Page 357 - Industrial Ventilation Design Guidebook

5,3 TOXICITY AND RISKS INDUCED BY OCCUPATIONAL EXPOSURE TO CHEMICAL COMPOUNDS 3 i 3

ever, experimental animal data provide evidence that exposure even at this stage
may lead to birth of a malformed pup. Organogenesis is the period between the
21st and 56th days of pregnancy in humans, when most organs are undergoing
rapid development. This time is the most sensitive period for a teratogen to exert
its effects. For example, the closure of the palate in humans takes place between
56th and 58th day of pregnancy. This is the time when the risk of cleft palate is
the greatest for the fetus if exposure to a teratogen occurs. After the end of organ-
ogenesis, morphological malformations are unlikely, but biochemical and func-
168
tional alterations are still possible.
Several chemical carcinogens are also chemical teratogens. In these cases,
both carcinogens and teratogens may have an ultimate common mechanism,
DNA damage. In this context, both chemical carcinogens and teratogens re-
quire metabolic activation to be able to react with the nucleic acids in DNA.
Like chemical carcinogenesis, chemical teratogenesis constitutes a cascade of
complex events, and is rarely induced by a single factor. This is exemplified by
the fact that, depending on the dose and timing of exposure, a chemical ter-
atogen may cause death of the fetus, induce a malformation, or result in
growth retardation of the fetus. If the dose is large, the fetus dies. If the dose is
lower than the lethal dose and exposure takes place during an early phase of a
critical period, compensatory hyperplasia may replace the dead cells in the
damaged organ, resulting in growth retardation in a morphologically normal
fetus. However, even a small dose of a teratogen may lead to specific malfor-
mations when the exposure takes place during a critical period of organogene-
sis of a given organ. In addition to chemical compounds, ionizing radiation
may also cause DNA damage potentially leading to teratogenesis. 169
In addition to direct effects of chemical compounds on the fetus, meta-
bolic disturbances in the mother, such as diabetes or hyperthermia, or defi-
ciencies of calories or specific nutrients such as vitamin A, zinc, and folk acid
may lead to teratogenesis. Compounds that inhibit placenta! functions may
also induce malformations, e.g., by inhibiting placental circulation. For exam-
ple, hydroxyurea disrupts the placental circulation and induces malforma-
tions. In addition, it also induces DNA damage. 170 173
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Chemical Teratogens
More than 900 teratogens have been identified in experimental animals.
However, only about 30 human teratogens have been identified. Human ter-
atogens have been listed in Table 5.20. In this section, some of the best-known
teratogenic compounds are briefly described. 167
Thalidomide was introduced in 1956 as a sedative which also prevented
nausea and vomiting. Since the compound was effective and did not induce
addiction, and because its acute side-effects were minor, it became popular to
prevent the nausea associated with early pregnancy. Within a few years after its
introduction, there was an outbreak of an epidemic of very rare malformations of
the extremities, hands, and legs. Typical malformations due to thalidomide were
lack of extremities (anamely), a shortening of long bones of the extremities
(phocomelia or seal-like limbs), and malformations of the heart, eyes, intestine,
external ears, and kidney. The sale of thalidomide was prohibited in 1961, and
within a year no more children were bom with its tragic trademark deformi-
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ties. Had the malformations induced by thalidomide been less spectacular and