An Evaluation of the Common Mechanism Approach to the Food Quality Protection Act: Captan and Four Related Fungicides, a Practical Example

Abstract

Under the Food Quality Protection Act (FQPA) of 1996 (Act), the United States Environmental Protection Agency (EPA) is mandated to conduct cumulative risk assessment on pesticides that act through a common mechanism of toxicity. Incumbent on the Agency is the development of sound scientific principles upon which to evaluate compounds for the presence of a common mechanism. Using the currently available draft guidance criteria, this paper employs five fungicides of the same general class, typified by captan, to evaluate both the criteria and the available scientific data.Captan and folpet are two chloroalkylthio fungicides currently registered with EPA under Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) for agricultural use. As such, these compounds are subject to the provisions of FQPA. Three additional fungicidal compounds—dichlofluanid, tolylfluanid, and captafol—are not registered for use in the United States; however, these five compounds have chemical structure and biological toxicity similarities and differences that permit their utility as test cases to determine what the EPA would conclude, with regard to common mechanism, if these draft guidelines were applied to these compounds.The results of the analyses are consistent and support the conclusion that captan and folpet share a common mode of toxicity for mouse duodenal tumors as defined in the Act. This common mode of toxicity is not shared by dichlofluanid, tolylfluanid, or captafol.The basis for concluding a common mechanism exists between captan and folpet. They include 1. Structural Similarity—The compounds are structural analogs having the identical biologically active moiety (i.e., the-SCCl3side chain). 2. Mechanisms of Pesticidal Action—The compounds have the same mechanism of action. The overwhelming body of evidence suggests they are active because of their reactions with thiols. Both compounds, in reacting with thiols, produce similar degradates. Differences in rates of reaction are attributable to physical-chemical properties of the two compounds. 3. General Mechanisms of Mammalian Toxicity—The compounds induce mammalian toxicity through the same mechanism that is responsible for their pesticidal action, reactions with thiols. Another, albeit less likely, mechanism (for both compounds) is cross-Unking of proteins with DNA, although the extremely short half-lives of these compounds (seconds) argues against this possibility. 4. Sites of Action—Both compounds express their primary toxicity as local rather than systemic effects. 5. Common Toxic Endpoint—These two compounds induce gastrointestinal tumors (in mice only). 6. Mode of Action—Both compounds express their common toxic endpoint through a nongenotoxic, compensatory proliferation mechanism. 7. Specificity of Action—For both compounds, the majority of tumors appear in the duodenum. Furthermore, these tumors are induced only in mice. Repeated carcinogenicity testing suggests that rats are refractive to the effects of captan and folpet. The significantly faster hydrolytic rate for folpet at the lower pH values (e.g., increased 8-fold at pH 5) encountered in the stomach is believed to account for the tumors of the stomach observed with folpet and not captan. 8. Other Toxic Endpoints—For other toxic endpoints where comparative data are available, captan and folpet show similar patterns of toxicity (e.g., mutagenicity, skin sensitization, and acute toxicity).