Male rabbits were treated with a single i.v. injection of 22.5 mg/kg methyl methane sulfonate (MMS). 0--24 h later [3H]-thymidine was injected in both testicles. Incorporation of the isotope in germ cell DNA was demonstrated in ejaculated sperms. In controls labeled sperms were demonstrated first on day 40--43. These cells were in the preleptotene spermatocyte phase at the time of [3H]-thmidine injection. In rabbits treated with MMS significant radioactivity occurred in sperms collected from day 19 onwards. These cells were in late spermatocyte and early spermatid phase of maturation when [3H]-thymidine was injected. Incorporation of thymidine in these cell populations is interpreted as an expression of unscheduled DNA synthesis, a repair process initiated after chemical damage of germ cell DNA by MMS. The usefulness of the rabbit test system within the framework of conventional mutagenicity screening tests is discussed.

The Final expression of chemical toxicity is determined by pharmacokinetic, pharmacodynamic, homeostatic, and adaptive favors. In order to understand differential toxicity at the cellular and organ levels, one must outsider Ow main factors which may modulate the toxic effects of chemicals. In the male gonads, such modifying factors are the bloodtestis barrier which restricts the testicular penetration of many foreign chemicals, differentially distributed mixed‐function oxidase(s) between the germ cell and interstitial cell compartments, and the presence of differing DNA repair capacities in the various stages of spermatogenic cells. DNA repair systems are present in spermatogonia and spermatocytes, while more mature spermiogenic cells (spermatids and testicular sperms) appear deficient in DNA repair capabilities. Furthermore, strain and species differences in the germ cell's ability to repair DNA suggest a diverse response of germ cells to DNA‐damaging agents. The capacity of prespermiogenic cells to respond to damage induced by certain chemical mutagens accounts for stage‐specific spermatogenic cell toxicity. Mono‐functional alkylating agents such as methylmethane sulfonate (MMS) cause single strand DNA breaks in prespermiogenic cells which are repaired expeditiously, while the same germ cell types are unable to repair DNA damage induced by bifunctional or polyfunctional alkylating agents. DNA damage induced by polyfunctional alkylating agents involves inactivation or DNA template as a result of inter‐ and/or intrastrand DNA, which is more slowly repaired with greater error frequency in the newly‐synthesized DNA. Thus, both bifunctional and polyfunctional alkylating agents are more toxic to male germ cells than are the monofunctional atkylating agents. DNA damage measured by the alkaline elution analysis appears to be a relatively simple, sensitive indicator of germ cell DNA damage. The DNA repair system appears to be another protective mechanism against monofunctional alkylating agents such as MMS, while the same adaptive system is ineffective in overcoming the effects of bifunctional or polyfunctional alkylating agents. DNA repair rates need to be quantified and factored into the phamacokinetic model being developed for extrapolation from laboratory animals to man.