PRINCIPLES OF TOXICOLOGY - Biology East Borneo

11.3 DEVELOPMENTAL TOXICOLOGY 227affected cells replaced. It is not clear how many toxicants could create developmental defects in thismanner, as they would likely have to be capable of producing specific, minor changes in DNA, nor isit clear that the experimental conditions are relevant to humans.Spontaneous abortion remains the most useful indicator of early embryonic toxicity, and thereare both experimental and occupational examples where chemical exposures appear to affectspontaneous abortion rates. One of the most investigated, and most controversial, occupationalexamples relates to anesthetic gases. Studies both large and small have reported both positive andnegative results when looking for elevated rates of spontaneous abortion among health careprofessionals using gas anesthetics such as nitrous oxide and halothane. The potential effect doesnot appear to relate to paternal exposure since there is not an observable elevation in thespontaneous abortion rate among the wives of occupationally exposed men. Methodological flawshave called some of the positive results into question. At this point, the most defensible conclusionis that based on the evidence there is an elevated incidence of spontaneous abortion among womenin such occupations; however, the association between anesthetic exposures and the spontaneousabortion rates cannot be reliably demonstrated. This suggests that other, unidentified factorspresent in the study populations could play an important role.Carbon disulfide, dimethylformamide, and some of the phthalates are other examples in whichinvestigations of spontaneous abortion rates have detected differences that may be attributable tooccupational exposures of women. The data for carbon disulfide are the most convincing in terms ofdocumenting an association, but even this conclusion is weakened because the proportionate increasesare small and not clearly out of the expected background range.Chloroprene, an industrial chemical used in polymer manufacture, is an example in which maleexposure may have subsequent effects on spontaneous abortion. In this case, the wives of occupationallyexposed men showed elevated spontaneous abortion rates. This could be classified as a malereproductive 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 anegg. While such a mechanism of toxicity could explain the observations, this is not recognized as acommon mode of toxic action, and it is thus difficult to exclude some other explanation not directlylinked 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 antineoplasticdrugs and heavy metals. Their cytotoxicity is well known, so embryonic interference is hardlysurprising. In addition, solvents such as benzene and toluene, many chlorinated pesticides andherbicides, PAH’s, and aldehydes such as formaldehyde can all experimentally cause early pregnancyfailure. In short, most cytotoxic chemicals have the ability to interfere with early development underexperimental 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 embryotoxicityoccurring in humans is the use of ethylene oxide. Large quantities of this chemical are usedin manufacturing, especially for the production of ethylene glycol antifreezes. Female workers clearlyhave potential industrial exposures. In terms of the number of exposed workers, even more significantis the use of ethylene oxide as a sterilant of medical devices. Ethylene oxide exposure during unloadingof sterilizers and in the area where the sterilized packages are aerated can be significant enough toproduce toxic responses in other organs systems. This was especially true prior to interest in thepotential long-term effects that grew during the 1980s. Also, ethylene oxide clearly causes embryotoxicityand death and structural abnormalities during the fetal stages in animal tests. These factorssuggest that ethylene oxide could be a developmental concern for occupational exposure levels.Epidemiological studies of ethylene oxide exposed workers are equivocal. Though occasionalfindings suggesting elevated spontaneous abortion rates among potentially exposed workers have beenreported, this result has been inconsistently observed. Furthermore, the largest studies, best designedto account for exposure levels and potential biases, have been routinely negative. So, the databasestacks up as follows: 1) the toxic potential from animal tests is clear, 2) the potential for human exposure