there were sporadic reports of increased respiratory disease potentially related to exposure to herbicides or TCDD, the results were inconsistent across studies. In addition, interpretation of individual studies was generally limited by a lack of information on cigarette smoking. In the one study that showed the strongest association between potential exposure and respiratory disease (O'Toole et al., 1996), veterans were much more likely to have smoked than nonveterans. Additional research, with adequate information on cigarette smoking and other risk factors for respiratory disease, is required to adequately assess the potential association between respiratory disease and herbicide or TCDD exposure.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides and 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. The evidence regarding association is drawn from occupational and veteran studies in which subjects were exposed to a variety of herbicides and herbicide components.

Biologic Plausibility

A thorough discussion of biologic plausibility with respect to exposure to TCDD or herbicides and respiratory disorders is contained in Chapter 3; a summary is presented in the conclusion to this chapter.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

IMMUNE SYSTEM DISORDERS

Background

Immunotoxicology is the study of the effects of xenobiotics (chemical compounds that are foreign to the human body) on the immune system. The compounds may produce an impaired immune response (immunosuppression) or an enhanced immune response (immune-mediated disease). Although alterations in the immune system can be related to increases in the incidence of infection and neoplasm (immune suppression) and immune-mediated diseases (allergy and autoimmunity), there has been no observed increase in infectious or immune-mediated disease in the populations examined after exposure to herbicides. However, alterations have been observed in measures of immune function or populations of immune cells. The question of possible increases in neoplastic diseases is dealt with in Chapter 7.

Immune Suppression

The immune system helps defend the host against foreign invaders. It confers resistance to infection by bacteria, viruses, and parasites; it is involved in the rejection of allografts (tissue transplants); and it may eliminate spontaneously occurring tumors (Paul, 1993). Proper function of the immune system is exquisitely sensitive to disruptions in physiologic homeostasis. The immune response is highly redundant, and several different mechanisms may be employed to eliminate an antigen. 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.

Suppression of the immune system leads to increased susceptibility to infection and neoplasia. However, the degree of immune suppression necessary to cause disease is unknown 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-1] can lead to AIDS), and exposure to immunosuppressive agents (Paul, 1993). Immune suppression can also occur in patients with autoimmune disease (discussed 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, the immune system may prevent or limit tumor growth, and a high incidence of tumors may follow immune suppression (Paul, 1993).

Allergy and Autoimmunity

A number of diseases involve hyperresponsiveness of the immune system to either foreign allergens (e.g., allergy) or self-antigens (autoimmunity). Allergic

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

responses have been noted to numerous environmental agents, including plant pollens and epithelial products of domestic 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 on subsequent exposure to antigen. The mediators of allergic reactions, such as histamine, are then released. The alterations discussed below reflect only in vitro immune parameters, not disease incidence. In fact, no increase in allergic disease related to herbicide exposure has been reported in any of the studies reviewed.

In general, the immune response is directed against foreign antigens. However, in some instances antibodies can be demonstrated that react with endogenous antigens (i.e., autoantibodies). Autoimmune disease is the pathological consequence of an immune response to autologous antigen. Some autoimmune diseases result when autoantibodies activate the complement cascade or interact with "killer" mononuclear cells to induce antibody-dependent cell-mediated cytotoxicity. Others 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 an autoimmune response from autoimmune disease. Autoimmunity, as indicated by the presence of autoantibodies, is relatively common, whereas autoimmune disease is relatively rare. Detecting 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.

Summary of VAO and Update 1996

The effects of herbicide exposure on the level of several immune parameters were presented in studies reviewed in VAO and Update 1996 . The data are divided into two categories: immune suppression and immune enhancement. No studies investigating the association of autoimmune disease or allergy with exposure to herbicides were identified.

Several studies were carried out on individuals occupationally exposed to TCDD, examining immunological markers, including immunoglobulin levels, complement components, and lymphocyte subpopulations. The changes described were marginal and varied from study to study, some showing increases and some decreases in these parameters. No changes in the incidence of infectious disease were noted. 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 these alterations in humans. Currently, the level of alteration in immune parameters necessary to affect the incidence of disease is unknown. Furthermore, since so many immune parameters were assessed in these studies, there is a high probability that at least some positive results would be noted based on chance alone, which would undermine interpretation of the few

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

positive results. The earlier committees reached the conclusion that no clinically significant changes in the human immune response could be attributed at that time to TCDD or other halogenated aromatic hydrocarbons.

Update of the Scientific Literature

Two studies have appeared relating to the incidence of infectious diseases in American Vietnam veterans. Visintainer et al. (1995) studied a cohort of 377,028 veterans who are on the Michigan Department of Management and Budget's Vietnam-Era Bonus List. This database differentiates between two groups of Vietnam era veterans: those who served in Vietnam (151,377) and those who served elsewhere (225,651). Vietnam veterans compared with non-Vietnam veterans had a slightly elevated proportionate mortality ratio from infectious and parasitic diseases (PMR = 1.6, CI 1.2-2.1, N = 56). The study, however, did not distinguish Vietnam veterans exposed to Agent Orange from those with no known exposure. A retrospective cohort mortality study was reported by Watanabe and Kang (1995). They studied all marines on active duty during 1967 through 1969. A total of 281,196 records were obtained, from which a sample of 26,158 was drawn. A search of their records divided this group into 11,167 who served in Vietnam and 9,412 who never served in Vietnam. The remaining 5,579 were not traced. Based on cause-specific mortality, comparing Vietnam Marines with non-Vietnam Marines, an estimated risk for infectious diseases of 2.8 (CI 0.8-10.3) was obtained. This difference was not determined to be significant. Two studies of Australian Vietnam veterans failed to show any increase in mortality due to infectious or parasitic diseases (Crane et al., 1997a,b).

Several studies were undertaken to relate exposure to halogenated aromatic hydrocarbons to shifts in lymphocyte subpopulations. Lovik et al. (1996) studied 24 fishermen with possible occupational and environmental exposure to a number of halogenated aromatic hydrocarbons, such as PCDDs and polychlorinated furans (PCFs) through fish and crab consumption. In a preliminary report, they found a tendency toward negative correlation between B lymphocytes and blood levels of PCDD or PCF. On the other hand, there was a positive correlation between the mitogenic responses of T lymphocytes and the blood levels of halogenated aromatic hydrocarbons. No relationship between NK (natural killer) cell number or function and blood level of these compounds was found. Of the serum immunoglobulins, there was a negative correlation with serum immunoglobulin M (IgM) levels and a tendency toward positive correlation for IgE. A negative relationship with autoantibodies, such as antinuclear antibodies, was observed. These preliminary results do not allow any firm conclusions to be drawn.

A study of 10 farmers who mixed and applied chlorophenoxy herbicides was carried out by Faustini et al. (1996). After one to twelve days of exposure, the proportions of circulating CD4+ T cells, CD8+ T cells, activated T cells, and NK

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

cells were significantly reduced compared with values before exposure. There was also a reduction in lymphocyte responses to mitogenic stimulation by phytohemagglutinin and concanavalin A. No correlation was found between the amount of herbicide applied and the decrease in percentage of lymphocyte subsets. These studies suggested that short-term immunological changes may occur following exposure to phenoxy herbicides in an agricultural setting. The changes, however, were short-lived, because most of the values returned to normal or near-normal ranges 50-70 days after exposure.

A study in Germany of the effects of inhalative exposure to TCDD and related compounds in wood preservatives on cell-mediated immunity in teachers at day care centers was reported by Wolf and Karmaus (1995). The study population consisted of 221 exposed persons and an unexposed control group of 189 persons. Exposed and unexposed populations did not differ with regard to the number of peripheral CD4+ T cells, CD8+ T cells, and the CD4:CD8 ratio. In a multitest format for delayed hypersensitivity, exposed subjects had a slightly higher overall score than unexposed controls. When exposure to TCDD was estimated, subjects with a TCDD burden of >0.6 pg/mg had a statistically significant higher risk of hypoergy than subjects who did not experience any exposure at their day care center workplace. There were, however, some methodological limitations that require caution in attributing the observed decrease in skin test responsiveness to inhalative TCDD exposure. The TCDD burden could not be assessed with precision, and the relatively low prevalence of hypoergy or anergy limited the estimation of an effect. Recruitment of the study population was also a problem because of the possibility of selection bias toward people with ill health or presumed harmful exposures.

The immunological effects of pre-and postnatal exposure to PCBs or TCDD in 207 Dutch infants from birth to 18 months of age were explored by Weisglas-Kuperus et al. (1995). Prenatal exposure was estimated from the total toxic equivalent level of each compound in human milk multiplied by the weeks of breast-feeding. No evidence was found of increased upper or lower respiratory tract symptoms or altered antibody production to mumps, measles, or rubella in relation to PCB or TCDD exposure. Although there were small differences in the T-cell, B-cell, and NK-cell populations between high-and low-exposed infants, all values were within the normal range. The investigators did find, however, that prenatal PCB or TCDD exposure was associated with changes in T-cell subpopulations in the blood. These changes were seen mainly at 18 months of age. At this age, higher prenatal exposure was associated with an increase in the number of CD4+ T cells, resulting in a relative change in the CD4:CD8 ratio. Higher prenatal as well as postnatal PCB or TCDD exposure was associated with lower monocyte and granulocyte counts only at 3 months of age. These results suggest that perinatal exposure to chlorinated aromatic hydrocarbons may influence the human fetal and neonatal immune system, but the changes are not reflected in increased susceptibility to infection.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

Tonn et al. (1996) examined the long-term effects of TCDD in 11 industrial workers who 20 years earlier had been exposed to high levels of TCDD for several years. Their current TCDD body burdens were still at least 10 times higher than the general population. No significant differences could be detected between individuals tested and controls with respect to lymphocyte subpopulations or mitogen-induced lymphocyte proliferation. The investigators noted a decrease in interleuken-2 (IL-2)-induced proliferation, suggesting a decrease in preactivated T cells in the blood. TCDD-exposed subjects showed a reduced response to allogeneic stimulation. This effect was attributed in part to an increase in a lymphocyte population that displayed a suppressive activity on allogeneic responses. There is no known relationship between this decreased alloresponse and any disease state.

One study was reported of autoimmunity following TCDD exposure. Chinh et al. (1996) examined 25 Vietnamese veterans and 36 control males. They found no increase in autoantibodies to sperm or in antinuclear antibodies.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides considered in this report and immune suppression or autoimmunity.

Biological Plausibility

Evidence for the effects of TCDD and other halogenated aromatic hydrocarbons on the immune system of animals is presented in Chapter 3; a summary is presented in the conclusion of this chapter. Similar observations have not been reported in humans.

Increased Risk of Disease Among Vietnam Veterans

No evidence is available to associate defects in the immune response with Agent Orange exposure. A more thorough discussion of the issue of increased risk of disease among Vietnam veterans is included in Chapter 1.

DIABETES

Background

Primary diabetes (i.e., not secondary to another known disease or condition, such as pancreatitis or pancreatic surgery) is a heterogeneous metabolic disorder

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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characterized by hyperglycemia and quantitative and/or qualitative deficiency of insulin action (Orchard et al., 1992). Two main types have been recognized based on the 1979 National Diabetes Data Group (NDDG) criteria and those of the World Health Organization (WHO, 1980, 1985): insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). In June 1997, the American Diabetes Association (ADA, 1997) suggested a revised classification, with IDDM being termed Type I and NIDDM, Type II. This new terminology is used in the remainder of this review, although the older diagnostic criteria are utilized as appropriate.

Type I diabetes is generally accepted to result from β-cell dysfunction, caused by a genetically based autoimmune destruction. It comprises approximately 10 percent of all cases of diabetes and characteristically has an abrupt onset in youth or young adulthood, although it may appear at any age. The usual autoimmune form results in complete β-cell destruction and complete insulinopenia, hence the ''insulin dependency" of earlier classifications. The genetic basis of the auto-immune form is linked to the human lymphocyte antigen (HLA) system (class II antigens). A number of environmental triggers of the autoimmune process and/or of symptomatic disease in genetically susceptible subjects have been proposed including viral infections.

Type II diabetes accounts for the majority (approximately 90 percent) of cases of primary diabetes. It is rare before age 30, but increases steadily with age thereafter. The age, sex, and ethnic prevalences are given in Table 11-1. The etiology of Type II is unclear, but three cardinal components have been proposed: (1) peripheral insulin resistance (thought by many to be primary) in target tissues (e.g., muscle, adipose and liver); (2) β-cell insulin secretory defect; and (3) hepatic glucose overproduction. Although the relative contributions of these features are controversial, it is generally accepted that the main factors for increased risk of Type II diabetes include age (with older individuals at higher risk), obesity, central fat deposition, a history of gestational diabetes (if female), physical inactivity, ethnicity (prevalence is greater in African Americans and Hispanic Americans, for example), and perhaps most important, a positive family

TABLE 11-1 Three-year Mean Prevalence of Diagnosed Diabetes (per 1,000 population) by Gender, Age, and Race: 1990-1992

Age

Total

Male

Female

White (men and women)

Black (men and women)

25-44

13.9

12.2

15.5

13.9

19.5

45-54

35.6

31.2

39.8

32.9

63.0

55-64

77.5

79.5

75.6

72.2

128.1

>65

101.1

101.4

100.8

93.5

178.6

 

SOURCE: Kenny et al., 1995, Appendix 4.5, Chapter 4 (1990-1992 National Health Interview Surveys).

