Problems in Applying Teratologic Observations in Animals to Man

In teratology you will have to deal with the question of the relation between animal experiments and legislative regulation. As one who has long been interested in human malformations and who has been in experimental teratology for 35 years, I will tell you about the application of animal experiments to human situations. Thirty-five years ago it was discovered that vitamin deficiencies were reliable teratogenic procedures, yet I have not seen any comparable effects in human beings. In 1959 we found that salicylates are excellent teratogens in rats. I still have not seen a child who was deformed by salicylates. With thalidomide, the situation is the other way around; its teratogenicity was first discovered in man and then one had to find susceptible animals. These experiences exemplify how cautious one must be in applying animal observations to man. I do not say that the animal studies were in vain. They gave us important concepts about general principles of teratogenesis, but one cannot simply apply observations in mice, rats, or monkeys to man. Yet, it is done all the time. We have also learned from experimentation about the variability of response in different species, and even within species there are strain differences in susceptibility. Furthermore, we have learned that a combination of genetic and environmental factors play an important role in the production of congenital malformations, as has been well demonstrated in mice in which cleft palate was produced by cortisone in certain but not all strains. Those who have been in the field for a long time are most hesitant in applying animal results to man.

Animal Tests to Screen for Human Teratogens

Despite Dr. Brent's statement earlier that animal models are not good for teratologic testing, they are all that we have at the moment. It is not reasonable to use new compounds without some preliminary experimental teratology, and it is not reasonable to think we can use human beings for toxicological screening of new compounds. Therefore, I should like to describe briefly, especially for the clinicians present, several aspects of teratologic testing in animals. First the question, "Is a given drug teratogenic?" To my mind that is the same type of question as, "Is a given drug toxic?" because teratogenesis is just one aspect of toxicology. For almost any compound someone could devise a system to show that it is teratogenic. When a drug or chemical is administered to a pregnant animal, it can affect either the mother first or the fetus first. If the fetus is more sensitive, low doses may produce malformations. At higher doses more severe effects occur, namely lethality. At still higher doses, the mothers themselves become ill. If the mother is more sensitive, no effects are observed on the fetus until the mother receives near-lethal doses, at which time one begins to see abnormal or defective fetuses. We have found that, generally, drugs which are teratogenic for the fetus at almost toxic levels for the mother are rather safe. Drugs that are teratogenic at doses much lower than the toxic levels for the mother are, on the whole, unsafe. The judgment is made without regard to the therapeutic dose of the drug.