Duration adjustment of acute exposure guideline level values for trichloroethylene using a physiologically-based pharmacokinetic model.
Acute Exposure Guideline Level (AEGL) recommendations are developed for 10-minute, 30-minute, 1-hour, 4-hours, and 8-hours exposure durations and are designated for three levels of severity: AEGL-1 represents concentrations above which acute exposures may cause noticeable discomfort including irritation; AEGL-2 represents concentrations above which acute exposure may cause irreversible health effects or impaired ability to escape; and AEGL-3 represents concentrations above which exposure may cause life-threatening health effects or death. The default procedure for setting AEGL values across durations when applicable data are unavailable involves estimation based on Haber's rule, which has an underlying assumption that cumulative exposure is the determinant of toxicity. For acute exposure to trichloroethylene (TCE), however, experimental data indicate that momentary tissue concentration, and not the cumulative amount of exposure, is important. We employed an alternative approach to duration adjustments in which a physiologically-based pharmacokinetic (PBPK) model was used to predict the arterial blood concentrations [TCE(a)] associated with adverse outcomes appropriate for AEGL-1, -2, or -3-level effects. The PBPK model was then used to estimate the atmospheric concentration that produces equivalent [TCE(a)] at each of the AEGL-specific exposure durations. This approach yielded [TCE(a)] values of 4.89 mg/l for AEGL-1, 18.7 mg/l for AEGL-2, and 310 mg/l for AEGL-3. Duration adjustments based on equivalent target tissue doses should provide similar degrees of toxicity protection at different exposure durations.
Boyes
William K
WK
National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. boyes.william@epa.gov
Evans
Marina V
MV
Eklund
Christopher
C
Janssen
Paul
P
Simmons
Jane Ellen
JE
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D008954:Models, Biological; D018570:Risk Assessment; D013997:Time Factors; D023382:Toxicity Tests, Acute / Q000706:statistics & numerical data; D014241:Trichloroethylene / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*
D014241:Trichloroethylene