A pharmacokinetic/mechanism-based analysis of the carcinogenic risk of ethylene oxide.
Center for Technology, Policy and Industrial Development, Massachusetts Institute of Technology, Cambridge, Massachusetts, CTPID 87-1, 1987 Aug; :1-223
An attempt was made to build an integrated series of pharmacokinetic models for low molecular weight alkylating agents in efforts to expand the understanding of risk assessment for various occupational carcinogens. The purpose was to allow for better assessment of biologically effective doses of activated metabolites delivered to target tissues and to arrive at a better translation of such units between species. The approach to pharmacokinetic modeling of ethylene-oxide (75218) was defined, and specific results were presented. Longer elimination was predicted to increase internal dose, so that greater internal doses would be expected in man compared to rodents. Lower respiration per body weight in man would decrease absorption rate, offsetting the higher predicted internal dose. In terms of human cancer risk, it is stated that substantial data is available showing carcinogenic response of rats and mice to ethylene-oxide. Equations were presented showing the risk resulting for different sites, species, and sexes using the measure of delivered dose in a multistage model. Implications for overall human cancer risk from 45 year 8 hour per day occupational exposures to 1 part per million ethylene-oxide were presented. Doses used in analysis did not yield markedly divergent estimates of human risk. The authors conclude that for a simple direct acting alkylator like ethylene-oxide, traditional approaches for dose and risk projection across species are supported by pharmacokinetic based analysis.
NIOSH-Cooperative-Agreement; Cooperative-Agreement-U60-CCU-100929; Computer-models; Kinetics; Exposure-levels; Ethylenes; Oxides; Disinfectants; Humans; Occupational-exposure; Carcinogenesis; Laboratory-animals; Metabolic-study; Risk-analysis
Final Cooperative Agreement Report
NTIS Accession No.
Center for Technology, Policy and Industrial Development, Massachusetts Institute of Technology, Cambridge, Massachusetts, CTPID 87-1, 223 pages, 56 references