derstanding the mechanisms underlying chemically induced developmental defects. Perhaps the most influential review and assessment of the state of knowledge published in that expansionary phase of teratology was J.G. Wilson’s landmark book Environment and Birth Defects (1973). To this day, Wilson’s book is useful as a summary of the principles of teratogenesis (described below) that were developed from the work of teratologists such as Josef Warkany, Lauri Saxen, Robert Brent, Jan Langman, and David Smith. This time period was also one in which numerous clinical discoveries were made of chemical agents that produce abnormal development in humans. Fetal alcohol syndrome, undoubtedly already a problem since antiquity, was first recognized and described in the scientific literature (Lemoine et al. 1968; Jones and Smith 1973; Jones et al. 1973). Unfortunately, in spite of the intervening years and educational efforts, this syndrome remains all too common and is currently estimated as affecting 1.95 of every 1,000 live births in the United States (Abel 1995). A retinoic-acid-induced human embryopathy was described soon after Accutane (13-cis retinoic acid) was introduced as an efficacious drug to treat severe cystic acne (Lammer et al. 1985). Anticonvulsant drugs were also recognized as associated with abnormal development (Finnell et al. 1997a). A large body of work on the heavy metal lead, a ubiquitous contaminant, has shown that it can produce subtle effects on neurobehavioral development (for a review, see Bellinger 1994), emphasizing the fact that abnormal development can manifest itself as subtle functional deficits and not just structural changes. Another heavy metal, mercury, also was identified as a human developmental toxicant after an epidemic of cerebral palsy with microcephaly in Minamata, Japan, was associated with the ingestion of fish contaminated with methyl mercury (Harada and Noda 1988).

PRINCIPLES OF TERATOLOGY

Prior to and shortly after the thalidomide crisis, a body of data had accumulated showing that many chemical, biological, and physical agents can induce malformations in mammalian species, such as mice, rats, rabbits, and guinea pigs. On the basis of those accumulated data, Wilson in the 1970s formulated six principles of teratology that have guided research in developmental toxicology to this day (Wilson 1973). These principles are relevant to cite because they provide the context for the specific mechanisms of toxicity considered later in the chapter.

1. “The access of adverse environmental influences to developing tissues depends on the nature of the influences (agent).” This is to say, developmental toxicants can be accessible to the conceptus (the embryo or fetus, plus the embryo-derived extra-embryonic tissues) in two ways, directly or indirectly. Examples of the former include ionizing radiation, microwaves, and ultrasound, which travel directly through maternal tissues without modification and then interact with the conceptus. Most known developmental toxicants gain access to



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