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Veterans and Agent Orange: Update 2000 (2001)

Chapter: 10 Other Health Effects

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Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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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

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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)

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

(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.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

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

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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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

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

to demonstrate such a risk. However, the RR for nonmalignant respiratory diseases, such as COPD, was 0.9 (86 observed, 0.7–1.1).

NIOSH conducted a follow-up study of 586 workers from two plants involved in the production of sodium trichlorophenol and the ester of 2,4,5-trichlorophenoxyacetic acid 2,4,5-T (Sweeney et al., 1997/98). Exposure levels had been documented 15 years before, and the relative exposure levels were confirmed by serum lipid-adjusted levels of TCDD. There was no statistical difference in the prevalence of chronic bronchitis, chronic obstructive pulmonary disease, or reductions in lung function by several measures in the exposed workers compared to an unexposed comparison group with documented low blood levels of TCDD. These findings were available for Update 1996 and Update 1998 but were reviewed and reconfirmed by NIOSH in 1998 (Sweeney et al., 1997/98).

Among Ranch Hand participants, respiratory conditions were assessed by questionnaire, physical examination, chest film, and spirometry. There was no excess reported for asthma, bronchitis, pneumonia, abnormal chest film (with the exception of one model that did not show an exposure-response relationship), or pulmonary function. Had differences been observed, it would be difficult to separate any potential effect of herbicide exposure from cigarette smoking in the Ranch Hand population. The unique Ranch Hand population shows a lifetime prevalence of cigarette smoking of 72 percent, with a mean consumption among smokers of 17.3 pack-years; 46 percent of smokers have a history exceeding 10 pack-years. Confounding any association with herbicide exposure, cigarette smoking covaries with 1987 dioxin levels, as do insecticide exposure and exposure to ionizing radiation. This would tend to obscure associations for respiratory outcomes and herbicide exposure (AFHS, 2000).

No further data have become available on the prevalence of cigarette smoking among Vietnam veterans outside the AFHS cohort, either current or historical.

Synthesis

New evidence suggests that there may be an increased risk for nonmalignant respiratory disorders, particularly chronic obstructive pulmonary disease, among individuals exposed to TCDD. This association is based on small numbers, is not adjusted for smoking, and is not internally consistent. This elevation is not obviously the result of different patterns of cigarette smoking, although some degree of confounding is possible. Other studies of occupationally exposed subjects do not show this association, although some of them are clearly large enough to have revealed it if it were present. It is biologically plausible that exposure to TCDD would affect the progression of nonmalignant respiratory diseases, especially among cigarette smokers. Additional evidence from following the Seveso population for a longer period will be required to determine whether the finding in this population is an anomaly or remains elevated over time. Comparison with other populations over similar time periods is required to determine whether any consistent risk in the Seveso population might be shared by other TCDD-exposed populations.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and nonmalignant respiratory disorders, including asthma in isolation, pleurisy, pneumonia, and tuberculosis, or associated or isolated measures of lung function, chest films, or abnormalities on physical examination. There is also inadequate or insufficient evidence to determine that an association exists between exposure to herbicides or TCDD and risk of death from chronic obstructive pulmonary disease, including emphysema, chronic bronchitis, and asthma in combination with these conditions. Notwithstanding the tentative evidence reviewed above, the committee concluded that the body of new evidence, taken as a whole, cannot be considered limited or suggestive of an association between exposure to TCDD and obstructive airways disorders. The tentative evidence mentioned above is drawn from small numbers in studies of residents of Seveso, who sustained exposure to relatively pure TCDD and represents an isolated finding that should be considered unconfirmed at this time, particularly given uncertainty about smoking patterns.

Biologic Plausibility

There is no evidence from animals that the respiratory system is a target of TCDD or the other herbicides. 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

There are insufficient data on nonmalignant respiratory disorders in Vietnam veterans to draw a specific conclusion as to whether or not they are at increased risk.

IMMUNE SYSTEM DISORDERS

Background

Immunotoxicology is the study of the effects of xenobiotics (chemical compounds that are foreign to the human body) on the immune system. The compounds may produce an impaired immune response (immunosuppression) or an enhanced immune response (immune-mediated disease). Although alterations in the immune system can be related to increases in the incidence of infection and

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

neoplasm (immune suppression) and immune-mediated diseases (allergy and autoimmunity), there has been no observed increase in infectious or immune-mediated disease in the populations examined after exposure to herbicides. However, alterations have been observed in measures of immune function or populations of immune cells. The question of possible increases in neoplastic diseases is dealt with in Chapter 7.

Immune Suppression

The immune system helps defend the host against foreign invaders. It confers resistance to infection by bacteria, viruses, and parasites; it is involved in the rejection of allografts (tissue transplants); and it may eliminate spontaneously occurring tumors (Paul, 1993). Proper function of the immune system is exquisitely sensitive to disruptions in physiologic homeostasis. The immune response is highly redundant, and several different mechanisms may be employed to eliminate an antigen. Therefore, a toxicant can affect one facet of the immune system without altering the ability of the host to survive challenge by an infectious agent.

Suppression of the immune system leads to increased susceptibility to infection and neoplasia. However, the degree of immune suppression necessary to cause disease is unknown and is the subject of intense scientific interest. Immune deficiency may result from genetic abnormalities (e.g., a deficiency in the enzyme adenosine deaminase, leading to severe combined immune deficiency), congenital malformations, surgical accidents, pregnancy, stress, disease (e.g., HIV-1 can lead to AIDS), and exposure to immunosuppressive agents (Paul, 1993). Immune suppression can also occur in patients with autoimmune disease (discussed below); for example, in systemic lupus erythematosus, the suppression of complement levels and leukocyte function has been noted. Impaired host defenses can result in severe and recurrent infections with opportunistic microorganisms. As noted, the immune system may prevent or limit tumor growth, and a high incidence of tumors may follow immune suppression (Paul, 1993).

Allergy and Autoimmunity

A number of diseases involve hyperresponsiveness of the immune system to either foreign allergens (e.g., allergy) or self-antigens (autoimmunity). Allergic responses have been noted to numerous environmental agents, including plant pollens and epithelial products of domestic animals. Allergy is the result of the formation of allergen-specific immunoglobulin E (IgE) antibodies, which bind to the surface of mast cells and lead to mastcell degranulation on subsequent exposure to antigen. The mediators of allergic reactions, such as histamine, are then released. The alterations discussed below reflect only in vitro immune parameters, not disease incidence. In fact, no increase in allergic disease related to herbicide exposure has been reported in any of the studies reviewed.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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In general, the immune response is directed against foreign antigens. However, in some instances antibodies can be demonstrated that react with endogenous antigens (i.e., autoantibodies). Autoimmune disease is the pathological consequence of an immune response to autologous antigen. Some autoimmune diseases result when autoantibodies activate the complement cascade or interact with “killer” mononuclear cells to induce antibody-dependent cell-mediated cytotoxicity. Others are caused by cytotoxic T cells acting directly on their targets or by injurious cytokines released by activated T cells.

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

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and immune system disorders. 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.

Update of the Scientific Literature

Suppression of the immune system can result in increased susceptibility to infectious and/or carcinogenic agents, while stimulation can result in allergy and/ or autoimmunity. TCDD exposure generally suppresses the immune response of laboratory animals. However, the immune effects described in humans exposed to TCDD have been marginal and have varied from study to study—some showing increases, others decreases, and others no effect. It has been suggested that perinatal exposure to chlorinated aromatic hydrocarbons may influence the human fetal and neonatal immune system, but the effects to date have not been correlated with increased susceptibility to infection. Further, workers exposed to high levels of TCDD for several years with body burdens at least 10 times higher than the general population had no significant differences in lymphocyte subpopulations or mitogen-induced lymphocyte proliferation compared to controls (IOM, 1994, 1999).

Several recent studies have evaluated the immunotoxic effects of poly chlorinated dibenzodioxins and dibenzofurans (PCDD/PCDF) in human workers. In a study in which blood concentrations of PCDD and PCDF were available from

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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187 workers of a pesticide plant that closed in 1984, no significant correlation between blood PCDD concentration and clinical impairment of the immune system was noted and immunological parameters did not correlate with the concentrations (Jung et al., 1998). However, the chromate resistance of phytohemagglutinin (PHA) stimulated lymphocytes of workers with the highest exposure was significantly lower than that of the control group. In another study where workers had been employed more than 15 years earlier in production of sodium trichlorophenol and 2,4,5-T ester, a positive relationship between serum 2,3,7,8-TCDD levels and CD3/Ta1 cells (helper lymphocytes) was noted (Sweeney et al., 1997/ 98). A comparative analysis was also conducted of phenotypes of peripheral blood leukocytes in former industrial workers who had high exposures to dioxins (Ernst et al., 1998). The median TCDD burden of exposed workers was 116 ng/ kg versus 4 ng/kg for the controls. There were no significant differences in the proportions of CD3+, CD4+, or CD8+ T lymphocytes, CD16+ natural killer cells, or CD19+ B lymphocytes between the two groups. However, the proportion of CD45Ro+ (CD+ memory T cells) was significantly higher than the CD45RA+ (naive) phenotype in TCDD-exposed workers, while the monocytes expressing human leukocyte antigen-DR (HLA-DR) molecules on their surface were significantly lower than in the control group. When the peripheral blood mononuclear cells were cultured, polyclonal-stimulated cytokine release did not differ between the two cohorts. Significantly reduced interferon release was noted in diluted whole blood cultures but not in cultures of isolated PBMCs in the TCDD-exposed cohort when the T-cells were stimulated with tetanus toxoid. In another group of workers exposed in 1951–1984 in a plant that produced organochlorine herbicides, pesticides, and opioids, peripheral blood lymphocytes were obtained from several cohorts of control or TCDD-exposed individuals (Germolec, 1999). The lymphocytes were mitogen stimulated in culture alone or in the presence of TCDD. In vitro treatment with TCDD resulted in a significant decrease in mitogen-stimulated interleukin-2 (IL2) and interferon-δ (IFN-δ) in the TCDD-exposed workers. The authors considered this primarily an in vitro TCDD effect.

