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Veterans and Agent Orange: Update 2004 (2005)

Chapter: 9 Other Health Effects

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Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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9
Other Health Effects

This chapter discusses data on the possible association between exposure to the herbicides used in Vietnam (2,4-dichlorophenoxyacetic acid [2,4-D], 2,4,5-trichlorophenoxyacetic acid [2,4,5-T], picloram, and cacodylic acid and 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], a contaminant of 2,4,5-T) and the following non-cancer health outcomes: chloracne, porphyria cutanea tarda (PCT), respiratory disorders, immune system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), circulatory disorders, amyloidosis, endometriosis, and adverse effects on thyroid homeostasis. Background information about each outcome is followed by a brief summary of the findings described in earlier Veterans and Agent Orange reports, a discussion of the most recent scientific literature, and a synthesis of the material reviewed. For studies new to this update that report only a single health outcome and that are not revisiting a previously studied population, their design information is summarized with their results; the design information for all other news studies can be found in Chapter 4. Within health outcome, the studies are grouped by exposure type (occupational, environmental, or Vietnam veteran). Each section ends with the Veterans and Agent Orange: Update 2004 committee’s conclusions regarding the strength of the evidence from epidemiologic studies, biologic plausibility, and evidence regarding Vietnam veterans. The categories of association and the committee’s approach to categorizing the health outcomes are discussed in Chapters 1 and 2.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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CHLORACNE

Chloracne is a skin disease that is characteristic of exposure to TCDD and other cyclic organochlorine compounds. It shares some pathologic processes (the occlusion of the orifice of the sebaceous follicle) with more common forms of acne (such as acne vulgaris), but it can be differentiated by the presence of epidermoid inclusion cysts, which are caused by proliferation and hyperkeratinization (horn-like cornification) of the epidermis and sebaceous gland epithelium. Although chloracne is typically distributed over the eyes, ears, and neck, patterns of chloracne among chemical industry workers exposed to TCDD also include the trunk, genitalia, and buttocks (Neuberger et al., 1998).

Chloracne has been studied extensively and is used as a marker of exposure in studies of populations exposed to TCDD and other organochlorine compounds, such as polychlorinated biphenyls (PCBs) and pentachlorophenol. It is one of the few findings consistently associated with such exposure and is a well-validated indicator of high exposure to those compounds, particularly TCDD (Sweeney et al., 1997/98). If chloracne occurs, however, it appears shortly after the chemical exposure, not after a long latency. Although it is refractory to acne treatments, it usually regresses over time. Therefore, new cases of chloracne would not be the result of exposures during Vietnam and are not a concern for this report. It also should be noted that lack of chloracne does not necessarily indicate the absence of exposure to substantial levels of TCDD, as is apparent from studies of individuals exposed in the Seveso accident. There is not necessarily a correlation between serum concentrations of TCDD and the occurrence or severity of chloracne.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO; IOM, 1994) determined there was sufficient evidence of an association between exposure to at least one compound of interest and chloracne. Additional information available to the committees responsible for Veterans and Agent Orange: Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), and Update 2002 (IOM, 2003) did not change that finding. Reviews of the studies that underlie the finding can be found in the earlier reports.

Update of the Scientific Literature

No relevant occupational or environmental studies have been published since Update 2002.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×
Vietnam-Veteran Studies

Kim J-S et al. (2003) conducted a cross-sectional study of Korean veterans who served in Vietnam to determine what adverse health effects might be associated with service in Vietnam and, by inference, attributable to exposure to Agent Orange. The Korean-veteran cohort consisted of 1,224 male veterans (27.6% participation rate); a non-exposed group consisted of 154 male Korean veterans (5.7% participation rate) who did not serve in Vietnam. Chloracne occurred in nine veterans who served in Vietnam; it did not occur in the veterans who served elsewhere. The prevalence of chloracne did not increase for higher exposures. Selection and recall bias could limit the usefulness of the results.

Synthesis

Chloracne is clearly associated with high exposure to cyclic organochlorine compounds, but because it appears shortly after exposure, a long latency would be inconsistent with information in previous studies. The study conducted by Kim J-S et al. (2003) had significant limitations and did not contribute to better understanding chloracne as it relates to organochlorines.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is sufficient evidence of an association between exposure to at least one compound of interest and chloracne.

Biologic Plausibility

As noted in previous reports, chloracne-like skin lesions have been reported to occur in several animal species in response to exposure to TCDD but not to purified phenoxyacetic herbicides. TCDD induces differentiation in human keratinocytes, and it is reported to decrease an acidic type I keratin involved in epidermal development and thus lead to keratinocyte hyperproliferation and skin irritations, such as chloracne. The data provide a biologically plausible mechanism for the induction of chloracne by TCDD.

Increased Risk of Disease Among Vietnam Veterans

Although there are data to suggest an association between exposure to the chemicals of interest and chloracne, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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PORPHYRIA CUTANEA TARDA

Porphyrias are uncommon disorders caused by deficiencies of enzymes involved in the heme (iron-containing, non-protein portion of the hemoglobin molecule) biosynthesis pathway. PCT is a heterogeneous group of disorders caused by a deficiency of a specific enzyme (uroporphyrinogen decarboxylase). PCT, the most common of the porphyries, can be inherited, but more often it is acquired. Type I PCT, which accounts for 80–90% of all cases, is an acquired disease that typically becomes evident in adulthood. Type I PCT can occur spontaneously, but more commonly it occurs in conjunction with environmental factors, such as alcohol consumption, exposure to estrogens, or use of some medications.

The most significant clinical finding is cutaneous photosensitivity. Sensitivity to sunlight is thought to result from the excitation of excess porphyrins in the skin by long-wave ultraviolet light, which leads to cell damage. Fluid-filled vesicles and bullae develop on sun-exposed areas of the face and on the dorsa of the hands, feet, forearms, and legs. Other features include hypertrichosis (excess hair) and hyperpigmentation (increased pigment), especially on the face. In individuals with PCT, porphyrins are increased in the liver, plasma, urine, and stools. Iron, estrogens, alcohol, viral hepatitis, and chlorinated hydrocarbons can aggravate the disorder. Iron overload is almost always present in individuals with PCT.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO determined that there was sufficient evidence of an association between exposure to at least one compound of interest (2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid) and PCT in genetically susceptible people. The data, however, indicated that PCT manifests shortly after exposure to TCDD. Therefore, new cases of PCT attributable to exposures during the Vietnam War will not occur. Additional information available to the committee responsible for Update 1996 led it to conclude that there was only limited or suggestive evidence of an association, and Update 1998, Update 2000, and Update 2002 did not change that conclusion. Reviews of the relevant studies are found in the earlier reports.

Update of the Scientific Literature

No relevant occupational or environmental studies have been published since Update 2002.

Vietnam-Veteran Studies

Kim J-S et al. (2003) conducted a cross-sectional study of Korean veterans who served in Vietnam to determine what adverse health effects might be associ-

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

ated with service in Vietnam and, by inference, attributable to exposure to Agent Orange. The Korean-veteran cohort consisted of 1,224 male veterans (27.6% participation rate); a non-exposed group consisted of 154 male Korean veterans (5.7% participation rate) who served elsewhere. Uroporphyrin (a common porphyrin that is increased in persons with PCT) occurred with greater frequency in the urine of veterans who served in Vietnam than it did in non-Vietnam veterans (p < 0.0001). However, the authors did not include uroporphyrin concentrations or specify urine collection procedures (24-h urine or spot urine sample) in their report.

Synthesis

PCT would be an early response to TCDD; recovery would occur after exposure ceased. Although PCT has been seen after exposure to TCDD in industrial settings, Vietnam veterans enrolled in the Ranch Hand study have not exhibited symptoms suggestive of the disorder.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one compound of interest and PCT.

Biologic Plausibility

PCT has not been replicated in animal studies with TCDD, although other porphyrin abnormalities have been reported. Porphyrin accumulation was found in fish and chick embryo hepatocyte cultures treated with TCDD.

Increased Risk of Disease Among Vietnam Veterans

Although there are data to suggest an association between exposure to the chemicals of interest and PCT in genetically susceptible people, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

RESPIRATORY DISORDERS

Non-malignant respiratory disorders comprise acute and chronic lung diseases other than cancer. Acute respiratory disorders include pneumonia and other

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

respiratory infections. Those disorders could be increased in frequency and severity when the normal defense mechanisms of the lower respiratory tract are compromised. Chronic non-malignant respiratory disorders generally take one of two forms: Airways disease is a general term for disorders characterized by obstruction of the flow of air out of the lungs, among them asthma and chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis. Parenchymal disease, or interstitial disease, generally includes numerous disorders that cause inflammation and scarring of the deep lung tissue, including the air sacs and supporting structures. Parenchymal disease is less common than is airways disease, and its disorders are characterized by reductions in lung capacity, although they can include a component of airway obstruction. Some severe chronic lung disorders, such as cystic fibrosis, are hereditary. Because Vietnam veterans received health screenings before entering military service, few severe hereditary chronic lung disorders are expected in that population.

The major risk factor for many non-malignant respiratory disorders is cigarette-smoking. Although cigarette-smoking is not associated with every disease of the lungs, it is the major cause of many airways disorders, it contributes to some interstitial disease, and it compromises host defenses in such a way that people who smoke are generally more susceptible to some types of pneumonia. Cigarette-smoking also makes almost every respiratory disorder more severe and symptomatic than would otherwise be the case. The frequency of habitual cigarette-smoking varies with occupation, socioeconomic status, and generation. For those reasons, cigarette-smoking is a major confounding factor in interpreting the literature on risk factors for respiratory disease. Vietnam veterans are reported to smoke more heavily than are non-Vietnam veterans (McKinney et al., 1997).

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to the compounds of interest (2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid) and the respiratory disorders specified above. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that finding. Update 2000 drew attention to findings from the Seveso cohort that suggested a higher mortality from non-malignant respiratory disorders among study subjects, particularly males, who were more heavily exposed to TCDD. Those findings were not replicated in several other relevant studies, although one showed an increase that did not attain statistical significance. The committee for Update 2000 concluded that although new evidence suggested an increased risk of non-malignant respiratory disorders, particularly COPD, among people exposed to TCDD, the observation is tentative and the information insufficient to determine an association between the exposures of interest and respiratory dis-

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

orders. Additional information available to the committee responsible for Update 2002 did not change that finding.

Update of the Scientific Literature

Dahlgren et al. (2003) described a cross-sectional environmental study that used questionnaires to gather information on potential adverse health effects among residents near a wood treatment plant. The plant always used creosote, and pentachlorophenol was used from 1951 to 1971. Soil and sediment samples from a ditch in the neighborhood contained dioxins and furans. The exposed population consisted of 1,269 residents of a neighborhood near the plant; they also were plaintiffs or potential plaintiffs in a lawsuit against the plant. A representative sample group of 214 residents was chosen to participate in the study. The unexposed population consisted of 139 age- and sex-matched residents of a distant neighborhood. Exposed and unexposed subjects completed questionnaires; were examined by a physician; and underwent blood, urine, and respiratory function tests.

Exposed residents reported greater frequency of chronic bronchitis by history (17.8% versus 5.7%, p < 0.0001) and asthma by history (40.5% versus 11.0%, p < 0.0001). Selection bias and recall bias limit the utility of the results. Also, it is unclear whether the authors adequately controlled for history of tobacco use. In addition, multiple environmental exposures occurred in the neighborhood near the plant, and the authors could not determine which exposures were responsible for the reported adverse health effects.

No relevant occupational or Vietnam-veteran studies have been published since Update 2002.

Synthesis

No new studies provide evidence of a direct risk of non-malignant respiratory disorders in adults since those reviewed in Update 2002.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and non-malignant acute or chronic respiratory disorders.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×
Biologic Plausibility

Lung tissue contains high concentrations of the aryl hydrocarbon receptor (AhR), which mediates the effects of TCDD. Recent data also show that human lung cells are responsive to TCDD in terms of altered gene expression. Therefore, it is biologically plausible that exposure to TCDD may result in acute and chronic lung disorders, but cigarette-smoking also is a major risk factor for those disorders. Cytochrome P450 (CYP) enzymes are responsible, in part, for the activation of such chemicals as those found in tobacco smoke (which also contains AhR ligands) to more toxic intermediates, so it is also biologically plausible that exposure to TCDD may synergize the toxic effects of a variety of compounds to which human lungs are exposed. Bronchiolar metaplasia of the alveolar epithelium has been observed in the lungs of rats exposed to TCDD for 2 years.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and the respiratory disorders specified above, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

IMMUNE SYSTEM DISORDERS

The immune system defends the body against infection by viruses, bacteria, and other disease-producing microorganisms (pathogens). The immune system also operates in cancer surveillance, destroying cells that have become transformed and might otherwise develop into tumors. As it recognizes the wide array of pathogens in the environment, the immune system relies on many different cell types that operate together to generate immune responses. The immune system’s cells arise from stem cells in the bone marrow; they are found throughout the body’s lymphoid tissues, and they circulate in the blood as white blood cells (WBCs).

