Toxicity of dipyridyl compounds and related compounds

Five dipyridyl isomers, 2,2′-, 2,3′-, 2,4′-, 3,3′-, and 4,4′-dipyridyl, are products resulting from the pyrolytic degradation of tobacco products and degradation of the herbicide paraquat, and therefore may be present in the environment. In this article, the toxicological properties of these dipyridyl isomers in humans and animals are reviewed. Epidemiological studies suggest that cancerous skin lesions in workers involved in the manufacturing of paraquat may be associated with exposure to dipyridyl compounds. Experimental animal studies suggest that dipyridyl isomers may have several toxicological effects. Three of the dipyridyl isomers (the 2,2′, 2,4′, and 4,4′ isomers) appear to be inducers of some metabolic enzymes. The 2,2′-dipyridyl isomer, an iron chelator, appears to influence vasospasm in primate models of stroke. The cytotoxic effects of 2,2′-dipyridyl on several leukemia cell lines have been reported, and a potent teratogenic effect of 2,2′-dipyridyl has been observed in rats. Based on the results of paraquat studies in experimental animal models, it has been proposed that paraquat may have deleterious effects on dopaminergic neurons. These findings support the epidemiological evidence that paraquat exposure may be associated with the development of Parkinson's disease. Studies designed to determine an association between paraquat exposure and Parkinson's disease are complicated by the possibility that metabolic changes may influence the neurotoxicity of paraquat and/or its metabolites. Preliminary unpublished data in mice show that 300-mg/kg doses of 2,2′-dipyridyl are neurotoxic, and 300-mg/kg doses of 2,4′- and 4,4′-dipyridyls are lethal. These results are consistent with earlier studies in Sherman rats using high 2,2′- and 4,4′-dipyridyl doses. New studies are needed to further explore the toxicological properties of dipyridyls and their potential public health impact.