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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history of Type II (for example, more than 90 percent of monozygotic twins are concordant for diabetes compared to less than 50 percent for dizygotic twins). Defects at many intracellular sites could account for the impaired insulin action and secretion seen in Type II diabetes (Kruszynska and Olefsky, 1996). The insulin receptor itself, insulin receptor tyrosine kinase activity, insulin receptor substrate proteins, insulin-regulated glucose transporters, enhanced protein kinase C (PKC) activity, tumor necrosis factor-α, rad (ras associated with diabetes), and PC1 have all been proposed as potential mediators of insulin resistance; impaired insulin secretion has been linked to hyperglycemia itself, to abnormalities of glucokinase and hexokinase activity, and to abnormal fatty acid metabolism.

Finally, an increasing number of "other" types of diabetes have been described that are linked to specific genetic mutations, for example, maturity-onset diabetes of youth, which results from a variety of mutations of the β-cell glucokinase gene.

The diagnosis of diabetes is problematic and a major concern for clinicians and investigators. Whereas Type I is often clearly diagnosed at onset (a blood sugar >200 mg/dl plus symptoms), up to half of the Type II population goes undiagnosed. This occurs because the degree of metabolic disturbance needed to meet both the old and the recently revised criteria does not necessarily produce symptoms, but nonetheless is likely to lead to the late complications of diabetes (cardiovascular disease, nephropathy, retinopathy, and neuropathy). It is partly because of this large population of undiagnosed cases and the impracticability of the standard diagnostic test (oral glucose tolerance test) in busy clinical practice that a more simplified diagnostic approach has been recommended by the ADA based on the fasting plasma glucose. Table 11-2 shows the earlier NDDG (WHO, 1979) and the current ADA (ADA, 1997) criteria. It should be noted that the vast majority of undiagnosed cases of diabetes under the 1979 criteria were diagnosable only by the 2-hour postglucose criterion (>200 mg/dl) and had fasting plasma glucose levels below the diagnostic level (140 mg/dl). This was one of the main reasons that current ADA recommendations have lowered the fasting criterion to 126 mg/dl (i.e., to capture those cases with the simpler [and more reproducible] fasting glucose test, as 126 mg/dl fasting approximates the 2-hour post challenge diagnostic level).

TABLE 11-2 Diagnostic Criteria for Diabetes (mg/dl plasma glucose)

 

1979 NDDG/1980 WHO

1997 ADA

Fasting

>140

> 126

2 hra

>200

>200b

Random glucosec

>200

>200

a Post 75-gm glucose load; midtest value also has to be >200 mg/dl for NDDG.

b Not recommended for routine use.

c In the presence of diabetes symptoms.

SOURCE: WHO, 1980; ADA, 1997.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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Epidemiologic Concerns in the Study of Diabetes

As can be surmised from the above brief description, the epidemiologic study of diabetes is filled with problems. Pathogenetic diversity and diagnostic uncertainty are two of the more significant problems.

Pathogenetic Diversity

Given the multiple likely pathogenetic mechanisms leading to diabetes, which include diverse genetic susceptibilities (ranging from autoimmunity to obesity) and a variety of potential environmental and health behavior factors (e.g., viruses, nutrition, activity), it is probable that many agents or behaviors contribute to diabetes risk, especially in genetically susceptible individuals. These multiple mechanisms may also lead to heterogeneous responses to various exposures.

Diagnostic Uncertainty

Because up to half the affected diabetic population is currently undiagnosed, the potential for ascertainment bias is high (i.e., more intensively followed groups or those with more frequent health care contact are more likely to be diagnosed), and the need for formal standardized testing (to detect undiagnosed cases) is great. Furthermore, the division of cases developing during young to middle age (i.e., 20-44 years) into Type I or Type II (which indicates the more likely pathogenetic mechanism) is very difficult. Indeed, it is now thought that as many as 10 percent of clinical "Type II" subjects may well have an incomplete form of "Type I" diabetes (Tuomi et al., 1993).

Epidemiologic Studies

Pazderova-Vejlupkova et al. (1981) reported on the 10-year follow-up of 55 workers who had become acutely ill while producing TCP and 2,4,5-T: 95 percent (52) developed chloracne and 8 percent (4) had diabetes at the onset of intoxication. Ten years later, one-fifth (N = 11) were reported to have a diabetic glucose tolerance test (diagnostic criteria are not stated, and the role of confounders is not addressed). In a survey of subjects up to 10 years after another industrial incident, May (1982) reported only two clinically recognized cases of diabetes in a total study group of 126 subjects including controls, with a mean age in the low forties. Reported diabetes did not increase in another study (after age adjustment) of 117 2,4,5-T production workers with chloracne compared to 109 without, 10-20+ years after mixed accidental and chronic TCDD exposure (Moses et al., 1984). Two mortality studies provide further negative data. Cook et al. (1987) examined mortality among 2,187 chemical workers and found a decreased SMR

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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(0.7) for diabetes; Bertazzi et al. (1989) reported the 10-year mortality of those living in the area of Seveso, Italy, at the time of the incident in 1976. The relative risk of diabetes mortality was 1.3 (95% CI 0.7-2.3) for men and 1.5 (0.9-2.5) for women. It should be noted that vital statistics data are known to be unreliable in terms of complete ascertainment of diabetes-related mortality.

More recently, Ott et al. (1994), reporting on 138 BASF workers exposed to TCDD in a 1953 industrial incident, found borderline (p = 0.06) increased fasting glucose levels approximately 37 years later. Further analysis suggested that this association was limited to subjects without chloracne who happened to be more obese. The authors raise the possibility that the TCDD-glucose association may be secondary to the link between obesity and diabetes. In a morbidity follow-up of 158 TCDD-exposed BASF workers, significantly fewer (6.3 percent versus 14.3 percent) exposed subjects had medical insurance diagnoses of diabetes (Zober et al., 1994). Interestingly, thyroid disease was increased (p < 0.05) in the exposed population. There is a considerable overlap between the subjects in this study and those in Ott et al. (1994). Reporting on a mortality study of 883 pulp and paper workers, Henneberger et al. (1989) did not find a statistically significant increase in diabetes (SMR 1.4, 95% CI 0.7-2.7). A German Cancer Research Center report (Von Benner et al., 1994) also found no TCDD effect on blood sugar levels in 153 TCDD-exposed workers from six chemical plants. Two recent mortality follow-up studies also found no increased diabetes (Ramlow et al., 1996) or endocrine mortality (Kogevinas et al., 1997) in chemical workers exposed to dioxins.

Early reports from the Air Force Health Study (the "Ranch Hand" study) of Vietnam veterans exposed to herbicide spraying and an unexposed comparison cohort suggested little relationship. At the first baseline exam in 1982, 10-20 years after exposure, no difference in the prevalence of an abnormal blood sugar (>120 mg/dl 2 hours after a standard carbohydrate load) was seen between the two groups (15 percent versus 17 percent) (AFHS, 1984). Reporting data using lipid-adjusted serum TCDD levels as a measure of exposure from the same cohort study, the Ranch Hand Study (AFHS, 1991) found a significant association between diabetic status on a 3-point scale—normal, impaired (2-hour post prandial glucose 140-200 mg/dl), and diabetic (verified past history or > 200 mg/dl 2-hour post prandial glucose)—and TCDD level in both the Ranch Hands (p = 0.001) and the comparison group (p = 0.028). However, this correlation may be influenced by the strong correlation between obesity (percentage of body fat) and TCDD level in the same analysis (r = 0.3, p < 0.001 in Ranch Hands; r = .15, p < 0.01 in comparison). It should also be noted that the prevalence of an abnormal 2-hour blood glucose, either impaired or diabetic together (25 percent versus 22 percent Ranch Hand versus comparisons, respectively), or diabetic alone (10 percent versus 8 percent), is not markedly increased despite a nearly fourfold difference in mean dioxin levels between the Ranch Hand and comparison groups. The major impact of obesity in deter-

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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TABLE 11-3 Selected Epidemiologic Studies—Diabetes

Reference

Study Population

Exposed

Cases

Estimated

Risk

(95% CI)

p Value

OCCUPATIONAL

New Studies

Ramlow et al., 1996

Pentachlorophenol production workers

4

1.2 (0.3-3.0)a

 

Studies reviewed in Update 1996

Ott et al., 1994

Trichlorophenol production workers

134 g

 

0.06c

Von Benner et al., 1994

West German chemical production workers

N/A

N/A

 

Zober et al., 1994

BASF production workers

10

0.5 (0.2-1.0)

 

Studies reviewed in VAO

Sweeney et al., 1992

NIOSH production workers

26

1.6 (0.9-3.0)

 

Henneberger et al., 1989

Paper and pulp workers

9

1.4 (0.7-2.7)

 

Cook et al., 1987

Production workers

4

0.7 (0.2-1.9)a

 

Moses et al., 1984

2,4,5-T and TCP production workers

22 (chloracne)

2.3 (1.1—4.8)

 

May, 1982

TCP production workers

2

Not available

 

Pazderova-Vejlupkova et al., 1981

2,4,5-T and TCP production workers

11

No referent group

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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Reference

Study Population

Exposed

Cases

Estimated

Risk

(95% CI)

p Value

ENVIRONMENTAL

Studies reviewed in VAO

Bertazzi et al., 1989b

Seveso residents

 

 

 

 

Males

15

1.3 (0.7-2.3)

 

 

Females

19

1.5 (0.9-2.5)

 

VIETNAM VETERANS

New Studies

Henriksen et al., 1997c

Ranch Hands

 

 

 

 

High-exposure category

57

1.5 (1.2-2.0)

 

 

All Ranch Hands

146

1.1 (0.9-1.4)

 

O'Toole et al., 1996

Australian Vietnam veterans

12

1.6 (0.4-2.7)c,d

 

Studies reviewed in VAO

AFHS, 1991b

Ranch Hands

85

 

0.001,e 0.028f

AFHS, 1984a

Ranch Hands

158

 

0.234

a Standardized mortality ratio compared to U.S. population.

b Mortality compared to referent population.

c Comparison of fasting glucose values to referents.

d Compared to Australian population.

e Differences for mean dioxin level across three groups—normal, impaired, and diabetic glucose tolerance—of Ranch Hands.

f Differences for mean dioxin level across three groups—normal, impaired, and diabetic glucose tolerance—of comparisons.

g Total sample size listed.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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mining both diabetes risk and serum dioxin level has to be fully controlled for before firm conclusions can be drawn.

In view of the potential importance of the most recent report from this ongoing Ranch Hand study, it is reviewed here in more detail. Henriksen et al. (1997) compared 989 dioxin-exposed Operation Ranch Hand veterans (1962-1971) to 1,276 nonexposed veterans serving at the same time. Exposure was classified on the basis of original exposure calculated from serum (lipid-adjusted) dioxin levels determined in 1987 or 1992. At follow-up (1992), the mean age of the comparison group was 53.5 years (+7.6) and that of the exposed group was 54.6 ± 7.2, 54.9 ± 7.6, and 50.9 ± 7.4 years, according to increasing exposure category. The prevalence of diabetes mellitus by 1995 was 13.2 percent in the comparison group and increased from 9.5 percent to 17.2 percent to 20.1 percent across the three Ranch Hand exposure categories. There was a statistically significant increase of the prevalence of the highest-exposure category relative to the comparison group (RR 1.5, 95% CI 1.2-2.0). Of the diabetic veterans, 41 percent were not following any treatment regimen, 27 percent were treated with diet alone, 21 percent with oral medications, and 10 percent by insulin.

Two concerns about this potentially important and well-conducted study are case definition and the focus on subgroup analysis with only limited control of confounders. Two somewhat conflicting definitions are given of a case of diabetes: one implies that all cases were clinically verified in medical records; the other is a combination of history and glucose testing after a standard meal or 100-g oral glucose tolerance test (OGTT).

Generally, half of the cases of diabetes go undiagnosed, and, in most cases, those that are diagnosed are found only after formal OGTT testing; the total prevalence of diabetes is the sum of previously diagnosed and currently discovered cases. (Technically an abnormal OGTT has to be repeated before a clinical diagnosis is made, but in epidemiologic studies this is not often done.) Although OGTTs were performed in the current study (at least in the 1992 examination; earlier reports refer to postprandial values), a 100-g glucose load was used, which inflates the positive rate a little compared to the recommended 75-g load. Since the OGTT was given only to those without a diagnosis of diabetes, the prevalence of undiagnosed diabetes is approximated in Henriksen et al. (1997, Table 8) by the 2-hour "postprandial" glucose values that are labeled abnormal (>200 mg/dl). Compared to the rates for 50-59-year-old, non-Hispanic whites from a recent national study (National Health and Nutrition Evaluation Survey III [NHANES III] 1988-1994), only the high-exposure group has a marked increase in prevalence of known diabetes, whereas all exposure groups have lower rates of discovered diabetes than reported in NHANES. Total prevalences (known and discovered) are therefore similar or lower for the background (9.5 percent) or low exposure group (17.2 percent) than in NHANES III (16.7 percent), with only the high-exposure group having an increased prevalence (20 percent). These results are consistent with the hypothesis that, generally, Ranch Hands have somewhat

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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lower rates of diabetes (which might be expected for a healthy military population) and that relatively more of the diabetic veterans have been diagnosed (reflecting their more intensive medical follow-up).

