EXPERIMENTAL MAMMALIAN TERATOLOGY 237 



It may be well to point out here the invalidity of the popular notion that a given 

 morphogenetic process is most sensitive to alteration by a teratogen at the time when 

 the process occurs. This is not necessarily true. Each teratogen usually has a period 

 of maximum efficiency in producing a particular malformation (the critical period) , 

 but this period may differ from one teratogen to another and often precedes the stage 

 when the morphogenetic process involved takes place. X irradiation, for instance, 

 produces cleft palate in mice with maximum frequency when given about 1 1 days 

 after insemination, 1118 whereas 6-aminonicotinamide is most effective on day 13, 

 about a day before the palate actually closes. 448 Presumably, normal palatal closure 

 depends on the normal sequence and interaction of a number of previous develop- 

 mental events, and interference with any one of them will interfere with closure of the 

 palate. Since X irradiation and 6-aminonicotinamide have different critical periods, 

 they presumably interfere at different points in the web of interacting processes leading 

 to closure of the palate. 



DOSE 



In general, the teratogenic dose of an agent is somewhat below that which causes 

 resorption or abortion of the litter. However, there are quite wide variations in the 

 range between the lethal and the teratogenic 923 doses for different teratogens. 



TERATOGENS AND THE ANALYSIS OF MALDEVELOPMENT 



Admittedly, some teratological experiments are begun simply because an agent is 

 at hand and an experimenter is curious about what it might do. Others, of course, 

 are conceived to answer specific questions about the nature of malformations and, by 

 inference, about normal development. A number of such approaches will be discussed 

 in the following pages. 



I. Is a given agent capable of producing malformations in humans? — Since it is usually 

 extremely difficult to demonstrate the existence of an environmental teratogen in 

 human beings, a reasonable first approach to the problem is to see whether the suspected 

 agent is teratogenic in experimental mammals. The work that gave the first great 

 impetus to the field of experimental mammalian teratology — the demonstration by 

 Warkany 1357 and his colleagues that specific maternal nutritional deficiencies caused 

 malformations in embryonic rats — was inspired by the desire to know whether 

 maternal nutritional deficiencies might cause human malformations. 



This approach will not, of course, give a definitive answer to the question that (as 

 Warkany has repeatedly emphasized) must rest ultimately upon observations on 

 human beings. If an agent is found to be teratogenic in experimental mammals, this 

 raises the possibility that it may be teratogenic in human beings, but so far very few 

 experimental teratogens have been shown to cause human malformations. On the 

 other hand, if an agent is found not to be teratogenic in experimental animals, even 



