A REVIEW OF THE CONTRIBUTION OF WHOLE-EMBRYO CULTURE TO THE DETERMINATION OF HAZARD AND RISK IN TERATOGENICITY TESTING

Whole embryo culture appears to be an excellent method to screen chemi cals for teratogenic hazard. Compared to in vivo testing it is cheap a nd rapid and does not involve experimentation on live adult animals. A lso in the important area of risk estimation whole embryo culture offe rs distinct advantages over in vivo teratogenicity testing. Adverse em bryonic outcomes (malformations or embryotoxicity) are directly relate d to the serum concentration of the compound being tested and can be c ompared to the serum concentration in the human. A similar comparison is not possible after in vivo testing because for most compounds there are major pharmacokinetic differences between humans and experimental animals. In vivo testing is also limited by the possibility that meta bolites that occur in the human do not occur in the test animal. This problem can be overcome in the in vitro system by adding the metabolit e directly at the desired concentration either with or without the par ent compound. There is only one major disadvantage to in vitro testing and that is the limited period of embryogenesis that is undertaken in the commonly used culture system. This restricts the range of malform ations that can be induced and may render the testing system unsuitabl e for compounds that are likely to exert their major toxicological eff ect late in gestation. Any evaluation of whole embryo culture for haza rd and risk assessment in teratology must take into account the limite d value of currently used in vivo methods. Over 2000 chemicals have be en reported to be teratogenic in experimental animals exposed in vivo (Shepard, Catalog of Teratogenic Agents, 1989). In comparison only abo ut 20 chemicals are known to cause birth defects in the human. This la rge number of in vivo false-positive cannot easily be distinguished fr om true-positives. In this respect in vivo testing is severely deficie nt. The embryo culture testing system would also be expected to produc e many false-positives; but by comparing effective drug concentrations with human therapeutic concentrations they can be differentiated from true-positives. The most serious deficiency for an in vivo or in vitr o teratogenicity testing system would be false-negatives. This has not been a problem in the validation of in vitro testing so far (except p erhaps procarbazine), but difficult drugs such as thalidomide were not included. Thalidomide remains an important index chemical because it is not teratogenic in rats or mice but is teratogenic in the rabbit an d human. It is likely that these species differences are due to metabo lic differences between species and it is possible that if the proxima te teratogen/s of thalidomide were identified they would be teratogeni c in rat embryo culture. Whole embryo culture remains a very powerful technique that should continue to contribute to the determination of t he safety of drugs and other chemicals during pregnancy.