10
Other Health Effects

INTRODUCTION

This chapter addresses a variety of noncancer health outcomes: chloracne, porphyria cutanea tarda, respiratory disorders, immune system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), and circulatory disorders. Additionally, in response to a request from the U.S. Department of Veterans Affairs (DVA), the scientific literature regarding AL-type primary amyloidosis and herbicide or dioxin exposure is evaluated.

The health outcomes reviewed in this chapter follow a common format. Each section begins by providing some background information about the outcome under discussion. A brief summary of the findings described in earlier Veterans and Agent Orange reports is then presented, followed by a discussion of the most recent scientific literature and a synthesis of the material reviewed. Where appropriate, reviews are separated by the type of exposure (occupational, environmental, Vietnam veteran) being addressed. Each section concludes with the committee’s finding regarding the strength of the evidence in epidemiologic studies, biologic plausibility, and evidence regarding Vietnam veterans.

CHLORACNE

Background

Chloracne is recognized to be an outcome of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other cyclic organochlorine compounds. It



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Veterans and Agent Orange: Update 2000 10 Other Health Effects INTRODUCTION This chapter addresses a variety of noncancer health outcomes: chloracne, porphyria cutanea tarda, respiratory disorders, immune system disorders, diabetes, lipid and lipoprotein disorders, gastrointestinal and digestive disease (including liver toxicity), and circulatory disorders. Additionally, in response to a request from the U.S. Department of Veterans Affairs (DVA), the scientific literature regarding AL-type primary amyloidosis and herbicide or dioxin exposure is evaluated. The health outcomes reviewed in this chapter follow a common format. Each section begins by providing some background information about the outcome under discussion. A brief summary of the findings described in earlier Veterans and Agent Orange reports is then presented, followed by a discussion of the most recent scientific literature and a synthesis of the material reviewed. Where appropriate, reviews are separated by the type of exposure (occupational, environmental, Vietnam veteran) being addressed. Each section concludes with the committee’s finding regarding the strength of the evidence in epidemiologic studies, biologic plausibility, and evidence regarding Vietnam veterans. CHLORACNE Background Chloracne is recognized to be an outcome of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other cyclic organochlorine compounds. It

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Veterans and Agent Orange: Update 2000 appears shortly after exposure and, although refractory to treatment, usually regresses over time and does not appear after a long latency. New cases of chloracne are therefore not a concern of this report. Chloracne is a highly characteristic form of acne. It shares some pathological processes, such as occlusion of the orifice of the sebaceous follicle, with much more common forms of acne such as acne vulgaris. However, it is marked by a unique feature, the epidermoid inclusion cyst, which is caused by proliferation and hyperkeratinization (horn-like cornification) of the epidermis. Although typically appearing in a characteristic distribution over the eyes, ears, and neck, patterns of chloracne among exposed chemical industry workers may involve the trunk, genitalia, and buttocks (Neuberger et al., 1998). Chloracne has been extensively studied and is used as a marker of exposure in studies of populations exposed to TCDD, as such residents involved in the 1976 industrial incident in Seveso, Italy, and to 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 these compounds, particularly TCDD (Sweeney et al., 1997/ 98). The predictive value of chloracne as a biomarker is suggested by its strong association with other health outcomes, such as goiter, arthritis, and anemia in the Taiwanese population affected by the “Yucheng” (cooking oil disease) incident in 1979, in which there was exposure to high levels of PCBs (Guo et al., 1999). Despite the utility of chloracne as a biomarker, and the general association with high blood levels of TCDD and related compounds, it has not been possible to identify a threshold level for the skin condition. Kimbrough (1998) suggests that this may be because blood levels do not necessarily reflect levels in skin. She also suggests that susceptibility due to different skin conditions may obscure the association or that direct dermal deposition may play a greater role in some situations. Kimbrough suggests that Ranch Hand veterans have too narrow and too low a range of blood levels from which to draw conclusions and also that the time elapsed after exposure until the studies were performed may have introduced confounding factors such as aging, obesity, and onset of diabetes, all of which change blood lipid levels in ways that may not affect skin changes and that may obscure relationships with chloracne. One new study to shed light on the elusive threshold for development of chloracne was contributed by Coenraads et al. (1999), reporting on four groups of Chinese workers involved in industrial incidents that exposed them to polycyclic organochlorines, particularly TCDD. They reported their findings in terms of 2,3,7,8-TCDD toxicity equivalents (TEQs) in pooled blood, levels of exposure to these compounds weighted by their TCDD-like activity. They inferred a threshold for chloracne (per gram of blood lipid) between 650 and 1,200 pg/g TEQ. They also suggested that in this population, the contribution to the risk of developing chloracne from exposure to TCDD itself was small compared to the hexachlorinated dibenzodioxins and furans, a finding that may be specific to this population and the exposure conditions.

