PRINCIPLES OF TOXICOLOGY

230 REPRODUCTIVE TOXICOLOGY
genitalia and may have disrupted the development of the steroid feedback loops in the hypothalamicpituitary-gonadal
axis of the females.
Additional Human Teratogens Other drugs that are established human teratogens include lithium,
tetracyclines, aminopterin, and the coumarin anticoagulants. Antineoplastic agents such as busulfan
and cyclophosphamide are teratogenic in addition to their multiple other reproductive toxicities.
Androgenic hormones, used to help maintain pregnancies, are also teratogenic and interfere with
reproductive development in the fetus, somewhat like the estrogenic DES. With all of these therapeutic
agents, the dose resulting in teratogenicity, the issues of leaving the underlying illness untreated, and
the actual likelihood of teratogenic effects must be considered in characterizing their toxicological
potential.
Drugs of Abuse and Maternal Nutrition Some of the drugs of abuse are teratogenic, but their effects
typically relate more to generalized metabolic disruptions than to interference with specific features
of development. Fetal alcohol syndrome (FAS) is the best example of this class of teratogens. The
primary features of FAS include growth retardation, psychomotor dysfunction, and craniofacial
anomalies. Growth retardation is the most sensitive and prevalent effect following alcohol consumption
during pregnancy. This can be demonstrated at fairly low doses, around 1 drink per day, but the effects
at low dose exposure are controversial. At higher doses, 5 or more drinks at a time and at least 2 each
day, however, the risk of having an infant classified as small-for-gestational-age increases three-fold.
Among children born to chronic alcoholics, one-third have been classified as FAS by some studies.
Subsequent development is characterized by reduced height and an inability to catch up during
postnatal development. Among children classified as FAS, the rate of mental retardation is 85 percent.
Impulsiveness, attention disorders, and language deficits are commonly observed.
The mechanism by which FAS is produced is not yet clear. Especially for the chronic alcoholics,
it seems most likely to relate primarily to the overall nutritional state, metabolic and endocrine
imbalances of the mother. Nutrient deficits and interference with placental metabolism and transport
are clearly mechanisms that can affect fetal growth and neural function. Infants born to heroin addicts
also exhibit growth retardation that is probably related to overall maternal nutritional and metabolic
status.
Cigarette smoking by the mother has also been associated with general developmental deficits.
Growth retardation of the fetuses of smokers is clear. The array of chemicals in tobacco smoke,
however, makes defining the key pathway difficult. It has been suggested that nicotine, carbon
monoxide, and cyanide interfere with the transport of amino acids across the placenta. In addition,
cadmium is capable of producing placental necrosis and could affect placental exchange. Also, the
PAH’s induce metabolic enzymes in the placenta that may create toxic reactive metabolites. Which of
these mechanisms actually operate in humans, and which are the major causes of growth retardation
is not clear.
Maternal deficiencies of specific nutrient factors have been reported to be associated with teratogenicity.
Zinc, folic acid, and retinoic acid deficiencies have all been reported to have negative effects
on development. It is clear that these nutrients are all required by the fetus, just as they are for any
human, but the degree of deficiency that must be reached to cause developmental defects is not clear.
Severe deficiencies of any of the vitamins, minerals, or amino acids could reasonably be expected to
interfere with development. Declines in zinc, folic acid, and retinoic acid may not be tolerated very
well because developmental growth processes are heavily dependent on them. Zinc and folic acid are
utilized extensively in metabolism within the rapidly growing tissue. The role of retinoic acid as a
major signal molecule during fetal growth has been described above.
Methylmercury Poisoning During the 1950s, Minamata disease was described and related to mercury
contamination of the Minamata Bay in Japan by industrial facilities. Fish from these coastal
waters, a major food source for women in the area, were accumulating elevated methylmercury levels.
Mercury levels realized by the women were not high enough to produce obvious signs of mercury