A proposed inhalation reference concentration for methanol

A biologically based approach was taken to developing an inhalation Reference Concentration (RfC) for methanol, a high production volume chemical with many commercial applications, including use as an alternative fuel for motor vehicles and as a hydrogen source for fuel cells. Benchmark Dose methodology was applied to the most sensitive toxic endpoint for assessing potential health risks in humans, cervical rib malformation data obtained using CD-1 mice. The concentration of methanol in circulating blood was employed as the dose metric, and the maximum likelihood estimate of the blood methanol increment causing a 10% extra risk of these malformations, was 215.4 mg/L, with a lower 95% confidence bound of 97.4 mg/L. A “Reference Increment” for blood methanol was then determined by dividing this value by a 3-fold factor for residual pharmacodynamic uncertainty between species and a 10-fold factor for interindividual variation in human sensitivity to methanol. The resulting Reference Increment in blood methanol was then converted to an equivalent inhalation Reference Concentration with a physiologically based pharmacokinetic model evaluated for continuous exposure conditions. The resulting maximum likelihood estimate for the inhalation RfC was 298 mg/m3, with a 95% lower confidence bound of 135 mg/m3.