Blood from breast-fed babies of mothers exposed to a mixture of PCDDs, PCDFs, and coplanar polychlorinated biphenyls (co-PCBs) was evaluated for percent CD4+ and CD8+ T lymphocytes (Nagayama et al., 1998). The toxic equivalent quantity converted to 2,3,7,8-TCDD equivalents correlated positively with the babies’ (1-year-old) CD4+ lymphocytes and negatively with the CD8+ lymphocytes. Thus, the CD4+/CD8+ ratio was increased.

Children born between 1978 and 1987 to women exposed to a high dose of PCBs and PCDFs through consumption of contaminated rice bran oil (1978– 1979) had a higher frequency of bronchitis during their first 6 months of life and of respiratory tract and ear infections for the first 6 years. In 1995, blood was collected from 29 in utero exposed and 24 control children. Serum immunoglobulin levels were similar between the two groups, there were no significant differences in the CD3+, CD4+, and CD8+ phenotypes, and the B-cell and natural

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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killer (NK) cell markers did not differ between exposed and control children (Yu et al., 1998). A dose-response relationship was not observed between exposure and immune markers. The authors concluded that 16 years after exposure, children exposed to high doses of PCBs or PCDFs in utero did not show suppressed immunity of serum immunological biomarkers.

Workers who were exposed to dioxin while manufacturing 2,4,5-trichlorophenate between 1951 and 1972 had a lipid-adjusted mean serum TCDD concentration of 229 parts per trillion (ppt) compared with a mean of 6 ppt in unexposed referents (Halperin et al., 1998). Immune parameters examined were lymphocyte subsets (CD3+, CD3+CD26, CD4+, CD4+CD29+, CD4+CD45RA+, CD8+, CD8+ CD116+/, CD20, CD56, and CD4/CD8 ratio), immunoglobulin concentrations (IgA, IgM, and IgG), complement, mitogen background and proliferation (concanavalin A [Con A], PHA, and pokeweed), antigen background and proliferation (tetanus, Candida, and mumps), and NK cell activity as well as complete blood counts. An association was noted between serum TCDD levels and a decrease in both the number of CD26 cells and spontaneous background proliferation of T cells. However, increases in T-lymphocyte proliferation were observed in the highest-TCDD-exposed workers when the lymphocytes were stimulated with Con A or PHA. The authors indicated that these results are unlikely to be of clinical importance, and there was no evidence that TCDD caused meaningful immunological changes in the exposed cohort.

The plasma concentrations of immunoglobulins (IgM, IgG, IgA, IgD) and selected cytokines (IL-1alpha, IL-1beta, IL-6, tumor necrosis factor-α [TNF-α]) were evaluated in worker volunteers who had increased body burdens of PCDD (Neubert et al., 2000). Volunteers were “grouped” according to low, medium, or high body burdens, with a “clearly exposed group” identified by definitely increased body burdens of PCDD. Although there was a slight but significant decrease in plasma concentration of IgG1 in this clearly exposed group, no influence of dioxin exposure occurred when all groups were pooled and a multiregression analysis against international TCDD toxicity equivalencies was performed. There were no effects of exposure on the plasma concentrations of other immunoglobulins or cytokines tested. The authors concluded that their results did not confirm any suspicion of a possible relationship between PCDD exposure and the production of immunoglobulins or cytokines that were measured in the plasma.

Immune parameters were measured in veterans of Operation Ranch Hand in 1992 (Michalek et al., 1999a; AFHS, 2000). Test groups included a comparison group (Air Force veterans who served in Southeast Asia during the same period as the Ranch Hand veterans but were not involved in spraying herbicides) and Ranch Hand background-, low-, and high-dioxin groups. The current median blood dioxin levels for the comparison and background categories were 4.0 and 5.7 ppt, respectively. The initial median blood dioxin levels for the low and high categories were 52.8 and 194.7 ppt, respectively. Immune assays performed were a composite skin

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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test (Canidida albicans, mumps, Trichophyton, and Staphylococcus aureus antigens); lymphocyte and lymphocyte subset counts; serum IgA, IgM, and IgG isotype concentrations; M proteins (serum monoclonal immunoglobulins of clonal B cells); and the presence of serum autoantibodies (antinuclear autoantibodies [ANAs], thyroid microsomal, smooth muscle, mitochondrial, parietal, and rheumatoid factor [RF]). Ranch Hand veterans in the background group had an increased (odds ratio [OR]=1.8) skin test, while the high group had a slight suppression (OR=0.7) of the skin test. There were no notable differences in immunoglobulin isotypes or monoclonal immunoglobulins between the four categories. The only significant effect on lymphocyte phenotyping was an increase in the absolute numbers of CD20+ cells in the background group and a decrease in the absolute count of CD16+CD56+CD3+in the higher category compared to the comparison group. No significant differences were noted in the other lymphocyte subpopulations including CD3+, CD5+, CD4+CD3+, CD8+CD3+, CD16+CD56+CD3–, CD25+, or CD25+ CD3+. Out of the six autoantibodies evaluated, thyroid microsomal autoantibodies were increased in the three Ranch Hand categories with a significant increase in the low group. The other five autoantibodies tested were within the normal odds ratio compared to the comparison group. In fact, three of them in the high category had a low odds ratio (ANA, 0.8; parietal cell autoantibodies PCA, 0.7; RF, 0.6). The authors concluded that there was no evidence of a consistent relationship between dioxin exposure and immune system alteration in these studies.

A prevailing perception is that dioxins suppress the immune response of humans. This perception putatively arises from the fact that dioxins are extremely immunosuppressive in animals and that they are considered to cause cancer in humans, which is often a consequence of a suppressed immune system. However, literature during the past several years has failed to demonstrate a consistent positive association between TCDD exposure and immune effects in humans, via either in utero, perinatal, or postnatal exposure. Many of the immune procedures conducted in humans, however, have not measured immune function (e.g., “action” of immunocytes and/or their secretory products) (Koller, 1990). These non-functional procedures are often considered “biomarkers,” which are indicators of events occurring in biological systems when a host is exposed to environmental substances. For instance, protein markers (CD) on the surface of immunocytes are usually specific for identifying and enumerating subpopulations of cells, but they do not test their functional capacity. Nevertheless, the available data indicate that the universal immunosuppressive effects observed in laboratory animals have not been confirmed in humans.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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T and its contaminant TCDD, cacodylic acid, and picloram) and immune suppression or autoimmunity.

Biologic Plausibility

There are a large number of studies in animals indicating that one of the most sensitive organ systems to TCDD toxicity is the immune system. TCDD can alter the number and function of immune cells. The effects seen are species and strain specific, but based on the sensitivity of this system in animals, effects on the immune system in humans might be expected. Studies of the effect of exposure to TCDD on immune response following infection with influenza A have been conducted in mice. These demonstrate that the humoral and cell-mediated response is suppressed while cytolytic activity is preserved. 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

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

DIABETES

Background

Primary diabetes (i.e., not secondary to another known disease or condition, such as pancreatitis or pancreatic surgery) is a heterogeneous metabolic disorder characterized by hyperglycemia and quantitative and/or qualitative deficiency of insulin action (Orchard et al., 1992). Historically, two main types have been recognized: insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM). In June 1997, the American Diabetes Association (ADA, 1997) suggested a revised classification, with IDDM being termed Type 1 and NIDDM, Type 2. This new terminology is used in the remainder of this review, although the older diagnostic criteria are utilized as appropriate.

Type 2 diabetes accounts for the majority (approximately 90 percent) of cases of primary diabetes. It is rare before age 30, but increases steadily with age thereafter. The etiology of Type 2 is unclear, but three cardinal components have been proposed: (1) peripheral insulin resistance (thought by many to be primary) in target tissues (e.g., muscle, adipose, liver); (2) beta-cell insulin secretory defect; and (3) hepatic glucose overproduction. Although the relative contributions of these features are controversial, it is generally accepted that the main factors

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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for increased risk of Type 2 diabetes include age (with older individuals at higher risk), obesity, central fat deposition, a history of gestational diabetes (if female), physical inactivity, ethnicity (prevalence is greater in African Americans and Hispanic Americans, for example), and perhaps most importantly, a positive family history of Type 2. Defects at many intracellular sites could account for the impaired insulin action and secretion seen in Type 2 diabetes (Kruszynska and Olefsky, 1996). The insulin receptor itself, insulin receptor tyrosine kinase activity, insulin receptor substrate proteins, insulin-regulated glucose transporters, enhanced protein kinase C (PKC) activity, TNF-α, rad (ras associated with diabetes), and PC1 have all been proposed as potential mediators of insulin resistance; impaired insulin secretion has been linked to hyperglycemia itself, to abnormalities of glucokinase and hexokinase activity, and to abnormal fatty acid metabolism. Finally, an increasing number of “other” types of diabetes have been described that are linked to specific genetic mutations, for example, maturity-onset diabetes of youth, which results from a variety of mutations of the beta cell glucokinase gene.

Pathogenetic diversity and diagnostic uncertainty are two of the more significant problems associated with the epidemiologic study of diabetes. Given the multiple likely pathogenetic mechanisms leading to diabetes—which include diverse genetic susceptibilities (ranging from autoimmunity to obesity) and a variety of potential environmental and health behavior factors (e.g., viruses, nutrition, activity) —it is probable that many agents or behaviors contribute to diabetes risk, especially in genetically susceptible individuals. These multiple mechanisms may also lead to heterogeneous responses to various exposures. Because up to half of the affected diabetic population is currently undiagnosed, the potential for ascertainment bias is high (i.e., more intensively followed groups or those with more frequent health care contact are more likely to be diagnosed), and the need for formal standardized testing (to detect undiagnosed cases) is great. Furthermore, it may be difficult to differentiate cases developing during young to middle age (i.e., 20–44 years) into Type 1 or Type 2.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and diabetes. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change this finding.

In 1999, in response to a request from the DVA, the IOM called together a committee to conduct an interim review of the scientific evidence regarding Type 2 diabetes. This review, which focused on information published since the deliberations of the Update 1998 committee, resulted in the report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000). The committee responsible for that report found there was limited/suggestive evi-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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dence of an association between Type 2 diabetes and exposure to the herbicide used in Vietnam. While the committee convened for the DVA request and the committee responsible for Update 2000 have worked concurrently, the committees functioned independently in reviewing, discussing, and summarizing the relevant literature on diabetes.

Reviews of the studies underlying these findings may be found in the earlier reports.