Granulocytes are WBCs that respond quickly to infection. They display a variety of protein receptors on their surfaces that can bind to molecules on different pathogens. When the receptors are bound, they signal the granulocytes to release toxins contained in their granules that kill the pathogens. Macrophages (“large eaters”) are WBCs that ingest bacteria and other microbes; once inside the macrophage, the microbes are killed by oxidative and enzymatic processes. Natural killer (NK) cells are WBCs that recognize and kill virus-infected cells and cancer cells. Granulocytes, macrophages, and NK cells are the first line of defense against infectious disease and cancer.

A second line of defense specifically targets the infecting microorganism. The response is mediated by the T and B lymphocytes. B lymphocytes produce

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

antibodies, which bind to infectious microbes or their toxins, causing them to be destroyed by other immune system cells. There are several antibodies (immunoglobulins [Ig]): IgM, IgG, IgA, IgE, and IgD. All have different functions, but each is quite specific in action. For example, antibodies produced in response to a tuberculosis infection will bind only to tuberculosis bacteria. T lymphocytes carry out many functions: They help B lymphocytes make antibodies, activate macrophages to kill bacteria more effectively, and directly kill tumor cells and virus-infected cells. T lymphocytes regulate the magnitude of the immune response and turn it off when the infection is cleared. T cells function primarily by secreting soluble chemical messengers called interleukins and they acquire their different functions by passing through the thymus gland before entering the blood and lymph nodes. An intact T and B lymphocyte response is highly effective at preventing disease. Once a person is exposed to a particular disease organism or is vaccinated against that disease, memory T and B cells are present in larger numbers. The cells respond more quickly upon reinfection to prevent disease.

When the immune system responds to a foreign substance that is not actually pathogenic, such as animal dander, pollen, or poison ivy, the immune system can generate an allergic response. Many allergic responses are associated with the production of IgE or sometimes IgG antibodies. Once produced, those antibodies bind to the surface of other cells—mast cells—that occur in tissues throughout the body, including lung airways, the gut wall, and blood vessel walls. When a person is exposed again to the allergen, the allergen binds to the antibodies on the mast cells, causing them to release histamine and leukotrienes, which cause the allergic symptoms. Allergic responses also are mediated by memory T cells that release inflammatory substances when the allergen binds to receptors. Rashes caused by contact with poison ivy or nickel are T-cell-mediated allergies.

Autoimmune disease is another example of the immune system’s causing rather than preventing disease. In this case, the immune system mistakenly attacks the body’s own cells and tissues as if they were foreign. The autoimmune reaction in multiple sclerosis is directed against the myelin sheath of the nervous system; in Crohn’s disease, the gut is the target of attack; in type 1 diabetes mellitus, the insulin-producing cells of the pancreas are destroyed by the immune response. In some autoimmune diseases, B cells mistakenly make antibodies against specific cellular components. Those autoantibodies may interfere with the normal function of the tissues or cause the tissue to break down. Sometimes altered T-cell function is the underlying cause of autoimmunity. Genetic predisposition and environmental factors such as infectious diseases and stress are thought to facilitate the development of autoimmune diseases.

Suppression of the immune response can result in reduced resistance to infectious disease and to increased risk of cancer. In persons suffering from allergies or autoimmune disease, immune suppression can relieve symptoms. Immune deficiencies can be congenital or acquired in a variety of ways. Infection with HIV is a well-recognized example of an acquired immune deficiency in

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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which a specific type of T cell is the target of the virus. The decline in the number of CD4+ T cells after HIV infection correlates with an increased incidence of infectious diseases, including fatal opportunistic infections, and with an increased incidence of several types of cancer. On a more modest scale, nutritional deficiencies, chronic stress, and exposure to toxic chemicals also have been shown to suppress some functions of the immune system. However, because the immune system has considerable reserve capacity and redundancy, that modest suppression does not usually translate directly into increased disease. The ability of an individual to combat infection depends on many factors that are difficult to control in a scientific study, including the virulence of the microbe; the presence of other diseases (diabetes); age; vaccination status; stress; and exposure to toxic compounds, both intentionally (alcohol, tobacco or drug use, medications) and unintentionally (through workplace or environmental exposures). Because of those many confounding factors, few studies have been able to identify significant changes in immune response after environmental exposure in humans, and the evidence of direct links between chemical-compound-induced changes in immune function and altered disease is not strong.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committees responsible for VAO, Update 1996, Update 1998, Update 2000, and Update 2002, concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and immune system disorders. Reviews of the studies that underlie those conclusions are presented in the previous reports (IOM, 1994, 1996, 1999, 2001, 2003).

Update of the Scientific Literature

Occupational Studies

No relevant occupational studies of immune disorders have been published since those reviewed in Update 2002.

Environmental Studies

In a new study about Seveso, Italy, Baccarelli et al. (2002) measured plasma immunoglobulin and complement concentrations in a random sample of the population in the most highly exposed zone (N = 62) and in the surrounding uncontaminated area (N = 58). Plasma IgG significantly decreased with increasing TCDD concentration. That association was present after adjusting for age, sex, tobacco use, and consumption of domestic livestock and poultry. There was no effect on concentrations of IgM, IgA, or complement; IgE was not measured.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Two studies have evaluated the influence of exposure to TCDD-like compounds on immune response in children. Van Den Heuvel et al. (2002) characterized the immune status of adolescent boys and girls in Flanders, Belgium, in relation to their blood concentrations of PCBs and dioxin-like compounds. The latter data were obtained using the chemical-activated luciferase expression (CALUX) bioassay. The percentages of eosinophils and NK cells in the blood and IgG concentrations in the serum were negatively correlated with increasing CALUX toxicity equivalents (TEQ). The concentrations of IgE to specific allergens were negatively correlated with CALUX TEQs, in parallel with a significant decrease in self-reported allergies. The decrease in IgE found in the adolescents might suggest a dioxin-induced suppression of the immune response, consistent with the findings in laboratory animals exposed to TCDD. In a follow-up study of 8-year-old Dutch children (N = 27) perinatally exposed to dioxin, ten Tusscher et al. (2003) found a decrease in allergy in relation to increasing dioxin exposure. They also found increased numbers of CD4+ T cells and CD45RA+ cells, a phenotype associated with naïve T cells. An increased percentage of naïve versus activated T cells is consistent with a generalized decrease in immune responsiveness associated with dioxin exposure.

Vietnam-Veteran Studies

Kim H-A et al. (2003) studied Korean Vietnam War veterans for evidence of immune system changes in relation to their operation in various areas of Vietnam. Study subjects were classified into three groups, based on self-reported Agent Orange exposure history and health status. A veteran patient group (N = 24) consisted of veterans exposed to Agent Orange and suffering from chronic illness; the veteran control group (N = 27) had similar exposure but no chronic illness. Control subjects (N = 36) were healthy age-matched subjects with no Vietnam War military service. A significant increase in plasma IgE was found in both groups of veterans compared with control subjects. The patient group also had significantly decreased plasma IgG1. Those changes correlated with decreased production of interferon gamma in the patient group and with increased production of interleukin 4 in both veterans’ groups when the T cells from the subjects were cultured in vitro. No changes in the plasma concentrations of antibodies against double-stranded DNA or extractable nuclear antigens, both markers of autoimmune disease, were found in the veterans, nor were changes found in frequency distribution of peripheral blood leukocyte subpopulations.

Synthesis

TCDD is a well-known immunosuppressive agent in laboratory animals; it is among the most potent immunotoxicants in the environment. Therefore, one would expect that exposure of humans to sufficiently high doses of TCDD would

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

result in immune suppression. However, several studies of various parameters of human immune function have failed to reveal consistent correlations with TCDD exposure, and no detectable pattern of increased infectious disease has developed in veterans exposed to high concentrations of TCDD or other herbicides used in Vietnam. Although suppression of the immune response by TCDD could increase the risk of some cancers in Vietnam veterans, there is no evidence to support that connection.

Recent studies that have examined the influence of TCDD on IgE production have generated additional conflicting data. Two studies revealed a significant reduction in IgE production and associated allergic responses correlated with increasing exposure to TCDD and related compounds among children in Belgium and the Netherlands (ten Tusscher et al., 2003; Van Den Heuvel et al., 2002). In contrast, Korean Vietnam veterans had increased rather than decreased IgE concentrations in plasma—independent of health status (Kim H-A et al., 2003). The basis for those different outcomes is not known; however, it is possible that the immunosuppressive effects of TCDD observed in the children resulted from exposure during development, which is a more sensitive period for the induction of immunotoxicity than is adulthood. The increase in IgE observed in the Korean veterans had not been reported in previous studies.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and immune suppression or autoimmunity.

Biologic Plausibility

TCDD is a known immunosuppressive chemical in laboratory animals, and exposure to TCDD has been shown to influence the incidence and severity of a variety of infectious diseases. The effects of TCDD on the immune system are species- and strain-specific. Relative to recent studies demonstrating an effect of TCDD on allergic disease in humans, Luebke et al. (2001) reported that TCDD exposure suppressed the allergic immune response of rats to house-dust-mite antigens and decreased allergen-associated lung pathology. Those effects occurred in the absence of any change in serum IgE. A study by Kimata (2003) isolated B cells from allergic (atopic) and non-allergic persons and cultured the cells with TCDD in vitro. Exposure to TCDD significantly enhanced IgE production by B cells isolated from atopic but not from non-atopic persons. The author suggested that TCDD exposure may aggravate preexisting allergic disease by

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

enhancing IgE production. In previous studies, TCDD treatment was shown to decrease the secretion of IgG1 and IgE in murine B-cell cultures stimulated with bacterial lipopolysaccharide and interleukin 4 (Karras et al., 1995). Hinsdill et al. (1980) reported that feeding juvenile and adult mice various quantities of TCDD for 5 weeks or more produced no evidence of enhanced IgE synthesis but reduced contact sensitization to dinitrofluorobenzene. Chapter 3 discusses recent toxicologic studies that demonstrate the immunotoxic effects of the compounds of interest.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and immune system disorders, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

DIABETES

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by hyperglycemia and quantitative or qualitative deficiency of insulin action (Orchard et al., 1992). Although all forms share hyperglycemia, the pathogenic processes involved in its development differ. Most cases of diabetes fall into two categories: type 1 diabetes is characterized by an absolute deficiency of insulin caused by the destruction of insulin-producing cells in the pancreas (β-cells); type 2 diabetes is characterized by a combination of resistance to the actions of insulin and inadequate secretion of insulin (called relative insulin deficiency). In old classification systems type 1 diabetes was called insulin-dependent diabetes mellitus or juvenile-onset diabetes mellitus; type 2 diabetes was called non-insulin-dependent diabetes mellitus or adult-onset diabetes mellitus. The modern classification system recognizes that type 2 diabetes can occur in children and also can require insulin. For both types, long-term complications can include cardiovascular disease, nephropathy, retinopathy, neuropathy, and increased vulnerability to infections. Maintaining blood sugar concentrations within the normal range is crucial for preventing complications.

About 90% of all cases of diabetes mellitus are type 2 cases. Onset can occur before 30 years of age, and incidence increases steadily with age thereafter. The main risk factors are age, obesity, central fat deposition, a history of gestational diabetes (if female), physical inactivity, ethnicity (prevalence is greater in blacks and Hispanics than in whites), and—perhaps most important—family history. The relative contributions of those features, however, are not known.

The etiology of type 2 diabetes is unknown, but three major components have been identified: peripheral insulin resistance (thought by many to be primary) in target tissues (muscle, adipose tissue, liver); a defect in β-cell insulin

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

secretion; and hepatic glucose overproduction. In states of insulin resistance, insulin secretion is initially higher for each concentration of glucose, compared with that for people without diabetes. That hyperinsulinemic state is a compensation for peripheral resistance and often can maintain normal glucose levels for years. Eventually, β-cell compensation becomes inadequate, and there is progression to overt diabetes with concomitant hyperglycemia. The reason the β-cells cease to produce sufficient insulin is not known.

