In all, only about 50 chemical and physical agents are known to cause developmental defects in humans (Friedman and Polifka 1994; Shepard 1998). They include so-called “life-style” chemicals, such as alcohol, accounting for 0.1-0.2% of defects in live-born infants and cocaine, a variety of pharmaceuticals, and several environmental agents (e.g., mercury, lead, and polychlorinated biphenyls). Table 2-2 lists several representative human developmental toxicants. There is information available on proposed mechanisms of action for these toxicants, however, it is infrequently synthesized into a cohesive and comprehensive mechanistic explanation. Over 80% of agents known to produce developmental defects in humans also cause developmental defects in at least one test animal (rat, mouse, or rabbit) (Shepard1998).

The actual percentage of environmental agents that are developmental toxicants in humans could be higher or lower than 3% for several reasons. For example, the epidemiological methods for identifying toxicants are inherently insensitive and depend on the systematic examination of large human populations. Such large-scale examination is difficult to do (Selevan 1985). Thalidomide was an exception. Because it caused such a distinctive outcome (bilateral limb shortening) of a rare human malformation, its effects were recognized in small patient groups. Even though the frequency of fetal alcohol syndrome is high compared with other developmental disorders, it took many years to identify alcohol as a human teratogen because the physical alterations are subtle, and the learning and social adjustment problems are sometimes not detectable until several years after birth. When a human exposure problem is suspected, epidemiological testing can be performed to assess toxicity, but few of the 1,200 agents have been so examined. Also, the number of agents that cause developmental toxicity might be higher if the multifactorial inheritance category of birth defects contains, as indeed is suspected, cases of human variants who are genetically more susceptible (predisposed) to particular environmental conditions than are others. Finally, the number might be higher if some toxicants (extrinsic causes) produce malformations as a consequence of their primary effect in causing genetic damage (intrinsic cause).

In conclusion, although it is recognized that environmental agents can, and some do, act as developmental toxicants, it is still unclear how large a role these agents play in producing human congenital anomalies relative to other sources of developmental toxicants such as pharmaceuticals and food additives, and relative to intrinsic causes such as genetic differences.


The “chemical universe” refers to the collective variety of chemicals that humans encounter. This variety is theoretically infinite if no limit is set on the molecular size of chemicals, because new and more complex compounds can always be made by coupling together simpler chemical units. In practice, how-

The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement