Blood Methanol Pharmacokinetics Reconciles Interspecies Response Differences and Strengthens Risk Assessment. T. B. Starr, TBS Associates; B. H. Hooberman, ENVIRON Corporation; J. L. Festa, American Forest & Paper Association
CD-1 mice appear most sensitive to methanol toxicity, which manifests as cervical rib malformations in the offspring of pregnant dams exposed to airborne methanol concentrations of 2,000 ppm or higher 7 hrs/day on days 6-15 of gestation (Rogers et al., 1993). Across species, toxicity appears to arise only after methanol metabolism saturates at high airborne methanol concentrations, leading to disproportionately higher blood methanol levels. When two pharmacokinetic models of methanol uptake and disposition (Perkins et al., 1995 and Horton et al., 1992) were analyzed to determine initial rates of blood methanol accumulation and steady state blood methanol concentrations for mice, rats, monkeys, and humans, a remarkable concordance across these species was revealed in the steady state blood methanol concentrations resulting from continuous exposure at a proposed Reference Concentration (RfC) of 64 ppm. Initial rates of accumulation were also in close agreement except in the mouse, whose initial rate of accumulation was 6- to 13-fold higher than those for the rat, monkey, and human, indicating that the mouse achieves steady state more rapidly than do the other species. Further, the steady state blood methanol concentration in mice exposed to the Rogers et al. NOAEL of 1,000 ppm is 406.8 mg/L, over 254-fold higher than that of humans (1.6 mg/L) exposed to the proposed RfC. For comparison, baseline human blood methanol levels (arising from normal metabolism of some dietary constituents) average about 1.8 mg/L (Lee et al., 1992). Thus, accounting for species differences in blood methanol pharmacokinetics at high airborne concentrations raises the margin of exposure at the proposed RfC to over 254-fold, and strengthens confidence that no adverse effects will arise from continuous human exposure at that level.
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