Update of the Scientific Literature

In the course of its evaluation of evidence, the committee responsible for the Type 2 Diabetes report reviewed scientific papers on this condition published since the release of Update 1998. The sections below briefly summarize those reviews; more complete information may be found in that report.

Occupational Studies

Two studies have combined information from multiple occupational cohorts with potential exposure to dioxin. The International Agency for Research on Cancer (IARC) mortality study included 36 cohorts with exposure to the production or spraying of phenoxy acid herbicides and chlorophenols (Vena et al., 1998). Data from each cohort were used to identify workers exposed to TCDD or higher-chlorinated dioxins, and analyses for diabetes contrasted the mortality experience of exposed (N=13,831) and nonexposed (N=7,553) workers. Exposure to dioxin was associated with a twofold increase in mortality from diabetes (RR=2.3, 0.5–9.5), with the imprecision attributable to the relatively small number of deaths (33 exposed, 11 nonexposed). Additional assessments of exposure duration and latency effects were also markedly imprecise. A separate analysis was conducted on data from the 12 U.S. cohorts included in the IARC study (Steenland et al., 1999). A standardized mortality ratio (SMR) analysis of mortality for all 12 cohorts found a slight and statistically nonsignificant excess mortality from diabetes (28 deaths, SMR=1.2, 0.8–1.7). Detailed information from 8 of the 12 cohorts enabled Steenland et al. to create a job-exposure matrix and assign a dioxin exposure score to the 3,538 workers from the 8 cohorts. Workers were divided into septiles of cumulative exposure to dioxin, and mortality was analyzed with an internal referent (the lowest septile of exposure). The analysis of diabetes mortality, based on deaths with diabetes as either the underlying or a contributing cause (55 deaths), found an unexpected inverse relationship between dioxin exposure and mortality, with p=.02 for the two-sided test of trend. A pattern of declining rate ratios was shown in the three highest septiles of exposure (1.0, 0.7, 0.5), although each estimate also had a broad confidence interval (e.g., 0.2–2.1 and 0.2–1.9 for the top two septiles).

The relationship between serum dioxin levels and diabetes morbidity in a NIOSH study of dioxin-exposed workers from chemical plants in New Jersey and

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Missouri was summarized in Update 1998 (Sweeney et al., 1997/98), but Calvert et al. (1999) provided a more detailed analysis of diabetes-related outcomes. Workers were recruited for the study 15 to 20 years after occupational exposure to dioxin, and a comparison group was formed by selecting neighbors matched to the workers on age, race, and gender. Examinations were conducted on 281 workers and 260 matched neighbors, and diabetes was defined by self-reported history of physician diagnosis (not verified) or elevated fasting glucose levels (≥7.8 mmol/l) on 2 consecutive days. All individuals in the neighborhood comparison group had current dioxin levels of less than 20 pg/g, while dioxin levels of the chemical workers ranged from nondetectable to 3,400 pg/g, with a median of 68 pg/g. Four subgroups of roughly equal size were defined among the chemical workers to represent levels of dioxin exposure for the analysis of data. Diabetes was found in 26 workers and 18 adults from the neighborhood comparison group. In the overall comparison of workers and their neighbors, the former were 50 percent more likely to have diabetes (OR=1.5) after adjustment for body mass index, family history of diabetes, and the matching characteristics. However, this estimate was imprecise (0.8–2.9), and there was no support for a dose-response trend in risk of diabetes across the four levels of serum dioxin. The chemical workers also had a slight and statistically nonsignificant elevation in fasting serum glucose levels; in detailed analyses of current and half-life extrapolated dioxin levels, only the subgroup with the highest half-life extrapolated concentration (1,860–30,000 pg/g) demonstrated a statistically significant elevation in fasting glucose.

Environmental Studies

The 15-year follow-up for the Seveso study was reported by gender for three levels of exposure (Bertazzi et al., 1998; Pesatori et al., 1998). For men, no deaths were attributed to diabetes in zone A, the zone of highest exposure (with 0.6 death expected), and a small, statistically nonsignificant excess in deaths from diabetes was reported in the areas with medium (zone B, 6 deaths, SMR=1.3) and low (zone R, 37 deaths, SMR=1.1) exposure to dioxin. In women after 15 years of follow-up, the SMRs for diabetes were 1.8 (0.4–7.3; based on 2 deaths), 1.9 (1.1–3.2; 13 deaths), and 1.2 (1.0–1.6; 74 deaths) for zones A, B, and R respectively. The analysis of data on diabetes from the 20-year follow-up of the Seveso study became available after the publication of the Type 2 Diabetes report and was limited to zones A and B (Bertazzi et al., 2001). In these data there is no evidence of elevated mortality from diabetes in men, and there is a reduced excess for women in zone A (SMR=1.3, 0.3–5.1; 2 deaths). The increased mortality from diabetes in women of zone B persisted (SMR=1.8, 1.1–2.9; 18 deaths), and analyses for latency show a consistent excess across the follow-up period.

The only other study of environmental effects was an analysis of serum dioxin and insulin among nondiabetic adults in a larger population-based study of

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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health effects from residing near the Vertac/Hercules Superfund site in Arkansas (Cranmer et al., 2000). Study subjects lived near the Superfund site or in a comparison community 25 miles away. A total of 69 individuals with no history of diabetes and a normal glucose response to an oral glucose tolerance test were divided into deciles of serum dioxin levels for the analysis of insulin at baseline (fasting) and 30, 60, and 120 minutes after the glucose challenge. Fasting insulin was elevated only among those in the top decile of exposure (dioxin>15 ppt), and elevated insulin levels in this subgroup were sustained for 6 of these 7 individuals during the subsequent 2 hours (compared with 6 of 62 in the remaining nine deciles of exposure, p<.05 using Fisher’s exact test). The seven subjects in the highest decile of dioxin exposure had slightly higher levels of lipids and body mass index, but the small numbers precluded mathematical adjustment for these differences.

Vietnam Veteran Studies

In a letter regarding the Ranch Hand publication by Henriksen et al. (1997), Slade (1998) suggested that the association observed between dioxin exposure categories and diabetes may have been attributable to the influence of triglycerides on the measurement of dioxin. In response to this letter, Michalek et al., (1998) presented analyses showing that adjustment (via stratification and logistic regression modeling) for serum triglyceride level at the time of the dioxin blood draw did not account for the association between dioxin and diabetes. In addition, there was no evidence in the logistic regression model for interaction between triglycerides and dioxin (i.e., the relationship between dioxin level and risk of diabetes did not vary by level of triglycerides).

Longnecker and Michalek (2000) published a study of serum dioxin and diabetes that focused exclusively on comparison veterans enrolled in the Ranch Hand study. These individuals were Air Force veterans who served in Southeast Asia between 1962 and 1971 but were not involved in the spraying of herbicides; in addition, all comparison veterans were required to have serum dioxin levels at or below 10 ng/kg in order to represent individuals with background levels of exposure. A total of 1,197 men were available for this analysis, and quartiles of serum dioxin levels were formed within the range of background exposure (between undetectable and 10 ng/kg) to evaluate the association between low-dose exposure to dioxin and diabetes, fasting and postchallenge glucose, and insulin. For most of these men, serum dioxin levels were measured in 1987, but others had measurements in 1992 or 1997. Glucose and insulin levels were measured in 1992, while diabetes was based on a verified physician diagnosis (at any time between the end of military service and 1995) or a postchallenge glucose level of 200 mg/dl in 1992. The number of men with diabetes by quartile of dioxin level was 26, 25, 57, and 61 for quartiles 1, 2, 3, and 4, respectively. In unadjusted analyses, the second quartile had no increase in diabetes, but men in the third (4– 5.1 ng/kg) and fourth (5.2–10 ng/kg) quartiles were approximately 2.5 times

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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more likely to have diabetes than men in the first quartile (below 2.8 ng/kg). The odds ratios for quartiles 3 and 4 were reduced to 1.8 (1.0–3.0) and 1.6 (0.9–2.7), respectively, after adjustment for age, race, military occupation, family history of diabetes, serum triglycerides, waist circumference, and body mass index. Fasting glucose and postchallenge glucose and insulin were directly related to quartile of dioxin in the simple analysis, while in the multivariate analysis, glucose and insulin levels in the top three quartiles were much closer to each other and only modestly above levels in the lowest quartile.

In February 2000, the Air Force Heath Study (AFHS) released a report based on data from the 1997 physical examination of Ranch Hand veterans and their comparison cohort (AFHS, 2000). The study included evaluations of Type 2 diabetes incidence, time to onset, and associated laboratory values using four statistical models based on a different approach to exposure measurement. All models were run both “unadjusted” and “adjusted” for a set of potential confounders: age, race, military occupation, personality type, body fat, and family history of diabetes. Individuals who were diagnosed with diabetes prior to their service in Southeast Asia were excluded from these analyses.

The composite diabetes indicator was coded “yes” if the participant had either a verified history of diabetes (a medical records measure) or a 2-hour postprandial glucose level of at least 200 mg/dl (a laboratory examination measure). Overall, approximately 17 percent of each cohort (16.9 percent of the Ranch Hands and 17.0 percent of the comparisons) were considered diabetic based on the indicator criteria. The unadjusted and adjusted comparisons of the groups did not yield statistically significant differences in the number of diabetic participants (RR=1.0, 0.8–1.3; Model 1). However, the percentage of Ranch Hands with diabetes varied in a dose-response fashion among the dioxin-categorized subgroups: 9.8 percent in the background category, 20.9 percent in the low category, and 23.8 percent in the high category. This pattern of results is consistent with the report by Henriksen et al. (1997), which was based on data collected through June, 1995 and was summarized in Update 1998. The adjusted forms of Models 2, 3, and 4 all yielded statistically significant associations between the exposure measure and the composite diabetes indicator. There was a significant positive association between initial serum dioxin level and the percentage of diabetic participants among Ranch Hands (RR=1.4, 1.1–1.7; Model 2). Ranch Hands in the low (RR=1.2, 0.8–1.8), high (RR=1.5, 1.0–2.2), and combined low and high (RR=1.3, 1.0–1.8) dioxin categories were more likely to be diabetic than were comparisons (Model 3). Finally, there was a significant positive association between 1987 serum dioxin levels and diabetes (RR=1.5, 1.2– 1.7; Model 4). The unadjusted form of Model 4 also yielded a statistically significant positive relationship; the unadjusted forms of Models 2 and 3 did not.