A high proportion (41 percent) of all cases are not being treated (even with diet), particularly if the cases were verified in medical records and thus carried a clinical diagnosis. Although comparable data are difficult to find, the 1989 National Health Interview Survey (NHIS) suggests that 43.6 percent of NIDDM subjects age 55-64 years use insulin and 51.7 percent use oral agents. Even given some overlap of these groups (i.e., those who use both insulin and oral agents), it would seem that the proportion of Ranch Hands with diabetes, but not on treatment (diet, insulin, or oral agents), is two to four times higher than expected.

The analyses are problematic since they partially ignore the matched design employed in the study. In the report, each exposure group is compared to the entire comparison group (which was chosen by an original matched design to be comparable to Ranch Hands as a whole). The three exposure groups should ideally be compared to appropriate subgroups of comparison subjects matched to the specific exposed group. Although the availability of serum dioxin levels enables a better measure of exposure and a focus on the risks of the low-and high-exposed groups is understandable, Ranch Hands as a group do not have an increased risk of diabetes:

Comparison group

13.2% (169/1,276)

Ranch Hands (all groups)

14.8% (146/989)

RR (95% CI)

1.1 (0.9-1.4)

The other major analytic concern involves the limited analyses concerning confounding. The authors note (Henriksen et al., 1997, Table 3) that the high-risk Ranch Hand group has both increased (body mass index [BMI]) and decreased (age) diabetes risk factors. Tables 4 and 5 in the paper list relative risks of diabetes based on the actual (or "raw") numbers of cases in each dioxin exposure category (Michalek and Ketchum, 1997). One analysis presented controls for obesity (Henriksen et al., 1997, Table 7) and appears to eliminate the significance of the negative coefficient of "time to onset of diabetes." A further matched analysis is described, including matching within 3 percent body fat, but relative risks (without confidence intervals) are given only for glucose and insulin values and not for diabetes risk or diabetes severity. In addition, the authors also reanalyzed the data using revised initial doses to take into account 1982 baseline body fat. The results are similar although the relative risk for the high exposure category is now lower than the low-exposure group. No confidence intervals are given so it is difficult to more fully assess these data. A fully adjusted multivariate model is strongly recommended (e.g., Cox Proportional Hazard with time to diabetes as the outcome), fully controlling for baseline age and obesity (BMI) and, if possible, for family history of diabetes, central fat

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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distribution, diabetogenic drug exposure, and a measure of obesity at the time of Vietnam service.

O'Toole et al. (1996), reporting on 641 Australian Vietnam veterans compared to the Australian population, found a response-adjusted RR of 1.6 (99% CI 0.4-2.7). There are a number of methodologic problems inherent in this study, including a lack of health outcome validation and the use of a control group that is not adequately representative of the cohort.

In a report of a NIOSH medical study of 281 dioxin-exposed workers from two chemical plants in New Jersey and Missouri, Sweeney et al. (1996, 1997) note a slight, statistically significant increase in the risk of diabetes (OR 1.1, p < 0.003) and high (>140 mg/dl) fasting serum glucose level (p < 0.001) with increasing serum concentrations of 2,3,7,8-TCDD. The authors suggest, without further documentation, that known diabetes risk factors (age, weight, family history of diabetes) appear more influential than TCDD exposure in explaining this result. An earlier report on this same cohort, published as a conference abstract (Sweeney et al., 1992), finds increased diabetes prevalence (9.2 percent) in the exposed workers compared to 258 nonexposed workers (5.8 percent).

Although not reported, this difference is not significant. However, in a multiple logistic regression analysis, significant associations between serum TCDD level and diabetic status or (in those without diabetes) fasting blood sugar, were apparently noted that were independent of major confounders (age, body mass index, race, and family history of diabetes). Since an OGTT was not performed, many cases (in both groups) may not have been detected. It is recommended that this study be documented more completely and published in the peer-reviewed literature, so that these potentially important findings can be evaluated fully.

Synthesis

The evidence suggesting that a connection between herbicide exposure and diabetes risk is equivocal. Consistency across studies is lacking in terms of early reports; however, the two recent studies using serum TCDD levels appear to have some consistency (Henriksen et al., 1997; Sweeney et al., 1996, 1997). In many studies, no association is detected and even in NIOSH and Ranch Hand studies it is not significant in univariate analyses for exposed subjects overall. Thus, only a small fraction of cases to date could be linked to herbicide exposure. However, the increased risk reported for the highest exposure groups suggests dose-responsiveness in both the Ranch Hand and the NIOSH studies. On the other hand, the much higher serum TCDD levels in the exposed groups in the NIOSH (Sweeney et al., 1996, 1997) and Ranch Hand study (Henriksen et al., 1997) compared to each study's control group do not lead to proportionately higher rates. Indeed in the 1991 Ranch Hand report (AFHS, 1991), the association with TCDD level was also seen in the comparison group. These observations raise the possibility of residual confounding by obesity. As obesity is a powerful determinant of both

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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TCDD level and diabetes, it is very difficult to determine whether TCDD has an independent pathogenetic role. More rigorous statistical analyses are, as suggested, needed to address the issue of residual confounding. A different possibility, namely that obesity is a mediator of TCDD-enhanced diabetes risk, has not been formally addressed in the analyses to date. This possibility remains open but difficult to explore as obesity or percent body fat measures at the time of initial Vietnam service would be needed along with equally precise TCDD exposure measures. Animal data suggest that rather than being associated with obesity, TCDD exposure, if anything, leads to a wasting syndrome. Other possibilities, for example, that there is some interaction between TCDD and obesity, could be more fully explored with statistical analyses of existing data, and researchers with relevant data are encouraged to critically examine these possibilities.

Potential pathogenetic mechanisms add to the biologic plausibility of herbicide exposure increasing diabetes risk. Empirically, the TCDD association with triglyceride and high-density lipoprotein (HDL) concentrations suggests a general consistency because these are the hallmarks of altered lipid metabolism in diabetes, since fatty acid metabolism, insulin resistance, and glucose metabolism are closely linked. The nature of the cases (i.e., few treated with insulin) does not suggest a Type I diabetes process with autoimmune β-cell destruction or chemical toxicity as seen with the rat poison Vacor (Drash et al., 1989). Nonetheless, measurement of glutamic acid decarboxylase (GAD) and insulin antibodies may be worthwhile given the uncertain nature of young adult-onset diabetes (Tuomi et al., 1993).

The well-established effect of TCDD on glucose transport in a variety of cells including human granulosa cells (by a cAMP [cyclic adenosine 5'-mono-phosphate] dependent protein kinase [Enan et al., 1996]), guinea pig adipose tissue (Enan and Matsumura, 1993), and mice and rats (by an Ah receptor-mediated mechanism [Enan and Matsumura, 1994]) provides some basis for biological plausibility. Furthermore, the association between TCDD and decreased PKC activity is of particular interest (Matsumura, 1995). TCDD may exert an influence on PKC activity which, in turn, may relate to insulin receptor kinase activity. Kruszynska and Olefsky report that increased PKC appears to inhibit insulin receptor kinase activity in humans (1996). Information about TCDD modulation of PKC is growing; for example, in vascular smooth muscle cells it appears to exhibit cell cycle dependence and isoform specificity (Weber et al., 1996) and is biphasic (Weber et al., 1994), while Bagchi et al. (1997) have shown that TCDD is a particularly strong stimulant of hepatic PKC in Sprague-Dawley rats. TCDD also has been reported to decrease glucose transporter 4 in adipose tissue and glucose transporter 1 in mice brains by the Ah receptor-dependent process operating at different levels (mRNA and protein, respectively) (Liu and Matsumura, 1995). Finally, since TCDD has been shown to affect hormone (including insulin) signaling, the likelihood that TCDD may be diabetogenic is further increased (Liu and Safe, 1996).

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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Thus, in summary, many animal studies provide potential biological mechanisms for an association between herbicide exposure and diabetes risk, and although the majority of earlier reports on humans suggest little association, the potentially more definitive 1997 report from the Ranch Hand study (Henriksen et al., 1997) raises the possibility that veterans in the highest herbicide exposure category may be at increased risk. Such a conclusion may be supported by a currently unpublished NIOSH study of workers exposed to TCDD. It is important to note that these studies used serum TCDD levels as the measure of exposure. At this time, questions concerning case definition and full control for obesity and other confounders (in the Ranch Hand study) preclude determining whether or not an association exists between herbicide exposure and diabetes in these studies.

The committee strongly urges that the NIOSH study be documented more completely and published in the peer-reviewed literature, so that its potentially important findings can be evaluated fully. It strongly recommends that the Ranch Hand study develop a fully adjusted multivariate model (e.g., Cox Proportional Hazard with time to diabetes as the outcome), fully controlling for baseline age and obesity (BMI) and, if possible, for family history of diabetes, central fat distribution, diabetogenic drug exposure, and a measure of obesity at the time of Vietnam service. The committee recommends that consideration be given to a combined analysis of the Ranch Hand and NIOSH studies to further examine the possibility that herbicide or dioxin exposure leads to an increased risk of diabetes. Using the new ADA definition of diabetes (i.e., fasting plasma glucose >126 mg/dl), outcome data from both studies could be made comparable.

Conclusions

Strength of Evidence in Epidemiologic Studies

When viewed in the context of the total literature, the committee concludes that, at this time, there is inadequate/insufficient evidence to determine whether an association exists between herbicide or dioxin exposure and increased risk of diabetes. Further analyses and full publication of existing studies may justify a reevaluation of this conclusion.

Biologic Plausibility

It is plausible that TCDD exposure could affect glucose metabolism and insulin action and thereby increase diabetes risk, although much of the evidence comes from animal studies. Whether these often short-term effects in animals and, occasionally in human cells can explain the possible small increase in diabetes prevalence 20-30+ years after exposure requires further human study, as does the apparent lack of a dose-response relationship across cohorts with very differ-

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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ent exposures. A discussion of the research related to biologic plausibility with respect to exposure to TCDD or herbicides and diabetes is contained in Chapter 3; a summary is presented in the conclusion to this chapter.

Increased Risk of Disease Among Vietnam Veterans

Currently, it is uncertain whether any increased risk of diabetes has been experienced by Vietnam veterans exposed to herbicides. Although the most recent Ranch Hand study report suggests that those with the highest exposure may experience an increased risk (up to 50 percent), it is not clear whether this is independent of other risk factors for diabetes, especially obesity. A more thorough discussion of the issue of increased risk of disease among Vietnam veterans is contained in Chapter 1.

LIPID AND LIPOPROTEIN DISORDERS

Background

Plasma lipid concentrations (notably cholesterol) have been shown to predict cardiovascular disease and are considered fundamental to the underlying atherosclerotic process (Kuller and Orchard, 1988). The two major lipids, cholesterol and triglycerides, are carried in the blood attached to proteins to form lipoproteins, which are classed according to their density: very low density lipoprotein (VLDL—the major ''triglyceride" particle) produced in the liver and progressively catabolized (hydrolyzed) mainly by an insulin-mediated enzyme (lipoprotein lipase) to form intermediate-density lipoprotein (IDL) or VLDL remnants, most of which are rapidly cleared by the liver B/E receptors, with the rest going to form low-density lipoprotein (LDL), the major "bad" cholesterol particle. This is cleared by LDL receptors in the liver and other tissues. The "good cholesterol" particle, high-density lipoprotein (HDL), is produced in the small intestine and the liver, and also results from of the catabolism of VLDL. Although LDL is thought to be involved in delivery of cholesterol to the tissues, HDL in contrast is involved in "reverse" transport and facilitates the return of cholesterol to the liver for biliary excretion (LaRosa, 1990).

Disorders of lipoprotein metabolism usually result from overproduction or decreased clearance of lipoproteins, or both. Common examples are hypercholesterolemia, which may be familial (due to an LDL receptor genetic defect) or polygenic (due to multiple minor genetic susceptibilities); familial hypertriglyceridemia (sometimes linked to diabetes susceptibility); and mixed hyperlipidemias in which both cholesterol and triglycerides are elevated. This group includes familial combined hyperlipidemia, thought by many to result from hepatic overproduction of VLDL and apoprotein B, and type III dyslipidemia (defective clearance of IDL-VLDL remnants, leading to a buildup of these athero-

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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genic particles). Although the bulk of blood lipid concentrations are genetically determined, diet, activity, and other factors (concurrent illness, drugs, age, gender, hormones, etc.) do have major effects. In particular, the saturated fat content of the diet may raise LDL cholesterol concentrations via decreased LDL receptor activity, whereas obesity and a high-carbohydrate diet may increase VLDL triglycerides, possibly linked to insulin resistance and reduced lipoprotein lipase activity. Intercurrent illness may increase the triglyceride (and lower the cholesterol) concentration. Diabetes is also associated with increased triglycerides and decreased HDL cholesterol, whereas other diseases (e.g., thyroid, renal) often result in hypercholesterolemia. It is thus evident that multiple host and environmental factors influence lipid and lipoprotein concentrations and that these influences must be accounted for before the effect of a new factor can be assessed (LaRosa, 1990). In the current context, obesity as a primary determinant of both triglyceride and TCDD concentrations has to be fully controlled for in any analysis. Furthermore, the ability of acute or chronic illness to raise triglycerides (and glucose) concentrations and lower HDL (and LDL) cholesterol must be recognized.