Type 1 diabetes occurs as a result of immunologically mediated destruction of β-cells in the pancreas and causes an absolute deficiency of insulin. It often develops during childhood, but it can develop at any age. As with many autoimmune diseases, genetic and environmental factors influence pathogenesis. Some viral infections are believed to be important environmental factors that could trigger the autoimmunity associated with type 1 diabetes.

Pathogenetic diversity and diagnostic uncertainty are among the important problems associated with epidemiologic study of diabetes. Given the multiple likely pathogenetic mechanisms that lead to diabetes mellitus—which include diverse genetic susceptibilities (ranging from autoimmunity to obesity) and the variety of potential environmental and behavioral factors (viruses, nutrition, activity)—many agents or behaviors can contribute to risk, especially in genetically susceptible people. The multiple mechanisms also can lead to heterogeneous responses to various exposures. Because up to half the affected diabetic population is undiagnosed, the potential for ascertainment bias in population-based surveys is high (more intensively followed groups or those with more frequent health care contact are more likely to be diagnosed), thereby emphasizing the need for formal standardized testing (to detect undiagnosed cases) in epidemiologic studies.

Summary of Previous IOM Reports

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and diabetes. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that finding.

In 1999, in response to a request from the Department of Veterans Affairs (VA), the Institute of Medicine (IOM) called together a committee to conduct an interim review of the scientific evidence regarding type 2 diabetes. That review focused on information published after the deliberations of the Update 1998 committee, and it resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000). The committee responsible for that report determined that there was limited or suggestive evidence of an association between type 2 diabetes and exposure to at least one compound of interest. The committees responsible for Update 2000 and Update 2002 upheld

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

that finding. Reviews of the pertinent studies are found in the earlier reports. Table 9-1 presents a summary.

Update of the Scientific Literature

Occupational Studies

No occupational studies have been published since those reviewed in Update 2002.

Environmental Studies

Fierens et al. (2003) completed a population-based cross-sectional study in several Belgian towns to assess the association between serum dioxin concentration and the prevalence of diabetes. Diabetes was reported by 3.6% of adults from the exposed communities (7/194) and in 3.2% of adults from a comparison community (2/63). No data were presented on the average dioxin concentrations in adults from either area. Although the incidence of diabetes was similar in both groups, analyses that compared the 9 diabetic adults with the 248 non-diabetic adults showed significantly higher concentrations of dioxins (diabetics, 46.6 picograms [pg] TEQ/g fat; non-diabetic, 25.2 pg TEQ/g fat, p < 0.05). In a covariate-adjusted analysis contrasting adults in the top decile of dioxin concentration with adults below the 90th percentile, the odds ratio (OR) for diabetes associated with the top decile was 5.1 (95% CI [confidence interval], 1.2–21.7). The dioxin concentrations at the 90th percentile and actual number of adults with diabetes in each category were not given.

Vietnam-Veteran Studies

Michalek et al. (2003) analyzed data from the Ranch Hand study to address a question of methodology: Is the association between serum TCDD concentration and diabetes incidence attributable to some characteristic that affects both diabetes and TCDD elimination rate? The researchers chose 343 participants from the Ranch Hand study who had multiple measurements of TCDD during their periodic examinations. An elimination rate was estimated for each veteran from those repeated measures. Proportional hazards and logistic regression models were computed to assess the association between TCDD elimination rate and the incidence of diabetes, both before and after adjustment for initial TCDD concentration and other risk factors for diabetes (age, family history, body mass index, tobacco use). The initial inverse association between TCDD elimination rate and diabetes was largely eliminated with the addition to the models of the other predictors. The baseline measurement of TCDD was a statistically significant (p = 0.03) predictor of time to onset of diabetes and a positive but non-

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 9-1 Selected Epidemiologic Studies—Diabetes and Health Outcomes Related to Diabetes

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

Studies Reviewed in Update 2002

Kitamura et al., 2000

Workers exposed to PCDD at a municipal waste incinerator

8

NS

Steenland et al., 2001

Ranch Hand veterans, workers exposed to TCDD-contaminated products, and comparison cohorts

 

 

 

Exposed vs nonexposed for Ranch Hands

147

1.2 (0.9–1.5)

Exposed vs nonexposed for NIOSH

28

1.2 (0.7–2.3)

Studies Reviewed in Update 2000

Calvert et al., 1999b

Workers exposed to 2,4,5-T and derivatives

 

 

 

All workers

26

1.5 (0.8–2.9)

Serum TCDD <20 pg/g (ng/kg) of lipid

7

2.1 (0.8–5.8)

20 <TCDD <75 pg/g (ng/kg) of lipid

6

1.5 (0.5–4.3)

75 < TCDD <238 pg/g (ng/kg) of lipid

3

0.7 (0.2–2.6)

238 <TCDD <3,400 pg/g (ng/kg) of lipid

10

2.0 (0.8–4.9)

Steenland et al., 1999b

Highly exposed industrial cohorts (N = 5,132)

 

 

 

Diabetes as underlying cause

26

1.2 (0.8–1.7)

Diabetes among multiple causes

89

1.1 (0.9–1.3)

Chloracne subcohort (N = 608)

4

1.1 (0.3–2.7)

Vena et al., 1998b

Exposed production workers and sprayers in 12 countriesa

33

2.3 (0.5–9.5)

Steenland et al., 1992b,c

Dioxin-exposed workers—Mortality

 

 

 

Diabetes as underlying cause

16

1.1 (0.6–1.8)

Diabetes among multiple causes

58

1.1 (0.8–1.4)

Studies Reviewed in Update 1998

Sweeney et al., 1997/98

NIOSH production workers

 

 

Ramlow et al., 1996

Pentachlorophenol production workers—Mortality

4

1.2 (0.3–3.0)

Studies Reviewed in Update 1996

Ott et al., 1994

Trichlorophenol production workers

 

p = 0.06

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—Mortality

4

SMR = 0.7 (0.2–1.9)

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Moses et al., 1984

2,4,5-T and TCP production workers with chloracne

22

2.3 (1.1–4.8)

May, 1982

TCP production workers

2

*

Pazderova-Vejlupkova et al., 1981

2,4,5-T and TCP production workers

11

*

ENVIRONMENTAL

New Study

Fierens et al., 2003

Belgium residents (142 women; 115 men) environmentally exposed to dioxins and PCBs

 

 

 

Subjects in the top decile for adjusted concentrations of dioxins

 

5.1 (1.2–21.7)

Studies Reviewed in Update 2002

Masley et al., 2000

Population based survey in Saskatchewan

28

*

Studies Reviewed in Update 2000

Bertazzi et al., 2001

Seveso residents—20-year follow-up

 

 

 

Zone A females

2

1.3 (0.3–5.1)

Zone B males

6

0.9 (0.4–2.0)

Zone B females

18

1.8 (1.1–2.9)

Cranmer et al., 2000b

Non-diabetic residents near the Vertac/Hercules Superfund site—OR for high insulin subjects with TCDD >15ppt (7 subjects) compared to persons with TCDD <15ppt (62 subjects)

 

 

 

Fasting (high insulin level, >4.5 µIU/ml)

3

8.5 (1.5–49.4)

30-minute insulin (high insulin level, >177 µIU/ml)

3

7 (1.3–39.0)

60-minute insulin (high insulin level, >228 µIU/ml)

4

12 (2.2–70.1)

120-minute insulin (high insulin level, >97.7 µIU/ml)

6

56 (5.7–556)

Bertazzi et al., 1998b

Seveso residents—15-year follow-up

 

 

 

Zone A females

2

1.8 (0.4–7.0)

Zone B males

6

1.2 (0.5–2.7)

Zone B females

13

1.8 (1.0–3.0)

Pesatori et al., 1998b

Seveso residents—15-year follow-up

 

 

 

Zone A females

2

1.8 (0.4–7.3)

Zone B males

6

1.3 (0.6–2.9)

Zone B females

13

1.9 (1.1–3.2)

Zone R males

37

1.1 (0.8–1.6)

Zone R females

74

1.2 (1.0–1.6)

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

VIETNAM VETERANS

New Studies

JS Kim et al., 2003

Korean veterans of Vietnam association between diabetes and exposure status

144

2.7 (1.1–6.7)

Michalek et al., 2003

Ranch Hand participating in a pharmacokinetic study (N = 343)

 

 

 

Rate of TCDD elimination and occurrence of diabetes (proportional hazards model)

92

NS

Rate of TCDD elimination and time to onset of diabetes (proportional hazards model)

92

NS

Studies Reviewed in Update 2000

AFHS, 2000b

Air Force Ranch Hand veterans and comparisons

(Numerous analyses discussed in the text of Herbicide/Dioxin Exposure and Type 2 Diabetes)

Longnecker and Michalek, 2000b

Ranch Hand unexposed referents only, OR by quartile and serum dioxin concentration

 

 

 

Quartile 1: <2.8 ng/kg (pg/g)

26

1.00—referent

Quartile 2:2.8–<4.0 ng/kg

25

0.9 (0.5–1.7)c

Quartile 3:4.0–<5.2 ng/kg

57

1.8 (1.0–3.0)c

Quartile 4: ≥5.2 ng/kg

61

1.6 (0.9–2.7)c

CDVA, 1998ab

Australian Vietnam veterans—male

2,391 reportede (6% of respondents)

1,780 expected (1,558–2,003)

CDVA, 1998bb

Australian Vietnam veterans—female

5 reportede (2% of respondents)

10 expected (9–11)

Henriksen et al., 1997b

Ranch Hand—high-exposure group

 

 

 

Glucose abnormalities

60

1.4 (1.1–1.8)

Diabetes prevalence

57

1.5 (1.2–2.0)

Use of oral medications for diabetes

19

2.3 (1.3–3.9)

Serum insulin abnormalities

18

3.4 (1.9–6.1)

Studies reviewed in Update 1998

Henriksen et al., 1997

Ranch Hand

 

 

 

High-exposure category

57

1.5 (1.2–2.0)

All Ranch Hand

146

1.1 (0.9–1.4)

O’Toole et al., 1996

Australian Vietnam veterans

12

1.6 (0.4–2.7)e

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Studies Reviewed in VAO

AFHS, 1991

Air Force Ranch Hand veterans

85

p = 0.001, p = 0.028

AFHS, 1984

Air Force Ranch Hand veterans

158

p = 0.234

a Given when available.

b Study is summarized in Update 2002 and discussed in greater detail in Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000).

c May include some of the same subjects covered in the NIOSH cohorts addressed in the other references cited in the Occupational cohorts category.

d Adjusted for age, race, body mass index, waist size, family history of diabetes, body mass index at the time dioxin was measured, serum triglycerides, and military occupation.

e Self-reported medical history; answer to question, “Since your first day of service in Vietnam, have you been told by a doctor that you have diabetes?”

* = Information not provided by study authors.

ABBREVIATIONS: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; AIHW, Australian Institute of Health and Welfare; CDC, Centers for Disease Control and Prevention; CI, confidence interval; EOI, exposure opportunity index; HDL, high-density lipoprotein; N/A, not applicable; NS, not significant; SS, statistically significant; TCP, trichlorophenol.

statistically significant (p = 0.16) predictor of incidence of diabetes in the subset of Ranch Hand veterans. The data suggest that the association between serum TCDD and diabetes is not simply attributable to a factor that causes diabetes and slows elimination of TCDD.

Kim J-S et al. (2003) reported the results of a cross-sectional study of exposure to Agent Orange and the prevalence of a large number of health outcomes in veterans from Korea. The researchers recruited male Vietnam veterans in 1995 from a list of veterans who had contacted the Korean government to be examined for possible medical care and compensation for service-related conditions. A total of 4,432 veterans were on the list; 1,514 (34.2%) agreed to participate in the study; 1,224 (27.6%) were age-eligible for the study (45–64 years) and completed the study interview and examination. Of the 2,682 male non-Vietnam veterans identified who received military pensions and resided near Seoul, only 154 (5.7%) of those persons agreed to participate as the comparison group for the study.

These researchers created an index to estimate exposure to Agent Orange in the Vietnam veterans. The index included information on time spent in different regions of Vietnam and on reports of exposure to Agent Orange on the skin, in the air, or through drinking or swimming in contaminated water. Quartiles were formed from scores on the index, and the categories of exposure were compared

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

with lipid-adjusted TCDD concentrations from pooled blood samples drawn during a 1995 examination for the study. The mean values of TCDD by quartile of the overall exposure index in the Vietnam veterans were 0.6, 0.62, 0.78, and 0.87 pg/g, respectively; non-Vietnam veterans had an average serum TCDD of 0.3 pg/g. As discussed in greater detail in Chapter 5, the decision to pool blood samples (from 745 sampled individuals to produce 13 analytic readings) greatly compromised validation of the exposure categories derived from interview responses. The resulting range of serum TCDD levels was very narrow, putting into question the biologic relevance of any differences. The assessment of health outcomes was done without knowledge of exposure status, but the researchers did not provide specific information on the definition of diabetes for the analysis.

