Drugs as Teratogens in Animals and Man

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Abstract
The proved teratogens for the human fetus include the growth-inhibiting anti-cancer drugs, of which the folic acid antagonists have been most carefully studied, the steroid hormones, and the sedative, thalidomide. The anti-cancer drug category is particularly hazardous, for, among other reasons, these drugs are used therapeutically at near-toxic doses. The known biological actions of the steroid hormones explain their effects. Thalidomide, however, remains an enigma, and is a discordant note in any attempt to predict which drugs may exhibit teratogenic activity in man. While a number of other drugs are suspected teratogens for the human fetus, none have been substantially implicated; in fact the inconsistencies in the response of the fetus to proved teratogens greatly increase the difficulties of interpreting the more tenuous relationships suggested in isolated reports of malformations. The apparent inconsistency in drug effects on the human fetus may be due, in part, to the fact that most drugs have a wide therapeutic index; and patients usually are treated in the dose range adequate to produce the desired beneficial effect. There are critical embryonic periods, such as implantation and organo-genesis during the first trimester; and the drug must be present in relation to these specific events to result in a significant effect, by causing either fetal destruction or developmental defects if the embryo survives. Drugs with presumed teratogenic activity can be studied in patients on whom a therapeutic abortion is planned; if this type of study were more generally feasible, many practical problems could be solved. Drugs of great therapeutic importance and deemed to be safe for the fetus could be examined in an appropriately designed large-scale prospective study. Meanwhile, the practical effects of the thalidomide episode have been to reduce the use of drugs in pregnant women, to look for evidence of drug exposure during pregnancy in the case of any malformed fetus, and to monitor the occurrence of malformations in the population. Results of studies on laboratory animals are of uncertain relevance to man. Each species has its characteristic placental functions, maternal endocrine status, embryonic biochemical differentiation, and organogenesis, etc. and operates on its own time schedule in terms of changing interrelationships of these different factors and the speed with which the processes of embryogenesis are completed. Superimposed on this complex and changing system is the introduction of the drug itself, at varying doses which are often greater on a body-weight basis than the therapeutic dose recommended in man, the frequency of administration and different stages of gestation, and the modification of its effects by its disposition in the body, its placental transfer, and its duration of action. While the significance of the animal data in relation to man is often difficult to interpret, testing drugs for teratogenic action in pregnanct laboratory animals will be an integral part of the preclinical pharmacological studies.