Detection of Effects on Male Reproduction—A Literature Survey

Abstract

The ICH (International , FL, U.S.A., emphasized the need for research into the suitability of various methods for the detection of effects on fertility in males. The current project was undertaken to compare the efficiency of methods by evaluating reports in the open literature. The results of the examination of 117 substances or substance classes support the view that histopathology and organ weight analysis provide the best general-purpose means of detecting substances with the potential to affect male fertility. Examinations at up to 4 weeks of treatment appear to be as effective as examinations conducted at later times. Mating with females for detection of effects unrelated to interference with sperm production appears to provide an optimal combination because adding other methodologies does not materially improve the detection rate. As to the timing of the mating trial, a 2-week premating period is as efficient as mating at 4 weeks and apparently more efficient than mating after prolonged premating treatment. of male fertility following treatment for 60 days (9 weeks) or more. Over the years, experience with the various designs for fertility tests, repeat-dose toxicity studies, and dominant-lethal assays generated doubt as to the sensitivity of mating or the necessity for such a long time of treatment prior to mating (Palmer, 1986). The first consideration of this doubt by agencies was during the discussions of the ICH Guideline on Detection of Toxicity to Reproduction for Medicinal Products (Bass et al., 1991), which placed more emphasis on direct methods for examination of effects on spermatogenesis and, in earlier drafts, recommended a shorter, 2-week, premating treatment period. Another example is OECD Guideline 421 for Industrial Chemicals, which requires a 2-week premating treatment. So far, this change in direction has not been incorporated into other guidelines.The ICH Guideline for Detection of Toxicity to Reproduction for Medicinal Products, adopted at the Second International Conference on Harmonization (Orlando, FL, U.S.A., 1993), suggested use of data from repeat-dose toxicity studies, additional sperm analysis, and a 4-week premating treatment for males. However, these can be considered interim measures as the guideline also recognized the need for research into the suitability of various methods for the detection of effects on male reproduction. The current project was undertaken to compare the relative efficiency of various methods by evaluating reports in the open literature. METHODSArticles were identified by way of a database search (DIMDI, Cologne) for substances that had been reported to affect males with respect to fertility, spermatogenesis, and mating behavior. Of some 150 substances (or groups of substances) identified, 117 were included in the evaluation on the basis of the amount of information available. Substances were included even with scarce animal data when effects had been reported in men. Additional information on some compounds came from agency files.Single endpoints that...

Spontaneous and Age-Related Testicular Findings in Beagle Dogs

“…However, small testicular or epididymal lymphocytic aggregates in the absence of other epididymal findings likely would be of negligible toxicological significance. Testicular histology and testicular weights are routinely used to detect drug toxicity in male reproductive organs (Ulbrich and Palmer 1995). Knowledge of the timing of sexual maturation is important to the design of preclinical toxicity studies, since sexually immature beagle dogs exhibit histologic findings similar to drug toxicity end points such as low testicular weight, hypospermatogenesis, multinucleate giant cells, reduced epididymal filling, intraluminal cell debris, and swollen, retained, and apoptotic germ cells .…”

“…Histopathology is a sensitive method for evaluating adverse effects of chemicals on spermatogenesis (Rehm 2000;Takayama et al 1995;Ulbrich and Palmer 1995). Knowledge of spontaneous microscopic findings in normal dog testes is required before drug-related lesions can be distinguished from spontaneous or age-related testicular findings.…”

Spontaneous Testicular Lesions in Purpose-Bred Beagle Dogs

“…Histologic evaluation of the testes has been shown to be the most sensitive method to evaluate possible drugrelated effects (15,16). However, limited information is available on spontaneous testicular lesions in beagle dogs, although they are frequently used as the nonrodent species in drug safety studies (2,6,8).…”

Review Article: Evaluation of Testicular Toxicity in Safety Evaluation Studies: The Appropriate Use of Spermatogenic Staging

“…Previous guidelines relied heavily on fertility (success in achieving pregnancy) as the main index of male reproductive function. However, a recent collaborative study among Japanese pharmaceutical companies, which investigated the effects of 14 known testicular toxicants over varying time periods, concluded that testicular histology was the most sensitive and reliable method for detecting effects on sperm production, whereas fertility index was the least sensitive (57,59 (33). An amendment to these guidelines, providing additional information on the premating dosing period and on observations to be made during the study, was finalized in December 1995 (34).…”