Possible role of the blood-testicular barrier in dominant lethal testing.

During dominant-lethal testing for muta-genic effects, chemicals are usually administered intraperitoneally or orally to male animals as a single dose. These treated animals are subsequently housed for mating with virgin females which are replaced at weekly intervals. For screening purposes, a reduction in total living implants is monitored as an indication of the induction of chromosomal anomalies which result in fetal deaths. This serial mating approach further allows the investigator to identify the sper-matogenic cell type affected by the test chemical (1). It is generally assumed that the test chemical gains access readily to the cells in the seminiferous tubules, tubuli recti, rete teste, efferent ducts, epididymis, and vas deferens. However, such an assumption ignores many pharmacokinetic concepts regarding the distribution of chemicals in the body and the role of biologic barriers (2). An especially important barrier in this regard could be the so-called blood-testicular barrier which has been adequately described only in the last few years (3-6). These reports and recent studies in our own laboratory (7, 8) as well as other physiologic and anatomical aspects of the testes suggest the possibility of many "false negative" results of the dominant-lethal test, i.e., instances where the test results could be negative for a true mutagenic agent. To produce any toxic effect, an environmental chemical must achieve adequate concentrations at its sites of action. This is obviously a function of exposure. However, the concentrations attained also depend upon the extent and rate of the chemical's absorption, distribution, binding, or localiza-tion in tissues, inactivation, and excretion. These factors are diagrammed in Figure 1 and are discussed further by Rall (9). After a chemical is absorbed into the blood stream, it must enter or pass through the various body fluid compartments-plasma, extracellular (interstitial) fluid, transcellular fluids, and intracellular fluids. Some chemicals cannot pass cell membranes easily and therefore are restricted in their distribution and in their potential effect, whereas others readily pass through cell membranes and thereby distribute throughout all fluid compartments. Thus, cellular and intracellular membranes present a formidable barrier to the penetration of many environmental agents to their intracellular sites of action. Even if the membranes serve only to slow somewhat the rate of penetration of a particular chemical, they still afford a degree of protection for the target tissue. This is especially true in cases of acute exposure, in which they restrict the exposure to the agents to sites of …