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Veterans and Agent Orange: Update 2000 Summary of VAO, Update 1996, and Update 1998 The committee responsible for the Veterans and Agent Orange: Health Effects of Herbicides used in Vietnam (hereafter referred to as VAO; IOM, 1994) report found there to be sufficient information to determine that an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and chloracne. Additional information available to the committees responsible for Veterans and Agent Orange: Update 1996 (IOM, 1996) and Update 1998 (IOM, 1999) did not change this finding. Reviews of the studies underlying these findings may be found in the earlier reports. Previous reports discuss chloracne extensively as a toxicological phenomenon but do not treat it extensively as a health outcome. New cases are not expected after the long latency, and new information on the mechanism of chloracne would not be expected to alter the interpretation of existing data from Vietnam veterans exposed to Agent Orange. Update of the Scientific Literature Vietnam veterans enrolled in the Ranch Hand study were not found to have chloracne. Burton et al. (1998) examined the same group for evidence of an increased risk for acne in general. Their working hypothesis was that levels of exposure insufficient to cause florid chloracne may increase the risk of other acneiform rashes because some of the mechanisms of comedone formation are similar. They also suggested that the florid appearance in-country of “tropical acne” among many troops, which was a major cause of morbidity during the conflict, may have been unrecognized chloracne. Despite the high frequency of skin disorders reported during service in Vietnam, the authors found no evidence for an increased risk of acne among Ranch Hand participants compared to other theater veterans, either during the Vietnam conflict or subsequently, and no cases of chloracne. The authors suggested that Ranch Hand participants may not have accumulated a sufficient dose to be at risk for chloracne. This study classified troops by serum dioxin levels and may be considered definitive. Synthesis Chloracne is clearly associated with exposure to high levels of cyclic organochlorine compounds. Blood levels that may reflect tissue threshold concentrations remain estimations. Estimates of the mean threshold of exposure, dose, blood level, or tissue level for induction of chloracne in human beings remain highly uncertain, and there is strong evidence of considerable variation among individuals. Ranch Hand veterans did not show evidence of chloracne, probably because the tissue concentrations required to induce this skin disorder were not reached. No new cases of chloracne from exposure in Vietnam will appear among Vietnam veterans at this late date.

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Veterans and Agent Orange: Update 2000 Conclusions Strength of Evidence in Epidemiologic Studies There is no change in the previous conclusion that there is sufficient and abundant evidence to conclude that chloracne is associated with exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and to TCDD in particular. The fact that Ranch Hand veterans did not experience this condition does not change the overall conclusion. Biologic Plausibility The formation of chloracne lesions after administration of TCDD is observed in some species of laboratory animals, supporting a biologic basis for these effects in humans. Similar observations have not been reported for the purified herbicides (i.e., without TCDD contamination). A discussion of toxicological studies that comprise the biologic basis for an association between exposure to TCDD or herbicides and toxicity end points is contained in Chapter 3; a general summary of the biologic basis for various end points is presented in the conclusion to this chapter. Increased Risk of Disease Among Vietnam Veterans Vietnam veterans in the AFHS study were not found to have chloracne. Because chloracne appears shortly after exposure, regresses over time, and does not appear after a long latency, no new cases from wartime exposures are expected. PORPHYRIA CUTANEA TARDA Background Porphyria cutanea tarda (PCT) is only incompletely understood, and investigation into its mechanisms may provide useful insights into iron metabolism and the formation of hemoglobin. For this reason, more than for its clinical benefit, there has been further investigation into the mechanisms of PCT. Unpublished data by Sinclair (2000) reporting on investigations using liver cells in tissue culture suggest that uroporphyrin accumulation following exposure to TCDD and other presumable inducers may be reduced by ascorbate (vitamin C) acting to inhibit the activity of a cytochrome P450 1A2 (CYP1A2) that is induced by TCDD. Human subjects who had developed PCT were also found to be ascorbate deficient in almost 80 percent of cases, suggesting that poor diet may be a risk factor along with the known risk factors of high alcohol intake, estrogens (as in oral contraceptives), liver disease, hemodialysis, HIV infection, and diabetes.