Epidemiologic Studies

Pazderova-Vejlupkova et al. (1981) reported that although increased lipid levels were seen in 50 percent of the sample of TCP and 2,4,5-T production workers at the time of an industrial accident in 1968, lipids were normal 10 years later. However, increased VLDL and decreased HDL lipoprotein fractions were noted compared to a control group. Potential confounders were not described. May (1982) reported on the results of a study of 126 British TCP production workers, laboratory, and administrative staff, which included 41 subjects who had been exposed to 2,3,7,8-TCDD in an industrial accident and subsequently developed chloracne. A nonsignificant increase in triglycerides and decrease in cholesterol were noted in the exposed groups. In a similar analytic approach, Martin (1984) studied the same group but used a different control group matched for age, social class, height-weight ratio, and smoking and alcohol intake habits. In this analysis, triglyceride and cholesterol concentrations were significantly increased in the exposed group compared to the controls, and HDL cholesterol concentrations were nonsignificantly lower. Moses et al. (1984), reporting on a mixed group of accidentally and chronically exposed TCP and 2,4,5-T production workers, found no difference 10-40 years after exposure in cholesterol concentrations between those with and without chloracne and only borderline higher triglycerides (p = 0.057, adjusted for age but not obesity) in those with chloracne.

In a detailed analysis of lipid values from a mixed accidentally and chronically exposed cohort of 2,4,5-T and TCP production workers from a plant in Nitro, West Virginia, no differences were noted 10-30 years after exposure in mean total HDL and LDL cholesterol and triglyceride levels for those exposed

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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(N = 204) compared to those not exposed (N = 163), although out-of-range HDL and LDL cholesterol levels were associated with chloracne status in the exposed group (Suskind and Hertzberg, 1984). Other negative studies include one of 1,500 children aged 6-10 years at the time of the 1976 Seveso accident, of whom 597 were exposed. No differences in cholesterol or triglycerides were noted compared to 874 nonexposed children, up to six years later (Mocarelli et al., 1986). A further follow-up (Assennato et al., 1989) of 193 subjects exposed at Seveso, again mainly children, who developed chloracne also failed to show triglyceride or cholesterol elevations up to nine years later in those with chloracne compared to a matched control group. However, in the exposed group, the 1983 values were significantly lower than at the time of accident which supports the hypothesis of an early elevation of both cholesterol and triglycerides. Confounding factors (e.g., obesity), were not considered beyond age and sex.

A recent report (Calvert et al., 1996) of 281 TCP production workers and 260 referents examined 15 years after exposure, revealed only modest associations between exposure category and lipid or lipoprotein concentrations. This detailed study adjusted for multiple confounders. No association with serum TCDD levels was observed for total cholesterol concentration (p = 0.44) or for the prevalence of abnormally high cholesterol concentrations (p = 0.71). In examining the association of serum TCDD levels and HDL cholesterol, weak trends were seen for concentration (p = 0.15) and the prevalence of low HDL concentration (p = 0.09); a borderline significant trend (p = 0.05) was seen for triglyceride concentration, but no difference (p = 0.21) was noted for prevalence of abnormally high levels (p = 0.21).

Four reports from the Air Force Health Study, which has followed a cohort of Vietnam veterans exposed to herbicide spraying, have included lipid measures. The first (AFHS, 1984; Wolfe et al., 1990), which reported data 10-20 years after exposure, showed minimally lower cholesterol and triglyceride concentrations in the exposed Ranch Hands compared to the comparison group, with no evidence of a trend for increased values with increased herbicide exposure.

Two reports include data from the 1987 examination (up to 25 years after exposure). The Air Force Health Study (AFHS, 1990) reported identical mean total and HDL cholesterol and triglyceride concentrations in Ranch Hands and comparison subjects. The second report of the same examination data (AFHS, 1991) using serum (lipid weight-adjusted) dioxin analyses as a measure of exposure, revealed low-order but significant correlations between HDL cholesterol and dioxin level (r = -0.14 for Ranch Hands and r = -0.10 for comparisons). Similar correlations for total cholesterol were nonsignificant, whereas for triglycerides in a different analytical format, significant positive associations with serum TCDD were seen (p < 0.001). It is possible, however, that these correlations at least partially reflect the correlations in the two groups between dioxin and percentage of body fat (r = 0.3 for the Ranch Hands and. 15 for the comparison group). The more recent 1992 examination data (AFHS, 1995) did not show

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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any of the dioxin-determined categories of Ranch Hands to differ from the comparison group for prevalence of high triglyceride levels or low HDL concentrations, or for a high ratio of total cholesterol to HDL cholesterol in a longitudinal analysis.

Four German reports have also reported on lipid values after industrial exposure to dioxin. Ott et al. (1994) studied 138 BASF subjects exposed to TCDD following a plant accident in 1953 and found nonsignificantly lower total and HDL cholesterol and triglycerides in the exposed subjects compared to controls. A medical insurance follow-up (Zober et al., 1994) of 158 BASF workers—including some of the same workers studied by Ott et al. (1994)—showed a nonsignificant increase in the recorded medical diagnosis of lipid disorders in exposed subjects compared to the referent population. Ott and Zober (1996) in another study of 34 male production workers potentially exposed to polybrominated dibenzo-p-dioxins found no significant elevations of total and LDL cholesterol or triglycerides and a borderline (p = 0.05) higher HDL cholesterol compared to nonexposed controls. The German Cancer Research Center, reporting on employees from six West German chemical plants found no apparent effect of TCDD on lipid metabolism (Von Benner et al., 1994).

A study of self-reported health problems of 641 Australian Vietnam veterans (O'Toole et al., 1996) found an increased frequency of elevated cholesterol compared to that expected from national Australian data (RR = 3.0, 95% CI 1.3-4.7).

Synthesis

The majority of studies reported do not suggest any major disturbance of cholesterol or triglyceride concentration in herbicide-exposed chemical workers or veterans. Five studies report increased triglycerides (two are of borderline significance), and six studies report lowered HDL cholesterol (four are of borderline significance). Given the liability of triglyceride concentration, the marginal nature of the few positive studies, and the equal or greater number of negative studies for each lipid or lipoprotein (except HDL cholesterol, which was not examined in more than half of the studies), the effect of herbicide exposure on lipid and lipoproteins is likely to be small. Furthermore, few studies have fully controlled for obesity and the many other potential confounders including diet.

The difficulties of interpreting relationships between serum dioxin levels (even lipid weight-adjusted levels) and lipid orlipoprotein concentrations, which may be a determinant as well as a consequence of dioxin level, have been fully discussed (Flanders et al., 1992). Lipoproteins are blood and possibly intracellular carriers of TCDD (Soues et al., 1989). This problem is further complicated by the effect of obesity, which independently plays a role in determining lipid or lipoprotein concentration, and the extent of available fat stores, thereby further confounding any attempt to determine the relationship between dioxin level and lipoprotein.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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The relatively weak and conflicting human data stand in contrast to the extensive animal data, which offer considerable biologic plausibility for the concept that herbicide and TCDD exposure may cause lipid and lipoprotein disturbances. The multiple effects of dioxin-type chemicals have been reviewed by Matsumura (1995) and include reduction in adipose tissue lipoprotein lipase in guinea pigs, hypertriglyceridemia in rabbits, and down-regulation of LDL receptors on the plasma membrane in guinea pig hepatocytes. These effects appear to be mediated by the Ah receptor. However the relevance of these observations to humans may be limited. These effects, even in animals, show considerable differences according to species, age, strain, and gender. For example, male and female guinea pigs differ in the effect of TCDD on lipoprotein lipase activity, lipid peroxidation, and glucose uptake by adipose tissue (Enan et al., 1996). Furthermore, TCDD exposure in guinea pigs causes a wasting syndrome with major loss of fat tissue. Such a syndrome does not seem to be present in the humans studied who have marginal lipid disturbances.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is inadequate/insufficient evidence to conclude that an association exists between herbicide exposure and lipid or lipoprotein levels. Further research is needed to better elucidate the small effects on HDL cholesterol and triglyceride concentrations observed in some studies.

Biologic Plausibility

Although animal studies suggest potential mechanisms whereby TCDD may cause lipid disturbances, human data (e.g., lipoprotein kinetic studies) are needed to determine whether, and how, TCDD-exposed subjects have altered lipoprotein metabolism. A discussion of biologic plausibility with respect to exposure to TCDD or herbicides and lipid and lipoprotein disorders is contained in Chapter 3; a summary is presented in the conclusion to this chapter.

Increased Risk of Disease Among Vietnam Veterans

Ranch Hand study data (AFHS, 1991) suggest that lipid and lipoprotein concentrations of Ranch Hands and comparison subjects do not differ overall, although significant correlation between HDL cholesterol (negative) or triglycerides (positive) and TCDD level are seen. Whether these correlations are fully independent of obesity is unresolved. It is concluded that Vietnam veterans have not experienced major lipid or lipoprotein disease as a result of herbicide expo-

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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sure. A more thorough discussion of the issue of increased risk of disease among Vietnam veterans is contained in Chapter 1.

GASTROINTESTINAL AND DIGESTIVE DISEASE, INCLUDING LIVER TOXICITY

Background

The discussion in this section of gastrointestinal and digestive disease, including liver toxicity, encompasses a variety of conditions included under ICD·9 codes 520-579. Conditions in this category include diseases of the esophagus, stomach, intestines, rectum, liver, and pancreas. As in VAO and Update 1996, the focus of this section is primarily ulcer disease and liver toxicity, since these were the conditions most frequently discussed in the literature reviewed. The symptoms and signs of gastrointestinal disease and liver toxicity are highly varied and often vague, depending on the specific condition involved.

The essential function of the gastrointestinal tract is to absorb nutrients and eliminate waste products. This complex task involves numerous chemical and molecular interactions at the mucosal surface, as well as complex local and distant neural and endocrine factors. One of the most common conditions affecting the gastrointestinal tract is motility disorder, which may be present in as many as 15 percent of adults. The range of diseases affecting the gastrointestinal system can most conveniently be categorized by the anatomic segment involved. These conditions include esophageal disorders that predominantly affect swallowing, gastric disorders related to acid secretion, and conditions affecting the small and large intestine and reflected by alterations in nutrition, mucosal integrity, and motility. Systemic disorders may also affect the gastrointestinal system; these include inflammatory, vascular, infectious, and neoplastic conditions.

Peptic Ulcer Disease

Peptic ulcer disease refers to ulcerative disorders of the gastrointestinal tract that are caused by the action of acid and pepsin on the stomach duodenal mucosa. Peptic ulcer disease is characterized as gastric ulcer or duodenal ulcer, depending on the anatomic site of origin. Peptic ulcer disease occurs when the corrosive action of gastric acid and pepsin exceeds the normal mucosal defense mechanisms protecting against ulceration. Approximately 10 percent of the population has clinical evidence of duodenal ulcer during their lifetime, with a similar percentage affected by gastric ulcer. The peak incidence for duodenal ulcer occurs in the fifth decade of life, whereas the peak for gastric ulcer occurs approximately ten years later. The natural history of duodenal ulcer is one of spontaneous remission (healing) and recurrences. It is estimated that 60 percent of healed

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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duodenal ulcers may recur in the first year and that 80-90 percent will recur within two years.

Increasing evidence indicates that the bacterium Helicobacter pylori (H. pylori) may be closely linked to both duodenal and gastric ulcer disease. This bacterium colonizes the gastric mucosa in 95-100 percent of patients with duodenal ulcer and 75-80 percent of patients with gastric ulcer. Healthy subjects in the United States under 30 years of age have gastric colonization rates of approximately 10 percent. Over age 60, colonization rates exceed 60 percent. Colonization alone, however, is not sufficient for the development of ulcer disease; only 15-20 percent of subjects with H. pylori colonization will develop ulcer disease in their lifetimes.

There are other risk factors for peptic ulcer disease. Genetic predisposition appears to be important; first-degree relatives of duodenal ulcer patients have approximately three times the risk of developing duodenal ulcer as the general population. Certain blood groups are associated with increased risk for duodenal ulcer, and HLA-B5 antigen appears to be increased among white males with duodenal ulcer. Cigarette smoking has also been linked to duodenal ulcer prevalence and mortality. Finally, psychological factors, particularly chronic anxiety and psychological stress, may act to exacerbate duodenal ulcer disease.

