Reconsideration of the genetic risk assessment for ethylene oxide exposures.
The US Environmental Protection Agency (EPA) developed a genetic risk assessment model for exposures to ethylene oxide utilizing data on the induction of reciprocal translocations in male germ cells [Rhomberg et al. 1990]. This particular approach served as a reasonable initial attempt, albeit somewhat limited with regard to endpoint and only partially attentive to the mechanisms of induction of genetic alterations and the behavior of chromosomes during meiosis. The present paper discusses the scientific basis for a reassessment of the EPA model, providing data and hypotheses related to effective dose to the target cells and shape of the dose-response relationship at low doses, and dose rates. While the present genetic risk assessment approach is discussed in terms of ethylene oxide, it would be applicable to most mutagenic chemicals. The outcome of the discussion is that the genetic risk for exposed males from reciprocal translocation induction will be negligible at low doses since the dose-response curve is likely to be a function of the square of the dose. In addition, the proportion of genetically unbalanced live born offspring in humans arising from reciprocal translocation carriers is less than 10% of the frequency formed through meiotic segregation and fertilization for such carriers. Simply from a consideration of mechanism--namely, the very high probability of DNA repair prior to the next S-phase for a resting oocyte--it would be predicted that there would be a very low to negligible frequency of translocations in female germ cells from ethylene oxide exposure. It is further stressed that additional components of a genetic risk model require a consideration of all germ cell stages in the male, and the inclusion of calculations for point and deletion mutations. Some indications of likely response are presented with these points in mind.
Preston
R J
RJ
Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.
Fennell
T R
TR
Leber
A P
AP
Sielken
R L
RL
Swenberg
J A
JA
D000818:Animals; D004260:DNA Repair; D005027:Ethylene Oxide / Q000633:toxicity*; D005260:Female; D005854:Germ Cells; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009153:Mutagens / Q000633:toxicity*; D009865:Oocytes / Q000187:drug effects; D017354:Point Mutation; D018570:Risk Assessment; D017384:Sequence Deletion; D013094:Spermatozoa / Q000187:drug effects; D014178:Translocation, Genetic; D014481:United States; D014484:United States Environmental Protection Agency
D009153:Mutagens; D005027:Ethylene Oxide