Diabetes was present in 5.8% (9/154) of the non-Vietnam veterans and in 12.6% (154/1,224) of the Vietnam veterans (prevalence ratio, 2.17; p = 0.02 with adjustment for age). Within the group of Vietnam veterans, the prevalence of diabetes varied only slightly by quartile of Agent Orange exposure index (range, 11.5–14.1%, p = 0.78 for differences across categories). In a logistic regression model adjusting for alcohol consumption, tobacco use, body mass index, education, age, and marital status, the odds ratio for diabetes in Vietnam versus non-Vietnam veterans was 2.69 (95% CI, 1.09–6.67, p = 0.03).

Synthesis

The study by Fierens et al. (2003) has several important weaknesses that limit its contribution to the literature on exposure to herbicides and the risk of developing diabetes. Diabetes is based on self-report, and there is no description of the communities or the study population to reveal differences in ascertainment of diabetes (attributable to differences in access to medical care). The small number of adults with diabetes is reflected in the imprecise results, and the confidence interval ranges from barely above one to a 22-fold increased risk. Dioxins are reported in aggregate, so the relationship between TCDD concentrations and diabetes cannot be ascertained.

Michalek et al. (2003) provide additional support for a causal relationship between TCDD exposure and the development of diabetes by demonstrating in data from the Ranch Hand study that the association is not an artifact of differences in the elimination rate of TCDD. The study of Korean veterans (Kim J-S et al., 2003) shows an elevated prevalence of diabetes in Vietnam veterans compared with those who served elsewhere. The difference is not attributable to confounding by several important risk factors for diabetes, and the Vietnam veterans did have higher serum TCDD than did the comparison group. However, the report does not significantly strengthen the evidence for an association between herbicide exposure and diabetes. Limitations in measurement could be responsible for the absence of any trend in diabetes among the Vietnam veterans by quartile of Agent Orange exposure index. A more serious concern is the

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

possibility of selection bias in the formation of the study population. As the authors concede, it is likely that veterans with chronic health conditions were overrepresented in the sample of Vietnam veterans because of their interest in potential compensation or medical care for the health effects of exposure to herbicides. The adjustment for confounders will not automatically correct for that form of selective participation. The relatively low participation in both groups (28% and 6% in Vietnam and non-Vietnam veterans, respectively) underscores the need for additional data on the influence of selection bias in this cross-sectional study.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is limited or suggestive evidence of an association between exposure to at least one compounds of interest and diabetes.

Biologic Plausibility

The evaluation of the potential of TCDD to induce clinical diabetes in animals has been impaired by the lack of an appropriate animal model for type 2 diabetes. TCDD’s effects on triglycerides and high-density lipoproteins, glucose transport, protein kinase C, and other lipoproteins in animals suggest that it could stimulate development of diabetes. Several studies have demonstrated that TCDD treatment decreases glucose transport and alters lipoprotein degradation in adipose tissue cell lines. That might constitute a physiologic mechanism for linking TCDD exposure to diabetes. Chronic active inflammation, acinar cytoplasmic vacuolization, acinar atrophy, and arterial chronic active inflammation have been observed in the pancreata of rats exposed to TCDD for 2 years. The lesions indicate that the pancreatic acinar cells are susceptible to the toxic effects of TCDD; the islet cells appear to be more resistant. Nevertheless, until appropriate animal models are developed to show the etiology and pathogenesis of diabetes, confirmation of TCDD’s ability to induce diabetes in animals will remain elusive.

Increased Risk of Disease Among Vietnam Veterans

Although there are data to suggest an association between exposure to the chemicals of interest and type 2 diabetes, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

LIPID AND LIPOPROTEIN DISORDERS

Plasma lipid (notably cholesterol) concentrations have been shown to predict cardiovascular disease and are considered fundamental to the underlying atherosclerotic process (Kuller and Orchard, 1988). Cholesterol and triglycerides, the two major types of lipids, are carried in the blood attached to proteins to form lipoproteins, which are classified by density. Very-low-density lipoprotein (VLDL—the major “triglyceride” particle) is produced in the liver and is progressively catabolized (hydrolyzed) mainly by an insulin-mediated enzyme (lipoprotein lipase) to form intermediate-density lipoprotein (IDL) or VLDL remnants. Most of the VLDL remnants are rapidly cleared by the liver LDL receptors (types B and E); the rest form low-density lipoprotein (LDL), the major “bad” cholesterol particle. LDL 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 liver; it also results from the catabolism of VLDL. LDL is thought to be involved in the delivery of cholesterol to the tissues; HDL 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 can be familial (because of an LDL receptor genetic defect) or polygenic (attributable to multiple minor genetic susceptibilities); familial hypertriglyceridemia (sometimes linked to susceptibility to diabetes); and mixed hyperlipidemias in which cholesterol and triglycerides are elevated. The mixed hyperlipidemias group includes familial combined hyperlipidemia, which could result from hepatic overproduction of VLDL and apoprotein B, and type III dyslipidemia, involves defective clearance of IDL–VLDL remnants and a buildup of those atherogenic particles. Although the bulk of blood lipid concentration is genetically determined, diet, activity, and other factors (concurrent illness, use of drugs, age, gender, hormones) have major effects. In particular, the saturated-fat content of the diet might raise LDL concentrations via decreased LDL-receptor activity; obesity and a high-carbohydrate diet can increase VLDL triglycerides and possibly are linked to insulin resistance and reduced lipoprotein lipase activity. Intercurrent illness can increase triglyceride concentration and decrease cholesterol concentration. Diabetes also is associated with increased triglycerides and decreased HDL cholesterol, whereas other diseases (thyroid and renal disorders) often result in hypercholesterolemia. It is evident, therefore, that multiple host and environmental factors influence lipid and lipoprotein concentrations and that those influences must be considered before the effect of a new factor can be assessed (LaRosa, 1990). In the current context, any analysis must control for obesity as a primary determinant of triglyceride and TCDD concentrations. The ability of acute or chronic illness to raise triglyceride and glucose and lower HDL and LDL cholesterol concentrations must be recognized.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and lipid and lipoprotein disorders. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Reviews of the relevant studies are found in the earlier reports. Table 9-2 provides a summary.

Update of the Scientific Literature

Environmental and Vietnam-Veteran Studies

No relevant environmental or Vietnam-veteran studies of lipid and lipoprotein disorders have been published since those reviewed in Update 2002.

Occupational Studies

Pelclová et al. (2002) measured cholesterol and triglyceride concentrations in 12 men who were exposed to extremely high concentrations of TCDD in the 1960s while they were employed in herbicide production at a chemical factory in the former Czechoslovokia. The exposure occurred because of excessive temperature and pressure in the production process over an extended period of time (between 1965 and 1968) rather than as a consequence of a major release at a single point in time. More than 80 workers were affected, but the researchers provided little information about those who were not included in the study. The average plasma TCDD concentrations for the 12 study participants in 1996 (approximately 30 years after the exposure) was 271 pg/g, with a range from 14 to 760 pg/g. Elevated triglycerides (>1.69 millimolar [mmol]/L) and cholesterol (>5.2 mmol/L) were observed in 6 and 7 of the 12 men, respectively. The correlation between TCDD in 1996 and highest recorded measurement of triglyceride or cholesterol at any point between 1968 and 2001 was 0.66 for triglyceride and 0.78 for cholesterol. No information was given about follow-up measures of lipids collected in standard or periodic fashion for participants and there is no discussion of how individual differences in treatment of elevated cholesterol could influence the highest recorded value for total cholesterol.

Hu et al. (2003) conducted a cross-sectional study of dioxin–furan exposures and lipids in workers at municipal-waste incinerator plants in Taipei City, Taiwan. A total of 133 workers were randomly sampled from 3 plants; workers had to have been employed for at least 6 months in the operation and control or maintenance departments. Nearly all (98.5%) who were randomly selected agreed to participate in the study. In all, 17 congeners were measured, including TCDD

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

(which had a range from undetectable to 14 pg/g, with a median of 1.6 pg/g). Workers with TCDD above the median had higher average cholesterol and were more likely to have cholesterol above 220 mg/dL (p < 0.05 for both measures of cholesterol, actual means and proportions not shown). The relationship between TCDD and cholesterol was not statistically significant when TCDD was measured by tertiles, quartiles, or as a continuous variable. TCDD was not associated with triglyceride as a continuous or categorical measure.

Synthesis

The report by Pelclová et al. (2002) has some important shortcomings—the small sample, uncertainty about whether the 12 exposed workers are representative of the exposed group, and the lack of an explicit comparison group. The correlation between TCDD and lipids is impressive but difficult to interpret because the lipids were measured as early as 1970 and as late as 2001. The relatively extreme concentrations of TCDD also affect the generalizability of the findings.

The study by Hu et al. (2003) successfully recruited a cross-section of workers and did show significant variation in cholesterol by a dichotomous measure of TCDD. The loss of statistical significance with more detailed categories or along the full continuum of TCDD values suggests that the findings from the initial analysis are not robust or consistent. The researchers adjusted for age and body mass index but not for diet (intake of fiber and specific fats) that are potential confounders. Several individual congeners other than TCDD were identified as statistically significant correlates of elevated cholesterol. The study design does not allow for isolation of the effect of any single exposure. The relationship between herbicide exposure and lipid remains uncertain.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and lipid and lipoprotein disorders.

Biologic Plausibility

The induction of lipid mobilization and alterations in lipid metabolism are well-known effects of high-dose exposure to TCDD in laboratory animals resulting in hyperpipidemia and loss of body fat. Increased serum triglycerides were

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

TABLE 9-2 Selected Epidemiologic Studies—Lipid and Lipoprotein Disorders

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

OCCUPATIONAL

New Studies

Hu et al., 2003

Workers exposed to PCDDs/PCDFs at 3 municipal waste incinerators in Taipei City

 

 

 

Comparison between high and low exposure groups using the low exposures group as controls

67 high; 66 low

 

Total cholesterol

 

2.8 (1.0–7.9)

Triglycerides

 

1.5 (0.5–4.3)

Pelclová et al., 2002

Workers exposed to 2,3,7,8-TCDD during herbicide production at a factory in Spolana, Czech Republic

12

 

 

Correlation between the year (1968 to 2001) in which the highest level of the parameter was measured and serum 2,3,7,8-TCDD level in 1966

 

 

Cholesterol

 

r = 0.78; p = 0.01

Triglycerides

r = 0.66; p = 0.02

Studies Reviewed in Update 2002

Kitamura et al., 2000

Workers exposed to PCDD at a municipal waste incinerator—elevated cholesterol

8

6.1, p = 0.02

Studies Reviewed in Update 1998

Calvert et al., 1996

Workers (N = 273) exposed to 2,4,5-T and derivatives vs matched referents (N = 259)

 

 

 

OR for abnormal total cholesterol concentration

 

 

Overall

95

1.1 (0.8–1.6)

High TCDD

18

1.0 (0.5–1.7)

OR for abnormal HDL cholesterol concentration

 

 

Overall

46

1.2 (0.7–2.1)

High TCDD

15

2.2 (1.1–4.7)

OR for abnormal mean total to HDL cholesterol ratio

 

 

Overall

131

1.1 (0.8–1.6)

High TCDD

36

1.5 (0.8–2.7)

OR for abnormal mean triglyceride concentration

 

 

Overall

20

1.0 (0.5–2.0)

High TCDD

7

1.7 (0.6–4.6)

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Ott and Zober, 1996

Production workers exposed to TCDD

42

 

 

Cholesterol

 

NSEb

Triglycerides

NSEb

HDL cholesterol

Increased; p = 0.05b

Studies Reviewed in VAO

Martin, 1984

Production workers exposed to TCDD Workers without chloracne

53

 

 

Cholesterol

 

Increased; p < 0.005b

Triglycerides

Increased; p < 0.005b

HDL cholesterol

NSEb

Workers with chloracne

39

 

Cholesterol

 

Increased; p < 0.05b

Triglycerides

Increased; p < 0.01b

HDL cholesterol

NSEb

Moses et al., 1984

TCP and 2,4,5-T production workers

118

 

 

Cholesterol

 