Liver Disease

Blood tests reflecting liver function are the mainstay of diagnosis for liver disease. Increases in serum bilirubin levels and in the serum activity of certain hepatic enzymes—including aspartate aminotransferase (AST or SGOT), alanine aminotransferase (ALT or SGPT), alkaline phosphatase, and gamma-glutamyltransferase (GGT)—are commonly noted in many liver disorders. The relative sensitivity and specificity of these enzymes for liver disease vary, and several different tests may be required for diagnosis. The only regularly reported abnormality in liver function associated with TCDD exposure in humans is an elevation in GGT. Estimates of the serum activity of this enzyme provide a sensitive indicator of a variety of conditions, including alcohol and drug hepatotoxicity, infiltrative lesions of the liver, parenchymal liver disease, and biliary tract obstruction. Elevations are noted with many chemical and drag 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., 1992). Moreover, elevation in GGT may be considered a normal biologic adaptation to chemical, drug, or hormone exposure.

Cirrhosis of the liver is the most commonly reported liver disease outcome in epidemiologic studies of herbicide and/or TCDD exposure. Pathologically, cirrhosis reflects irreversible chronic injury of the liver, with extensive scarring and resultant loss of liver function. Clinical symptoms and signs include jaundice, edema, abnormalities in blood clotting, and metabolic disturbances. Ultimately,

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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cirrhosis may lead to portal hypertension with associated gastroesophageal varices, enlarged spleen, abdominal swelling due to ascites, and ultimately hepatic encephalopathy, which may progress to coma. It is generally not possible to distinguish the various causes of cirrhosis by the clinical signs and symptoms or pathological characteristics. The most common cause of cirrhosis in North America and many parts of Western Europe and South America is excessive alcohol consumption. Other causes include chronic viral infections (hepatitis B or hepatitis C), a poorly understood condition called primary biliary cirrhosis, chronic right-sided heart failure, and a variety of less common metabolic and drug-related causes.

Summary of VAO and Update 1996

In VAO, the risk of ulcers in populations exposed to TCDD or herbicides had not been sufficiently studied to determine an association. However, the detection of a specific association was felt to be unlikely, given the frequency of ulcer disease and the many factors 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 was considered unlikely that new cases of ulcer disease directly related to herbicide exposure would occur. Subsequent occupational studies by Zober et al. (1994) and Ott et al. (1994) revealed no increases in the frequency of ulcers in the exposed group versus the controls (even in the highest TCDD subgroup), and no increases with increasing severity of chloracne.

Changes in liver function in humans exposed to TCDD have been limited to an increase in GGT and alkaline phosphatase; 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. Results from studies relating liver enzyme measurements or the diagnosis of chronic liver disease to serum TCDD levels or clinical indices of dioxin exposure (e.g., chloracne) have been inconsistent. 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 toxic chemical exposures. Given the long observation period since TCDD exposure in most studies and the 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.

Update of the Scientific Literature

Occupational Studies

Becher et al. (1996) examined mortality among workers in four German facilities that produced phenoxy herbicides and chlorophenols. The population

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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included workers who had a least one month of employment and resulted in a cohort consisting of 2,479 male workers. SMRs and 95% CI were calculated using West German mortality rates by five-year age and calendar intervals. SMRs for digestive disease among the four plants ranged from 0.7 to 0.8; none were statistically significant.

Ott and Zober (1996) updated the experience of workers exposed to TCDD during the cleanup of a TCP reactor that exploded in 1953 at a BASF plant in Ludwigshafen, Germany. They studied disease incidence and mortality up to 1992 for a group of 243 men and developed TCDD dose estimates based on work activity information, blood TCDD determinations on a subset of the population, and estimates of TCDD elimination rates. Expected numbers of incident cases and cause-specific deaths were obtained from German sources by five-year age and calendar intervals. The overall SMR (CI) for digestive diseases was 0.7 (0.2-1.7); in the highest TCDD dose group, the SMR was 1.6 (0.4-4.2).

Ramlow et al. (1996) examined mortality in a cohort of workers exposed to pentachlorophenol, as part of a larger study of Dow chemical manufacturing workers exposed to the higher chlorinated dioxins. The study cohort was assembled from company records, starting with a cohort of 2,192 workers ever employed in a department with potential PCDD exposure between 1937 and 1980. From this cohort, 770 workers were identified who were considered to have potential PCP exposure based on work history records. Cumulative exposure indices for PCP and dioxin were calculated using scores described by Ott et al. (1987). In the study analysis, the U.S. white male death rates (five-year age and calendar time specific) and the non-PCP and non-PCDD male Dow Michigan employees for 1940 to 1989 were both used as reference values to calculate expected deaths. The overall SMR (CI) for digestive system disease was 1.3 (0.7-2.2). For gastric and duodenal ulcer (ICD·9 531-533) the SMR was 3.6 (1.2-8.3) when considering no latency, and 5.6 (1.8-13.0) when allowing for 15 years of latency. The SMRs for liver cirrhosis were 1.1 (0.4-2.3), and 1.5 (0.6-34) with allowance for a 15-year latency. Overall digestive disease was higher in subjects with higher estimated PCP exposure (RR 2.3, CI 1.3-4.2) in more highly exposed workers versus 0.9 (CI 0.3-2.7) in workers with lower exposures ( p = 0.01). However, the RR for ulcer disease decreased significantly with exposure (p < 0.01), whereas liver cirrhosis significantly increased with estimated exposure level (p = 0.04). Four of the six cirrhosis deaths were clearly identified as related to alcoholism by death certificate review.

In the updated and expanded IARC cohort study, Kogevinas et al. (1997) examined mortality in a cohort of 26,615 male and female workers engaged in the production or application of phenoxy herbicides. Exposure information varied between cohorts, but in general, exposures were reconstructed from job records. Based on job categories and information on production processes and the composition of the materials used, exposed workers were classified into three categories: exposed to TCDD or higher chlorinated dioxins, unexposed to the same, and

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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unknown exposure to the same. Analysis was performed by calculating SMRs and 95% CI, using the WHO mortality data bank to calculate national mortality rates by sex, age (five-year intervals), and calendar period (five years). Overall, a decrease in gastrointestinal and digestive disease was observed in exposed workers compared to unexposed workers for males (SMR 0.8, CI 0.7-1.0), with no significant differences observed for women (SMR 1.3, CI 0.6-2.5).

Veterans Studies

In a study of postservice suicide among Vietnam veterans, Bullman and Kang (1996) reported subsequent cause-specific mortality for 34,534 veterans who had been hospitalized for wounds suffered in Vietnam, compared to U.S. men. They observed a significant decrease in deaths due to digestive disease (SMR 0.7, CI 0.6-0.9).

O'Toole et al. (1996) described the results of a simple random sample of Australian Army Vietnam veterans on self-reported health status. Data were obtained on 641 veterans from the Australian Bureau of Statistics Health Interview Survey 1989-90, and illness rates were compared to the age-and sex-matched Australian population. Ulcer disease (RR 2.7, 99% CI 1.7-3.8) and other digestive diseases (RR 4.0, 99%, CI 2.2-5.9) were reported significantly more frequently by veterans. Ulcer disease was significantly associated with an index of combat exposure. The authors conjectured that this relationship may be related to long-term psychological factors associated with battle (e.g., post-traumatic stress disorder). They also observed that veterans were significantly more likely to report high alcohol consumption than the age-and sex-matched Australian general population (RR 2.0, 99% CI 1.5-2.5).

Watanabe and Kang (1996) reported on the mortality of 33,833 U.S. Army and Marine Corps Vietnam veterans who died during 1965-1988, compared to mortality among 36,797 deceased non-Vietnam veterans, using PMRs. They observed no increase in digestive disease mortality among Army Vietnam veterans (PMR 1.0) and a slight decrease among Marine Vietnam veterans (PMR 0.9, p < 0.05).

Dalager and Kang (1997) reported a study comparing 2,872 Vietnam veterans with 2,737 non-Vietnam veterans (all of whom served in Chemical Corps specialties). All study subjects served at least 18 months' active duty between 1965 and 1973, and vital status ascertainment was complete for both groups. They reported a RR (CI) of 3.9 (1.1-13.5) for digestive system disease overall and 4.4 (1.0-20.2) for liver cirrhosis. No data were available on alcohol use, but the Centers for Disease Control and Prevention (CDC) Vietnam Experience Study had reported that 13 percent of Vietnam veterans and 11 percent of non-Vietnam veterans described heavy alcohol use (CDC, 1988).

A report on Australian Vietnam veterans (Crane et al, 1997a) compared cause-specific mortality rates of 59,036 male Vietnam veterans with those of

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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other Australian males. They found no significant increase in digestive system disease (SMR [CI]) for deaths 1964-1979:0.7 [0.5-1.1] and for 1980-1994:1.0 [0.8-1.2]. There was specifically no increase in cirrhosis of the liver.

A second cohort study of Australian veterans (Crane et al., 1997b) compared mortality for 1982-1994 for 18,949 national servicemen who had served in Vietnam (veterans) with 24,646 national servicemen who had not served in Vietnam (nonveterans). An RR (95% CI) for veterans compared to nonveterans of 1.0 (0.7-1.3) for all circulatory diseases and 1.0 (0.7-1.4) for ischemic heart disease (IHD) was observed.

The ongoing study of Ranch Hand veterans (AFHS, 1996), reported cause-specific mortality among 1,261 Ranch Hand personnel compared to 19,080 Air Force veterans from the same era who did not handle herbicides. An increase was observed in deaths due to digestive disease (SMR 1.8, 0.9-3.2), mostly from chronic liver disease and cirrhosis (seven of nine deaths).

Synthesis

Although there have been sporadic reports of increased gastrointestinal disease potentially related to exposure to herbicides or TCDD, the results are inconsistent across studies. In addition, interpretation of individual studies was generally limited by a lack of information on alcohol consumption and other risk factors. In the studies that showed the strongest association between potential exposure and gastrointestinal disease (cirrhosis of the liver), there was strong evidence that excess alcohol consumption was the etiology for the cirrhosis. Additional research, with adequate information on alcohol consumption and other risk factors for gastrointestinal disease, is required to adequately assess the potential association between gastrointestinal disease and herbicide or TCDD exposure.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides considered in this study and gastrointestinal and digestive disease including liver toxicity. The evidence regarding association is drawn from occupational and veterans studies in which subjects were exposed to a variety of herbicides and herbicide components.

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 animals. A more thorough discussion of biologic plausibility with respect to exposure to

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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TCDD or herbicides and gastrointestinal disease, digestive disorders, and liver toxicity is contained in Chapter 3; a summary is presented in the conclusion to this chapter.

CIRCULATORY DISORDERS

The circulatory diseases reviewed in this section cover a variety of conditions encompassed by ICD·9 codes 390-459, including hypertension, heart failure, arteriosclerotic heart disease, peripheral vascular disease, and cerebrovascular disease. In morbidity studies, a variety of methods were used to assess the circulatory system, including analysis of symptoms or history, physical examination of the heart and peripheral arteries. Doppler measurement of peripheral pulses, electrocardiograms, and chest radiographs. Doppler measurements and physical examinations of the pulses in the arms and legs are used to detect decreased strength of the pulses, which can be caused by thickening and hardening of the arteries. Electrocardiograms 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. Mortality studies attribute cause of death to one or more of the circulatory disorders, with varying degrees of diagnostic confirmation.

Summary of VAO and Update 1996

In general, the usefulness of mortality studies has been limited, because in most studies, no a priori hypotheses were provided regarding herbicide exposure and particular circulatory outcomes. Their usefulness is also limited by a failure to adjust for independent risk factors for circulatory disease. Among the morbidity studies, strong rationales for examining circulatory outcomes were not given. However, the Air Force Health Study (AFHS, 1991) reported associations between serum TCDD and both diabetes and blood lipids, suggesting a reason to examine coronary artery disease in subjects exposed to dioxins because of the possible association between risk factors for coronary artery disease and serum TCDD level.

A follow-up of the Ranch Hand cohort (AFHS, 1992) found significant associations between dioxin levels and several lipid-related variables and some cardiovascular effects. The authors suggested that these effects may be related to diabetes mellitus, since no consistent evidence of an adverse effect of dioxin was seen in nondiabetic individuals. An additional complicating factor in these analyses was that many of the effects correlated with dioxin level were related to body fat content. Causal relationships could not be established, because of the relationship between body fat itself and dioxin level. A more complete discussion of this study is included in Chapter 3.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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Update of the Scientific Literature

Occupational Studies

Becher et al. (1996) examined mortality among workers in four German facilities that produced phenoxy herbicides and chlorophenols. The population included workers who had a least one month of employment, resulting in a cohort consisting of 2,479 male workers. SMRs (95% CI) were calculated using West German mortality rates by five-year age and calendar year intervals. SMRs for circulatory system disease among the four plants ranged from 0.3 to 1.1; none were significantly elevated.

Flesch-Janys et al. (1995) described cancer and circulatory system mortality among 1,189 male workers in a chemical plant in Hamburg, Germany. Workers had been exposed in varying degrees to herbicides contaminated with PCDD/F. The authors developed a quantitative estimate of PCDD/F exposure for the entire cohort derived from blood and adipose tissue levels measured in a subgroup of 190 workers. An unexposed cohort of gas workers served as an external reference group. Overall circulatory system disease mortality was elevated among exposed workers in a dose-dependent fashion (p for trend = 0.01), with an RR of 2.0 (95% CI 1.2-3.3) among men in the highest decile of estimated TCDD exposure. The increased risk appeared restricted to IHD (ICD·9 codes 410-414) where the RR was 2.5 (1.3-4.7) in the highest estimated exposure group. Information was not available for confounding factors related to IHD; the authors reasoned that the use of an unexposed referent population combined with the strong dose-response relationship argued against attributing the results to confounding factors. They also noted that the smoking rates and socioeconomic status of both cohorts appeared to be similar.