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Veterans and Agent Orange: Update 2000 Cigarette smoking also induces CYP1A2 and may be a risk factor, but this was not investigated. The results were interpreted to suggest that PCT is not more common because adequate ascorbate levels are present in the normal diet but that deficiencies may predispose to the disease (Sinclair, 2000). An adequate diet may be protective against manifestations of the disease following exposure to TCDD, at least in most people. This finding may explain why PCT was not observed among Ranch Hand participants and was not identified as a health problem among Vietnam veterans exposed to Agent Orange. The genetic basis for PCT has also been further elucidated since Update 1998 with the identification of at least three genes determining susceptibility to hexachlorophene-induced PCT in mice. If the human disorder is as complex, the observation would explain why susceptibility to PCT is as rare as it is in humans (Akhtar and Smith, 1998). Summary of VAO, Update 1996, and Update 1998 The committee responsible for VAO found there to be sufficient information to determine that an association existed between exposure to herbicides used in Vietnam or the contaminant dioxin and PCT in genetically susceptible individuals. Additional information available to the committee responsible for Update 1996 led it to conclude that there was limited or suggestive evidence of an association; Update 1998 did not change this finding. Reviews of the studies underlying these findings may be found in the earlier reports. PCT has been discussed extensively in both VAO and the two prior updates. VAO reviewed case reports of PCT among chemical workers who showed subsequent resolution following removal from the workplace. These reports are anecdotal and difficult to interpret because of multiple exposures. Update 1998 hypothesized that the absence of detectable PCT may also have been explained by the fortuitous absence of genetically predisposed individuals among exposed Vietnam veterans. Contemporary research suggests that susceptibility to the disease is indeed a rare trait and that adequate diet may have been protective for those who were susceptible. PCT is an early response to TCDD and is therefore no longer of current concern because new cases are not expected. Update of the Scientific Literature Neuberger et al. (1999), following a group of 159 Austrian chemical workers exposed to TCDD in herbicide production in the 1970s, reported that urinary porphyrins remained abnormal, although not clinically characteristic of PCT. Coproporphyrinogen levels were within the normal range, but there was a reversal in the normal ratio of isomers (I compared to III) in almost half of the subjects. The authors inferred that this indicated persistent liver injury and abnormal por-

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Veterans and Agent Orange: Update 2000 phyrin metabolism due to TCDD and implied that exposed workers may be at risk for related conditions, including PCT, for much longer than had been assumed previously. Conclusions Strength of Evidence in Epidemiologic Studies There is no basis for changing the previous conclusion that there is limited/ suggestive evidence of an association between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and PCT. Biologic Plausibility There is some evidence that TCDD can be associated with porphyrin abnormalities in laboratory animals, although PCT has not been reported. Porphyria has not been reported in animals exposed to the other herbicides relevant to Agent Orange. A discussion of toxicological studies that comprise the biologic basis for an association between exposure to TCDD or herbicides and toxicity end points is contained in Chapter 3; a general summary of the biologic basis for various end points is presented in the conclusion to this chapter. Increased Risk of Disease Among Vietnam Veterans PCT is an early response to TCDD and therefore no new cases due to wartime exposure are expected among Vietnam veterans. RESPIRATORY DISORDERS Background In Update 1998, only passing mention was made of inflammation and immune function in relation to respiratory disorders and their possible association with exposure to Agent Orange. Recent findings of a possible association with exposure to TCDD and related organochlorines among Seveso residents require closer attention to this issue. The lung expresses injury resulting from inflammation in two general ways. Inflammation may result in changes in resistance to airflow in the conducting airways. Inflammation may also result in permanent scarring, or fibrosis, in the tissue of the air sacs (alveoli), which leads to stiffening of lung tissue and impairment of the capacity of the lung to fully expand. As described in Update 1998, airflow obstruction is measured primarily by the forced expiratory volume at 1 second (FEV1) and secondarily by the ratio of FEV1 to forced vital capacity (FVC)

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Veterans and Agent Orange: Update 2000 (i.e., FEV1/FVC) and other forced expiratory flow rates. Lung capacity is measured primarily by the FVC and secondarily by measurements of total lung capacity. Airflow obstruction is variable; it may be completely reversible in asthma, or it may be constant in whole or in part in emphysema. Chronic bronchitis is a less common condition characterized by sputum production, which often accompanies asthma, and may also progress to fixed airway obstruction. These three conditions are associated with varying degrees and sites of inflammation occurring on a prolonged basis. Asthma is fundamentally a disorder of chronic inflammation of the larger airways, which may be a response to allergy, infection, or irritation and expresses itself as constriction of smooth muscle tissue and edema in the wall of the airway. These inflammatory processes reduce the caliber of the airway inside diameter, or lumen, and—following a physical law that resistance increases exponentially with reduced diameter of the passage—obstruct airflow. Asthma commonly occurs in persons with other expressions of allergy, especially children, but it can develop in adults without a clear connection to allergies. Mild degrees of airflow reduction may not be noticed by the person so affected. Moderate to severe airflow obstruction is perceived as wheezing and shortness of breath. Cough in response to the inflammatory process is common and may be the principal manifestation of asthma. Asthma is reversible because these inflammatory processes can get better or worse and are usually controlled on medication, so that individuals with asthma experience the disease as a series of episodes, often occurring in response to allergic reactions, infections, stress, or irritation. Severe asthma does occur, and the frequency of deaths from asthma has risen in many countries, at least in part associated with suboptimal treatment or inadequate access to medical care. The prevalence of asthma is also rising in most developed and affluent countries for reasons that are not clear but are suspected to reflect changes in immune response to common allergens in homes. Asthma is identified by a compatible history of episodic shortness of breath and wheezing and by pulmonary function tests showing obstruction to airflow that varies in response to drugs that dilate the airways. In surveys, asthma is difficult to identify reliably by symptoms alone in a self-administered questionnaire, and the subject is usually asked whether the diagnosis of asthma has ever been made. Emphysema is a disorder of chronic inflammation and disintegration of lung tissue adjacent to smaller airways such that their supporting structure is lost and the thin-walled airways collapse at pressures within the chest that are required to expel air. When this happens, airflow is obstructed and more than normal amounts of air may be trapped in the lung after an exhaled breath. The inflammatory process of primary significance in emphysema is localized to the lung tissue immediately surrounding the airway, as opposed to the airway itself as in asthma and chronic bronchitis. Aside from rare hereditary disorders and occupational exposures, the cause of emphysema is overwhelmingly cigarette smoking. Emphysema is identified by pulmonary function studies and often by chest films.