NSEc

Triglycerides

 

NSEc

Suskind and Hertzberg, 1984

TCP production workers

204

 

Cholesterol

 

NSEb

 

Triglycerides

 

NSEb

 

HDL cholesterol

 

NSEb

May, 1982

TCP production workers

94

 

 

Cholesterol

 

NSEb

Triglycerides

 

NSEb

Pazderova-Vejlupkova et al., 1981

TCP and 2,4,5-T production workers

55

 

 

Cholesterol

 

NSEb

 

Triglycerides

 

Increased VLDL; p = 0.01b

ENVIRONMENTAL

Studies Reviewed in VAO

Assennato et al., 1989

Seveso Zone A subjects who developed chloracne

193

 

 

Cholesterol

 

NSEb

 

Triglycerides

 

NSEb

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

Mocarelli et al., 1986

Children exposed near Seveso

63

 

 

Cholesterol

 

NSEb

 

Triglycerides

 

NSEb

VIETNAM VETERANS

Studies Reviewed in Update 2000

AFHS, 2000

Air Force Ranch Hand veterans

858

 

 

Cholesterol

 

NSE

 

Triglycerides

 

NSE

Studies reviewed in Update 1998

AFHS, 1996

Air Force Ranch Hand veterans (1992 exam data)

884

 

 

Cholesterol

 

NSE (cholesterol: HDL ratio)b

 

Triglycerides

 

NSEd

 

HDL cholesterol

 

NSEd (cholesterol: HDL ratio)

O’Toole et al., 1996

Australian Vietnam veterans, compared with the Australian population

20

 

 

Cholesterol

 

3.0 (1.3–4.7)

Studies reviewed in VAO

AFHS, 1991

Air Force Ranch Hand veterans Serum dioxin analysis (1987 exam data)

283–304 f

 

 

Cholesterol

 

p = 0.175e

Triglycerides

 

p < 0.001e,g

HDL cholesterol

 

p < 0.001e

AFHS, 1990h

Air Force Ranch Hand veterans Original exposure group analysis (1987 exam data)

8–142f

 

 

Cholesterol

 

1.2 (0.9–1.5)

Triglycerides

 

1.3 (0.9–1.8)

HDL Cholesterol

 

1.0 (0.4–2.4)

AFHS, 1984; Wolfe et al., 1990

Air Force Ranch Hand veterans exposed to herbicide spraying (1982 data)

1,027

 

 

Cholesterol

 

NSEh

Triglycerides

 

NSEh

HDL cholesterol

 

NSEh

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Reference

Study Population

Exposed Casesa

Estimated Relative Risk (95% CI)a

a Given when available.

b p-values comparing means of subjects and controls. Univariate analysis.

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

d Comparing change over time between exposed and comparison groups.

e Comparing mean dioxin across lipid groups.

f Number of exposed Ranch Hand with “high” lipid values.

g Continuous analysis.

h Comparing means.

NOTE: Estimated risk and 95% CI reported unless p-values are specified.

ABBREVIATIONS: HDL, High-density lipoprotein; NSE, no significant effect; PCDD, polychlorinated dibenzodioxins; TCP, trichlorophenol; VLDL, very low density lipoprotein.

also seen in TCDD-exposed rhesus monkeys. The mechanism underlying altered lipid metabolism has not been elucidated.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and lipid and lipoprotein disorders, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

GASTROINTESTINAL AND DIGESTIVE DISEASE, INCLUDING LIVER TOXICITY

This section discusses a variety of conditions encompassed by International Classification of Diseases, Ninth Edition (ICD-9) codes 520–579—diseases of the esophagus, stomach, intestines, rectum, liver, and pancreas. Additional details on peptic ulcer and liver disease—the two conditions most often discussed in the literature reviewed—are provided below. The symptoms and signs of gastrointestinal disease and liver toxicity are highly varied and often vague.

The essential functions of the gastrointestinal tract are to absorb nutrients and eliminate waste. Those complex tasks involve numerous chemical and molecular interactions on the mucosal surface and complex local and distant neural and endocrine activity. One common condition of the gastrointestinal tract is motility disorder, which could be present in 15% of adults. The most convenient way to categorize diseases that affect the gastrointestinal system is by the

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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affected anatomic segment. Esophageal disorders predominantly affect swallowing; gastric disorders are related to acid secretion; and conditions that affect the small and large intestines are reflected in alterations in nutrition, mucosal integrity, and motility. Some systemic disorders also affect the gastrointestinal system (inflammatory, vascular, infectious, 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 or duodenal ulcer, depending on the site of origin. Peptic ulcer disease occurs when the corrosive action of gastric acid and pepsin exceeds the normal mucosal defense mechanisms that protect against ulceration. About 10% of the population has clinical evidence of duodenal ulcer at some period in life; a similar percentage is affected by gastric ulcer. The peak incidence for duodenal ulcer occurs in the fifth decade of life, and the peak for gastric ulcer occurs about 10 years later. The natural history of duodenal ulcer is one of spontaneous remission (healing) and recurrence. About 60% of healed duodenal ulcers recur in the first year; 80–90% recur within 2 years.

Increasing evidence indicates that the bacterium Helicobacter pylori is linked to peptic ulcer disease (duodenal and gastric). H. pylori colonizes the gastric mucosa in 95–100% of patients with duodenal ulcer and in 75–80% of patients with gastric ulcer. Healthy subjects in the United States under 30 years old have gastric colonization rates of about 10%. Over the age of 60 years, colonization rates exceed 60%. Colonization alone, however, is not sufficient for the development of ulcer disease; only 15–20% of subjects with H. pylori colonization will develop ulcers 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 about 3 times the general population’s risk of developing duodenal ulcer. Some blood groups are associated with increased risk of duodenal ulcer, and HLA-B5 antigen appears to be increased among white males with duodenal ulcer. Cigarette-smoking also has been linked to duodenal ulcer prevalence and mortality. Finally, psychological factors, particularly chronic anxiety and stress, could exacerbate duodenal ulcer disease.

Liver Disease

Blood tests reflecting liver function are the mainstay of diagnosis of liver disease. Increases in serum bilirubin and in the serum activity of some hepatic enzymes—aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and γ-glutamyltransferase (GGT)—are commonly noted in liver dis-

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

orders. The relative sensitivity and specificity of those enzymes for diagnosing liver disease vary, and several tests can be required for diagnosis. The only regularly reported abnormality in liver function associated with TCDD exposure in humans is an increase in GGT. Estimated serum activity of that enzyme constitutes 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. Increases are noted after many chemical and drug exposures that are not followed by evidence of liver injury. The confounding effects of alcohol use (often associated with increased GGT) make interpretation of changes in GGT in exposed people difficult (Calvert et al., 1992). An increase in GGT can be considered a normal biologic adaptation to chemical, drug, or hormone exposure.

Cirrhosis is the most commonly reported liver disease in epidemiologic studies of herbicide or TCDD exposure. Cirrhosis reflects irreversible chronic injury of the liver, with extensive scarring and resulting loss of liver function. Clinical symptoms and signs include jaundice, edema, abnormalities in blood clotting, and metabolic disturbances. Cirrhosis can lead to portal hypertension with associated gastroesophageal varices, enlarged spleen, abdominal swelling attributable to ascites; and, ultimately, to hepatic encephalopathy that can progress to coma. It generally is impossible to distinguish the various causes of cirrhosis by clinical signs and symptoms or by 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 infection (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, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and gastrointestinal and digestive disease, including liver toxicity. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Reviews of the pertinent studies underlying are found in the earlier reports.

Update of the Scientific Literature

Occupational Studies

Hu et al. (2003) studied dioxin exposure on hepatic function in 133 male workers at municipal-waste incinerators in Taiwan. Mean GGT, total bilirubin,

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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and triglyceride concentrations in the high-exposure group were slightly but not statistically significantly higher than were those in the low-exposure group. There was no statistically significant interaction between dioxin exposure and hepatitis B surface antigen status on a liver function test result.

No relevant environmental or Vietnam-veteran studies have been published since Update 2002.

Synthesis

Evaluation of the effect of herbicide and TCDD exposure on non-cancer gastrointestinal ailments is more difficult than is evaluation of the effect on some of the other outcomes examined in this report. Clinical experience suggests that medical history and physical examination are undependable diagnostic tools for some ailments, so incidence data are more problematic. The strong interdependence among the characteristics of a given person (weight and laboratory indexes of hepatic function and health) and body burden of TCDD complicate the already difficult task of assessing association.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and gastrointestinal and digestive diseases.

Biologic Plausibility

The liver is a primary target organ of TCDD in animals. Therefore, TCDD would be expected to induce liver toxicity in humans after sufficiently high doses. Direct effects of TCDD and herbicides on other gastrointestinal and digestive diseases have not been seen. Chapter 3 discusses recent toxicologic studies that form the biologic basis of an association between exposure to TCDD or herbicides and toxicity endpoints.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and gastrointestinal and digestive disease, including liver toxicity, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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CIRCULATORY DISORDERS

This section covers a variety of conditions encompassed by ICD-9 codes 390–459, including hypertension, heart failure, arteriosclerotic heart disease, peripheral vascular disease, and cerebrovascular disease. Various methods have been used in morbidity studies to assess the circulatory system, including analysis of symptoms or history, physical examination of the heart and peripheral arteries, Doppler measurements of peripheral pulses, electrocardiography (ECG), and chest radiography. Doppler measurements and physical examination of pulses in the arms and legs are used to detect decreases in pulse strength, which can be caused by thickening and hardening of the arteries. ECG can be used to detect heart conditions and such abnormalities as arrhythmia (abnormal heart rhythm), heart enlargement, and previous heart attack. Chest radiography can be used to assess enlargement of the heart, which can result from heart failure and other heart conditions. Mortality studies attribute cause of death to circulatory disorders with various degrees of diagnostic confirmation.

There is growing evidence that exposure to inorganic arsenic is a risk factor for cardiovascular disease, and cacodylic acid (DMA) is a metabolite of inorganic arsenic. As discussed in Chapter 2, however, there are insufficient data to conclude that studies of inorganic arsenic exposure are directly relevant to exposure to cacodylic acid. Therefore, the literature on inorganic arsenic is not considered in this section.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The committee responsible for VAO concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and circulatory disorders. Additional information available to the committees responsible for Update 1996, Update 1998, Update 2000, and Update 2002 did not change that finding. Reviews of the relevant studies are published in the earlier reports.

Update of the Scientific Literature

Occupational Studies

Swaen et al. (2004) presented results for a 21-year follow-up of mortality in a cohort of 1,341 licensed herbicide applicators working for government agencies in the Netherlands. The study period was from January 1980 to January 2001; information was available on the types and amounts of herbicides used in all municipal spraying projects in 1980, but those data could not be linked to the work of individual applicators. No data were available on any potential risk factors other than age. Standardized mortality ratios (SMRs) were calculated

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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based on the age and calendar-year, cause-specific mortality rates of the general population of the Netherlands. The SMR for deaths attributable to circulatory conditions was 0.68 (70 deaths observed; 102.6 deaths expected; 95% CI, 0.53–0.86).

Environmental Studies

Fukuda et al. (2003) conducted an ecological study of 590 municipalities in Japan to examine the relationship between several indexes of dioxin emissions from incineration plants and cause-specific mortality among residents. The Ministry of Health and Welfare provided data from 1996 and 1997 on total dioxin emissions from incineration plants. Data on dioxin concentrations, population size, and land area were used to compute four indexes for 426 municipalities: concentration of dioxins, amount of dioxins per unit of population, cumulative amount of dioxin from year of plant construction, and cumulative amount of dioxin per unit of land area. Several socioeconomic indicators also were created from census data on income, unemployment, education, size of residence, and amount of parkland. Mortality data were for 1994–1996. No analyses assessed the effects of different assumptions regarding latency and patterns of mortality.

Municipalities with and municipalities without incineration plants had similar age-adjusted mortality from ischemic heart disease (p = 0.77 and p = 0.24 for men and women, respectively). Stroke mortality did not vary by the presence of incineration plants for men but was slightly higher among women in municipalities with incineration plants (73.3/100,000 among women in municipalities with plants vs. 70.5/100,000 among women in municipalities without plants; p = 0.04). In analyses restricted to municipalities with incineration plants, there was a positive and statistically significant (p < 0.05) correlation between stroke mortality and 2 dioxin indexes (the concentration of dioxins released and the amount of dioxins released per population) for men and women. The sex-specific correlations between the dioxin indexes and stroke mortality were modest, ranging from 0.13 to 0.15. In addition, the value of the correlations declined to 0.03–0.05 (p < 0.05) after adjustment for socioeconomic characteristics.

