PRINCIPLES OF TOXICOLOGY

11.3 DEVELOPMENTAL TOXICOLOGY 229
risk for becoming pregnant from taking the drug, developmental deformities related to isotretinoin
exposure continue to be reported.
The defects associated with isotretinoin are wide ranging and include craniofacial deformities,
including cleft palate, and cardiac and central nervous system abnormalities. This can be understood
on the basis of the role of the retinoids in normal development. Isotretinoin is a synthetic retinoid, or
chemical relative of Vitamin A. Gradients of certain retinoids in tissues appear to play a major role in
the organization and orientation of tissue growth. The direction of cellular growth needed to extend a
limb, for instance, is guided by retinoid signals. Disrupting this road map with exogenous retinoids
could clearly be a basis for inappropriate development. Exogenous exposure to most retinoids can
produce developmental defects, at least experimentally. Isotretinoin is a good example of a teratogen
that works by interfering with the chemical signaling used to guide development.
Fetal Hydantoin Syndrome Another class of teratogenic drugs is still used by pregnant women
because the developmental risks are less than the risks of removing the drug. Diphenylhydantoin—
phenytoin, valproic acid, and other anticonvulsants are used in epileptics to prevent seizures. They are
also teratogenic. In these cases, however, the therapeutic regimens are not associated with substantial
numbers of congenital defects, and the potential for injury to both the fetus and mother should a seizure
occur is more of a concern.
A specific set of characteristic developmental features associated with anticonvulsant treatment has
been classified as Fetal Hydantoin Syndrome. There are craniofacial features, limb alterations, as well
as growth and learning deficits. While the structural effects may be mild, the growth and learning
retardation are commonly permanent. The syndrome is not particularly common, however, and many
studies conclude that the risk is low, especially when the potential for epileptic seizures is considered.
In experimental protocols, phenytoin produces more severe, specific craniofacial defects, including
cleft palate when given in the window of time associated with palatogenesis. Later exposures produce
the limb effects.
Valproic acid is clearly teratogenic in experimental protocols as well. The primary effects appear
to be on the central nervous system, however, skeletal and craniofacial defects can also be produced.
There are reports of neural tube defects and spina bifida in humans exposed to valproic acid through
maternal treatment, and the occurrence appears to be higher than expected in some studies. However,
most of these studies have selected cases to examine, and it is not clear what the actual incidence rate
of valproic acid-related human defects is. Again, the concurrent epilepsy confounds the situation.
DES: A Teratogen Associated with Cancer Endpoints Another type of teratogen is exemplified by
another human tragedy. Diethylstilbestrol (DES) is a synthetic steroid hormone that was used to help
prevent miscarriage in women with difficulty maintaining a pregnancy. In this case, rather than the
half decade it took for thalidomide’s effects to become clear, around a quarter of a century passed
between the mid-1940s and 1970 before the teratogenicity of DES became clear. An extremely rare
form of reproductive tract cancers, clear cell adenocarcinomas, was detected in a series of women
whose mothers had taken DES during the first trimester of pregnancy. Though the cancer risk was first
noted in some early teenage girls, it peaked around age 19–22. This explains the delay in discovering
DES’s effects and illustrates an example where the congenital defect was not immediately obvious.
DES is also an interesting example of a teratogen that produces cancer as its congenital defect. It is
currently the only established human carcinogen that acts transplacentally.
In addition to the cancer risk associated with DES, a variety of other reproductive disorders were
noted as the exposed children grew up. Among the female children, these included an increased risk
of ectopic pregnancy, spontaneous abortion, menstrual irregularities and infertility. For the male
children, abnormalities of the genitals, decreased sperm production, cryptorchidism, and a possible
increase in testicular cancer were observed. All of these reproductive tract defects help point out the
likely actions of DES in the developing children. The development of the internal and external genitalia
is coordinated by steroid hormone production, primarily by the fetal gonads. The hyperestrogen
environment produced by DES is consistent with improper formation of the male internal and external