The date on which a participant was first diagnosed with diabetes was used to measure a time to diabetes onset by determining the number of years between the date of diagnosis and the end date of the last tour of duty in Southeast Asia. Models adjusted for known confounders showed that time to onset was signifi-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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cantly shorter for Ranch Hand veterans with higher initial (Model 2, p=.013) and 1987 serum dioxin levels (Model 4, p<.001), compared to other Ranch Hand veterans. However, diabetic Ranch Hand and comparison subjects did not differ significantly in time to onset (Model 1), and only Ranch Hand veterans with background levels of dioxin showed a significantly shorter time to onset than the comparison groups (Model 3). It should be noted that for a condition like Type 2 diabetes, time to onset might be affected by characteristics associated with the utilization of medical care. The relationship between measures of exposure and potential variation in post-Vietnam utilization of medical care was not assessed in this analysis.

The government of Australia conducted mail surveys of males (CDVA, 1998a) and females (CDVA, 1998b) who served in Vietnam, comparing the self-report data with age-matched Australian national data. Questionnaires were mailed to 49,944 male veterans (80 percent response rate) and 278 female veterans (81 percent response rate). The authors found an excess of diabetes among male veterans and a deficit among female veterans when comparing the number of Vietnam veterans responding yes to the question, Since your first day of service in Vietnam, have you been told by a doctor that you have diabetes? compared to expected national rates: 6 percent (2,391) of the male veterans responded yes compared to the expected 4.5 percent (1,780; range 1,558–2,003) for an observed-expected ratio of 1.34. For female veterans 2 percent (5) responded yes, while 10 (9–11) were expected, for an observed-expected ratio of 0.5. The reports acknowledge that the questionnaire did not define diabetes and that misreporting was possible since respondents whose doctors had informed them of a single high blood sugar measure may have interpreted that as “having diabetes.”

Synthesis

The new literature on mortality from diabetes is somewhat inconsistent. A general pattern of increased mortality from diabetes continued among women from zone B of Seveso but is not present for men. Elevated mortality was reported for exposed workers in the IARC analyses, but most of the estimates are very imprecise. Furthermore, a refined study of exposure effects in eight U.S. cohorts included in the IARC study documented an inverse relationship between exposure gradient and diabetes mortality. This inconsistency may be due in part to differences in the outcome studied; the Steenland et al. (1999) study used deaths with any mention of diabetes (underlying or contributing cause), while Vena et al. (1998) limited their analysis to underlying cause of death only. As mentioned in earlier VAO reports, mortality studies of diabetes are invariably problematic because of the uncertain validity of the assigned cause of death and the likely (but often unrecorded) contribution of diabetes to many deaths assigned to diabetes-related causes such as coronary heart disease, stroke, and renal failure.

Among the diabetes morbidity studies, the Update 1998 summary of the NIOSH study of chemical workers from New Jersey and Missouri had been

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

based on an abstract and review paper. More complete information is now available in the 1999 paper by Calvert and colleagues. This paper and the analysis of AFHS data by Henriksen et al. (1997) (with elaboration by Michalek et al., 1998 and AFHS, 2000) suggest that dioxin exposure may be associated with an increased risk of developing diabetes. The association in each study is modest and imprecise, but the rough consistency across studies compensates in part for the imprecision. Each study also provides some evidence that the association cannot be attributed to other factors (e.g., measures of obesity, family history of diabetes, lipid profile). Longnecker and Michalek’s (2000) study of the Ranch Hand comparison cohort raises the possibility of low-dose effects of dioxin on risk for diabetes; if valid, a revised definition of the referent group employed by Calvert et al. and Henriksen et al. may reveal a clearer association between exposure and risk of diabetes.

In summary, positive associations are reported in multiple mortality studies, which may underestimate the incidence of diabetes, and in most of the morbidity studies identified by the committee. Taken together, these studies and the reports reviewed in VAO, Update 1996, and Update 1998 meet the definition established for limited/suggestive evidence—that is, evidence is suggestive of an association between herbicides and the outcome, but limited because chance, bias, and confounding could not be ruled out with confidence. Although some of the risk estimates in the studies examined by the committee are not statistically significant and, individually, studies can be faulted for various methodological reasons, the accumulation of positive evidence is suggestive.

Conclusions

Strength of Evidence in Epidemiologic Studies

Based on its evaluation of the epidemiologic evidence reviewed in this and previous Veterans and Agent Orange reports, the committee finds 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 diabetes. This change from previous Update report findings reflects the availability of multiple studies with direct measures of diabetes and adjustment for several important potential confounders. The report Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000) provides additional detail for the reasoning underlying this conclusion.

Biologic Plausibility

Animal, laboratory, and human data provide reasonable evidence that TCDD exposure could affect Type 2 diabetes risk in humans. TCDD’s association with triglyceride and high-density lipoprotein concentrations suggests a general consistency because these are the hallmarks of altered lipid metabolism in diabetes,

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

since fatty acid metabolism, insulin resistance, and glucose metabolism are closely linked. Other observed effects include alteration of glucose transport in a variety of cells, modulation of protein kinase C activity, reduction in adipose tissue lipoprotein lipase in guinea pigs, hypertriglyceridemia in rabbits, and downregulation of low-density lipoprotein receptors on the plasma membrane in guinea pig hepatocytes.

Recently published studies of humans report a compensatory metabolic relation between dioxin and insulin regulation in Air Force Health Study participants (Michalek et al., 1999b), an apparent association between serum dioxin levels and fasting glucose levels among nondiabetic AFHS comparison group members with less than 10 ppt serum dioxin (Longnecker and Michalek, 2000), and an elevated incidence of hyperinsulinemia among a nondiabetic cohort with serum TCDD levels greater than 15 ppt (Cranmer et al., 2000). These studies, however, have methodologic limitations—primarily, inadequate measures of individual characteristics such as percentage of body fat at the time of exposure—that prevent more definitive conclusions from being drawn.

Increased Risk of Disease Among Vietnam Veterans

Presently available data allow for the possibility of an increased risk of Type 2 diabetes in Vietnam veterans. It must be noted, however, that these studies indicate that the increased risk, if any, from herbicide or dioxin exposure appears to be small. The known predictors of diabetes risk—family history, physical inactivity, and obesity—continue to greatly outweigh any suggested increased risk from wartime exposure to herbicides.

TABLE 10-1 Selected Epidemiologic Studies—Diabetes

Reference

Study Population

Exposed Cases

Estimated Risk (95% CI)

OCCUPATIONAL

New Studies

Calvert et al., 1999

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

 

All workers

26

1.49 (0.77–2.91)

 

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

7

2.11 (0.77–5.75)

 

20<TCDD <75

6

1.51 (0.53–4.27)

 

75<TCDD <238

3

0.67 (0.17–2.57)

 

238<TCDD <3,400

10

1.97 (0.79–4.90)

Steenland et al., 1999

Highly exposed industrial cohorts (N=5,132)

 

Diabetes as underlying cause

26

1.18 (0.77–1.73)

 

Diabetes among multiple causes

89

1.08 (0.87–1.33)

 

Chloracne subcohort (N=608)

4

1.06 (0.29–2.71)

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Reference

Study Population

Exposed Cases

Estimated Risk (95% CI)

Vena et al., 1998

Exposed production workers and sprayers in 12 countriesa

33

2.25 (0.53–9.5)

Calvert et al., 1996c

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

 

 

 

OR for abnormal total cholesterol concentration

95

Overall: 1.1(0.8–1.6)

 

 

18

High TCDD: 1.0 (0.5–1.7)

 

OR for abnormal HDL cholesterol concentration

46

Overall: 1.2(0.7–2.1)

 

 

16

High TCDD: 2.2 (1.1–4.7)

 

OR for abnormal mean total/HDL cholesterol ratio

131

Overall: 1.1(0.8–1.6)

 

 

36

High TCDD: 1.5 (0.8–2.7)

 

OR for abnormal mean triglyceride cholesterol ratio

20

Overall: 1.0(0.5–2.0)

 

 

7

High TCDD: 1.7 (0.6–4.6)

Steenland et al., 1992b

Dioxin-exposed workers-mortality rates

 

 

 

Diabetes as underlying cause

16

1.07 (0.61–1.75)

 

Diabetes among multiple causes

58

1.05 (0.80–1.36)

Studies Reviewed in Update 1998

Sweeney et al., 1997/98

NIOSH production workers

 

 

Ramlow et al., 1996

Pentachlorophenol production workers

4

SMR=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

4

SMR=0.7 (0.2–1.9)

Moses et al., 1984

2,4,5-T and TCP production workers

22 (chloracne)

2.3 (1.1–4.8)

May, 1982

TCP production workers

2

Pazderova-Vejlupkova et al., 1981

2,4,5-T and TCP production workers

11

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Reference

Study Population Exposed

Cases

Estimated Risk (95% CI)

ENVIRONMENTAL

New Studies

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., 2000

Vertac/Hercules Superfund site nondiabetic residents

 

OR for “high” fasting insulin-subjects 7: >15 ppt with serum TCDD>15 ppt vs. <15ppt 62: <15 ppt

 

8.5 (1.49–49.4)

 

“high” 30-minute insulin…

7 (1.26–39.0)

 

“high” 60-minute insulin…

12 (2.23–70.1)

 

“high” 120-minute insulin…

56 (5.7–556)

Bertazzi et al., 1998

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., 1998

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)

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans and comparisons

 

(Numerous analyses discussed in text)

Longnecker and Michalek, 2000

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

0.91 (0.50–1.68)c

 

Quartile 3:4.0–<5.2 ng/kg

57

1.77 (1.04–3.02)c

 

Quartile 4: ≥5.2 ng/kg

61

1.56 (0.91–2.67)c

CDVA, 1998a

Australian Vietnam veterans—male

2,391 reportedb (6% of respondents)

1,780 expected (1,558–2,003)

CDVA, 1998b

Australian Vietnam veterans— female

5 reportedd (2% of respondents)

10 expected (9–11)

Henriksen et al., 1997

Ranch Hands—high-exposure group

 

Glucose abnormalities

 

1.4 (1.1–1.8)

 

Diabetes prevalence

 

1.5 (1.2–2.0)

 

Use of oral medications for diabetes

 

2.3 (1.3–3.9)

 

Serum insulin abnormalities

 

3.4 (1.9–6.1)

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Reference

Study Population

Exposed Cases

Estimated Risk (95% CI)

Studies reviewed in Update 1998

Henriksen et al., 1997

Ranch Hands

 

High-exposure category

57

1.5 (1.2–2.0)

 

All Ranch Hands

146

1.1 (0.9–1.4)

O’Toole et al., 1996

Australian Vietnam veterans

12

1.6 (0.4–2.7)d

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

NOTE: N/A=not applicable; TCP=trichlorophenol, HDL=high-density lipoprotein; OR=Odds Ratio; 2,4,5-T=2,4,5-trichlorophenoxyacetic acid

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

bStudies are not discussed in this report, but discussed as new studies in Veterans and Agent Orange: Type 2 Diabetes (IOM, 2000).

cAdjusted 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.

dSelf-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?

