PRINCIPLES OF TOXICOLOGY

228 REPRODUCTIVE TOXICOLOGY
is clear, 3) suggestive associations have been reported in relatively few worker studies that have been
criticized for inability to clearly establish exposure levels and for sensitivity to possible biases, and 4)
no association is supported by the biggest and best controlled studies.
Toxic Responses of the Embryo and Fetus
For many people, the possibility of congenital defects is the most alarming aspect of reproductive
toxicology. Congenital defects are any morphological, biochemical, or functional abnormalities that
result from an occurrence prior to birth. The defect may not be detected until later, as with some learning
deficits, but the biological basis for the defect occurs during uterine development. Most congenital
defects are not due to chemical exposures, but it is clear that some defects have been caused by drugs
and environmental exposure.
The rate of major congenital structural malformations runs at about two to three percent of live
births. When other more subtle congenital defects are added in, the rate reaches about seven percent
of live births. Approximately 15 percent of these defects are linked to an inheritable disorder at a known
gene locus, such as Tay Sachs disease or hemophilia. Another 10 percent are linked to major
chromosomal malformations, such as monosomies or trisomies. Overall, genetic factors can account
for up to 35 percent of congenital defects. Identifiable external factors (physical, biological, and
chemical) account for around 10 percent of congenital defects. Estimates of additional, uncharacterized
chemical and drug-induced defects account for between one and five percent. There remains a large
proportion of defects without a well understood cause.
Teratogens are agents, chemical or otherwise, capable of creating congenital defects. They are
generally considered to create specific defects during the period of organogenesis, which begins around
five weeks after fertilization for humans, and continues for various organs through most of the second
trimester of pregnancy. For many teratogens with specific structural targets, the fetus shows a period
of sensitivity corresponding to the development of the target structure. This is significant to human
concerns since it means that to cause a defect, exposure must generally occur in a particular window
of time during pregnancy.
Disruptions of Tissue Organization The prototypical example of a teratogen with a narrow window
for toxic potential is thalidomide. This drug was widely used in the late 1950s and into the 1960s to
treat morning sickness and as a sedative. A sudden rise in children with limb deformities was associated
with mothers who had taken thalidomide. The critical window of sensitivity was identified based on
the severity of the deformities and period during which the mother had used the drug. A relatively
narrow window in weeks 6–7 of gestation was identified in which exposure to thalidomide produced
deformities in nearly all infants. Exposures after this time were associated with minor and less prevalent
defects. In addition to the striking limb deformities, thalidomide exposed infants also exhibited
congenital heart and renal defects along with ear deformities.
Despite extensive animal experimentation in the aftermath of the thalidomide incident, the mechanism
of action has still not clearly been determined. The probable reactive metabolites have been
identified, and mechanisms of actions, such as interference with vitamin or amino acid metabolism in
the developing limb bud and direct disruption of DNA in this region, have been suggested. It seems
unfortunately ironic that while so many chemicals have a clear potential mechanism of action, yet no
clearly observable human effects, perhaps the best example of an actual human teratogen has been
recalcitrant to the studies that might identify the mechanisms that actually operate to disrupt human
development.
With thalidomide removed from use by pregnant women, the most significant teratogenic drug is
isotretinoin, or Accutane, a highly effective agent against cystic acne. This drug is especially important
in relation to teratogenicity, precisely because it is so effective and there is not a suitable replacement.
Thus, despite its ability to effectively produce major fetal deformities, its use continues. Despite
aggressive warnings by physicians and many exclusionary policies that attempt to prevent patients at