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Tissue dosimetry for reactive metabolites.

In recent pharmacokinetically based risk assessments for methylene chloride, Andersen et al. argued that total reactive metabolite (TRM) divided liver weight was the proper measure of dose to target tissue, while the EPA argued that TRM divided by body weight to the two-thirds power was more appropriate. We demonstrate that the proper tissue metric for a reactive metabolite is dependent upon the mode of deactivation: metabolic or spontaneous. It is argued that the most appropriate measure of tissue dosimetry is: (1) TRM divided by the three-fourths power of body weight if the reactive metabolite is metabolically deactivated; or (2) TRM divided by body weight if the reactive metabolite is spontaneously deactivated.