Svensson et al. (1995) studied mortality and disease incidence in two cohorts of Swedish fishermen. One group (2,896 men) resided on the east coast of Sweden and consumed fish from the Baltic Sea. These fatty fish (particularly salmon and herring) are reported to contain elevated levels of PCB, PCDD, and PCDF. The other group of fishermen (8,477) resided on the west coast of Sweden and were presumed to have a higher intake of lean (and less contaminated) fish, including cod and flat fish. A slight but significant decrease in cardiovascular disease was observed among east coast fishermen, attributed to the protective effect of some components of fish oil.

Ott and Zober (1996) updated the experience of workers exposed to TCDD during cleanup of a TCP reactor, Germany. They studied disease incidence and mortality up to 1992 for a group of 243 men and developed TCDD dose estimates based on work activity information, blood TCDD determinations on a subset of the population, and estimates of TCDD elimination rates. Expected numbers of incident cases and cause-specific deaths were obtained from German sources by five-year age and calendar intervals. The overall SMR (95% CI) for circulatory

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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system diseases was 0.8 (0.6-1.2); in the highest TCDD dose group, the SMR was 1.0 (0.5-1.7). There was also no significant elevation in deaths from is-chemic heart disease when evaluated separately.

Ramlow et al. (1996) examined mortality in a cohort of workers exposed to PCP, as part of a larger study of Dow chemical manufacturing workers exposed to the higher chlorinated dioxins. The study cohort was assembled from company records, starting with a cohort of 2,192 workers ever employed in a department with potential PCDD exposure between 1937 and 1980. From this, 770 workers were identified who were considered to have potential PCP exposure based on work history. Cumulative exposure indices for PCP and dioxin were calculated using the method described by Ott et al. (1987). The U.S. white male death rates (five-year age and calendar time specific) and the non-PCP and non-PCDD male Dow Michigan employees for 1940 to 1989 were used as reference values to calculate expected deaths. The overall SMR (95% CI) for circulatory system disease was 1.0 (0.8-1.1), with no significant increase in specific disease subsets and no influence of latency or estimated PCP exposure.

In the update and expansion of the IARC cohort study, Kogevinas et al. (1997) examined mortality in a cohort of 26,615 male and female workers engaged in the production or application of phenoxy herbicides. Exposure information varied between cohorts, but in general exposures were reconstructed from job records. Based upon job categories and information on production processes and the composition of the materials used, the exposed workers were classified into three categories: exposed to TCDD or higher chlorinated dioxins, unexposed to the same, and unknown exposure to the same. Analysis was performed by calculating SMRs and 95% CI, using the WHO mortality data bank to calculate national mortality rates by sex, age (five-year intervals), and calendar period (five years). Overall, a decrease in circulatory system disease was observed in exposed workers compared to unexposed workers for males (SMR 0.9, CI 0.9-1.0), with no significant differences observed for women (SMR 1.0, CI 0.7-1.3).

Mortality among a cohort of rice growers in northern Italy was investigated by Gambini et al. (1997). Using a set of registered farm owners consisting of 1,493 males who worked on farms from 1957 to 1992, they examined the cause of death for 958 subjects and compared this with expected numbers calculated from national rates. No direct exposure information was available, so employment on the farm served as a surrogate for exposure to the range of phenoxy herbicides used during the study period. They observed a decrease in deaths from myocardial infarction (SMR 0.7, 95% CI 0.6-0.9) and other ischemic heart disease (SMR 0.4, CI 0.3-0.5), but not stroke (SMR 1.0, CI 0.8-1.1) among rice growers.

Studies of Vietnam Veterans

In a study of postservice suicide among Vietnam veterans, Bullman and Kang (1996) reported subsequent cause-specific mortality for 34,534 veterans

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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who had been hospitalized for wounds suffered in Vietnam, compared to U.S. men. They observed a significant decrease in circulatory system disease deaths (SMR 0.7, 95% CI 0.6-0.8).

O'Toole et al. (1996) described the results of a simple random sample of Australian Army Vietnam veterans on self-reported health status. Data were obtained on 641 veterans from the Australian Bureau of Statistics Health Interview Survey 1989-1990, and illness rates were compared to the age-and sex-matched Australian population. Hypertension (RR 2.2, 99% CI 1.7-2.6) and other circulatory system disease (RR 2.4, CI 1.6-3.2) were reported significantly more frequently by veterans. None were significantly associated with an index of combat exposure. Veterans were significantly more likely to be current or former smokers than the general population (RR for never smoked 0.7, CI 0.5-0.8). O'Toole et al. (1996) also observed that veterans were significantly more likely to report high alcohol consumption than the age-and sex-matched Australian general population (RR 2.0, CI 1.5-2.5).

Watanabe and Kang (1996) reported on the mortality experience of 33,833 U.S. Army and Marine Corps Vietnam veterans who died during 1965-1988, compared to mortality among 36,797 deceased non-Vietnam veterans, using PMRs. They observed no increase in circulatory system disease mortality among Army Vietnam veterans (PMR 1.0) and a slight decrease among Marine Vietnam veterans (PMR 0.9, p < .05).

Dalager and Kang (1997) compared 2,872 Vietnam veterans with 2,737 non-Vietnam veterans (all of whom served in Chemical Corps specialties). All study subjects served at least 18 months active duty between 1965 and 1973, and vital status ascertainment was complete for both groups. They reported an RR (95% CI) of 1.1 (0.6-1.8) for circulatory system disease overall. No data was available on alcohol use, but a previous CDC study had reported that 13 percent of Vietnam veterans and 11 percent of non-Vietnam veterans described heavy alcohol use (CDC, 1988).

A report on Australian Vietnam veterans (Crane et al., 1997a) compared cause-specific mortality rates of 59,036 male Vietnam veterans with those of other Australian males. They found no significant increase in circulatory system disease (SMR [95% CI]) for deaths in 1964-1979 (0.7 [0.6-0.9]) and 1980-1994 (1.0 [1.0-1.1]). There was also no increase in any subset of circulatory system disease.

A second cohort study of Australian veterans compared mortality for 1982-1994 for 18,949 national servicemen who had served in Vietnam (veterans) with 24,646 national servicemen who had not served in Vietnam (nonveterans) (Crane et al., 1997b). They observed a RR (95% CI) for veterans compared to non-veterans of 1.0 (0.7-1.3) for diseases of the circulatory system.

The ongoing study of Ranch Hand veterans (AFHS, 1996), reported cause-specific mortality among 1,261 Ranch Hand personnel compared to 19,080 Air Force veterans from the same era who did not handle herbicides. They observed

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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a significant increase among ground troops (SMR 1.5, CI 1.0-2.2), with nearly half of the increase due to atherosclerotic heart disease (SMR 1.4, CI 0.8-2.1). Data on smoking and alcohol use were not available.

Synthesis

Although there were sporadic reports of increased circulatory disease potentially related to exposure to herbicides or TCDD, the results were inconsistent across studies. In addition, interpretation of individual studies was generally limited by a lack of information on cigarette smoking, obesity, serum lipid levels, presence of diabetes, and other risk factors. In studies that showed the strongest association between potential exposure and gastrointestinal disease, there was evidence that cigarette smoking was greater among veterans than nonveterans. Additional research, with adequate information on the numerous risk factors for circulatory disease, is required to adequately assess the potential association between circulatory disease and herbicide or TCDD exposure. Further research on the potential relationships between TCDD exposure and diabetes or lipid abnormalities may also shed further light on any potential relationships to circulatory diseases.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is inadequate or insufficient evidence to determine whether an association exists between exposure to the herbicides considered in this report and the following circulatory outcomes: circulatory disease mortality, various subgroups of cardiovascular disease, and symptoms or history of circulatory illnesses (e.g., heart disease, hypertension, coronary artery disease, angina, or myocardial infarction). The evidence regarding association is drawn from occupational and veteran studies in which subjects were exposed to a variety of herbicides and herbicide components.

Biological Plausibility

A discussion of biologic plausibility with respect to exposure to TCDD or herbicides and circulatory disease is contained in Chapter 3; a summary is presented in the conclusion to this chapter.

SUMMARY

Based on the occupational, environmental, and veterans studies reviewed, the committee reached one of four conclusions about the strength of the evi-

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

dence regarding association between exposure to herbicides and/or TCDD and each of the other health effects under study. As explained in Chapter 4, these distinctions reflect the committee's judgment that if an association between exposure and an outcome were ''real," it would be found in a large, well-designed epidemiologic study in which exposure to herbicides or dioxin was sufficiently high, well characterized, and appropriately measured on an individual basis. Consistent with the charge to the Committee by the Secretary of Veterans Affairs in Public Law 102-4 and with accepted standards for scientific reviews, the distinctions between these standard conclusions are based on statistical association, not on causality. The committee used the same criteria to categorize diseases by the strength of the evidence as were used in VAO and Update 1996.

Health Outcomes with Sufficient Evidence of an Association

In VAO and Update 1996, the committee found sufficient evidence of an association between exposure to herbicides and/or TCDD and chloracne. The scientific literature continues to support the classification of chloracne in the category of sufficient evidence. Based on the literature, there are no additional health effects discussed in this chapter that satisfy the criteria necessary for this category.

For diseases in this category, a positive association between herbicides and the outcome must be observed in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. The committee also regarded evidence from several small studies that are free from bias and confounding, and that show an association that is consistent in magnitude and direction, as sufficient evidence for an association.

Health Outcomes with Limited/Suggestive Evidence of Association

In Update 1996, the committee found limited/suggestive evidence of an association between herbicide/dioxin exposure and porphyria cutanea tarda. The scientific literature continues to support the classification of this disorder in the category of limited/suggestive evidence. Based on the literature, there are no additional health effects discussed in this chapter that satisfy the criteria necessary for this category.

For outcomes in this category, the evidence must be suggestive of an association between herbicides and the outcome, but may be limited because chance, bias, or confounding could not be ruled out with confidence. Typically, at least one high-quality study indicates a positive association, but the results of other studies may be inconsistent.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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TABLE 11-4  Selected Epidemiologic Studies—Lipids and Lipoprotein Disorders

Reference

Study Population

Exposed

Cases

Cholesterol

Triglycerides

HDL

Cholesterol

OCCUPATIONAL

New Studies

Calvert et al., 1996c

Production workers

18, 16, 7

1.0 (0.5-1.7)

1.7 (0.6-4.6)

2.2 (1.1-4.7)

Ott and Zober, 1996a

Production workers

42 NS

NS

p = 0.05

 

Studies reviewed in VAO

Martin, 1984a

Production workers

53 (some exposure)

p < 0.005

p < 0.05

NS

 

 

39 (chloracne)

p < 0.005

p < 0.01

NS

Moses et al., 1984b

TCP and 2,4,5-T production workers

118 (chloracne)

NS

NS

No data

Suskind and Hertzberg, 1984a

TCP production workers

204

NS

NS

NS

May, 1982a

TCP production workers

94 NS

NS

No data

 

Pazderova-Vejlupkova et al., 1981a

TCP and 2,4,5-T production workers

55 NS

VLDL

No data

 

 

 

 

p = 0.01

 

 

ENVIRONMENTAL

Studies reviewed in VAO

Assennato et al., 1989a

Adults exposed near Seveso

193 (chloracne)

NS

NS

No data

Mocarelli et al., 1986a

Children exposed near Seveso

63 NS

NS

No data

 

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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Reference

Study Population

Exposed

Cases

Cholesterol

Triglycerides

HDL

Cholesterol

VIETNAM VETERANS

New Studies

AFHS, 1996i

Longitudinal analysis (1992 exam data)

884

NS

NS

NS

 

 

(cholesterol: HDL ratio)

 

(cholesterol: HDL ratio)

 

O'Toole et al., 1996d

Australian Vietnam veterans

20 3.0 (1.3-4.7)

No data

No data

 

Studies reviewed in VAO

AFHS, 1991g

Serum dioxin analysis (1987 exam data)

283-304f

p = 0.175

p < 0.001h

p < 0.001

AFHS, 1990f

Original exposure group analysis (1987 exam data)

8-142f

1.2 (0.9-1.5)

1.3 (0.9-1.8)

1.0 (0.4-2.4)

AFHS, 1984e Wolfe et al., 1990

Vietnam Veterans exposed to herbicide spraying (1982 data)

1,027 total exposed

NS

NS

NS

Estimated risk and 95% confidence interval reported unless P-values are specified

NS = Not significant

ap-values comparing means to controls. Univariate analysis.

bP-values comparing means in production workers with subsequent chloracne to those without.

cOR for abnormal lipid in highest exposure category.

dCompared to Australian population.

eComparing means.

fNumber exposed RH with "high" lipid values.

gComparing mean dioxin across lipid groups.

hContinuous analysis.

iComparing change over time between exposed and comparison groups.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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Health Outcomes with Inadequate/Insufficient Evidence to Determine Whether an Association Exists

The scientific data for many of the health effects reviewed by the committee were inadequate or insufficient to determine whether an association exists. For the health effects discussed in this chapter, the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to control for confounding or have inadequate exposure assessment. This category includes respiratory disorders, immune system disorders (immune suppression and autoimmunity), diabetes, lipid and lipoprotein disorders, gastrointestinal diseases, digestive diseases, liver toxicity, and circulatory disorders.

