Use of quantitative modelling in methylene chloride risk assessment.
The benefits of basing quantitative risk assessment on measures of 'internal dose', i.e. target organ exposures as estimated, for instance, by pharmacokinetic models, have been extensively discussed. Recasting risk assessment methods at the level of internal dose raises novel issues, however, some of which are explored by examining the 1987 revision by the US Environmental Protection Agency (EPA) of its cancer risk assessment for inhaled methylene chloride, which was based on the 1987 pharmacokinetic model results of Andersen and coworkers. The internal dose measure was the daily amount of methylene chloride metabolized by a glutathione-S-transferase pathway per 1 of target organ (liver and lung). Owing to high-dose saturation of a competing detoxification reaction, this metabolic activation is less-than-proportionally active at low exposure levels. For a given inhalation exposure, humans have relatively less metabolic activation than do mice, but this is shown to be a foreseeable consequence of their relatively lower breathing rate, a cross-species difference already accounted for in standard EPA methodology. Indeed, many species differences in the rates and tempos of physiological processes evince regular 'scaling' relationships across differently sized mammals. EPA's practice of scaling carcinogen doses by body surface area for cross-species extrapolation, often viewed as a correction for metabolic activation, is shown to be more reasonably regarded as an accommodation for the more general species variation in the pace of physiological processes underlying both pharmacokinetics and the carcinogenic response to internal doses. Under this view, the issue of cross-species dose scaling is not obviated by the use of pharmacokinetics.
D000280:Administration, Inhalation; D000818:Animals; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008752:Methylene Chloride / Q000378:metabolism / Q000493:pharmacokinetics* / Q000633:toxicity; D051379:Mice; D008954:Models, Biological; D018570:Risk Assessment; D013045:Species Specificity
D002273:Carcinogens; D008752:Methylene Chloride