Vietnam-Veteran Studies

Kim J-S et al. (2003) reported the results of a cross-sectional study of exposure to Agent Orange and the prevalence of a large number of health outcomes in Korean veterans who had served in Vietnam. The researchers recruited male veterans in 1995 from a list of those who had served in Vietnam and had contacted the Korean government to be examined for possible medical care and compensation for service-related conditions. In all, 4,432 veterans were on this list; 1,514 (34.2%) agreed to participate in the study. Of that group, 1,224 (27.6%) who were age-eligible for the study (45–64 years) completed the study interview

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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and examination. A comparison group consisted of 2,682 male non-Vietnam veterans who received military pensions and lived near Seoul. Only 154 (5.7%) agreed to participate in the study and provide complete data.

Kim J-S et al. (2003) created an index to estimate exposure to Agent Orange in the Vietnam veterans. The index included information about time spent in different regions of Vietnam and on their reports of exposure to Agent Orange on the skin, in the air, or through drinking or swimming in contaminated water. Quartiles were formed from scores on the index and the categories of exposure were compared with lipid-adjusted TCDD concentrations from blood samples drawn at the 1995 examination. The mean values of TCDD by quartile of the overall exposure index in the Vietnam veterans were 0.6, 0.62, 0.78, and 0.87 pg/g, respectively. The non-Vietnam veterans had an average serum TCDD of 0.3 pg/g. The assessment of health outcomes was done without knowledge of exposure status, but the researchers did not provide specific information on the definition of any health outcomes.

Hypertension was diagnosed in 27.9% (43/154) of non-Vietnam veterans and in 31.3% (383/1,224) of Vietnam veterans. The age-adjusted probability value for the difference in prevalence of hypertension was 0.01; among the Vietnam veterans, the prevalence of hypertension did not vary by quartile of Agent Orange exposure index (p = 0.90). In a logistic regression model that adjusted for age, body mass index, education, marital status, alcohol consumption, and tobacco use, the odds ratio for hypertension in Vietnam versus non-Vietnam veterans was 2.29 (95% CI, 1.33–3.95).

None of the other cardiovascular conditions was present in the sample of 154 non-Vietnam veterans. There was a statistically significant variation in the age-adjusted prevalence of disease in the Vietnam veterans, by exposure to Agent Orange for valvular heart disease (p = 0.002) and ischemic heart disease (p = 0.03). The result for valvular heart disease was attributable to a highly skewed distribution of a few cases—only 8 cases were diagnosed, and 6 were in the third quartile (with single cases in the first and fourth quartiles). Ischemic heart disease was more prevalent in the highest exposure quartile (10.1%) than in the lower quartiles (2%, 3.3%, and 1.6%, respectively). There was no adjustment for potential confounders other than age.

Synthesis

The new occupational and environmental studies of circulatory conditions do not support an association for exposure to herbicides, but they also do not represent compelling evidence for the lack of an association. The study of herbicide applicators (Swaen et al., 2004) uses mortality rates from the general population as the basis for comparison. The relatively low cardiovascular mortality observed for the herbicide applicators can be attributed to the “healthy worker effect,” rather than to any health-related benefit of herbicides per se. Comparing

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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the herbicide applicators with a similar (but non-exposed) group of employed individuals would lead to a more definitive test of the association. The ecological study by Fukuda et al. (2003) reported no association between measures of dioxin emissions and cardiovascular or cerebrovascular mortality after adjustment for socioeconomic correlates of dioxin emissions. However, the study design precludes inferences about the relationship between exposure and disease among individuals. Furthermore, the aggregate measure of dioxins prevents conclusions regarding any specific congeners. For those reasons, the reports by Swaen et al. (2004) and Fukuda et al. (2003) cannot be interpreted as important evidence of no association.

The study of Korean veterans (Kim J-S et al., 2003) shows an elevated prevalence of hypertension in Vietnam veterans compared with that for veterans who served elsewhere. This difference is not the result of confounding by important risk factors for hypertension, and the Vietnam veterans did have higher serum TCDD concentrations than did the comparison veterans. Ischemic heart disease was not diagnosed in any of the non-Vietnam veterans, but it was found in Vietnam veterans and was most prevalent among veterans in the highest quartile of the Agent Orange exposure index. However, some of the weaknesses noted in previous reviews of this literature are also present in this study. There is no information on the measurement of disease, and therefore no opportunity to comment on the quality of measurement. For example, is hypertension based on more than one measurement of blood pressure or measurement on more than one occasion? Is ischemic heart disease diagnosed from direct examination or from self-report of a previous diagnosis? If the latter, is the self-report confirmed by medical records that reveal clinical symptoms, ECG changes, and cardiac enzyme concentrations? Confounding has been addressed for hypertension but not for ischemic heart disease, despite the availability of the data.

The most serious concern with the data is the possibility of selection bias in the formation of the study population. A law in Korea to support medical care and compensation for herbicides victims became effective in May 1993, and the sample of Vietnam veterans for the study apparently was drawn from a list of veterans who applied to a government agency for health examinations and potential compensation for health conditions. Therefore, increased participation might be predicted for Vietnam veterans with chronic health conditions, and the selective participation could vary by exposure status (both the “external” and the “internal” comparisons could be biased). The relatively low participation in each group (28% and 6% in Vietnam and non-Vietnam veterans, respectively) underscores the need for additional data on the influence of selection bias in the study.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and specific circulatory disorders (coronary artery disease, myocardial infarction, stroke, hypertension) or circulatory conditions in general. As noted in earlier reports, important sources of uncertainty include the quality of measurement of health outcomes, incomplete assessment of confounding, and inconsistency of findings among magnitudes of exposure.

Biologic Plausibility

Many studies have indicated that TCDD can affect the developing cardiovascular system, but there is only limited evidence that the cardiovascular system is a target of TCDD in adult animals. There have been reports of developmental defects in the cardiovascular systems of TCDD-treated birds and fish. Recently, a dose-dependent increase in myocardial fibrosis has been observed in marmosets acutely exposed to TCDD at relatively low doses. Subchronic treatment with TCDD of hyperlipidemic ApoE-deficient mice caused a trend for earlier onset and greater severity of atherosclerotic lesions compared with vehicle-treated mice. Notably, ApoE-deficient mice have a lipoprotein profile similar to that of humans with type III hyperlipoproteinemia and develop extensive aortic and coronary atherosclerosis with lesions that are similar to those observed in humans. Therefore, there are data that suggest some biologic plausibility for an association between TCDD exposure and increased risk of cardiovascular disease. However, it is clear that additional studies are needed to confirm the relationships and to determine their relevance to humans.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and circulatory disorders, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

AL AMYLOIDOSIS

Amyloidosis (ICD-9 code 277.3) is a group of related disorders that share the common feature of the deposition of insoluable, fibrous amyloid protein, mainly in the extracellular spaces of organs and tissues. Depending on the nature of the

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

amyloid precursor protein, amyloid fibrils can be deposited in one location or involve multiple organ systems. The deposition of amyeloid might have no clinical consequences or it can lead to severe compromise of organ function; the different consequences occur because some amyloid proteins are more fibrillogenic than others.

AL amyloidosis is the most common form of systemic amyloidosis. Amyloidosis is classified according to the biochemical properties of the fibril-forming protein: the letter “A” (for amyloid) is the first designation; “L” is the protein designation (light chain). Annual incidence is estimated at 1/100,000, or more than 2,000 new cases annually in the United States. Amyloidosis occurs mainly in people 50–70 years old and more often in males than in females (Solomon, 1999).

AL amyloid proteins are derived from immunoglobin light chains. The proteins are common to primary amyloidosis and amyloidosis associated with other disorders, such as multiple myeloma, B-cell lymphomas, or other plasma cell dyscrasias. AL amyloidosis results from a monoclonal population of plasma cells that consistently produce immunoglobulin light chains. Clinical findings can include monoclonal immunoglobulin or immunoglobulin fragment in the urine or serum, nephrotic syndrome, hepatomegaly, carpal tunnel syndrome, macroglossia, peripheral neuropathy, and cardiomegaly. The diagnosis is usually made late in the course of the disease (Buxbaum, 2004).

AL amyloidosis can occur in the setting of other diseases that are associated with exposure to compounds of interest, such as multiple myeloma and B-cell lymphomas. However, most often patients diagnosed with AL amyloidosis do not have multiple myeloma or any other B-cell neoplasm. A common finding is of a modest increase in the number of plasma cells in the bone marrow. The most common disorder associated with AL amyloidosis is multiple myeloma; AL amyloidosis occurs in 15–20% of patients with multiple myeloma. Other associated disorders include monoclonal gammopathies, light chain disease, and agammaglobulinemia (producing light chains but not intact immunoglobulins).

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

The VA identified AL amyloidoisis as a concern after the publication of Update 1998. AL amyloidosis was examined specifically by the committees responsible for Update 2000 and Update 2002. Those committees concluded that there was inadequate or insufficient evidence to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and AL amyloidosis.

Update of the Scientific Literature

No relevant occupational, environmental, or Vietnam-veteran studies have been published since Update 2002.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
×

Synthesis

There is insufficient evidence of an association with AL amyloidosis and the compounds of interest. Although AL amyloidosis and multiple myeloma are similar—they both result from a clonal proliferation of plasma cells—there is insufficient evidence to link the increased risk for multiple myeloma from exposure to the compounds of interest with a possible increased risk in AL amyloidosis.

Conclusions

Strength of Evidence from Epidemiologic Studies

On the basis of its evaluation of the epidemiologic evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine an association between exposure to the compounds of interest and AL amyloidosis.

Biologic Plausibility

An association was reported between primary AL amyloidosis and TCDD exposure in a single study in mice (Toth et al., 1979). However, the TCDD exposure was relatively high (0.007–7.0 µg/kg per week for 1 year) and the amyloidosis was regarded as occurring only secondary to chronic skin lesions.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and AL amyloidosis, coupled with the lack of exposure information on Vietnam veterans, precludes quantification of any possible increase in their risk.

ENDOMETRIOSIS

Endometriosis (ICD-9 code 617) is a disease that affects 5.5 million women in the United States and Canada (NICHD, 2004). The endometrium is the tissue that lines the inside of the uterus that is built up and shed each month during menstruation. In endometriosis, endometrium is found outside the uterus—usually in other parts of the reproductive system, the abdomen, or the tissues near the reproductive organs. That misplaced tissue develops into growths or lesions that continue to respond to hormonal changes in the body and break down and bleed each month in concert with a woman’s menstrual cycle. Unlike blood released from endometrium in the uterus, blood released from the tissue in endometriosis has no way to leave the body, and the result is inflammation, internal bleeding,

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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and degeneration of blood and tissue from the growth that can cause scarring, pain, infertility, adhesions, and intestinal problems.

There are several theories about the etiology of endometriosis, including genetics, but the exact cause remains unknown. It has been proposed that endometrium is distributed through the body via blood or the lymphatic system; that menstrual tissue backs up into the fallopian tubes, implants in the abdomen, and grows; and that all women experience some form of tissue backup during menstruation but only those with immune system or hormonal problems experience the tissue growth associated with endometriosis. Despite numerous symptoms that can indicate endometriosis, diagnosis of the disease is possible only through laparoscopy or a more invasive surgical technique. Several treatments for endometriosis are available, but there is no cure.

Suspicion that TCDD is involved in the etiology of endometriosis began after the observation that the incidence of endometriosis was higher in monkeys treated with low doses of TCDD than in control monkeys (Rier et al., 1993). Experimental and epidemiologic studies have been conducted. Several epidemiologic studies have investigated non-dioxin-like PCBs, and some have examined a possible association with TCDD or dioxin-like compounds.

Summary of VAO, Update 1996, Update 1998, Update 2000, and Update 2002

Endometriosis was first reviewed in this series of reports in Update 2002, which identified two relevant studies. Both were small and showed elevated odds ratios, but for both the confidence intervals were very wide and included 1.0. Relevant studies reviewed earlier and in this update are summarized in Table 9-3.