Health Outcomes with Limited/Suggestive Evidence of No Association

In VAO and Update 1996, the committee did not find any evidence to conclude that there is limited/suggestive evidence of no association between the health effects discussed in this chapter and exposure to TCDD or herbicides. The most recent scientific evidence continues to support this conclusion.

In order to classify outcomes in this category, several adequate studies coveting the full range of levels of exposure that human beings are known to encounter must be mutually consistent in not showing a positive association between exposure to herbicides and the outcome at any level of exposure. These studies must also have relatively narrow confidence intervals. A conclusion of "no association" is inevitably limited to the conditions, level of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded.

Biologic Plausibility

Chapter 3 details the committee's evaluation of evidence from animal and cellular-level studies regarding the biological plausibility of a connection between exposure to dioxin or herbicides and various noncancer health effects. This section summarizes that evidence. Some of the preceding discussions of other health outcomes include references to specific relevant papers.

TCDD has been shown to elicit a diverse spectrum of sex-, strain-, age-, and species-specific effects, including immunotoxicity, hepatotoxicity, chloracne, loss of body weight, and numerous biological responses, including the induction of phase I and phase II drug-metabolizing enzymes, the modulation of hormone systems and factors associated with the regulation of cellular differentiation and proliferation.

Effects of TCDD on the liver include modulation of the rate at which liver cells multiply, increasing the rate of cell death for other cell types, increasing fat

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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levels in liver cells, decreasing bile flow, and increasing the levels of protein and of substances that are precursors to heme synthesis. TCDD also increases the levels of certain enzymes in the liver, but this effect in itself is not considered toxic. Mice and rats are susceptible to TCDD-induced liver toxicity, but guinea pigs and hamsters are not. It is possible that liver toxicity is associated with susceptibility to liver cancer, but the extent to which TCDD effects mediate noncancer end points is not clear.

The mechanism by which TCDD induces hepatotoxicity is still under investigation. Some studies provide evidence that hepatotoxicity of TCDD involves AhR-dependent mechanisms. Specifically, there is evidence that the Ah-receptor plays a role in the co-mitogenic action of TCDD with epidermal growth factor and in the induction of liver enzymes involved in the metabolism of xenobiotics. Acute exposures to TCDD have been correlated with effects on intermediary metabolism and hepatomegaly.

TCDD has been shown to inhibit hepatocyte DNA synthesis, decrease hepatic plasma membrane epidermal growth factor receptor; inhibit hepatic pyruvate carboxylase activity, and induce porphyrin accumulation in fish and chick embryo hepatocyte cultures. Studies have been conducted to examine the short-and long-term effects of TCDD on rat EROD activity and liver enzymes. Oral dosing induced EROD and glutamyltranspeptidase (GT) activity and inhibited hepatic phosphoenolpyruvate carboxykinase (PEPCK) activities. EROD and PEPCK activity reverted to normal levels after ninety days while GT activity remained elevated. Hepatomegaly has been shown to occur following high subchronic doses. The myocardium has also been shown to be a target of TCDD toxicity; impairment of a cAMP-modulated contraction has been implicated.

Recent evidence suggests that the inhibition of glucose transport in adipose tissue, pancreas, and brain may be one of the major contributing factors to the wasting syndrome. In vitro studies have identified glomerular mesangial cells as sensitive cellular targets. These findings are consistent with epidemiologic reports that aromatic hydrocarbons result in glomerulonephritis.

TCDD has also been shown to have a number of effects on the immune systems of laboratory animals. Studies in mice, rats, guinea pigs, and monkeys indicated that TCDD suppresses the function of certain components of the immune system in a dose-related manner; that is, as the dose of TCDD increases, its ability to suppress immune function increases. TCDD suppressed cell-mediated immunity, primarily by affecting the T-cell arm of the immune response. It is not known whether TCDD directly affects T-cells. TCDD may indirectly affect T-cells and cell-mediated immunity by altering thymus gland function or cytokine production. The generation of antibodies by B cells, an indication of humoral immunity, may also be affected by TCDD.

Increased susceptibility to infectious disease has been reported following TCDD administration. In addition, TCDD increased the number of tumors that formed in mice following injection of tumor cells. It should be emphasized,

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

however, that very little change to the overall immune competence of the intact animal has been reported.

Despite considerable laboratory research, the mechanisms underlying the immunotoxic effects of TCDD are still unclear. TCDD immunotoxicity appears to be primarily mediated through Ah-receptor-dependent processes, but some components of immunosuppression have been shown to act independently of the Ah receptor. Some studies indicate that an animal's hormonal status may contribute to its sensitivity to immunotoxicity. The fact that TCDD induces such a wide variety of effects in animals suggests that it is likely to have some effect in humans as well.

Generally, TCDD has a wide range of effects on growth regulation, hormone systems, and other factors associated with the regulation of activities in normal cells. These effects may influence the formation of noncancer health disorders. Studies in animals indicate that some TCDD effects are mediated through the Ah-receptor, a protein in animal and human cells to which TCDD can bind. It is hypothesized that TCDD, together with the AhR, can interact with sites on DNA and alter the information obtained from DNA in a way that transforms normal cells into abnormal cells. Although structural differences in the AhR have been identified, this receptor operates in a similar manner in animals and humans. Evidence has also begun to accumulate for non-Ah receptor mediated effects.

TCDD has been shown to induce differentiation in human keratinocytes, which may be initiated by TCDD binding to the AhR. This effect is antagonized by retinoids and may involve interactions between TCDD and retinoids in the regulation of epithelial differentiation. TCDD has been reported to decrease an acidic type I Keratin involved in epidermal development, leading to keratinocyte hyperproliferation and skin irritations such as chloracne.

Limited information is available on health effects of the herbicides discussed in the report. These herbicides, however, have been reported to elicit adverse effects in a number of organs in laboratory animals. The liver is a target organ for toxicity induced by 2,4-D, 2,4,5-T, and picloram, with changes reportedly similar to those induced by TCDD. Some kidney toxicity was reported in animals exposed to 2,4-D and cacodylic acid. Exposure to 2,4-D has also been associated with effects on blood, such as reduced levels of heme and red blood cells. Cacodylic acid was reported to induce renal lesions in rats. Other studies provide evidence that 2,4-D binds covalently to hepatic proteins and lipids; the molecular basis of this interaction and its biologic consequences are unknown.

The potential immunotoxicity of the herbicides used in Vietnam has been studied to only a very limited extent. Effects on the immune system of mice were reported for 2,4-D administered at doses that were high enough to produce clinical toxicity, but these effects did not occur at low doses. The potential for picloram to act as a contact sensitizer (i.e., to produce an allergic response on the skin) was tested, but other aspects of immunotoxicology were not examined.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

The foregoing evidence suggests that a connection between TCDD or herbicide exposure and human health effects is, in general, biologically plausible. However, differences in sensitivity and susceptibility across individual animals, strains, and species; lack of strong evidence of organ-specific effects across species; and differences in route, dose, duration, and timing of exposure complicate any more definitive conclusions about the presence or absence of a mechanism for the induction of specific noncancer health disorders.

Considerable uncertainty remains over how to apply this information to the evaluation of potential health effects of herbicides or dioxin exposure in Vietnam veterans. Scientists disagree over the extent to which information derived from animals and cellular studies predicts human health outcomes, and the extent to which the health effects resulting from high-dose exposure are comparable to those resulting from low-dose exposure. Research on biological mechanisms is burgeoning, and subsequent Veterans and Agent Orange updates may have more and better information on which to base conclusions.

Increased Risk of Disease Among Vietnam Veterans

Under the Agent Orange Act of 1991, the committee is asked to determine (to the extent that available scientific data permit meaningful determinations) the increased risk of the diseases it studies among those exposed to herbicides during their service in Vietnam. Chapter 1 presents the committee's general findings regarding this charge. Where more specific information about particular health outcomes is available, this information is related in the preceding discussions of those diseases.

REFERENCES

Air Force Health Study (AFHS). 1984. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Baseline Morbidity Study Results. Brooks AFB, TX: USAF School of Aerospace Medicine. NTIS AD-A138 340.

Air Force Health Study. 1990. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 2 vols. Brooks AFB, TX: USAF School of Aerospace Medicine. USAFSAM-TR-90-2.

Air Force Health Study. 1991. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Serum Dioxin Analysis of 1987 Examination Results. 9 vols. Brooks AFB, TX: USAF School of Aerospace Medicine.

Air Force Health Study. 1992. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Reproductive Outcomes. Brooks AFB, TX: Armstrong Laboratory. AL-TR-1992-0090.

Air Force Health Study. 1995. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. 1992 Followup Examination Results. 10 vols. Brooks AFB, TX: Epidemiologic Research Division. Armstrong Laboratory.

Air Force Health Study. 1996. An Epidemiologic Investigation of Health Effects in Air Force Personnel Following Exposure to Herbicides. Mortality Update 1996. Brooks AFB, TX: Epidemiologic Research Division. Armstrong Laboratory. AL/AO-TR-1996-0068.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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American Diabetes Association (ADA). 1997. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20(7):1183.

Assennato G, Cervino D, Emmett E, Longo G, Merlo F. 1989. Follow-up of subjects who developed chloracne following TCDD exposure at Seveso . American Journal of Industrial Medicine 16:119-125.

Bagchi D, Bagchi M, Tang L, Stohs SJ. 1997. Comparative in vitro and in vivo protein kinase C activation by selected pesticides and transition metal salts. Toxicology Letters 91(1):31-37.

Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindorf K, Manz A, Wahrendorf J. 1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes and Control 7(3):312-321.

Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989. Mortality in an area contaminated by TCDD following an industrial incident. Medicina Del Lavoro 80:316-329.

Bullman TA, Kang HK. 1996. The risk of suicide among wounded Vietnam veterans. American Journal of Public Health 86(5):662-667.


Calvert GM, Hornung RV, Sweeney MH, Fingerhut MA, Halperin WE. 1992. Hepatic and gastrointestinal effects in an occupational cohort exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin. Journal of the American Medical Association 267:2209-2214.

Calvert GM, Sweeney MH, Fingerhut MA, Hornung RW, Halperin WE. 1994. Evaluation of porphyria cutanea tarda in U.S. workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. American Journal of Industrial Medicine 25:559-571.

Calvert GM, Willie KK, Sweeney MH, Fingerhut MA, Halperin WE. 1996. Evaluation of serum lipid concentrations among U.S. workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Archives of Environmental Health 51(2):100-107.

Cantoni L, Dal Fiume D, Ruggieri R. 1984. Decarboxylation of uroporphyrinogen I and III in 2,3,7,8-tetrachlorodibenzo-p-dioxin induced porphyria in mice. International Journal of Biochemistry 16:561-565.

Centers for Disease Control (CDC). 1988. Health status of Vietnam veterans. II. Physical health. Journal of the American Medical Association 259:2708-2714.

Chinh TT, Phi PT, Thuy NT. 1996. Sperm auto-antibodies and anti-nuclear antigen antibodies in chronic dioxin-exposed veterans. Chemosphere 32(3):525-530.

Cook RR, Bond GG, Olson RA, Ott MG. 1987. Update of the mortality experience of workers exposed to chlorinated dioxins. Chemosphere 16:2111-2116.

Crane PJ, Barnard DL, Horsley KW, Adena MA. 1997a. Mortality of Vietnam Veterans: The Veteran Cohort Study: A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans. Canberra: Department of Veterans' Affairs.

Crane PJ, Barnard DL, Horsley KW, Adena MA. 1997b. Mortality of National Service Vietnam Veterans: A Report of the 1996 Retrospective Cohort Study of Australian Vietnam Veterans. Canberra: Department of Veterans' Affairs.


Dalager NA, Kang HK. 1997. Mortality among Army Chemical Corps Vietnam veterans. American Journal of Industrial Medicine 31(6):719-726.

De Verneuil H, Sassa S, Kappas A. 1983. Effects of polychlorinated biphenyl compounds, 2,3,7,8-tetrachlorodibenzo-p-dioxin, phenobarbital and iron on hepatic uroporphyrinogen decarboxylase. Implications for the pathogenesis of porphyria. Biochemical Journal 214:145-151.

Drash A, Cho N, Tajima N, Rewers M, LaPorte R. 1989. The epidemiology of diabetes in childhood with special reference to the Orient: implications for mechanism of beta cell damage. Indian Journal of Pediatrics 56(Suppl 1):S15-S32.


Enan E, Matsumura F. 1993. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induced alterations in protein phosphorylation in guinea pig adipose tissue. Journal of Biochemical Toxicology 8(2):89-99.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
×

Enan E, Matsumura F. 1994. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced changes in glucose transporting activity in guinea pigs, mice, and rats in vivo and in vitro. Journal of Biochemical Toxicology 9(2):97-106.

