In VAO, the committee found limited/suggestive evidence of an association for three cancers: respiratory cancer, prostate cancer, and multiple myeloma. The recent scientific literature continues to support the classification of these diseases in the category of limited/suggestive evidence. The literature also indicates that three additional conditions satisfy the criteria necessary for this category: spina bifida, acute and subacute (transient) peripheral neuropathy, and porphyria cutanea tarda (PCT). For outcomes in this category, the evidence must be suggestive of an association with herbicides, but the association 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.
The evidence that supports the committee's conclusions for respiratory cancer and multiple myeloma is detailed in Chapter 7 and is not substantially changed from VAO. Because prostate cancer is one of the three cancer types of special interest to the DVA, a brief summary of the relevant scientific evidence is provided here. Because spina bifida, acute and subacute (transient) peripheral neuropathy, and porphyria cutanea tarda have been classified in the category of limited/suggestive since VAO, evidence for these associations is also provided.
Several studies have shown an elevated risk for prostate cancer in agricultural or forestry workers. In a large cohort study of Canadian farmers (Morrison, et al., 1993), an elevated risk of prostate cancer was associated with herbicide spraying, and the risk increased with increasing number of acres sprayed. The proportionate mortality from prostate cancer was elevated in a study of USDA forest conservationists (PMR = 1.6, CI 0.9-3.0) (Alavanja et al., 1989), and a case-control study of white male Iowans who died of prostate cancer (Burmeister et al., 1983) found a significant association with farming (OR = 1.2) that was not associated with any particular agricultural practice. These results are strengthened by a consistent pattern of nonsignificant elevated risks in studies of chemical production workers, agricultural workers, pesticide applicators, paper and pulp workers, and the population of Seveso, Italy. The largest recent study demonstrated a significantly increased risk of death from prostate cancer in both white and nonwhite farmers in 22 of the 23 states that were studied (Blair et al., 1993). Studies of prostate cancer among Vietnam veterans or among people who have been exposed environmentally, have not consistently shown an association. However, prostate cancer is generally a disease of older men, and the risk among Vietnam veterans would not be detectable in today's epidemiologic studies. Because there was a strong indication of a dose-response relationship in one study (Morrison et al., 1993) and a consistent positive association in a number of others, the committee felt that the evidence for association with herbicide exposure was limited/suggestive for prostate cancer.
There have been three epidemiologic studies that suggest an association between paternal herbicide exposure and an increased risk of spina bifida. In the Ranch Hand study (Wolfe et al., 1995), neural tube defects (spina bifida, anencephaly) were increased among offspring of Ranch Hands with four total (rate of 5 per 1,000), in contrast to none among the comparison infants (exact p=.04). The Centers for Disease Control and Prevention (CDC) VES cohort study (Centers for Disease Control, 1989) found that more Vietnam veterans reported that their children had a central nervous system anomaly (OR=2.3; 95% CI 1.2-4.5) than did non-Vietnam veterans. The odds ratio for spina bifida was 1.7 (CI 0.6-5.0). In a substudy, hospital records were examined in an attempt to validate the reported cerebrospinal defects (spina bifida, anencephaly, hydrocephalus). While a difference was detected, its interpretation is limited by differential participation between the veteran groups and failure to validate negatives reported; that is, the veterans not reporting their children having a birth defect. Thus, the issue of a recall bias is of major concern with this study. In the CDC Birth Defects Study which utilized the population-based birth defects registry system in the metropolitan Atlanta area (Erickson et al., 1984), there was no association between Vietnam veteran status and the risk of spina bifida (OR=1.1, CI 0.6-1.7) or anencephaly (OR=0.9, CI 0.5-1.7).
However, the exposure opportunity index (EOI) based upon interview data was associated with an increased risk of spina bifida; for the highest estimated level of exposure (EOI-5) the OR was 2.7 (CI 1.2-6.2). There was no similar pattern of association for anencephaly. Thus, all three epidemiologic studies (Ranch Hand, VES, CDC Birth Defects Study) suggest an association between herbicide exposure and an increased risk of spina bifida in offspring. In contrast to most other diseases, for which the strongest data have been from occupationally exposed workers, these studies focused on Vietnam veterans. Although the studies were judged to be of relatively high quality, they suffer from methodologic limitations, including possible recall bias, nonresponse bias, small sample size, and misclassification of exposure. For these reasons, the committee concludes that there is limited/suggestive evidence for an association between exposure to herbicides used in Vietnam and spina bifida in offspring.
There is also limited/suggestive evidence of an association between exposure to herbicides and acute and subacute (transient) peripheral neuropathy. There are several published studies relevant to this health outcome, but they are primarily case histories from occupational studies and chemical reports following the Seveso accident, which describe transient symptoms of peripheral neuropathies in highly exposed intervals (Todd, 1962; Berkley and Nagle, 1963; Goldstein et al., 1959; Boeri et al., 1978; Pocchiaari et al., 1979; Filippini et al., 1981). Todd (1962) reported a sprayer of 2,4-D weedkiller who developed a gastrointestinal disturbance and, within days, after contact with the chemical, a severe sensory/motor polyneuropathy. Recovery occurred over a period of months. Berkley and Magee (1963) reported another patient who developed a polyneuropathy four days after exposure to a liquid solution of 2,4-D, which was being sprayed in a cornfield. The neuropathy was purely sensory in type. The patient's symptoms gradually resolved over months. Goldstein et al. described three patients with sensory/motor polyneuropathies that developed over several days and progressed over several weeks after exposure to 2,4-D. All had incomplete recovery after several years. Although these patients were not examined neurologically before their exposure, the temporal relationship between the development of their clinical deficit and the herbicide exposure was clearly documented in the study (1959). Nonetheless, the possibility that their occurrence was unrelated to the herbicide exposure and was due to other disorders such as idiopathic Guillain-Barre syndrome cannot be entirely excluded. The trend to recovery in the individual cases reported and the negative findings of many long-term follow-up studies of peripheral neuropathy suggest that if a peripheral neuropathy indeed develops, it resolves with time.
Case reports and animal studies led to the conclusion in VAO that porphyria cutanea tarda (PCT) was associated with TCDD or herbicide exposure in genetically predisposed individuals. However, three recent reports (Jung et al., 1994; Calvert et al., 1994; and Von Benner et al., 1994) failed to support this association. Two studies (Calvert et al., 1994, and Jung et al., 1994) included extensive analysis of porphyrin levels on 451 workers with demonstrated or potential exposure to herbicides and TCDD. The studies found no relationship between porphyrin levels and TCDD levels, and no excess of PCT in these cohorts. However, some workers had evidence of increased porphyrins in their in urine, suggesting that further investigation is warranted. These new reports, combined with the literature reviewed in VAO, led the committee to conclude that there is limited/suggestive evidence of an association between PCT and exposure to herbicides and/or TCDD.
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