Application for the Reassessment of a Hazardous Substance under ...

concurrent studies for comparison with the treated groups. Of the male rats,76% of the high-dose and 64% of the low-dose group survived to the end ofthe study as did 84% of the high-dose and 80% of the low-dose females.“Numerous inflammatory, degenerative, and proliferative lesions commonlyseen in aged rats occurred with approximately equal frequency in the treatedand the pooled control rats. Several non-neoplastic lesions occurred morefrequently in the treated rats than in the controls. These included aggregatesof alveolar macrophages in the lungs, interstitial fibrosis of the myocardium,and focal follicular cell hyperplasia of the thyroid gland in the male rats.Benign endocrine neoplasms occurred frequently in both test and controlrats. There was a high incidence of benign mammary neoplasms in bothcontrol and treated rats. Because of the low survival of the matched controlrats, control animals from other concurrent studies were pooled forstatistical analysis. The authors stated that on the basis of variability of boththe incidence and type of spontaneous lesions and the lack of significantproportions of tumors in the dosed groups compared to the controls, nostatistical significance could be attached to the incidence of the tumors seenin the dichlorvos-treated rats in this study. Because of the poor survival ofcontrol animals in this study, the results are difficult to interpret.”“The mechanism of dichlorvos-induced carcinogenicity is not known. A studyof B6C3F1 mouse forestomach from mice treated with dichlorvos by gavagein corn oil (Benford et al., 1994) showed increases in replicative DNAsynthesis (associated with increased cell proliferation). Unscheduled DNAsynthesis (associated with DNA repair) was not increased by dichlorvostreatment, but was increased by 1 -methyl-3-nitro-1 -nitrosoguanidine, aknown genotoxic forestomach carcinogen. The authors concluded that theforestomach tumors seen in the 2-year carcinogenicity study (NTP 1989)may have been mediated by enforced cellular proliferation rather than by agenotoxic mechanism.“Two organizations have reviewed the evidence for dichlorvoscarcinogenicity in humans from the results obtained in test systems. The EPAhas classified dichlorvos as a probable human carcinogen (Category B2) onthe basis of significant increases of forestomach tumors in mice andleukemiasand pancreatic acinar adenomas in rats. Supporting evidenceincluded observation of tumors at other sites in the rat and the observationthat dichlorvos and a major metabolite, dichloroacetaldehyde, are mutagenicin in vitro test systems. A structurally related compound, dichloropropene,also causes forestomach tumors in rodents (IRIS 1995).” (Originals notesighted; ATSDR, 1997)The IARC (1991) summary and evaluation for dichlorvos:“5.1 Exposure data―Dichlorvos has been used widely as an insecticide since 1961 to control internaland external parasites in livestock and domestic animals, to control insects inhouses, and in crop protection.Dichlorvos reassessment – application Page 203 of 436