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Veterans and Agent Orange: Update 2000 Chronic bronchitis is a more gross and nonspecific process of airway inflammation often associated with either asthma or emphysema when it occurs. It is characterized by increasing production of sputum and frequent coughing. Chronic bronchitis has become much less common in recent years and, when it occurs today, is almost always associated with cigarette smoking, although it can accompany allergies, severe air pollution, and occupational exposures. Acute bronchitis is much more common, is usually self-limited, occurs in response to common illnesses such as influenza in addition to environmental irritants, and does not carry the same risk of permanent respiratory injury. Chronic bronchitis is diagnosed by a history of productive cough and can be reliably screened for by a questionnaire. Because the three conditions causing airflow obstruction frequently occur together, they are often difficult to distinguish. They all have a common association with cigarette smoking and are interrelated by inflammatory processes. Because these conditions often occur together and are interrelated, they are usually aggregated into a collective category of chronic obstructive pulmonary disease (COPD), which is considered a distinct entity in treatment and coding for most epidemiologic purposes. For practical purposes, COPD should be understood to include all three disorders occurring together, any two of them if they occur together, and either chronic bronchitis or emphysema if it occurs separately. Further, there is some evidence to suggest that these conditions are associated biologically, through common hereditary predisposition, and may be associated with an increased risk of lung cancer for a given history of cigarette smoking. Asthma requires separate consideration. Asthma is always coded separately in hospital discharge summaries and death certificates if it occurs in isolation from the other two because asthma in isolation has distinct risk factors and is considered a distinct disease. Asthma is a common disease, but fatal asthma is rare, notwithstanding the fact that mortality rates rose in many countries in the 1980s. There are usually insufficient numbers to report asthma deaths separately, and the mortality rate for asthma varies from year to year because of the small numbers. For this reason, asthma is usually aggregated for epidemiologic purposes with the other two disorders under COPD or a category of nonmalignant respiratory disorders when causes of death are considered. Asthma is counted separately in prevalence surveys or incidence studies of respiratory disease. Fibrosis of lung tissue is a response to inflammation resulting in diffuse damage to the walls of the air sacs, or alveoli, and supporting structures. The scarring that occurs reduces the resilience, or compliance, of the lung and reduces its capacity to expand. This is called restrictive lung disease. The scarring also has secondary effects on the distribution of blood to various parts of the lung where oxygen is taken up more or less efficiently and, as it progresses, may cause reduction (desaturation) in oxygenation of blood. Pulmonary fibrosis may occur as a consequence of severe injury deep in the lung due to infection, inhalation of a toxic chemical that is poorly soluble in water (and therefore not cleared in the

