The complete battery of tests with full histology and the development of a final report can take as long as 2 years. In general, only some of the mutagenicity studies are completed, and perhaps 1-3 month reports of animal testing are available when male Phase I dosing volunteer studies commence. All animal studies do not commence at the same time but are usually sequential. Some, such as postexposure weaning and subsequent second-generation drug effect studies will be time-consuming and expensive. Often, if mutagenicity tests, e.g. Ames' test or mouse lymphoma test, are positive (Ames test has 30% false-positive rate), then females will be excluded until more data is collected. Thus, only limited data are available prior to the first human exposure. (For further reference Fed Reg 1994, 1996).
Volunteer dose-ranging studies will, by design, include high enough doses to provoke unpleasant adverse effects; also, information on 'target organs' (organs likely to be most affected or harmed) is usually predictable but unconfirmed at this point. Generally, as a result of animal studies, it is thought that the effect of drugs on reproductive function in males is less than that in females and only affects the sperm viability or, rarely, the size and function of the testicles, which is usually reversible. This is unduly optimistic, as one report by Yazigi et al (1991) suggests that spermatozoa may not be immobilized or destroyed by cocaine, but may interact, and the spermatozoa themselves have the potential to act as an active transport mechanism for drugs, pesticides and even environmental chemicals to the unfertilized ovum. They may also alter the genetic make-up of either spermatozoa or ovum. In addition, spermatozoa can be made sluggish by calcium channel blockers, leading to male infertility while on medication. Hence, the European guidelines call for male animal testing prior to start of Phase 2.
The blastocyst (early embryo) is relatively resistant to damage in the first 7 days, for up to 75% of cells can be destroyed before tissue differentiation and the embryo can still survive. What might happen if garden pesticides, or house builders' formaldehyde containing glue and chemicals, are combined into the genetic material? If it is ever confirmed, then we may have the inkling of what makes up the 65% of the 'unknown' causes of developmental defects mentioned by Wilson (1972). If it could be shown that the synthetic chemicals are incorporated into the blastocyst, the field of male Phase I testing would be transformed, as would that of genetic counseling.
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