Some aspects relating to the evaluation of the effects of chemicals on male fertility.
Reviews and studies on individual compounds were analyzed as to the suitability of different study designs and endpoints for detecting adverse effects of chemicals on male reproduction in animal species. Of the endpoints investigated, the most sensitive proved to be histopathology of the testes. Using refined histopathology, effects could be detected with a high degree of sensitivity as early as 4 weeks after treatment. Other sensitive endpoints were the weights of reproductive organs, including accessory glands, i.e., testis, epididymis, prostate, and of the seminal vesicle, as well as sperm parameters such as sperm count, sperm morphology, and sperm motility. Sperm motility was found to be in some cases more sensitive than histopathology. The above parameters showed a higher sensitivity than fertility parameters. In fact, in most cases, not only one but several endpoints were affected. Continuous breeding studies and 90-day studies with additional measurements of sperm parameters were similarly effective in detecting compounds which affect male fertility. Interspecies extrapolation factors (IEFs) have been derived for the most sensitive endpoints in laboratory animals. If the calculation is based on caloric demand and a sensitive endpoint of reproductive toxicity, many IEFs tend to be about 1, indicating that humans are generally not more susceptible to reproductive toxicants than laboratory animals. With respect to hazard identification, it is possible to detect adverse effects on male reproduction in a standard subacute study with concentrations that produce significant general toxicity. If effects are found, for the risk assessment the NOAEL has to be determined by testing specific sensitive parameters as specified above.
Mangelsdorf
Inge
I
Fraunhofer Institute of Toxicology and Experimental Medicine, Drug Research and Clinical Inhalation, Nikolai-Fuchs-Str. 1, 30625, Hannover, Germany. mangelsdorf@ita.fraunhofer.de
Buschmann
Jochen
J
Orthen
Bruno
B
D000818:Animals; D023381:Endpoint Determination; D005298:Fertility / Q000187:drug effects*; D006801:Humans; D007248:Infertility, Male / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D011817:Rabbits; D051381:Rats; D018570:Risk Assessment; D013045:Species Specificity; D013737:Testis / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D018675:Toxicity Tests / Q000379:methods*; D015262:Xenobiotics / Q000633:toxicity*
D015262:Xenobiotics