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Veterans and Agent Orange: Update 2000 upper respiratory tract), inflammatory conditions caused by inhalation of particles to which there is an allergy, and a variety of immunological disorders. Pneumonia and other lung infections generally run a much more acute course, and although they may occur more frequently in cigarette smokers, they usually have different and distinct risk factors not necessarily shared with chronic lung diseases. Their clinical course and risk of death may also be modified by changes in host defenses and especially by reductions in immune function. This is why pneumonia is a frequent cause of death following aggressive cancer chemotherapy and viral infections such as AIDS that depress the immune response to bacterial and parasitic infections. These conditions may be modified in their frequency and their expression by modifications in the immune process and other protective mechanisms. These mechanisms often occur together and may be mechanical (cough), immunological, or inflammatory, with or without an associated immune response. Collectively, these protective responses are called host defense mechanisms. If TCDD affects host defense mechanisms of the lung, it is most likely to affect immune mechanisms, as it is known to do elsewhere in the body. The immune system in the lung is partly compartmentalized, with its own sites of lymphocyte and alveolar macrophage proliferation, and partly shared with the rest of the body. Circulating immunoglobulins, polymorphonuclear white cells, and lymphocytes play an especially important role in the initial response. Thus, TCDD-induced immunomodulation of these responses could occur in response to exposure whether or not concentrations in lung tissue reach a toxic level. TCDD is a potent immunotoxic agent and may be expected to have effects on the expression of immune function in the lung. However, the net effect of TCDD exposure is unpredictable. The effect of TCDD may be to reduce or vary the expression of immune response in the lung. There are no studies that have investigated the response of the immune system in the lung, either to systemic exposure to TCDD or to TCDD levels in the lung that reflect actual tissue levels observed in exposed individuals. Iida et al. (1999) demonstrated that in human beings, levels of TCDD in lipids extracted from the lung correlated closely with concentrations in lipid extracted from blood and were greater by a factor of approximately 1.7, but did not correlate closely for other dioxins and furans (except the relatively nontoxic octochloro variety). The concentration of dioxins and furans in lipid derived from lung was higher than in lipid derived from liver, brain, spleen, muscle, kidney, and adipose tissue. This raises the possibility of local effects in the lung that may be stronger than the effects in other tissues for a given level of personal exposure. Summary of VAO, Update 1996, and Update 1998 The committee responsible for VAO found there to be inadequate or insufficient information to determine whether an association existed between exposure

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Veterans and Agent Orange: Update 2000 to herbicides used in Vietnam or the contaminant dioxin and the respiratory disorders discussed above. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding. Reviews of the studies underlying these findings may be found in the earlier reports. Cigarette smoking is a major, often overwhelming, confounding exposure that dominates as a risk factor for respiratory disorders and may obscure weaker associations. Vietnam veterans are reported to smoke more heavily than non-Vietnam veterans (McKinney et al., 1997), making any such association more difficult to discern. Update of the Scientific Literature Bertazzi and colleagues (Bertazzi et al., 1998; Pesatori et al., 1998) continued their follow-up of residents of the town of Seveso, Italy, site of the industrial incident in 1976 that exposed the local population to substantial amounts of relatively pure TCDD. This is one of the few nonoccupationally exposed populations that has been studied in detail, the largest such population studied, and certainly the nonoccupational population with the highest exposure and best exposure assessment. Until long-term follow-up data became available for 15 years following the incident, no evidence had been observed for respiratory impairment. An elevated mortality for respiratory disorders that achieves statistical significance has now been observed among exposed residents of Seveso compared to unexposed residents in surrounding communities. Residents of zone A, the area most heavily contaminated by TCDD showed a relative risk (RR) for males of 2.4 (5 deaths observed, 95 percent confidence interval [95%CI] 1.0–5.7) and for females of 1.3 (2 deaths observed, 0.3–5.3). Residents of zone B, the “medium” contaminated area, showed a relative risk for males of 0.7 (13 observed, 0.4–1.2) and for females of 1.0 (10 observed, 0.5–1.9). Residents of zone R, the least exposed area, showed a relative risk for males of 1.1 (133 observed, 0.9–1.3) and for females of 1.0 (84 observed, 0.8–1.2). This pattern is consistent with an effect, primarily among males, at the highest exposure levels but is not sufficient to conclude that there is an exposure-response relationship for respiratory disorders as a whole. Mortality from respiratory disorders in the adult Seveso population, as in most populations in developed societies of the world, is driven by deaths from chronic obstructive pulmonary disease, which is overwhelmingly attributable to cigarette smoking. Mortality from COPD is usually higher among males than females because of increased smoking prevalence, frequency, and duration among men, although women are thought to be more susceptible to the effects of cigarette smoke. The residents of zone A showed a RR for males of 3.7 (4 deaths observed, 1.4–9.8) and for females of 2.1 (only 1 case observed, 0.3–14.9). Residents of zone B showed a relative risk for males of 1.0 (9 observed, 0.5–1.9) and for females of 2.5 (8 observed, 1.2–5.0). Residents of zone R showed a RR