Update of the Scientific Literature

Three environmental studies have been conducted since Update 2002 that examined the relationship between exposures to some of the compounds of interest and endometriosis. Eskenazi et al. (2002) investigated the development of endometriosis among participants of the Seveso Women’s Health Study. The cohort consisted of women who had lived in proximity to the Seveso accident site in 1976 and had TCDD serum measurements in blood collected between 1976 and 1980. Among 601 participants examined 20 years after the accident, 19 had confirmed endometriosis cases; 277 were non-diseased; 305 had symptoms but unconfirmed diagnoses and were classified as “uncertain.” Women in the highest exposure group (TCDD >100 parts per trillion [ppt]) showed a doubling in the risk of endometriosis compared with the lowest exposure group (TCDD ≤20 ppt), although the increase was not statistically significant (relative risk [RR] = 2.2, 95% CI, 0.5–8.0), possibly because of the small number of confirmed cases (N = 9). No increase was found among the highly exposed uncertain group or among the mid-exposure cases (20.1–100 ppt). Grouping women in the uncertain

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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TABLE 9-3 Selected Epidemiologic Studies—Endometriosis

Reference

Study Population

Study Results

ENVIRONMENTAL

New Studies

De Felip et al., 2004

Pilot study of Italian and Belgian women of reproductive age; compared concentrations of TCDD and total TEQ in pooled blood samples from women diagnosed with endometriosis to controls

Mean Concentration TCDD (pg/g lipid)

Italy:

Controls (10 pooled samples) = 1.6;

Cases (2 sets of 6 pooled samples) = 2.1, 1.3

Belgium:

Controls (7 pooled samples) = 2.5;

Cases (Set I, 5 pooled samples; Set II, 6 pooled samples) = 2.3,2.3

Mean Concentration (pg TEQ/g lipid)

Italy:

Controls (10 pooled samples) = 8.9±1.3 (99% CI, 7.2–11);

Cases (2 sets of 6 pooled samples) = 10.7±1.6; 10.1±1.5

Belgium:

Controls (7 pooled samples) = 24.7±3.7 (99% CI, 20–29);

Cases (Set I, 5 pooled samples; Set II, 6 pooled samples) = 18.1±2.7; 27.1±4.0

Fierens et al., 2003

Belgian women with environmental exposure to PCDDs/PCDFs or dioxins; compared analyte concentrationsa in cases vs controls

Mean concentrations (pg TEQ/g lipid):

Cases (n = 10) = 26.2 (95% CI, 18.2–37.7)

Controls (n = 132) = 25.6 (95% CI, 24.3–28.9)

No significant difference

Eskenazi et al., 2002

Residents of Seveso Zones A and B ≤30 years of age in 1976; compared incidence of endometriosis across serum TCDD concentrations

Serum TCDD 20.1–100 ppt:

8 exposed cases; OR = 1.2 (90% CI, 0.3–4.5)

Serum TCDD >100 ppt:

9 exposed cases; OR = 2.1 (90% CI, 0.5–8.0)

Studies Reviewed in Update 2002

Pauwels et al., 2001

Patients undergoing infertility treatment in Belgium; compared number of women with endometriosis and without endometriosis who had serum dioxin levels ≥100 pg TEQ/g serum lipid

6 exposed cases; OR = 4.6 (95% CI, 0.5–43.6)

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Reference

Study Population

Study Results

Mayani et al., 1997

Residents of Jerusalem being evaluated for infertility; compared number of women with elevated TCDD concentrations in diagnosed with endometriosis (n=44) with subjects not diagnosed with endometriosis (n=35)

8 exposed cases; OR = 7.6 (95% CI, 0.9–169.7)

a Dioxin TEQs calculated using the WHO (1998) Toxic Equivalency Factor methodology.

ABBREVIATIONS: PCDD, polychlorinated dibenzodioxin; PCDF, polychlorinated dibenzofurans; TCDD, tetrachlorodibenzo-p-dioxin; TEQ, toxicity equivalents.

category with the non-diseased women resulted in an increasing trend with exposure (RR, 1.6, and RR, 2.8 for the mid- and high-exposure groups, respectively), but the findings were not significant. A major limitation of the study was the inability to confirm with laparoscopy the disease state of the largest group, those with an uncertain diagnosis. All participants had resided in the two zones closest to the Seveso plant, so no truly unexposed control group was included in the study for comparison.

Fierens et al. (2003) completed a population-based cross-sectional study of residents in several Belgian towns in the vicinity of industrial sites or municipal solid-waste incinerators and a control group with no known exposures to dioxins or PCBs. The research included an assessment of the association between serum dioxin concentration and the prevalence of endometriosis. Self-administered questionnaires identified 10 cases of endometriosis in 142 females responding. Mean analyte concentrations were determined based on measurements of seventeen 2,3,7,8-polychlorinated dibenzodioxins or dibenzofurans. There was no difference in mean TEQ concentrations between the 10 cases and 132 controls (26.2 pg TEQ/g lipid [95% CI, 18.2–37.7] and 25.6 pg TEQ/g lipid, respectively). The study’s usefulness is compromised because of reliance on self-reports and because of the small number of cases.

De Felip et al. (2004) conducted a pilot case–control study of women of reproductive age in Italy (N = 22) and Belgium (N = 18) to determine whether there is a correlation between blood concentrations of dioxin-like compounds and endometriosis. Subjects were selected from patients at the gynecological department of one hospital each in Italy and in Belgium. Selection criteria included nulliparity, absence of a chronic disease, and absence of an ascertained professional exposure to environmental contaminants. Controls were those patients

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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suspected of having a benign adnexal mass; cases were suspected of having endometriosis. Dietary habits were documented by a questionnaire. All patients underwent a 10 mm laparoscopy, and the presence of endometriosis was confirmed by histologic examination of lesions. Of the subjects, 12 Italian and 11 Belgian women had endometriosis (cases). Blood samples were pooled for analyte analyses in sets (all including women ranging in age from 18 to 40 years), as follows: For Italian subjects, one set from controls (N = 10) and two sets from the cases (each set, N = 6). For Belgian subjects, one set from the controls (N = 7) and two sets from the cases (N = 5 and N = 6). Congener-specific concentrations were reported for 2,3,7,8-TCDD. The pooled blood concentrations, expressed in pg/g lipid, were as follows: In Italy, 1.6 for controls, 2.1 and 1.3 for the case sets; in Belgium, 2.5 for controls, 2.3 and 2.3 for the case sets. The data, therefore, do not indicate that the concentration of 2,3,7,8-TCDD was elevated in women with endometriosis. Looking at total TEQ (from PCDDs, PCDFs, and dioxin-like PCBs), the mean concentration was 8.9 ± 1.3 pg TEQ/g lb (99% CI, 7.2–11) in Italian controls, and 10.7 ± 1.6 and 10.1 ± 1.5 pg TEQ/g lb in Italian cases. In Belgian women the corresponding values were 24.7 ± 3.7 pg TEQ/g lb (99% CI, 20–29) in controls and 18.1 ± 2.7 and 27.1 ± 4.0 pg TEQ/g lb in cases. Overall, the study did not show that women with endometriosis had higher 2,3,7,8-TCDD or total TEQ than did controls. The study is limited in its ability to detect differences, however, by the small number of subjects. The selection criteria, which allowed all women with suspected gynecological abnormality, also introduced bias. The study did show that blood concentration of dioxin tend to be higher among Belgian women than in Italian women; concentrations in the Belgian group were comparable to those in the Belgian subjects in the study by Fierens et al. (2003).

No relevant occupational or Vietnam-veteran studies have been published since Update 2002.

Synthesis

None of the three studies discussed in this report demonstrated an increased risk for endometriosis with exposure to dioxin or dioxin-like compounds. Those results are consistent with the two case–control studies reviewed previously (IOM, 2003), both of which showed elevated odds ratios, but for which the confidence intervals were very wide and included 1.0. It should be noted, however, that all those studies were limited in their ability to detect an increase in endometriosis with exposure to dioxin or dioxin-like compounds, especially considering the small number of confirmed cases of endometriosis in most of the studies.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Conclusions

Strength of Evidence from Epidemiologic Studies

There is inadequate or insufficient evidence to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and endometriosis.

Biologic Plausibility

There is evidence from animal studies that TCDD can exacerbate or cause endometriosis. Other evidence demonstrates that TCDD inhibits progesterone-associated transforming growth factor b2 expression and endometrial matrix metalloproteinase suppression; those effects have been suggested as mechanisms that underlie an association between TCDD and endometriosis. The ability of TCDD to alter the expression of several growth factors, cytokines, and hormones also could mediate the promotion of endometriosis. Notably, the AhR and several AhR target genes are expressed in human endometriotic tissues. Functional AhRs are present in endometrial and endometriotic stromal cells and TCDD up-regulates RANTES (regulated on activation, normal T expressed and secreted) expression on those cells—also a possible mechanism in dioxin’s activity in endometriosis. Other data, however, do not support the hypothesis that dioxin may lead to the development of endometriosis. Because some animal data and the sparse human data support the biologic plausibility of an association between TCDD exposure and endometriosis, the investigations should continue.

Increased Risk of Disease Among Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and endometriosis, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

THYROID HOMEOSTASIS

The earlier volumes in this series of reports (IOM, 1994, 1996, 1998, and 2001) did not specifically address the thyrotoxic potential of TCDD and the herbicides used in Vietnam. The topic of thyroid homeostasis was first subjected to an integrated review in Update 2002 (IOM, 2003).

The thyroid gland secretes the hormones thyroxine (T4) and triiodothyronine (T3), which stimulate metabolism. The thyroid also secretes calcitonin, a hormone that controls calcium concentration in the blood and storage of calcium in bones. Secretion of T4 and T3 is under the control of thyroid-stimulating hormone (TSH), which is secreted by the anterior pituitary gland. Iodine operates in thyroid

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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physiology both as a constituent of thyroid hormones and as a regulator of glandular function. Control of circulating concentrations of those hormones is regulated primarily by a negative-feedback pathway that involves three organs: the thyroid, which produces thyroid hormones, and the pituitary and hypothalamus, which help maintain optimal T3 and T4 concentrations. In the hypothalamus–pituitary–thyroid feedback scheme, the hypothalamus stimulates the pituitary through thyrotropin-releasing hormone (TRH) to produce TSH, which triggers the thyroid to produce T4 and T3. Cells in the hypothalamus and pituitary respond to concentrations of circulating T4 and T3. When T4 and T3 are low, the pituitary is stimulated to deliver more TSH to the thyroid to increase T4 and T3 output. When circulating T4 and T3 are high, they signal to reduce the output of TRH and TSH. This negative-feedback loop maintains hormone homeostasis. Chemical-induced alterations in thyroid homeostasis can hamper the development of many organ systems, including the nervous and reproductive systems. Most adverse effects are caused by lack of thyroid hormone alone rather than by increases in TSH.

Effects on the thyroid can be stimulatory (hyperthyroidism) or suppressive (hypothyroidism). Graves’ disease is an example of hyperthyroidism; cretinism is an extreme example of hypothyroidism. Insufficient iodine intake resulting in goiter is not usually associated with either hyperthyroidism or hypothyroidism.

TCDD affects the concentrations of thyroid hormones; the effects appear to be species dependent and could reflect both the dose and the duration of exposure (IOM, 2001). TCDD influences the metabolism of thyroid hormones and TSH. However, contrasting results confuse interpretation of the effects of TCDD on the production and activity of the hormones.

Summary of Update 2002

The thyrotoxic potential of the compounds of interest was first addressed in this series of reports in Update 2002 (IOM, 2003). The committee responsible for Update 2002 concluded that there was inadequate or insufficient information to determine an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and adverse effects on thyroid homeostasis. In humans, some effects on thyroid homeostasis have been observed, mainly after exposure in the perinatal period, but the functional importance of those changes is unclear because adaptive capacity may be adequate to accommodate them.

Update of the Scientific Literature

Occupational Studies

Johnson et al. (2001) measured serum hormone and TCDD concentration in 37 men who had sprayed 2,4,5-T in Victoria, Australia. In correlation analysis,

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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TCDD concentrations were inversely related to T3 and TSH. The association was strongest when historical, but not current, serum TCDD concentrations were considered. In a paper reviewed in Update 1998, Zober et al. (1994) examined 138 BASF workers exposed to TCDD in a 1953 industrial incident. The researchers reported that thyroid disease was increased (p < 0.05) in the exposed population.

Environmental Studies

No relevant environmental studies have been published since Update 2002.

