A COLLABORATIVE STUDY IN JAPAN ON OPTIMAL TREATMENT PERIOD AND PARAMETERS FOR DETECTION OF MALE-FERTILITY DISORDERS INDUCED BY DRUGS IN RATS

The tripartite-harmonized International Conference on Harmonization re productive guideline (1993) recommends administration of test substanc es for 4 weeks to male rats before mating. However, scientific or expe rimental rationale for this recommendation is not firmly based, and th e most appropriate parameters have not been established in experimenta l models. Therefore, a team consisting of 16 Japanese pharmaceutical c ompanies and the National Institute of Health Sciences performed a col laborative study to determine the optimal period and parameters for de tection of male fertility disorders in rats. Sixteen compounds, includ ing four anticancer drugs, two psychotropic drugs, two nootropic drugs , two vitamins, two hormones, one antihypertensive agent, one diuretic drug, and two general chemicals were administered to male rats for 4 or 9 weeks before mating. Parameters used to examine effects on the ma le reproductive system were organ weights, spermatogenic endpoints, ma ting behavior, cesarean section findings, and histopathology. From the results, treatment for 4 weeks before mating was concluded to be suff icient to detect adverse effects on male fertility, with the histopath ology of the testis being the most sensitive index for the drugs used. Sperm parameters, especially number, and genital organ weight determi nation provided information confirming toxicity. Tests of reproductive activity were generally found to be insensitive, except where the dru gs affected sperm maturation. Based on this study, it is concluded tha t a 4-week treatment period is appropriate for detection of drug effec ts on male fertility, and that histopathological examination of the te stis is the most sensitive approach.