LIPID AND LIPOPROTEIN DISORDERS

Background

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

Disorders of lipoprotein metabolism usually result from overproduction or decreased clearance of lipoproteins, or both. Common examples are hypercho-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

lesterolemia, which may be familial (due to an LDL receptor genetic defect) or polygenic (due to multiple minor genetic susceptibilities); familial hypertriglyceridemia (sometimes linked to susceptibility to diabetes); and mixed hyperlipidemias in which both cholesterol and triglycerides are elevated. This group includes familial combined hyperlipidemia, thought by many to result from hepatic overproduction of VLDL and apoprotein B, and type III dyslipidemia (defective clearance of IDL-VLDL remnants, leading to a buildup of these atherogenic particles). Although the bulk of blood lipid concentration is genetically determined, diet, activity, and other factors (concurrent illness, drugs, age, gender, hormones, etc.) do have major effects. In particular, the saturated fat content of the diet may raise LDL cholesterol concentrations via decreased LDL receptor activity, whereas obesity and a high-carbohydrate diet may increase VLDL triglycerides, possibly linked to insulin resistance and reduced lipoprotein lipase activity. Intercurrent illness may increase the triglyceride (and lower the cholesterol) concentration. Diabetes is also associated with increased triglycerides and decreased HDL cholesterol, whereas other diseases (e.g., thyroid, renal) often result in hypercholesterolemia. It is thus evident that multiple host and environmental factors influence lipid and lipoprotein concentrations and that these influences must be accounted for before the effect of a new factor can be assessed (LaRosa, 1990). In the current context, obesity as a primary determinant of both triglyceride and TCDD concentrations has to be fully controlled in any analysis. Furthermore, the ability of acute or chronic illness to raise triglyceride (and glucose) concentrations and lower HDL (and LDL) cholesterol must be recognized.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and lipid and lipoprotein disorders. 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.

Update of the Scientific Literature

Occupational and Environmental Studies

No new findings have appeared in occupational or environmental studies in the peer-reviewed epidemiologic literature regarding dioxin exposure and the occurrence of elevated lipids or lipoproteins since publication of the last VAO series report. Recently published results for triglyceride and HDL cholesterol levels of chemical plant workers in New Jersey and Missouri (Calvert et al., 1998; Sweeney et al., 1997/98) were identical to those given in Update 1998.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×
Vietnam Veteran Studies

The most recent report of the Air Force Health Study (AFHS, 2000) provided analyses of total cholesterol, HDL cholesterol, and triglyceride levels at the 1997 examination and across examinations between 1982 and 1997.1 Regression analyses of lipids included adjustment for age, race, military occupation, current and lifetime alcohol use, and history of industrial or degreasing chemical exposure. Some analyses also adjusted for body fat at the time of blood measurement of dioxin. In regression analysis with body fat and the covariates listed above, the 238 Ranch Hands in the highest category of dioxin (initial level>94 ppt, 1987 level>10 ppt) had a small, statistically nonsignificant elevation in total cholesterol (217.3 mg/dl versus 212.9 mg/dl in comparison veterans, p=.12). Continuous and categorical measures of dioxin were not related to change in total cholesterol over time, and results by occupation were inconsistent (e.g., Ranch Hand veterans had slightly more favorable trends in cholesterol among officers but slightly less favorable trends among enlisted ground crew).

Level of HDL cholesterol in 1997 was inversely associated with level of dioxin in 1987 (49.2 mg/dl versus 46.3 mg/dl for low versus high tertiles of dioxin, p=. 04). However, body fat was not included in regression models for the analysis of 1987 dioxin levels, and other potential predictors of HDL (e.g., change in body fat, distribution of body fat, smoking status, physical activity, medication use) were not assessed. In addition, HDL levels were not associated with occupational definitions of dioxin exposure or estimates of initial dioxin level. Longitudinal analyses of change in HDL cholesterol revealed no relationships to any measures of exposure to dioxin. The aforementioned Ranch Hand veterans with the highest combination of initial dioxin level (>94 ppt) and 1987 dioxin level (>10 ppt) had elevated triglyceride levels in 1997 (118.2 mg/dl versus 105.9 mg/ dl in comparison veterans, p=.01). The longitudinal analysis also revealed that this category of Ranch Hand veterans experienced the largest increase in trigyceride levels over the 15-year follow-up (+13.1 mg/dl versus +1.3 mg/dl in comparison veterans, p=.02). No elevation in triglyceride level was evident in Ranch Hands with low or background levels of dioxin.

Synthesis

The new reports from the Air Force Health Study offer useful but incomplete evidence on the association between dioxin exposure and lipid abnormalities. The longitudinal analyses are particularly valuable in addressing alternative explanations for these associations (e.g., antecedent-consequent uncertainty and the effect of lipid level on dioxin level). The findings for total cholesterol and

1  

This material is also reviewed in Veterans and Agent Orange: Herbicide/Dioxin Exposure and Type 2 Diabetes (IOM, 2000).

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

HDL cholesterol, in aggregate, do not suggest a clear or consistent relationship with dioxin exposure. A stronger association was observed for serum triglyceride level, but the role of body fat and its distribution as a shared determinant of dioxin and lipid levels must be evaluated more rigorously. Unfortunately, there are no other new studies to add in order to evaluate any evolving direction in the body of evidence.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and lipid and lipoprotein disorders. No peer-reviewed studies have been added to a literature of weak and inconsistent findings summarized in Update 1998, and more detailed analyses are needed from the Air Force Health Study on the role of obesity and other predictors of triglyceride and cholesterol levels.

Biologic Plausibility

Although animal studies suggest potential mechanisms whereby TCDD may cause lipid disturbances, human data (e.g., lipoprotein kinetic studies) are still needed to determine whether, and how, TCDD-exposed subjects have altered lipoprotein metabolism. A discussion of animal toxicological studies that could contribute to a biologic basis for an association between exposure to TCDD and 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

As indicated above, the most recent AFHS study (AFHS, 2000) reports an inconsistent association between dioxin exposure and lipid abnormalities in U.S. veterans of Vietnam. Data are at present insufficient to permit a conclusion about whether or not they are at increased risk for these disorders.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

TABLE 10-2 Selected Epidemiologic Studies—Lipid and Lipoprotein Disorders

Reference

Study Population

Exposed Cases

Cholesterol

Triglycerides

HDL Cholesterol

OCCUPATIONAL

Studies Reviewed in Update 1998

Calvert et al., 1996c

Production workers

18, 16, 7

1.0 (0.5–1.7)

1.7 (0.6–4.6)

2.2 (1.1–4.7)

Ott and Zober, 1996a

Production workers

42

NS

NS

p=.05

Studies Reviewed in VAO

Martin, 1984a

Production workers

53

(some exposure)

p<.005

p<.005

NS

 

 

39

(chloracne)

p<.05

p<.01

NS

Moses et al., 1984b

TCP and 2,4,5-T production workers

118

(chloracne)

NS

NS

No data

Suskind and Hertzberg, 1984a

TCP production workers

204

NS

NS

NS

May, 1982a

TCP production workers

94

NS

NS

No data

Pazderova-Vejlupkova et al., 1981a

TCP and 2,4,5-T production workers

55

NS

↑ VLDL p=.01

No data

ENVIRONMENTAL

Studies Reviewed in VAO

Assennato et al., 1989a

Adults exposed near Seveso

193

(chloracne)

NS

NS

No data

Mocarelli et al., 1986a

Children exposed near Seveso

63

NS

NS

No data

VIETNAM VETERANS

New Studies

AFHS, 2000

Air Force Ranch Hand veterans

858

NS

NS

NS

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

Studies reviewed in Update 1998

AFHS, 1996i

Longitudinal analysis (1992 exam data)

884

NS

(cholesterol: HDL ratio)

NS

NS

(cholesterol: HDL ratio)

O’Toole et al., 1996d

Australian Vietnam veterans

20

3.0 (1.3–4.7)

No data

No data

Studies reviewed in VAO

AFHS, 1991g

Serum dioxin analysis (1987 exam data)

283–304g

p=.175

p<.001d

p<.001

AFHS, 1990f,j

Original exposure group analysis (1987 exam data)

8–142g

1.2 (0.9–1.5)

1.3 (0.9–1.8)

1.0 (0.4–2.4)

AFHS, 1984;e Wolfe et al., 1990

Vietnam veterans exposed to herbicide spraying (1982 data)

1,027 total exposed

NS

NS

NS

NOTE: Estimated risk and 95% CI reported unless p-values are specified; NS=not significant; TCP=trichlorophenol.

ap-values comparing means to controls. Univariate analysis.

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

cOR for abnormal lipid in highest-exposure category.

dCompared to Australian population.

eComparing means.

fNumber of exposed Ranch Hand with “high” lipid values.

gComparing mean dioxin across lipid groups.

hContinuous analysis.

iComparing change over time between exposed and comparison groups.

jModel 1, Ranch Hands vs. Comparisons-Adjusted.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

GASTROINTESTINAL AND DIGESTIVE DISEASE, INCLUDING LIVER TOXICITY

Background

The discussion in this section of gastrointestinal and digestive disease, including liver toxicity, encompasses a variety of conditions included under International Classification of Diseases, Ninth edition (ICD•9) codes 520–579. Conditions in this category include diseases of the esophagus, stomach, intestines, rectum, liver, and pancreas. Additional detail on peptic ulcer and liver disease—the two conditions most frequently discussed in the literature reviewed—is provided below. The symptoms and signs of gastrointestinal disease and liver toxicity are highly varied and often vague, depending on the specific condition involved.