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Veterans and Agent Orange: Update 2000 for males of 1.2 (74 observed, 0.9–1.5) and for females of 1.3 (37 observed, 0.9– 1.9). This is a stronger and somewhat more consistent correlation suggesting, but not proving, an exposure-response relationship and the possibility of an effect on both sexes (Bertazzi et al., 1998; Pesatori et al., 1998). These findings were essentially unchanged in the exposed groups after 20 years and did not show suggestive evidence of a latency effect overall, with one exception. Women in zone A did show highest mortality in two peaks, one at 0 to 4 years, no mortality at 5 to 9 years, and another at 10 to 20 years, but this pattern, which could be compatible with an immediate effect, exhaustion of susceptibles, and a latent effect, is the result of only 3 cases (Bertazzi et al., 2001). It is possible that these findings are confounded by cigarette smoking, but this is judged to be highly unlikely. Bertazzi and colleagues (Bertazzi et al., 1998; Pesatori et al., 1998) offer the observation that their survey data do not demonstrate a higher prevalence of smoking by Seveso residents of the exposed zones compared to their unexposed neighbors. They correctly point out that the proportionate differences in cigarette smoking required to achieve such an elevation in risk of morbidity or mortality would be highly unlikely (Pesatori et al., 1998). Such a lopsided result would also be obvious in the survey data. They also point out that smoking-related lung cancers are not increased among exposed residents. They ruled out misclassification and coding as plausible sources of error (Pesatori et al., 1998). Bertazzi et al. (1998) suggest that a stress-related or host defense-related impairment may be responsible that is not mediated by behavioral changes resulting in increased smoking. They state that “early deaths among persons with impaired respiratory systems may have been caused by the social and emotional impact of the disaster” and imply that changes in the immune response as a result of TCDD exposure may have altered the inflammatory response to cigarette smoking in earlier stages of the habit, presumably enhancing the adverse effects, accelerating the loss of lung function, and hastening the onset of COPD (Bertazzi et al., 1998). This mechanism is speculative and not further defined. If this hypothesis is correct, it may be predicted that the elevation in risk is confined to cigarette smokers. Occupational studies of exposed workers have not duplicated the finding in Seveso of increased mortality from nonmalignant respiratory disease. The National Institute of Occupational Safety and Health (NIOSH) conducted a cohort mortality study of 5,132 chemical workers at 12 plants in the United States who were known to have been exposed to TCDD (Steenland et al., 1999). This synthetic population, consisting of four previously studied cohorts pooled together, showed an increased risk for all cancers combined (RR=1.1, 1.0–1.3), an increased risk for lung cancer that did not achieve statistical significance, and exposure-response relationships with lung cancer and with all smoking-related cancers that were statistically significant (two-sided test for trend, p<.03 and p<.02, respectively). This suggests that if it were present, an effect reflecting TCDD exposure could be observed in this group, which is large enough to have the statistical power

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Veterans and Agent Orange: Update 2000 trichlorophenoxyethanol (TCPE) containing dioxin and of pure dioxin in outbred Swiss/H/Riop mice. TCPE, like 2,4,5-T, is a derivative of TCP. Mice were dosed via gastric tube once a week for a year, beginning at 10 weeks of age, and followed for the remainder of their lives. The authors reported that “TCDD caused severe chronic, ulcerous skin lesions (probably similar to chloracne in humans) followed by generalized lethal amyloidosis, which can be regarded as a process secondary to chronic lesion.” The lesions and amyloidosis both exhibited a dose-response relationship to TCDD. These results are consistent with a small literature reporting amyloidosis secondary to chronic chemical insults in humans (Jacob et al., 1978; Scholes et al., 1979). The committee did not identify any literature addressing primary amyloidosis in animals or people exposed to the herbicides used in Vietnam or dioxin. Synthesis There is no direct evidence on which to base a finding concerning whether or not AL-type primary amyloidosis is associated with exposure to the herbicides used in Vietnam or dioxin. Although multiple myeloma and primary systemic amyloidosis are both clonal plasma cell proliferative disorders, there is no scientific reason to believe that available information regarding multiple myeloma and herbicide or dioxin exposure informs the question of an association with amyloidosis. Conclusions Strength of Evidence in Epidemiologic Studies There is inadequate/insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and AL-type primary amyloidosis. Biologic Plausibility The single animal study (Tóth et al., 1979) reporting secondary amyloidosis in a strain of mice chronically exposed to TCDD suggests that the disease “should be considered a possible later complication of the most severe forms of human chloracne induced by TCDD.” However, this study is only tangentially related to the issue of primary amyloidosis in humans. A discussion of toxicological studies that comprise the biologic basis for an association between exposure to TCDD or herbicides and toxicity end points is contained in Chapter 3; a general summary of the biologic basis for various end points is presented in the conclusion to this chapter.

