PRINCIPLES OF TOXICOLOGY

11.3 DEVELOPMENTAL TOXICOLOGY 227
affected cells replaced. It is not clear how many toxicants could create developmental defects in this
manner, as they would likely have to be capable of producing specific, minor changes in DNA, nor is
it clear that the experimental conditions are relevant to humans.
Spontaneous abortion remains the most useful indicator of early embryonic toxicity, and there
are both experimental and occupational examples where chemical exposures appear to affect
spontaneous abortion rates. One of the most investigated, and most controversial, occupational
examples relates to anesthetic gases. Studies both large and small have reported both positive and
negative results when looking for elevated rates of spontaneous abortion among health care
professionals using gas anesthetics such as nitrous oxide and halothane. The potential effect does
not appear to relate to paternal exposure since there is not an observable elevation in the
spontaneous abortion rate among the wives of occupationally exposed men. Methodological flaws
have called some of the positive results into question. At this point, the most defensible conclusion
is that based on the evidence there is an elevated incidence of spontaneous abortion among women
in such occupations; however, the association between anesthetic exposures and the spontaneous
abortion rates cannot be reliably demonstrated. This suggests that other, unidentified factors
present in the study populations could play an important role.
Carbon disulfide, dimethylformamide, and some of the phthalates are other examples in which
investigations of spontaneous abortion rates have detected differences that may be attributable to
occupational exposures of women. The data for carbon disulfide are the most convincing in terms of
documenting an association, but even this conclusion is weakened because the proportionate increases
are small and not clearly out of the expected background range.
Chloroprene, an industrial chemical used in polymer manufacture, is an example in which male
exposure may have subsequent effects on spontaneous abortion. In this case, the wives of occupationally
exposed men showed elevated spontaneous abortion rates. This could be classified as a male
reproductive effect, if it results from an effect on the sperm that necessarily occurs prior to fertilization,
and suggests that some types of sperm damage may still be compatible with the ability to fertilize an
egg. While such a mechanism of toxicity could explain the observations, this is not recognized as a
common mode of toxic action, and it is thus difficult to exclude some other explanation not directly
linked to the chloroprene exposure of the men.
There are many compounds that can be shown experimentally to cause spontaneous abortions.
Some of the classes might be expected based on their common toxic effects, such as the antineoplastic
drugs and heavy metals. Their cytotoxicity is well known, so embryonic interference is hardly
surprising. In addition, solvents such as benzene and toluene, many chlorinated pesticides and
herbicides, PAH’s, and aldehydes such as formaldehyde can all experimentally cause early pregnancy
failure. In short, most cytotoxic chemicals have the ability to interfere with early development under
experimental conditions. The relevance to human exposure conditions and potential dose levels,
especially in the occupational setting, is not clear.
A common occupational chemical exposure that illustrates the difficulties in establishing embryotoxicity
occurring in humans is the use of ethylene oxide. Large quantities of this chemical are used
in manufacturing, especially for the production of ethylene glycol antifreezes. Female workers clearly
have potential industrial exposures. In terms of the number of exposed workers, even more significant
is the use of ethylene oxide as a sterilant of medical devices. Ethylene oxide exposure during unloading
of sterilizers and in the area where the sterilized packages are aerated can be significant enough to
produce toxic responses in other organs systems. This was especially true prior to interest in the
potential long-term effects that grew during the 1980s. Also, ethylene oxide clearly causes embryotoxicity
and death and structural abnormalities during the fetal stages in animal tests. These factors
suggest that ethylene oxide could be a developmental concern for occupational exposure levels.
Epidemiological studies of ethylene oxide exposed workers are equivocal. Though occasional
findings suggesting elevated spontaneous abortion rates among potentially exposed workers have been
reported, this result has been inconsistently observed. Furthermore, the largest studies, best designed
to account for exposure levels and potential biases, have been routinely negative. So, the database
stacks up as follows: 1) the toxic potential from animal tests is clear, 2) the potential for human exposure