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

Peptic Ulcer Disease

Peptic ulcer disease refers to ulcerative disorders of the gastrointestinal tract that are caused by the action of acid and pepsin on the stomach duodenal mucosa. Peptic ulcer disease is characterized as gastric ulcer or duodenal ulcer, depending on the anatomic site of origin. Peptic ulcer disease occurs when the corrosive action of gastric acid and pepsin exceeds the normal mucosal defense mechanisms protecting against ulceration. Approximately 10 percent of the population has clinical evidence of duodenal ulcer during their lifetime, with a similar percentage affected by gastric ulcer. The peak incidence for duodenal ulcer occurs in the fifth decade of life, whereas the peak for gastric ulcer occurs approximately 10 years later. The natural history of duodenal ulcer is one of spontaneous remission (healing) and recurrences. It is estimated that 60 percent of healed duodenal ulcers may recur in the first year and that 80–90 percent will recur within 2 years.

Increasing evidence indicates that the bacterium Helicobacter pylori (H. pylori) may be closely linked to both duodenal and gastric ulcer disease. This bacterium colonizes the gastric mucosa in 95–100 percent of patients with duode-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
×

nal ulcer and 75–80 percent of patients with gastric ulcer. Healthy subjects in the United States under 30 years of age have gastric colonization rates of approximately 10 percent. Over age 60, colonization rates exceed 60 percent. Colonization alone, however, is not sufficient for the development of ulcer disease; only 15–20 percent of subjects with H.pylori colonization will develop ulcer disease in their lifetimes.

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

Liver Disease

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

Cirrhosis of the liver is the most commonly reported liver disease outcome in epidemiologic studies of herbicide and/or TCDD exposure. Pathologically, cirrhosis reflects irreversible chronic injury of the liver, with extensive scarring and resultant loss of liver function. Clinical symptoms and signs include jaundice, edema, abnormalities in blood clotting, and metabolic disturbances. Ultimately, cirrhosis may lead to portal hypertension with associated gastroesophageal varices, enlarged spleen, abdominal swelling due to ascites, and ultimately hepatic encephalopathy, which may progress to coma. It is generally not possible to distinguish the various causes of cirrhosis by the clinical signs and symptoms or pathological characteristics. The most common cause of cirrhosis in North America and many

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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parts of Western Europe and South America is excessive alcohol consumption. Other causes include chronic viral infections (hepatitis B or hepatitis C), a poorly understood condition called primary biliary cirrhosis, chronic right-sided heart failure, and a variety of less common metabolic and drug-related causes.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and gastrointestinal and digestive disease, including liver toxicity. 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.

Update of the Scientific Literature

Occupational Studies

Hooiveld et al. (1998) conducted a retrospective cohort study of Dutch production and contract workers exposed to phenoxy herbicides, chlorophenols, and contaminants between 1950 and 1976. Of the 1,129 workers identified in the original cohort, 562 exposed and 567 unexposed workers were included in this study. The standardized mortality ratio for “digestive system disorders” (ICD•9 520–579) was 0.6 (0.1–2.2), based on 2 deaths. Neither of these deaths was in a subcohort of 140 workers with presumed higher exposures due to an industrial accident. An analysis was also conducted of digestive system disease deaths among workers with medium and high TCDD levels compared to workers with low TCDD levels. Limited measurements of serum TCDD level were combined with information on occupation and duration of employment to form the TCDD level estimates. The relative risks were 1.0 (0.1–17.2) for workers with medium TCDD levels and 0.8 (0.1–14.4) for the high-TCDD group.

An Austrian cohort of 159 TCDD-exposed workers reporting chloracne between 1968 and 1975 was examined by Neuberger et al. (1999). The workers were involved in the production of 2,4,5-T and 2,4,5-trichlorophenol (TCP). In 1996, blood and urine samples were taken from 50 surviving exposed workers and matched controls. Liver disease, as evidenced by blood chemistry analyses and medical records data, was more frequent in exposed workers than in controls. Within the exposed cohort, the mean serum TCDD level was significantly higher in workers with a history of liver disease (801 pg/g; 7 cases) than those without (407 pg/g). Adjustment for smoking did not affect the statistical significance of the result. Analyses that controlled for age, alcohol, and TCDD concentration found the effects of TCDD and its interaction with age to be significant, suggest-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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ing chronic liver damage after high TCDD exposure at a young age. The authors raised the idea that liver disease might affect the toxicokinetics of dioxin but did not have the data that would allow this hypothesis to be tested empirically. They also acknowledged that other unmeasured occupational exposures could have influenced the results.

Vena et al. (1998) examined noncancer mortality among 21,863 phenoxy acid herbicide and chlorophenol production workers and sprayers included in the I ARC study. This international study comprises 36 cohorts from 12 countries. An analysis of the 4,159 deaths occurring from 1939 to 1992 revealed 96 deaths from diseases of the digestive system (SMR=0.7, 0.6–0.9) among 13,831 workers exposed to TCDD or higher chlorinated dioxins (TCDD/HCD) and 47 deaths (SMR=1.0, 0.7–1.3) among 7,553 nonexposed workers. When liver cirrhosis (ICD•9 571) was treated as a separate category, 53 deaths (0.8, 0.6–1.1) were identified among exposed workers; and 19 (1.3, 0.8–2.0) among nonexposed.

Environmental Studies

Bertazzi et al. (1998) conducted a review of early and long-term effects of dioxin exposure following a 1976 industrial accident in Seveso, Italy, where a large population was exposed to a substantial amount of relatively pure 2,3,7,8-TCDD. Extensive monitoring of soil levels and measurements of a limited number of human blood samples allowed for classification of the exposed population into three categories: zone A—highest exposure, zone B—medium exposure, and zone R—lowest exposure. When the authors looked at digestive disease mortality in zone A males, 2 deaths were observed when 3.1 (RR=0.7, 0.2–2.6) were expected. Among females, 2 deaths were observed when 1.6 were expected (RR =1.2, 0.3–5.0). In zone B, 15 digestive disease deaths among males were observed when 20.8 were expected (RR=0.7, 0.4–1.2), and there were 13 deaths among females when 10.3 were expected (RR=1.3, 0.7–2.2). For males in zone R, there were 165 deaths from digestive diseases when 144.3 (RR=1.1, 1.0–1.3) were expected. Among females in this zone, there were 89 deaths when 83.5 (RR=1.1, 0.8–1.3) were expected.

A later study (Bertazzi et al., 2001) extends the mortality analysis to 20 years following the event for zones A and B only. For zone A, there were no additional deaths from digestive system ailments among males (0.5, 0.1–2.1) and one additional death among females (1.4, 0.4–4.3). In zone B, there were 7 additional deaths among males (RR=0.9, 0.6–1.3; based on 22 deaths total) and 3 additional deaths among females (RR=1.2, 0.7–1.9). An examination of these deaths as a function of years since first exposure did not indicate a time trend in the data. The analysis also separated data for cirrhosis of the liver from other gastrointestinal diseases. There were no deaths from the ailment among females in zone A; the number of deaths among zone A males (2) was slightly lower than expected (RR=0.7, 0.2–3.0).

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Liver cirrhosis deaths in zone B males (0.8, 0.5–1.4; 14 deaths) and females (0.7, 0.3–1.6; 5 deaths) were also slightly lower than expected.

Vietnam Veteran Studies

Michalek et al. (1998) conducted a 15-year follow-up study examining postservice mortality of U.S. Air Force veterans occupationally exposed to herbicides in Vietnam. Although cause-specific mortality did not differ from that expected regarding deaths from accidents, cancer, or circulatory system diseases, the authors found an increased number of deaths due to digestive diseases. When comparing 1,261 exposed Ranch Hands to a group of 19,080 veterans who were not involved in spraying operations, 9 deaths were observed when 5.1 were expected (SMR=1.7, 0.9–3.2). Chronic liver disease and cirrhosis accounted for most of the increase in digestive disease deaths.

The latest in the series of Air Force Health Study reports describes the results of the 1997 physical examination of Ranch Hand veterans and their comparison cohort (AFHS, 2000). More details on this study series are contained in Chapter 3. An extensive assessment of liver disease outcomes was conducted: data were collected on eight medical conditions and 29 laboratory measurements or indices. Analyses were adjusted for age, race, military occupation, alcohol history, industrial chemical exposure, and degreasing chemical exposure. Participants with a pre-Southeast Asia diagnosis of a condition were excluded from the analysis of that condition.

The authors evaluated the incidence of uncharacterized hepatitis, jaundice, acute necrosis of the liver, chronic liver disease and cirrhosis (both alcohol and non-alcohol related), liver abscess and sequelae of chronic liver disease, enlarged liver (hepatomegaly), and what was termed “other liver disorders.” There were too few cases of acute necrosis of the liver and of liver abscess and sequelae of chronic liver disease to draw conclusions about incidence. Uncharacterized hepatitis incidence was similar among Ranch Hand (17 of 863) and comparison (21 of 1,244) veterans (RR=1.2, 0.6–2.4; Model 1, adjusted). Significantly more comparison (35 of 1,219) than Ranch Hand veterans (12 of 846) experienced unspecified jaundice (RR=0.5, 0.3–1.0; Model 1, adjusted). Eleven of the twelve cases in the Ranch Hand cohort were among veterans with background levels of serum dioxin. Proportionately more Ranch Hand (14 of 870) than comparison (14 of 1,250) veterans experienced non-alcohol-related chronic liver disease and cirrhosis, but the difference did not achieve statistical significance in the various models employed by AFHS researchers (RR=1.4, 0.7–3.0; Model 1, adjusted). There was no association between serum dioxin level and incidence among Ranch Hand veterans for this outcome. The incidence of alcohol-related liver disease and cirrhosis was similar in the two cohorts. More comparison (27 of 1,249) than Ranch Hand (14 of 869) veterans experienced an enlarged liver (0.7, 0.4–1.4;

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Model 1, adjusted). While the authors note that diagnosis of this condition is problematic in obese individuals, they do not adjust for weight in their analysis.