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Veterans and Agent Orange: Update 2000 Increased Risk of Disease Among Vietnam Veterans There are no data on which to base a conclusion concerning whether Vietnam veterans may or may not be at increased risk for AL-type primary amyloidosis due to exposure to herbicides. SUMMARY Based on the occupational, environmental, and veterans studies reviewed, the committee reached one of four conclusions about the strength of the evidence regarding association between exposure to herbicides and/or TCDD and each of the other health effects under study. As explained in Chapter 4, these distinctions reflect the committee’s judgment that if an association between exposure and an outcome were “real,” it would be found in a large, well-designed epidemiologic study in which exposure to herbicides or dioxin was sufficiently high, well characterized, and appropriately measured on an individual basis. Consistent with the charge to the committee by the Secretary of Veterans Affairs in Public Law 102– 4 and with accepted standards for scientific reviews, the distinctions between these standard conclusions are based on statistical association, not on causality. The committee used the same criteria to categorize diseases by the strength of the evidence as were used in VAO, Update 1996, and Update 1998. Health Outcomes with Sufficient Evidence of an Association In VAO, Update 1996, and Update 1998, the committee found sufficient evidence of an association between exposure to herbicides and/or TCDD and chloracne. The scientific literature continues to support the classification of chloracne in the category of sufficient evidence. Based on the literature, there are no additional health effects discussed in this chapter that satisfy the criteria necessary for this category. For diseases in this category, a positive association between herbicides and the outcome must be observed in studies in which chance, bias, and confounding can be ruled out with reasonable confidence. The committee also regarded evidence from several small studies that are free from bias and confounding, and that show an association that is consistent in magnitude and direction, as sufficient evidence for an association. Health Outcomes with Limited/Suggestive Evidence of Association In Update 1996 and Update 1998, the committee found limited/suggestive evidence of an association between herbicide or dioxin exposure and porphyria cutanea tarda. The scientific literature continues to support the classification of this disorder in the category of limited/suggestive evidence.

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Veterans and Agent Orange: Update 2000 Based on its evaluation of newly available scientific evidence as well as the cumulative findings of research reviewed in the previous Veterans and Agent Orange reports, the committee responsible for the Type 2 Diabetes report found there was limited/suggestive evidence of an association between exposure to the herbicides used in Vietnam or the contaminant dioxin and Type 2 diabetes. Evidence reviewed in this report continues to support that finding. No other changes have been made to the list of health outcomes in the limited/suggestive evidence category. For this category, the evidence must be suggestive of an association between herbicides and the outcome, but may be limited because chance, bias, or confounding could not be ruled out with confidence. Typically, at least one high-quality study indicates a positive association, but the results of other studies may be inconsistent. Health Outcomes with Inadequate/Insufficient Evidence to Determine Whether an Association Exists The scientific data for many of the health effects reviewed by the committee were inadequate or insufficient to determine whether an association exists. For the health effects discussed in this chapter, the available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. For example, studies fail to control for confounding or have inadequate exposure assessment. This category includes nonmalignant 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; and circulatory disorders. Since Update 1998, the committee responsible for this report has been asked to address the possible association between exposure to the herbicides used in Vietnam or the contaminant dioxin and AL-type primary amyloidosis. Based on the scientific literature reviewed, there is inadequate/insufficient evidence to determine whether an association exists between herbicide or dioxin exposure and AL-type primary amyloidosis. Health Outcomes with Limited/Suggestive Evidence of No Association In VAO, Update 1996, and Update 1998, the committee did not find any evidence to conclude that there is limited/suggestive evidence of no association between the health effects discussed in this chapter and exposure to TCDD or herbicides. The most recent scientific evidence continues to support this conclusion. In order to classify outcomes in this category, several adequate studies covering the full range of levels of exposure that human beings are known to encoun-

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Veterans and Agent Orange: Update 2000 ter must be mutually consistent in not showing a positive association between exposure to herbicides and the outcome at any level of exposure. These studies must also have relatively narrow confidence intervals. A conclusion of “no association” is inevitably limited to the conditions, level of exposure, and length of observation covered by the available studies. In addition, the possibility of a very small elevation in risk at the levels of exposure studied can never be excluded. Biologic Plausibility This section summarizes the biologic plausibility of a connection between exposure to dioxin or herbicides and various noncancer health effects on the basis of data from animal and cellular studies. Details of the committee’s evaluation of data from those studies are presented in Chapter 3. Some of the preceding discussions of reproductive and developmental outcomes include references to papers relevant to specific effects. TCDD has been shown to elicit a diverse spectrum of effects, including immunotoxicity, hepatotoxicity, chloracne, loss of body weight, and numerous biological responses, including the induction of phase I and phase II drug-metabolizing enzymes, the modulation of hormone systems, and factors associated with the regulation of cellular differentiation and proliferation. These effects are dependent upon sex, strain, age, and species. Effects of TCDD on the liver include modulating of the rate at which liver cells multiply, increasing the rate of cell death for other types of cells, increasing fat levels in liver cells, decreasing bile flow, and increasing the levels of protein and of substances that are precursors to heme synthesis. TCDD also increases the levels of certain enzymes in the liver, but this effect in itself is not considered toxic. 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 effects mediate noncancer end points is not clear. TCDD has been shown to inhibit hepatocyte DNA synthesis; 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 levels and activity. Hepatomegaly has occurred following high subchronic doses. The myocardium has also been shown to be a target of TCDD toxicity; impairment of a contraction modulated by adenosine 3′,5′-cyclic-monophosphate has been implicated. 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 aryl hydrocarbon receptor (AhR), a protein in animal and human cells to which TCDD can bind. Following the binding of TCDD, the TCDD-AhR complex is

