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The Use of Animal Models in Understanding Human Teratogens
Author(s) -
WEBSTER William S.
Publication year - 1988
Publication title -
congenital anomalies
Language(s) - English
Resource type - Journals
eISSN - 1741-4520
pISSN - 0914-3505
DOI - 10.1111/j.1741-4520.1988.tb00591.x
Subject(s) - teratology , metabolite , dosing , pharmacology , drug , embryo , isotretinoin , developmental toxicity , toxicity , physiology , toxicology , in vivo , biology , medicine , fetus , pregnancy , endocrinology , microbiology and biotechnology , genetics , acne
The testing of drugs and other chemicals in pregnant animals is required by legislation in a number of countries as a screening procedure for teratogenic potential in the human. The testing procedure involves methodology designed in the 1960s which was based on regimens established in the 1940s for toxicity testing. The requirement that animals are dosed to maternally toxic levels, frequently means that the embryos are exposed to inappropriately high concentrations of the test substance. Positive results in this type of experiment may have no relevence to the human situation where the exposure profile is often quite different, with the human embryo being exposed for prolonged periods to much lower drug concentrations. One way of duplicating the anticipated human exposure is to grow rat embryos in serum containing the drug and/or its metabolites at concentrations determined in the human during early clinical testing. It is proposed that mammalian embryos will respond in a similar manner to a particular concentration of a test substance. In vitro experiments using isotretinoin and its main metabolite 4‐oxo‐isotretinoin showed that the metabolite was teratogenic at concentrations which occurred in the human during normal repetitive dosing and hence the metabolite was the likely human teratogen. Similarly, rat embryo culture studies showed that the anticonvulsant drug, valproic acid, was teratogenic at blood concentrations which occurred during normal dosing in the human. Other in vitro studies showed that cadmium is unlikely to be a human teratogen, despite the fact that it is well established as a teratogen in experimental animals in vivo. It is proposed that embryo culture should be used as an adjunct procedure during teratology testing making use of metabolic and pharmacokinetic data obtained from the human during clinical testing.