There was a marginally significant excess of so-called other liver disorders (ICD•9 573.0–573.9, 790.4, 790.5, and 794.8) among Ranch Hand veterans. The 249 (of 866) Ranch Hand cases were proportionately greater than the 312 (of 1,240) cases found among comparison veterans (RR=1.2, 1.0–1.5; Model 1, adjusted). Analyses that factored serum dioxin levels yielded a statistically significant excess among Ranch Hand veterans in the high dioxin category (1.5, 1.1– 2.1; Model 3, adjusted) but not the background or low dioxin categories. The authors note that they are preparing a separate report that will examine the relationship between other liver disorders and herbicide exposure and dioxin levels in greater detail.

Laboratory indices included measurements of hepatic (liver) enzyme activity, hepatobiliary function, lipid and carbohydrate indices, a protein profile, and tests for the presence of hepatitis and fecal occult blood. Combinations of these tests are often used to inform the diagnosis of gastrointestinal ailments because physical examination results and reporting of symptoms are not always reliable indicators of problems or good health. However, the presence of altered levels does not by itself indicate an adverse health effect.

Analyses of discrete measures of three of the four hepatic enzymes—ALT, AST, and GGT—and serum triglycerides showed borderline or statistically significant associations between serum dioxin level and elevated enzyme levels. The authors noted that these results were consistent with a dose-response effect but could also be explained by the hyperlipidemia and fatty infiltration of the liver that occur in association with obesity. Analyses of other laboratory indices yielded inconsistent and generally nonsignificant results that depended on whether the measure was treated as a continuous or discrete variable, the particular model used, and whether confounding influences were factored.

The government of Australia conducted mail surveys of approximately 50,000 male and female nationals who served in Vietnam, including those involved in combat, medical teams, war correspondents, entertainers, and philanthropy workers (CDVA, 1998a, b). The self-report data that were gathered were compared with age-matched Australian national data. The authors examined three gastrointestinal conditions: stomach and duodenal ulcers, cirrhosis of the liver, and gastric reflux. There was an excess of male veterans reporting a doctor had told them that they had a stomach or duodenal ulcer since their first day of service in Vietnam compared to age-standardized expected rates: 4,732 cases of stomach ulcer and 3,114 cases of duodenal ulcer were reported (CDVA, 1998a), with many veterans reporting both types (K.Horsley, Commonwealth Department of Veterans Affairs, personal communication, December 10, 2000). In contrast, 3,089 total cases were expected (range 2,872–3,306). The authors noted that there was some uncertainty in the number of cases, given that veterans may or may not have reported ulcers that were identified and treated in the past. The number of

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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reported cases of cirrhosis of the liver, 1,132, was within the bounds of the expected number (41–1,207). Because the expected range for this condition was derived from European rather than Australian data, doubt was expressed about its applicability to Australian veterans. Thirty percent of male veterans reported that a doctor had told them they had gastric reflux. No conclusion was drawn from this result because no baseline was available from which to calculate an expected number of cases.

The survey of female veterans (CDVA, 1998b) included estimates of the range of “observed” number of cases because problems in locating veterans limited the size of the sample cohort. Stomach ulcers were reported by 15 (range 8–22) female veterans and duodenal ulcers by 9 (3–15). A total of 22 (15–29) veterans reported one or both types of ulcers when 17 (15–18) were expected. As noted in the survey of male veterans, there was some uncertainty in the numbers of cases, given that veterans may or may not have reported ulcers that were identified and treated in the past. One case of cirrhosis of the liver was reported— no estimated range was given. Of the veterans surveyed 56 (46–66) reported that they had been told by a doctor that they had gastric reflux since their first day of service in Vietnam. This was higher than the two estimates of expected prevalence, 11 and 33 cases, although the authors stated that this finding should be interpreted with caution because of the lack of precision in defining this condition in both the survey population and the community comparison.

Synthesis

Evaluation of the impact of herbicide and dioxin exposure on noncancer gastrointestinal ailments is more difficult than some of the other outcomes examined in this report. Clinical experience suggests that medical history and physical examination are undependable diagnostic tools for some of these ailments, making incidence data more problematic. The strong interdependence between weight, laboratory indices of hepatic function, and health, and body burden of dioxin, complicate the already difficult task of assessing association.

Most of the analyses of occupational or environmental cohorts reviewed for the first time in this report had insufficient numbers of cases to draw confident conclusions. The one study with a relatively large number of observations (Vena et al., 1998) found lower digestive system disease and liver cirrhosis mortality among exposed workers than unexposed controls. A set of studies of Australian veterans suggested a higher incidence of stomach and duodenal ulcers in both men and women, but the information was self-reported and the analyses were not controlled for confounding influences. The latest AFHS (2000) report found a significantly higher percentage of other liver disorders among Ranch Hands in the high-dioxin category than among comparisons. Data were consistent with an interpretation of a dose-response relationship, but other explanations were also plausible. The com-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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mittee will give careful scrutiny to a planned paper by AFHS researchers that specifically addresses the results concerning other liver disorders.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and gastrointestinal and digestive diseases.

Biologic Plausibility

The liver is a primary target organ of TCDD exposure in animals. Therefore, TCDD would be expected to induce liver toxicity in humans at appropriate doses. Direct effects of TCDD and herbicides on other gastrointestinal and digestive diseases have not been seen. 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

The available data on Vietnam veterans do not permit a conclusion about whether they are at elevated risk for gastrointestinal and digestive diseases.

CIRCULATORY DISORDERS

Background

The circulatory diseases reviewed in this section cover a variety of conditions encompassed by ICD•9 codes 390–459, including hypertension, heart failure, arteriosclerotic heart disease, peripheral vascular disease, and cerebrovascular disease. In morbidity studies, a variety of methods were used to assess the circulatory system, including analysis of symptoms or history, physical examination of the heart and peripheral arteries, Doppler measurement of peripheral pulses, electrocardiograms (ECG), and chest radiograph. Doppler measurements and physical examinations of the pulses in the arms and legs are used to detect decreased strength of the pulses, which can be caused by thickening and hardening of the arteries. ECGs can be used to detect heart conditions and abnormalities such as arrhythmias (abnormal heart rhythms), heart enlargement, and previous

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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heart attacks. Chest radiographs can be used to assess whether the heart is enlarged, which can result from heart failure and other heart conditions. Mortality studies attribute cause of death to one or more of the circulatory disorders, with varying degrees of diagnostic confirmation.

Summary of VAO, Update 1996, and Update 1998

The committee responsible for VAO found that there was inadequate or insufficient information to determine whether an association existed between exposure to the herbicides used in Vietnam or the contaminant dioxin and circulatory disorders. 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.

Update of the Scientific Literature

Occupational Studies

The most recent report (Vena et al., 1998) of the IARC international cohort study of phenoxy herbicide and chlorophenol production workers stratified subjects by likely exposure to dioxins and assessed mortality for exposed (N= 13,831) and nonexposed (N=7,553) workers in relation to each other and to the general population. Both exposed and nonexposed workers exhibited a “healthy worker effect” for circulatory diseases (i.e., both employed groups had an SMR <1.0 for circulatory diseases, ischemic heart disease and stroke, indicating lower levels of mortality than those found in the general population). However, an analysis conducted within the cohort of workers revealed that exposure to dioxins was associated with a 50 percent increase in death from all circulatory diseases (1,151 deaths in the exposed; 582 deaths in the nonexposed; RR=1.5, 1.2–2.0). This estimate was adjusted for age, gender, country, and calendar period, and the increased risk was evident for both ischemic heart disease and stroke (RR=1.7 and 1.5, respectively). No clear patterns were present in the additional analyses of latency and duration of exposure.

Separate reports have also been published on some of the individual cohorts included in the IARC study. The analysis of a Dutch cohort was based on 549 exposed and 482 nonexposed male workers and included adjustment for age, time since first exposure, and calendar year at end of follow-up (Hooiveld et al., 1998). Workers exposed to phenoxy herbicides, chlorophenols, and contaminants were at increased risk of death from all circulatory diseases (45 deaths in the exposed, 16 deaths in the nonexposed; RR=1.4, 0.8–2.5), ischemic heart disease (33 deaths in the exposed, 10 deaths in the nonexposed; RR=1.8, 0.9–3.6) and stroke (9 deaths in the exposed; 3 deaths in the nonexposed; RR=1.4, 0.4–5.1). A dose-response analysis based on TCDD levels extrapolated from serum analy-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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ses of a subgroup found a dose-response pattern for ischemic heart disease but not for stroke or circulatory diseases in general. When a similar procedure was used to evaluate the presence of a dose-response relationship across quintiles of exposure in a German cohort of 1,189 workers (Flesch-Janys, 1997/98), the test for trend was statistically significant (p<.05) for all circulatory diseases and for ischemic heart disease, but this was influenced primarily by a protective effect in the lowest two quintiles of exposure (e.g., RR=0.7 and 0.7 for circulatory diseases) and an elevated risk in the highest decile of exposure (e.g., RR=1.7, 1.0–2.9). Steenland et al. (1999) created an ordinal exposure score based on a job-exposure matrix for eight American cohorts included in the IARC study. A total of 3,538 workers were included in this analysis, and 290 deaths from ischemic heart disease were ascertained. A direct relationship was observed between cumulative exposure to TCDD and ischemic heart disease mortality, with RR=1.8 (1.1–2.9) for the highest septile of exposure (43 deaths) compared to the lowest septile of exposure (29 deaths).

Morbidity from circulatory diseases was assessed in a cross-sectional study of 281 chemical plant workers and a comparison group of 260 neighbors with matching on age, race, and gender (Calvert et al., 1998). In the simple analysis of myocardial infarction (defined by ECG evidence or self-report of a physician diagnosis), workers in the highest quartile of serum TCDD (>238 pg/g) had nearly a twofold increase (9 cases in the exposed, 20 cases in the nonexposed; OR=1.9, 0.8–4.4). This association was eliminated (adjusted OR=1.1, 0.2–5.1) in a logistic regression model that adjusted for age, smoking, alcohol consumption, and family history of heart disease. Dioxin level was not related to the prevalence of angina, cardiac arrhythmias, or hypertension in either the simple or the multivariate analysis.