Enan E, Lasley B, Stewart D, Overstreet J, Vandevoort CA. 1996. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) modulates function of human luteinizing granulosa cells via cAMP signaling and early reduction of glucose transporting activity. Reproductive Toxicology 10(3):191-198.

Faustini A, Settimi L, Pacifici R, Fano V, Zuccaro P, Forastiere F. 1996. Immunological changes among farmers exposed to phenoxy herbicides: Preliminary observations. Occupational and Environmental Medicine 53(9):583-585.

Flanders WD, Lin L, Pirkle JL, Caudill SP. 1992. Assessing the direction of causality in cross-sectional studies. American Journal of Epidemiology 135:926-935.

Flesch-Janys D, Berger J, Gum P, Manz A, Nagel S, Waitsgott H, Dwyer. 1995. Exposure to polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort of workers from a herbicide-producing plant in Hamburg, Federal Republic of Germany. American Journal of Epidemiology 142(11):1165-1175.


Gambini GF, Mantovani C, Pira E, Piolatto PG, Negri E. 1997. Cancer mortality among rice growers in Novara Province, Northern Italy. American Journal of Industrial Medicine 31(4):435-441.

Grossman ME, Poh-Fitzpatrick MB. 1986. Porphyria cutanea tarda: diagnosis, management, and differentiation from other hepatic porphyrias. Dermatologic Clinics 4:297-309.


Henneberger PK, Ferris BG Jr, Monson RR. 1989. Mortality among pulp and paper workers in Berlin, New Hampshire. British Journal of Industrial Medicine 46:658-664.

Henriksen GL, Ketchum NS, Michalek JE, Swaby JA. 1997. Serum dioxin and diabetes mellitus in veterans of operation ranchhand. Epidemiology 8(3):252-258.


Institute of Medicine (IOM). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press.

Institute of Medicine. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press.


Jung D, Konietzko J, Reill-Konietzko G, Muttray A, Zimmermann-Holz HJ, Doss M, Beck H, Edler L, Kopp-Schneider A. 1994. Porphyrin studies in TCDD-exposed workers. Archives of Toxicology 68:595-598.


Kenny SJ, Aubert RE, and Geiss LS. 1995. Appendix 4.5, Chapter 4. Diabetes in America, 2nd Edition. Harris MI, ed. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases. NIH Publication No. 95-1468.

Kogevinas M, Becher H, Benn T, Bertazzi PA, Boffetta P, Bueno-de-Mesquita HB, Coggon D, Colin D, Flesch-Janys D, Fingerhut M, Green L, Kauppinen T, Littorin M, Lynge E, Mathews JD, Neuberger M, Pearce N, Saracci R. 1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study. American Journal of Epidemiology 145(12):1061-1075.

Kruszynska YT, Olefsky JM. 1996. Cellular and molecular mechanisms of non-insulin dependent diabetes mellitus. Journal of Investigative Medicine 44(8):413-428

Kuller LH, Orchard TJ. 1988. The epidemiology of atherosclerosis in 1987: Unraveling a common-source epidemic. Clinical Chemistry 34(8B):B40-B48


LaRosa JC. 1990. Lipid Disorders. Endiocrinology and Metabolism Clinics of North America. Philadelphia: WB Saunders Company.

Liu PC, Matsumura F. 1995. Differential effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the "adipose-type" and "brain-type" glucose transporters in mice. Molecular Pharmacology 47(1):65-73.

Liu H, Safe S. 1996. Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on insulin-induced responses in MCF-7 human breast cancer cells. Toxicology and Applied Pharmacology 138(2): 242-250.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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Lovik M, Johansen HR, Gaarder PI, Becher G, Aaberge IS, Gdynia W, Alexander J. 1996. Halogenated organic compounds and the human immune system: preliminary report on a study in hobby fishermen. Archives of Toxicology Supplement 18:15-20.

Martin JV. 1984. Lipid abnormalities in workers exposed to dioxin. British Journal of Industrial Medicine 41:254-256.

Matsumura F. 1995. Mechanism of action of dioxin-type chemicals, pesticides, and other xenobiotics affecting nutritional indexes. American Journal of Clinical Nutrition 61 (3 Suppl):695S-701S.

May G. 1982. Tetrachlorodibenzodioxin: a survey of subjects ten years after exposure. British Journal of Industrial Medicine 39:128-135.

McKinney WP, McIntire DD, Carmody TJ, Joseph A. 1997. Comparing the smoking behavior of veterans and nonveterans. Public Health Reports 112(3):212-217.

Michalek JE, Ketchum NS. 1997. Personal Communication. Subject: Answers to Questions Regarding Dioxin and Diabetes Mellitus posed by the Committee to Review the Health Effects of Exposure to Herbicides in Vietnam Veterans. Population Research Branch, Epidemiologic Research Division, Armstrong Laboratory, Brooks Air Force Base, Texas. October 15.

Mocarelli P, Marocchi A, Brambilla P, Gerthoux P, Young DS, Mantel N. 1986. Clinical laboratory manifestations of exposure to dioxin in children. A six-year study of the effects of an environmental disaster near Seveso, Italy. Journal of the American Medical Association 256:2687-2695.

Moses M, Lilis R, Crow KD, Thornton J, Fischbein A, Anderson HA, Selikoff IJ. 1984. Health status of workers with past exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-trichlorophenoxyacetic acid: comparison of findings with and without chloracne. American Journal of Industrial Medicine 5:161-182.

Muhlbauer JE, Pathak MA. 1979. Porphyria cutanea tarda. International Journal of Dermatology 18:767-780.


National Diabetes Data Group. 1979. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 28:1039-1057.


O'Toole BI, Marshall RP, Grayson DA, Schureck RJ, Dobson M, Ffrench M, Pulvertaft B, Meldrum L, Bolton J, Vennard J. 1996. The Australian Vietnam Veterans Health Study: II. Self-reported health of veterans compared with the Australian population. International Journal of Epidemiology 25(2):319-330.

Odom R. 1993. Dermatological Disorders in Vietnam Veterans. Presentation to the Institute of Medicine Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides. February 8, 1993.

Orchard TJ, LaPorte RE, Dorman JS. 1992. Diabetes. In: Last JM, Wallace RB, eds., Public Health and Preventive Medicine, 13th Ed. Stamford, Conn.: Appleton and Lange. Chapter 51:873-883.

Ott MG, Zober A. 1996. Cause specific mortality and cancer incidence among employees exposed to 2,3,7,8-TCDD after a 1953 reactor accident. Occuptional and Environmental Medicine 53(9): 606-612.

Ott MG, Olson RA, Cook RR, Bond GG. 1987. Cohort mortality study of chemical workers with potential exposure to the higher chlorinated dioxins. Journal of Occupational Medicine 29:422-429.

Ott MG, Zober A, Germann C. 1994. Laboratory results for selected target organs in 138 individuals occupationally exposed to TCDD. Chemosphere 29:2423-2437.


Paul W, ed. 1993. Fundamental Immunology, 3rd ed. New York: Raven Press.

Pazderova-Vejlupkova J, Lukas E, Nemcova M, Pickova J, Jirasek L. 1981. The development and prognosis of chronic intoxication by tetrachlorodibenzop-dioxin in men. Archives of Environmental Health 36:5-11.

Suggested Citation:"11 Other Health Effects." Institute of Medicine. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: The National Academies Press. doi: 10.17226/6415.
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Ramlow JM, Spadacene NW, Hoag SR, Stafford BA, Cartmill JB, Lerner PJ. 1996. Mortality in a cohort of pentachlorophenol manufacturing workers, 1940-1989. American Journal of Industrial Medicine 30(2):180-194.

Smith AG, De Matteis F. 1990. Oxidative injury mediated by the hepatic cytochrome P-450 system in conjunction with cellular iron. Effects on the pathway of haem biosynthesis. Xenobiotica 20:865-877.

Soues S, Fernandez N, Souverain P, Lesca P. 1989. Intracellular lipoproteins as carriers for 2,3,7,8-tetrachlorodibenzo-p-dioxin and benzo(a)pyrene in rat and mouse liver . Biochemical Pharmacology 38(17):2841-2847.

Suskind RR, Hertzberg VS. 1984. Human health effects of 2,4,5-T and its toxic contaminants. Journal of the American Medical Association 251:2372-2380.

Svensson BG, Mikoczy Z, Stromberg U, Hagmar L. 1995. Mortality and cancer incidence among swedish fishermen with a high dietary intake of persistent organochlorine compounds. Scandinavian Journal of Work, Environment and Health 21(2):106-115.

Sweeney MH, Hornung RW, Wall DK, Fingerhut MA, Halperin WE. 1992. Diabetes and serum glucose levels in TCDD-exposed workers. Abstract of a paper presented at the 12th International Symposium on Chlorinated Dioxins (Dioxin '92), Tampere, Finland, August 24-28.

Sweeney MH, Calvert G, Egeland GA, Fingerhut MA, Halperin WE, Piacitelli. 1996. Review and update of the results of the NIOSH medical study of workers exposed to chemicals contaminated with 2,3,7,8-tetrachlorodibenzodioxin. Presented at the symposium, Dioxin Exposure and Human Health—An Update, June 17, Berlin, Germany.

Sweeney MH, Calvert GM, Egeland GA, Fingerhut MA, Halperin WE, Piacitelli LA. 1997. Review and update of the results of the NIOSH medical study of workers exposed to chemicals contaminated with 2,3,7,8-tetrachlorodibenzodioxin . Teratogenesis, Carcinogenesis, and Mutagenesis 17(4-5):241-247.

Sweeney GD. 1986. Porphyria cutanea tarda, or the uroporphyrinogen decarboxylase deficiency diseases. Clinical Biochemistry 19:3-15.


Tonn T, Esser C, Schneider EM, Steinmann-Steiner-Haldenstatt W, Gleichmann E. 1996. Persistence of decreased T-helper cell function in industrial workers 20 years after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environmental Health Perspectives 104(4):422-426.

Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR. 1993. Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42(2):359-362.


Visintainer PF, Barone M, McGee H, Peterson EL. 1995. Proportionate mortality study of Vietnam-era veterans of Michigan. Journal of Occupational and Environmental Medicine 37(4):423-428.

Von Benner A, Edler L, Mayer K, Zober A. 1994. 'Dioxin' investigation program of the chemical industry professional association. Arbeitsmedizin Sozialmedizin Praventivmedizin 29:11-16.


Watanabe KK, Kang HK. 1995. Military service in Vietnam and the risk of death from trauma and selected cancers. Annals of Epidemiology 5(5):407-412.

Watanabe KK, Kang HK. 1996. Mortality patterns among Vietnam veterans: a 24-year retrospective analysis. Journal of Occupational and Environmental Medicine 38(3):272-278.

Weber TJ, Ou X, Merchant M, Wang X, Safe SH, Ramos KS. 1994. Biphasic modulation of protein kinase C (PKC) activity by polychlorinated dibenzo-p-dioxins (PCDDs) in serum-deprived rat aortic smooth muscle cells. Journal of Biochemical Toxicology 9(3):113-120.

Weber TJ, Chapkin RS, Davidson LA, Ramos KS. 1996. Modulation of protein kinase C-related signal transduction by 2,3,7,8-tetrachlorodibenzop-dioxin exhibits cell cycle dependence. Archives of Biochemistry and Biophysics 328(2):227-232.

Weisglas-Kuperus N, Sas TC, Koopman-Esseboom C, van der Zwan CW, De Ridder MA, Beishuizen A, Hooijkaas H, and Sauer PJ. 1995. Immunologic effects of background prenatal and postnatal exposure to dioxins and polychlorinated biphenyls in Dutch infants. Pediatric Research 38(3):404-410.

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Wolf N, Karmaus W. 1995. Effects of inhalative exposure to dioxins in wood preservatives on cell-mediated immunity in day-care center teachers. Environmental Research 68(2):96-105.

Wolfe WH, Michalek JE, Miner JC, Rahe A, Silva J, Thomas WF, Grubbs WD, Lustik MB, Karrison TG, Roegner RH, Williams DE. 1990. Health status of Air Force veterans occupationally exposed to herbicides in Vietnam. I. Physical health. Journal of the American Medical Association 264:1824-1831.

World Health Organization. 1980. WHO Expert Committee on Diabetes Mellitus (Tech. Rep. Ser., No. 646). Second Report. Geneva: World Health Organization.

World Health Organization. 1985. Diabetes Mellitus: Report of a WHO Study Group (Tech. Rep. Ser., No. 727). Geneva: World Health Organization.

Zober A, Ott MG, Messerer P. 1994. Morbidity follow up study of BASF employees exposed to 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) after a 1953 chemical reactor incident. Occupational and Environmental Medicine 51:479-486.

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Next: Appendix A: Information Gathering »
Veterans and Agent Orange: Update 1998 Get This Book
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Third in a series of six congressionally mandated studies occurring biennially, this book is an updated review and evaluation of the available scientific evidence regarding the statistical association between exposure to herbicides used in Vietnam and various adverse health outcomes suspected to be linked with such exposures. As part of the review, the committee convened a workshop at which issues surrounding the reanalysis and the combination of existing data on the health effects of herbicide and dioxin exposure were addressed.

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

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