To investigate the mechanism and toxicological significance of testicular interstitial cell
tumors (ICT) observed in a long-term rat study with
procymidone, N-(3,5-dichlorophenyl)-1,2-dimethylcyclopropane-1,2-dicarboximi de, male Sprague-Dawley rats were fed
procymidone in diets for up to 6 months with a positive control group receiving a single
subcutaneous injection of
cadmium chloride. Examinations mainly for gonadal functions such as serum
testosterone and
luteinizing hormone (LH), reproductive organ weight and histopathology presented evidence of the indirect involvement of
gonadotropins in the production of ICT in rats. A significant increase in both serum
testosterone and LH was observed in the early stage at high dietary concentrations of
procymidone without any lesion in gonadal systems in histopathology, whereas administration of
cadmium chloride produced the expected substantial increase in serum LH and a concomitant decrease in serum
testosterone with a marked damaging effect on gonadal systems. Increases in serum
testosterone and LH levels in animals receiving
procymidone were reversible. The no-effect level for
procymidone on serum
testosterone and LH was 300 ppm over six months of treatment. The possible mechanism of ICT production in rats by non-genotoxic
procymidone, structurally similar to
flutamide, a synthetic non-steroidal
antiandrogen, is likely to be derived from its induction of a hypergonadotropism due to the competitive binding to the
androgen receptor, preventing the normal effect of
testosterone to control the circulating level of LH.