Vietnam-Veteran Studies

Pavuk et al. (2003) examined thyroid hormone status in the AFHS cohort. At each examination (1982, 1985, 1987, 1992, 1997) there was a trend toward an increasing concentration of TSH, which was not accompanied by changes in circulating T4 or in the percentage uptake of T3 (measured only in the earlier years). In a repeated-measures linear regression adjusted for age, race, and military occupation, the low-exposure and high-exposure Ranch Hands had TSH significantly higher than did the comparison population, and the trend test showed a significant linear increase over the comparison and background-, low-, and high-exposure groups (p = 0.002). No changes in microsomal or antithyroid antibodies were observed, nor was there any evidence of changes in clinical thyroid disease. The percentage with abnormally high TSH was higher at each examination in the high-exposure Ranch Hand group than in the comparison population, but the confidence intervals were wide and included 1 at each examination (1982: OR, 1.8, 95% CI, 0.7–5.9; 1985: OR, 1.4, 95% CI, 0.7–3.2; 1987: OR, 1.9, 95% CI, 0.8–4.5; 1992: OR, 1.7, 95% CI, 0.8–3.9; 1997: OR, 1.8, 95% CI, 0.9–3.4).

An earlier study of the Ranch Hand cohort (AFHS, 1991) was reviewed in VAO, but not reconsidered in Update 2002. The assessment of endocrine function in that study included a series of thyroid function tests, which showed no difference in thyroid function between exposed and control veterans.

Synthesis

Numerous animal experiments and several epidemiologic studies show that TCDD and dioxin-like compounds appear to exert an influence on thyroid homeostasis. The effects are hypothesized to provide a mechanism by which TCDD may affect early development of neurologic and sensory organs and of motor function when exposure occurs in utero or during lactation. However, clear effects of TCDD on thyroid homeostasis have also been observed when adult animals were exposed. Several human studies observed increases in TSH without evidence of increases in T4, indicating that the infants (selected for uncompli-

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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cated gestation, labor, and delivery) and the Ranch Hand Air Force personnel were able to adapt to the changes in thyroid status that might have been induced by the higher body burdens of TCDD and TEQ.

Conclusions

Strength of Evidence from Epidemiologic Studies

There is inadequate or insufficient evidence of an association between exposure to the compounds of interest and adverse effects on thyroid homeostasis. Some effects have been observed in humans, but the functional importance of those changes is unclear because adaptive capacity could be adequate to accommodate them.

Biologic Plausibility

TCDD affects concentrations of T4, T3, and TSH in experimental animals, but the effects lack consistency in demonstrating either a definite hyperthyroidism or hypothyroidism after exposure to TCDD. Nevertheless, long-term exposure of animals to TCDD usually results in suppressed T4 and T3 and stimulated TSH. The National Toxicology Program reported that female rats exposed chronically to TCDD demonstrated altered thyroid follicles. This was further characterized as being attributable to a reversible hypertrophic response of the follicular cell. Chapter 3 discusses recent toxicologic studies relevant to the biologic plausibility of the effects of TCDD and the herbicides on the thyroid gland.

Increased Risk of Disease in Vietnam Veterans

The lack of data on the association between exposure to the chemicals of interest and adverse effects on thyroid homeostasis, coupled with the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

SUMMARY

On the basis of the occupational, environmental, and veterans’ studies reviewed, the committee reached one of four conclusions about the strength of the evidence regarding an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and each of the health effects discussed in this chapter. As explained in Chapter 2, the conclusions reflect the committee’s judgment that if an association between exposure and an outcome exists, it would be found in a large, well-designed epidemiologic study in which exposure to herbicides or TCDD was sufficiently high, well-characterized, and appropriately measured on

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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an individual basis. To be consistent with the charge to the committee by the Secretary of Veterans Affairs in Public Law 102-4 and with accepted standards of scientific reviews, the distinctions between the conclusions are based on statistical association, not on causality. The committee used the same criteria that were used in VAO, Update 1996, Update 1998, Update 2000, and Update 2002 to categorize diseases by the strength of the evidence.

Health Outcomes with Sufficient Evidence of an Association

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

For VAO, Update 1996, Update 1998, Update 2000, and Update 2002, the committees concluded that there was sufficient evidence of an association between exposure to at least one compound of interest and chloracne. The scientific literature continues to support the classification of chloracne in the category of sufficient evidence. On the basis of the literature, no additional health effects discussed in this chapter satisfy the criteria necessary for this category.

Health Outcomes with Limited or Suggestive Evidence of Association

For this category, the evidence must suggest an association between exposure and outcome, it can 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 might be inconsistent.

For Update 1996, Update 1998, Update 2000, and Update 2002, the committees determined there was limited or suggestive evidence of an association between exposure to at least one compound of interest and porphyria cutanea tarda. The scientific literature continues to support the classification of this disorder in the category of limited or suggestive evidence.

On the basis of its evaluation of available scientific evidence, the committee responsible for the Type 2 Diabetes report concluded that there was limited or suggestive evidence of an association between exposure to at least one compound of interest and type 2 diabetes. The committee responsible for Update 2002 reached that same conclusion. Evidence reviewed in this report continues to support that finding.

No other changes have been made in the list of health outcomes in the category of limited or suggestive evidence.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Health Outcomes with Inadequate or Insufficient Evidence to Determine Association

The scientific data on many of the health effects reviewed by the committee were inadequate or insufficient to determine an association between exposure to the compounds of interest and the health outcome. For the health effects in this category, the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of association. Some studies failed to control for confounding or used inadequate exposure assessment. This category includes non-malignant respiratory disorders, such as asthma in isolation, pleurisy, pneumonia, and tuberculosis; immune system disorders (immune suppression and autoimmunity); lipid and lipoprotein disorders; gastrointestinal diseases; digestive diseases; liver toxicity; circulatory disorders; AL amyloidosis; endometriosis; and thyroid homeostasis disorders.

Health Outcomes with Limited or Suggestive Evidence of No Association

To classify outcomes in this category, several adequate studies covering the full range of known human exposure must be consistent in not showing a positive association between exposure and outcome at any magnitude of exposure. The studies also must have relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the conditions, magnitudes of exposure, and periods of observation covered by the available studies. The possibility of a very small increase in risk at the exposure studied can never be excluded.

The committees responsible for VAO, Update 1996, Update 1998, Update 2000, and Update 2002 concluded that none of the health outcomes discussed in this chapter had limited or suggestive evidence of no association with the exposures of interest (2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid). The most recent scientific evidence continues to support that conclusion.

Biologic Plausibility

This section summarizes the biologic plausibility of a connection between exposure to the compounds of interest and various non-cancer health effects on the basis of data from animal and cellular studies. The preceding discussions of individual health outcomes include a discussion of biologic plausibility for the specific effects. Details of the committee’s evaluation of data from recent toxicologic studies are presented in Chapter 3.

TCDD elicits a diverse spectrum of effects in animal and experimental studies, including immunotoxicity, hepatotoxicity, chloracne, loss of body weight, induction of phase I and phase II drug-metabolizing enzymes, modulation of hormone systems, and modulation of factors associated with the regulation of

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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cellular differentiation and proliferation. Those effects depend on sex, strain, age, and species.

Effects of TCDD on the liver include modulation of the rate at which hepatocytes multiply, increasing the rate of death of other types of liver cells, increasing the fat content of liver cells, decreasing bile flow, and increasing proteins and substances that are precursors to heme synthesis. TCDD also alters the amount of some enzymes in the liver, but this effect is not necessarily considered toxic. Liver toxicity is species specific; 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’s effects mediate non-cancer endpoints is not clear. TCDD has been shown to inhibit hepatocyte DNA synthesis, alter vitamin A homeostasis, decrease hepatic plasma membrane epidermal growth factor receptor, inhibit hepatic pyruvate carboxylase activity, induce porphyrin accumulation in fish and chick embryo hepatocyte cultures, and alter liver enzyme concentrations and activity. Hepatomegaly has occurred after high subchronic doses. The mechanism of TCDD hepatoxicity is not established, but most studies are consistent with the hypothesis that the effects of TCDD are mediated by the AhR, a protein in animal and human cells to which TCDD can bind. The TCDD–AhR complex is thought to bind DNA and to lead to changes in transcription (differential regulation of genes) that alter cell function. Although structural differences in the AhR have been identified in various species, the receptor operates similarly in animals and humans. Animal data support a biologic basis for TCDD’s toxic effects. Because of the many species and strain differences in TCDD responses, however, the extent to which animal data inform the evaluation of human health outcomes is controversial.

There is little evidence that the cardiovascular system is a sensitive target of TCDD toxicity in adult animals. It has been proposed however, that dioxin may increase the incidence of ischemic heart disease by exacerbating its severity. For example, treatment of rats with dioxin-like chemicals was found to affect several cardiovascular risk factors including heart weight, serum cholesterol, and blood pressure.

The immune system is particularly sensitive to TCDD toxicity. Studies in mice, rats, guinea pigs, and monkeys indicate that TCDD suppresses the function of some 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 suppresses cell-mediated immunity, primarily by affecting the T-cell arm of the immune response, and that results in a decrease in the number and response some types of T cells. Some recent evidence suggests that TCDD directly affects T cells and their ability to undergo activation. TCDD could indirectly affect T cells and cell-mediated immunity by altering thymus function or cytokine production. The generation of antibodies by B cells, an indication of humoral

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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immunity, also could be affected by TCDD. The function and commitment patterns of hematopoietic stem cells may also be affected by TCDD. As with other effects of TCDD, the immunotoxic effects are species and strain specific. Increased susceptibility to infectious disease has been reported after TCDD administration. In addition, TCDD increased the number of tumors that formed in mice after injection of tumor cells. Despite considerable laboratory research, the mechanisms that underlie the immunotoxic effects of TCDD are still unclear, but most studies are consistent with the hypothesis that the effects are mediated by the AhR. TCDD’s wide range of effects on growth regulation, hormone systems, and other factors also could mediate its immunotoxicity. As with other TCDD-mediated effects, the similarity in function of the AhR among animals and humans suggests a possible common mechanism of immunotoxicity. Nevertheless, the available data have not confirmed in humans the universal immunosuppressive effects observed in laboratory animals.

Although data on the health effects of the herbicides discussed in this report are not extensive, effects have been seen in several organs in laboratory animals. The liver is a target organ for 2,4-D, 2,4,5-T, and picloram, with effects 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 also has been associated with effects on blood, such as reduced heme and red 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 the interaction and its biologic consequences are unknown. 2,4,5-T has been shown to be a weak myelotoxin.

Few studies have examined the potential immunotoxicity of the herbicides used in Vietnam. Effects on the immune systems of mice were reported for 2,4-D administered at doses that were high enough to produce clinical toxicity; the effects did not occur at low doses. The potential for picloram to act as a contact sensitizer (that is, to produce an allergic response on the skin) was tested, but other aspects of its immunotoxicity were not examined.

The foregoing suggests that a connection between TCDD or herbicide exposure and human toxic effects is, in general, biologically plausible. However, definitive conclusions about the presence or absence of a mechanism for the induction of specific toxicity by these compounds in humans are complicated by the differences in sensitivity and susceptibility among individual animals, strains, and species; by the lack of strong evidence of organ-specific effects among species; and by differences in route, dose, duration, and timing of exposure. Investigating the biologic mechanisms that underlie TCDD’s toxic effects continues to be an area of active research, and future updates of this report might be able to present more and better information on which to base conclusions, at least for that compound.

Suggested Citation:"9 Other Health Effects." Institute of Medicine. 2005. Veterans and Agent Orange: Update 2004. Washington, DC: The National Academies Press. doi: 10.17226/11242.
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Increased Risk of Disease Among Vietnam Veterans

Although there are data to suggest an association between exposure to the chemicals of interest and some of these health effects, the lack of exposure information on Vietnam veterans precludes quantification of any possible increase in their risk.

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Veterans and Agent Orange: Update 2004 Get This Book
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Sixth in a series of congressionally mandated studies, this book is an updated review and evaluation of the available evidence regarding the statistical assoication between exposure to herbicides used in Vietnam and various adverse health outcomes suspected to be linked with such exposure.

This book builds upon the information contained in the earlier books in the series:

  • Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (1994)
    • Veterans and Agent Orange: Update 1996
    • Veterans and Agent Orange: Update 1998
    • Veterans and Agent Orange: Update 2000
    • Veterans and Agent Orange: Update 2002
    • Veterans and Agent Orange: Herbicides and Dioxin Exposure and Type 2 Diabetes (2000)
    • Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans (2002)

      Veterans and Agent Orange: Update 2004 focuses primarily on scientific studies and other information developed since the release of these earlier books. The previous volumes have noted that sufficient evidence exists to link chronic lymphocytic leukemia, 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 of an association between exposure and respiratory cancers, prostate cancer, multiple myeloma, the metabolic disorder porphyria cutanea tarda, early-onset transient peripheral neuropathies, Type 2 diabetes, and the congenital birth defect spinal 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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