Effects of nitrofurantoin on the primary and secondary reproductive organs of female B6C3F mice

Abstract

The National Toxicology Program (NTP) has reported female mice fed high doses of Nitrofurantoin (NFT) were found to have ovarian atrophy as diagnosed histologically and increased benign ovarian tumors after 24 months of exposure (30). This result contrasts with 4 other recent carcinogenicity assays in rodents with NFT, all with no evidence of an ovarian effect. An extensive database documents benign tubular adenomas develop secondary to ovarian atrophy in many mouse strains, including B6C3F1 (see ref 11). The present study was initiated to confirm this mechanism could be responsible for the ovarian tumors in the NTP study and to investigate the time course of ovarian changes seen in female B6C3F1 mice. Mice were provided diet containing NFT at doses of 350 and 500 mg/kg body weight/day and examined after 4, 8, 13, 17, 43 and 64 weeks. A dose-related decrease in feed consumption, feed efficiency and body weight gain was seen and persisted throughout the study. Sexual maturity was delayed in a dose-related fashion, compatible with previously reported effects of reduced food consumption in rodents (12, 16). All groups of mice eventually did have normal estrous cycles, but cycle lengths were increased in a dose-related fashion. Both doses of NFT resulted in histological evidence of senile ovarian atrophy by week 43. Based on the reported association between sterility and ovarian tumors, we conclude the benign tubular adenomas seen at 2 yr in the NTP carcinogenicity study with NFT were secondary to the ovarian atrophy induced in this strain of mouse and not an indication NFT, itself, is a carcinogen.