Environmental Studies

Two papers presented results from the 15-year follow-up of mortality in Seveso, Italy, after the population-based exposure to dioxin (Bertazzi et al., 1998; Pesatori et al., 1998). In the report of the 10-year follow-up, Bertazzi et al. (1989) noted that both men and women in zone A (the most exposed region) had similarly elevated SMRs for circulatory diseases (men: SMR=1.8, 1.0–3.2; women: SMR=1.9, 0.8–4.2). These estimates were based on few deaths (11 male, 6 female) and represented different cardiovascular diagnoses. With 5 additional years of follow-up, the SMR for circulatory diseases in zone A remained modestly elevated for men (21 deaths; SMR=1.6, 1.1–2.5) but was not elevated for women (12 deaths; SMR=1.0, 0.6–1.7). Elevated SMRs for some specific cardiovascular diagnoses (e.g., chronic rheumatic heart disease and hypertension for women in zone A), are difficult to interpret in view of the small number of deaths (3 for each of these outcomes). There was no evidence of increased general cardiovascular or cerebrovascular mortality in the region with intermediate levels

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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of exposure (zone B). In the area with the lowest level of exposure (zone R), modest increases in deaths due to hypertension and chronic ischemic heart disease led to SMRs of 1.1 (1.0–1.2; 719 deaths) and 1.2 (1.0–1.6; 759 deaths) for circulatory diseases in men and women, respectively. This pattern of results remained essentially unchanged with the extension of mortality follow-up to 20 years (Bertazzi et al., 2001). The SMR for circulatory diseases in men of zone A was 1.4 (1.0–2.2; 24 deaths), with the increased risk attributable to both ischemic heart disease and cerebrovascular disease during the first 9 years of follow-up. There was no clear evidence of elevated risk of mortality from circulatory diseases in residents of zone B (SMR=0.9 and 1.0 for women and men, respectively) or women from zone A (SMR=0.7). A small excess in mortality from hypertension (SMR=1.3, 1.1–1.6; 130 deaths), and chronic ischemic heart disease (SMR=1.2, 1.1–1.4; 328 deaths), was noted for men and women combined in zone R.

Vietnam Veteran Studies

Michalek et al. (1998) presented the results of the 15-year mortality follow-up of Ranch Hand veterans. These findings were included in Update 1998 based on the AFHS (1996) report. Mortality was analyzed for 1,261 Ranch Hand veterans, with expected mortality based on data from 19,080 nonexposed Air Force veterans who also served in Southeast Asia. In general, Ranch Hand veterans and comparison veterans experienced similar mortality from all circulatory diseases (39 deaths in Ranch Hand veterans; SMR=1.0, 0.7–1.3), but an analysis by military occupation showed that among enlisted ground personnel, Ranch Hand veterans were at somewhat increased risk (24 deaths in Ranch Hand veterans; SMR=1.5, 1.0–2.2).

Data on morbidity were reported from the Air Force Health Study 1997 Follow-up Examination Results (AFHS, 2000). Multiple models were computed to contrast Ranch Hands with comparison veterans (overall and by rank) and to analyze health effects in Ranch Hands by dioxin level (in 1987 or extrapolated to initial exposure). Myocardial infarction, stroke, and transient ischemic attack were unrelated to dioxin levels or exposure categories in all models. Null findings were also reported for all analyses of systolic and diastolic blood pressure and most analyses of the prevalence of hypertension, although the latter was modestly associated with 1987 dioxin levels (OR=1.2, 1.0–1.3 for a twofold increase in dioxin). A general measure of self-reported history of heart disease (excluding hypertension) was more common among Ranch Hand personnel than comparison veterans (66.1 percent versus 60.8 percent, p=.01), and this difference persisted following adjustment for covariates. However, the prevalence of self-reported heart disease was not consistently related to more detailed gradients of exposure as defined by specific occupation or dioxin level. While the investigators re-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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ported use of medical records to verify self-reports, the high frequency of heart disease (more than 60 percent among the study sample) raises questions about validity for this outcome.

The government of Australia conducted mail surveys of approximately 50,000 male and female nationals who served in Vietnam, including those involved in combat, medical teams, war correspondents, entertainers, and philanthropy workers (CDVA, 1998a, b). The self-report data that were gathered were compared with age-matched Australian national data. An excess of male veterans reported that a doctor had told them they had ischemic heart disease since their first day of service in Vietnam, compared to age-standardized expected rates: 5,965 cases were reported while 3,236 (range 2,732–3,739) were expected (CDVA, 1998a). The authors noted that although there was the possibility of other circulatory ailments being misreported as ischemic heart disease, elevated mortality rates (SMR=1.1, 1.0–1.2) found in an earlier study of this population (Crane et al., 1997) lent support to this finding.

The survey of female veterans (CDVA, 1998b) included estimates of the range of “observed” number of cases because problems in locating veterans limited the size of the sample cohort. Ischemic heart disease was reported by 25 (16–34) female veterans. Expected rate estimates depended on the definition of the disease used, varying from 9 (8–10) to 15 (14–17). As noted in the survey of male veterans, there was some uncertainty in the numbers of cases due to possible misreporting.

Synthesis

Evidence of increased circulatory disease mortality persists in the extended follow-up of the Seveso population, but the pattern is somewhat inconsistent across levels of exposure and the statistical power remains limited, particularly for women. The new studies from occupational epidemiology offer additional insight by providing “internal” comparisons among employed populations, thereby reducing the potential for the healthy worker effect and exposure effects to offset each other. In the comparison among workers, there is evidence of an association between dioxin and mortality from circulatory diseases in three separate studies and one larger study incorporating these three studies and others. However, key limitations recognized in Update 1998 still generally exist—the reliance on mortality as an outcome, the unassessed validity of assigned cause of death, and the inability to address potential confounding by other causes of cardiovascular and cerebrovascular disease. It is noteworthy that in the occupational study that examined morbidity and measured potential confounders, an initial association between exposure and myocardial infarction was eliminated with mathematical adjustment for confounding.

Findings on circulatory conditions in the Air Force Health Study also tend to be inconsistent and inconclusive. Excess mortality is reported for enlisted ground personnel from Operation Ranch Hand, but this pattern of findings is not sup-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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ported in subsequent analyses of cardiovascular and cerebrovascular morbidity. More generally, the most current AFHS (2000) report shows no dioxin-related increased risk for myocardial infarction and the combination of stroke and transient ischemic attack. In the 20 multivariable analyses of blood pressure (four definitions of exposure; five definitions of outcome: hypertension, diastolic— continuous, diastolic—discrete, systolic—continuous, systolic—discrete), only one model identifies a statistically significant association (prevalence of hypertension in relation to 1987 dioxin level). The magnitude of association is modest (OR=1.2), and no adjustment is possible for pre-exposure level of blood pressure. A general measure of heart disease is more prevalent among Ranch Hand veterans and some categories of increased dioxin levels, but the gradients of risk are inconsistent and more information is needed to determine the validity of the outcome measure. Elevated rates are reported in both male and female Australian veterans studies.

Conclusions

Strength of Evidence in Epidemiologic Studies

There is no information contained in the research reviewed for this report to change the conclusion that there is inadequate or insufficient evidence to determine whether an association exists between exposure to herbicides (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and specific circulatory disorders (e.g., 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 for health outcomes, incomplete assessment of confounding, and inconsistency of findings across levels of exposure.

Biologic Plausibility

There have been reports of developmental defects in the cardiovascular system of TCDD-treated birds and fish. However, little information is available to suggest that TCDD is a cardiovascular toxin following postnatal exposure of mammals to TCDD. 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

The available data on Vietnam veterans do not permit a conclusion about whether they are at an elevated risk for circulatory disorders.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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AMYLOIDOSIS

Background

Amyloidosis (ICD•9 code 277.3) is the name given to a poorly understood and relatively rare group of bone marrow diseases. The name derives from amy-loid, an abnormal type of protein that can be produced by bone marrow cells. Amyloid cannot be broken down by the body—it builds up in the bloodstream and is deposited in various organs as it circulates throughout the body. Amyloidosis occurs when enough amyloid builds up in one or more organs of the body to cause the organ(s) to malfunction (Mayo Clinic, 2000). Most cases of amyloidosis affect the heart, kidneys, nervous system, or gastrointestinal tract. Amyloid deposits can also build up in the skin.

There are several different types of amyloidosis, which are distinguished by the type of amyloid protein produced, the organ(s) affected, and whether the disease occurs alone or as a complication of another disease. AL-type primary amyloidosis is the most common form of systemic (i.e., occurring throughout the body) amyloidosis. AL is a reference to the type of amyloid involved (amyloid light chain); primary, to the fact that it occurs in the absence of a discernible preceding disease.

Systemic amyloidosis is a complication that occurs in approximately 15–20 percent of patients with multiple myeloma, which is also a bone marrow disease. Differentiation of the amyloid associated with myeloma from that of primary amyloidosis is artificial because the amyloid is of similar genesis and tissue distribution, and the conditions are more appropriately considered as parts of the spectrum of the same basic disease process.

Amyloidosis, like multiple myeloma, occurs primarily in individuals between 50 and 70 years of age and in more males than females. Annual incidence is estimated to be approximately 1 per 100,000, or approximately 2,000 new cases per year in the United States (Solomon, 1996).

Summary of VAO, Update 1996, and Update 1998

The Department of Veterans Affairs asked the committee responsible for this report to address the possible association between exposure to the herbicides used in Vietnam or the contaminant dioxin and AL-type primary amyloidosis, a condition that has not been examined in previous Veterans and Agent Orange reports.

Update of the Scientific Literature

The committee identified a single report that addressed exposure to the herbicides used in Vietnam and amyloidosis. In a letter to the journal Nature, Tóth et al. (1979) described the results of carcinogenicity tests of the herbicide 2,4,5-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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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.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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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.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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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-

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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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

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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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.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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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.

Suggested Citation:"10 Other Health Effects." Institute of Medicine. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: The National Academies Press. doi: 10.17226/10098.
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Next: Appendix A: Summary of Workshop »
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Veterans and Agent Orange: Update 2000 examines the state of the scientific evidence regarding associations between diseases and exposure to dioxin and other chemical compounds in herbicides used in Vietnam. It is the fourth in a series of comprehensive reviews of epidemiologic and toxicologic studies of the agents used as defoliants during the Vietnam War. Over forty health outcomes in veterans and their children are addressed.

Among the report's conclusions is that there is sufficient evidence of a link between exposure and the development of soft-tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, and chloracne in veterans. Additionally, it found that scientific studies offer "limited or suggestive" evidence of an association with other diseases in veterans—including Type 2 diabetes, respiratory cancers, prostate cancer, multiple myeloma and some forms of transient peripheral neuropathy—as well as the congenital birth defect spina bifida in veterans' children.

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