Use of Pharmacokinetic Models As an Alternative to Haber’s-based Adjustments. W. K. Boyes, C. Eklund, and J. E. Simmons, US Environmental Protection Agency, NC
Chemical toxicity data are often available for only one set of exposure durations, but risk must be evaluated for other conditions. Traditional procedures for estimating changes in toxicity across exposure durations are based on Haber’s rule: concentration (C) x duration (t) = a constant toxic effect (K). Alternatives to Haber’s formula involve exponential functions of C and/or t, where the exponents are empirically fit to experimental data. These approaches are limited in the lack of a hypothetical basis for the extrapolations, poor predictability across exposure durations particularly for the linear form, and the need for empirical data over the range of durations for empirically derived formulas. We present an alternative in which a physiologically based pharmacokinetic model (PBPK) is used to estimate the target tissue dose producing the critical adverse effect, and then the PBPK model is used to estimate other exposure conditions producing the same target tissue dose. This approach was used to estimate equivalent exposures to trichloroethylene (TCE) at exposure durations of 10 and 30 min and 1, 4,and 8 hr. For AEGL-1 standards, a human NOAEL of 300 ppm for 2 hr was used as critical effect, and then other concentration/duration combinations were calculated to yield equivalent blood TCE levels (i.e. 4.78 ± 0.02 mg TCE/lblood). An alternative calculation was conducted using a NOAEL of 200 ppmfor 7 hr, yielding a critical blood concentration of 3.93 ± 0.02 mg/l.ForAEGL-2, a critical effect at 1000 ppm for 2 hrs yielded a blood concentration of 18.3 ± 0.2 mg/l. The exposure concentrations predicted at each respective duration should yield equivalent tissue doses and, thus, equivalent health effects.
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