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Veterans and Agent Orange: Update 2000 thought to bind DNA, leading to changes in transcription (i.e., genes are differentially regulated), that alter cell function. Although structural differences in the AhR have been identified among different species, this receptor operates in a similar manner in animals and humans. Data in animals support a biological basis for TCDD’s toxic effects. Because of the many species and strain differences in TCDD responses, however, controversy remains regarding the extent to which animal data inform the evaluation of human health outcomes. The immune system is one of the most sensitive organs to TCDD toxicity. Studies in mice, rats, guinea pigs, and monkeys indicate that TCDD suppresses the function of certain components of the immune system in a dose-related manner; that is, as the dose of TCDD increases, its ability to suppress immune function increases. TCDD suppresses cell-mediated immunity, primarily by affecting the T cell arm of the immune response, including a decrease in the number and response of certain types of T cells. It is not known whether TCDD directly affects T cells. TCDD may indirectly affect T cells and cell-mediated immunity by altering thymus gland function or cytokine production. The generation of antibodies by B cells, an indication of humoral immunity, may also be affected by TCDD. Effects of arachidonic acid have also been hypothesized to mediate TCDD’s immunotoxicity, but recent evidence indicates that not all of TCDD’s immunotoxic effects are mediated by arachidonic acid. As with other effects of TCDD, the immunotoxic effects are species and strain specific. Increased susceptibility to infectious disease has been reported following TCDD administration. In addition, TCDD increased the number of tumors that formed in mice following injection of tumor cells. It should be emphasized, however, that very little change in the overall immune competence of the intact animal (i.e., animals not knowingly challenged with a pathogen or tumor cells) has been reported. Despite considerable laboratory research, the mechanisms underlying the immunotoxic effects of TCDD are still unclear, but most studies are consistent with the hypothesis that these immunotoxic effects are mediated by the AhR. TCDD’s wide range of effects on growth regulation, hormone systems, and other factors could also 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, from the data available, the universal immunosuppressive effects observed in laboratory animals have not been confirmed in humans. TCDD has been shown to induce differentiation in human keratinocytes. TCDD has been reported to decrease an acidic type I keratin involved in epidermal development, leading to keratinocyte hyperproliferation and skin irritations such as chloracne. These data provide a biologically plausible mechanism for the induction of chloracne by TCDD.

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Veterans and Agent Orange: Update 2000 Although there is limited information on the health effects of the herbicides discussed in this report, they have been reported to elicit adverse effects in a number of organs in laboratory animals. The liver is a target organ for toxicity induced by 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-T, and picloram, with changes reportedly similar to those induced by TCDD. Some kidney toxicity was reported in animals exposed to 2,4-D and cacodylic acid. Exposure to 2,4-D has also been associated with effects on blood, such as reduced levels of heme and red blood cells. Cacodylic acid was reported to induce renal lesions in rats. Other studies provide evidence that 2,4-D binds covalently to hepatic proteins and lipids; the molecular basis of this interaction and its biologic consequences are unknown. 2,4,5-T has been shown to be a weak myelotoxin. The potential immunotoxicity of the herbicides used in Vietnam other than TCDD has been studied to only a limited extent. Effects on the immune system of mice were reported for 2,4-D administered at doses that were high enough to produce clinical toxicity, but these effects did not occur at low doses. The potential for picloram to act as a contact sensitizer (i.e., to produce an allergic response on the skin) was tested, but other aspects of immunotoxicology were not examined. The foregoing evidence suggests that a connection between TCDD or other herbicide exposure and human toxic effects is, in general, biologically plausible. However, differences in sensitivity and susceptibility across individual animals, strains, and species; the lack of strong evidence of organ-specific effects across species; and differences in route, dose, duration, and timing of exposure complicate definitive conclusions about the presence or absence of a mechanism for the induction of specific toxicity by these compounds in humans. Considerable uncertainty remains about how to apply this information to the evaluation of potential health effects of herbicides or dioxin exposure in Vietnam veterans. Scientists disagree about the extent to which information derived from animals and cellular studies predicts human health outcomes and the extent to which the health effects resulting from high-dose exposure are comparable to those resulting from low-dose exposure. Investigating the biological mechanisms underlying TCDD’s toxic effects continues to be a very active area of research, and subsequent updates of this report might have more and better information on which to base conclusions, at least for that compound. Increased Risk of Disease Among Vietnam Veterans Under the Agent Orange Act of 1991, the committee is asked to determine (to the extent that available scientific data permit meaningful determinations) the increased risk of the diseases it studies among those exposed to herbicides during their service in Vietnam. Where specific information about particular health outcomes is available, it is related in the preceding discussions of those diseases.

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