Predictiveness and limitations of test methods in teratology: overview.

Compounds intended for marketing by the pharmaceutical industry are tested for possible effects on reproductive processes in much the same way today as was carried out even before November 1961, when the drug thalidomide was related to human malformations. At that time, effects on male and female fertility were sought, but generally only for agents considered likely to alter the endocrinologic status of the patient or that were designed primarily for use by young women. The test species was usually the rat. When it became evident that this system did not detect the teratogenic potential of thalidomide, it was realized that a model that would detect this type of activity was needed. Thalidomide was under study in my laboratory at the William S. Merrell Company (1) within three days of Lenz's announcement of the relationship between thalidomide and human malformations. Hence, routine testing was being conducted in at least one industrial laboratory when the FDA guidelines were circulated in 1966. These guidelines and the principles published by WHO in 1967 have been followed by private industry, which has conducted most of the routine testing carried out to date to determine the teratogenic potential of agents. These test results on prospective therapeutic agents now represent most of the information available on the teratogenic potential of chemicals. With the increased commitment of resources currently available for the testing of additional components of our environment , it is necessary to determine whether such test procedures are doing the job. We have come to realize that the teratogenicity of thalidomide represented the exception rather than the rule for most tranquillizers and for drugs in general. Today chemicals are known to be responsible for no more than 5% of the structural malformations seen in man. Less than 25 chemicals are known teratogens in man, yet more than 800 are identified as being teratogenic in laboratory animals. Is this because man is more resistant, or is this difference merely a reflection of the difficulties encountered in determination of positive teratogenicity in man? Of the human malformations seen, 60% are still of unknown etiology, in spite of continued testing. Does this mean the value of the test system is in question, that we have not tested the human teratogens yet, or that most of the unidentified etiology involve combinations of genetic and environmental factors that are not present in test animals? Does the high incidence of apparent …