In this study, we examined the association between 5 organochlorine insecticides, 39 other pesticides, and self-reported history of physician-diagnosed thyroid disease in female spouses of pesticide applicators. The population of female spouses in the Agricultural Health Study is large, and these data support the role of the organochlorines aldrin, DDT, heptachlor, lindane, and chlordane; the fungicides benomyl and maneb/mancozeb; and the herbicide paraquat in the etiology of thyroid disease.
We found the prevalence of self-reported, clinically diagnosed thyroid disease in female spouses in the Agricultural Health Study to be 12.5%. This prevalence is higher than previously reported in the Third National Health and Nutrition Examination Survey (2
) and the Colorado Health Study (1
) for both clinical (abnormal TSH and abnormal T4 and/or T3 levels) and subclinical (abnormal TSH but normal T4 and T3 levels) thyroid disease in the general population. Clinical thyroid disease was estimated at 0.8%–7.5% (1
) and subclinical thyroid disease at 5%–9.4% in these populations (1
). Ethnicity in the Colorado thyroid disease prevalence study was similar to that for spouses in the Agricultural Health Study; both populations were predominantly white (94% for the Colorado Health Study vs. 98% for the Agricultural Health Study). Agricultural Health Study participants were slightly younger than the Colorado population: 39% were aged >55 years and 52.5% were aged >54 years (1
), respectively. Thyroid disease is more prevalent with increasing age, but given that the Agricultural Health Study population is slightly younger than the Colorado study population, differences in age are unlikely to explain differences in thyroid disease prevalence between the 2 studies. Note, however, that the Agricultural Health Study is assessing only women with thyroid disease, and other studies evaluate both men and women. The fact that women have a higher rate of thyroid disease could contribute to higher overall reported rates of thyroid disease in this population. Because this study assessed self-reported, physician-diagnosed thyroid disease rather than actual medical records, the definition of thyroid disease is very heterogeneous, which may limit our interpretation regarding the different categories of thyroid disease represented in this study.
We found elevated odds of hypothyroid disease for all of the organochlorine insecticides assessed—aldrin, chlordane, DDT, heptachlor, and lindane—as well as the organochlorine fungicide chlorothalonil. Lindane and chlordane are both organochlorine insecticides, which have been reported to affect thyroid hormone levels in humans (17
). Elevated chlordane levels in breast milk have been associated with higher levels of congenital hypothyroidism (24
). A study assessing formulators of both organochlorines, specifically lindane, and organophosphate insecticides showed an increase in TSH levels and a decrease in T3 levels in workers compared with controls (25
). Malathion is an organophosphate insecticide and has been reported to affect thyroid hormone levels in freshwater catfish and bullfrog tadpoles (26
), but it was not associated with thyroid disease in our study. Consistent with our hypothesis, the organochlorine chlordane was associated with hypothyroidism, and, even though not all associations were statistically significant, the remainder of the organochlorines were all associated with an elevated odds of developing hypothyroidism.
We found that the fungicides benomyl and maneb/mancozeb were both strongly associated with increased odds of thyroid disease. Benomyl and maneb/mancozeb are both fungicides with carbamate groups. The dithiocarbamate pesticides ethylenebisdithiocarbamate and ethylenethiourea have been associated with thyroid dysfunction. Maneb/mancozeb has been shown to cause hypothyroidism in rabbits (28
), and human workers exposed to ethylenethiourea showed significantly lower levels of total T4 compared with unexposed controls (29
). In another study of unprotected workers heavily exposed to ethylenebisdithiocarbamate, TSH levels were elevated, but T4 levels were no different from those of controls (30
). In this study, maneb/mancozeb was found to be associated with both hyperthyroidism and hypothyroidism. A potential mechanism to explain its association with both types could be via a direct toxic effect on the thyroid gland, resulting in inflammation of the thyroid gland, thyroiditis, release of preformed thyroid hormone, and hyperthyroidism. This process may then result in transient or permanent hypothyroidism, similar to the mechanism of action for other medications known to cause direct toxic effects on the thyroid. To our knowledge, the observed increased risk of hyperthyroidism with use of maneb/mancozeb is novel. Overall, it is unknown whether the effect of pesticides on human thyroid function is transient, associated with contemporaneous pesticide exposure, or sustained.
We found an increased odds of hypothyroidism with ever use of chlorothalonil, an organochlorine fungicide. Chlorothalonil has not previously been reported to cause hypothyroidism, but it has been shown to increase the size of thyroid glands in animals (31
We also found an association between the herbicide paraquat and hypothyroidism. Paraquat is a quaternary nitrogen herbicide commonly used for broadleaf control. Paraquat has not been reported to be associated with altered thyroid function; however, the US Environmental Protection Agency website (http://www.epa.gov/iris/subst/0183.htm
) reports that thyroid adenomas were observed in Fischer rats exposed to increasing concentrations of paraquat, yet the thyroid adenomas were not thought to be attributable to the paraquat administration. Postmortem analysis of humans with paraquat poisoning revealed detectable amounts of paraquat in the thyroid gland, higher for women than for men (32
), suggesting that the thyroid could be susceptible to the effects of paraquat when exposed. We are not aware of a previously published association between paraquat and hypothyroidism in humans, making this finding also novel.
Although we have the advantage of a large sample size, our results are based on self-report of diagnosed thyroid disease and not physician confirmation. In addition, when evaluating 44 pesticides and 3 outcomes, it is possible that by chance alone we would find approximately 7 statistically significant associations; we found 4. Our finding of a higher prevalence of thyroid disease may reflect increased risk associated with pesticides or may indicate overreporting given that the population was entirely women. It is also possible that the higher prevalence may be associated with other farm-related exposures not assessed. Because the Agricultural Health Study did not focus specifically on thyroid disease, and because only selected chemicals were associated with hypothyroidism, we have no reason to think that any such overreporting was related to pesticide use.
We could not distinguish between prevalent and incident disease, and our exposure measure—ever use of pesticides—may not always reflect an exposure that antedated disease onset. Furthermore, we did not have information on timing or level of exposure, and some of the associations were based on small numbers of exposed women.
We found an association of organochlorines and fungicides with hypothyroidism. Exposure to these classes of pesticides and thyroid dysfunction is plausible given that the main effects of these compounds are thought to be elevation of TSH levels and reduction of circulating thyroid hormone (T3 and T4). However, we do not know why this does not occur for the entire class of fungicides or whether these specific compounds cause a combination of goiter and biochemical thyroid dysfunction or just biochemical dysfunction alone. Unfortunately, we did not have access to blood samples in this study to evaluate the prevalence of subclinical thyroid disease. Finally, although we focused on self-reported use of pesticides by the female spouses of pesticide applicators, spouses who do not apply pesticides may also be indirectly exposed to these same and other pesticides by virtue of living on the farm. Thus, there is the possibility of exposure misclassification that might lead to bias toward the null.
In conclusion, we found that the prevalence of self-reported clinical thyroid disease in female spouses of pesticide applicators is 12.5%, higher than in the general population. Hypothyroidism is the most common abnormality and is associated with the use of benomyl, maneb/mancozeb, and paraquat in addition to the class of organochlorines that includes aldrin, DDT, heptachlor, lindane, and chlordane. Maneb/mancozeb was also found to be associated with hyperthyroidism. Further studies are needed to confirm these novel findings, to determine whether pesticide exposure is also associated with thyroid disease in male pesticide applicators, and to evaluate mechanisms of action.