A physiologic mathematical model was developed to describe the time course of 14C-methylene chloride (14CH2Cl2) distribution and elimination in mice following single i.v. administrations of 10 and 50 mg/kg. A whole-body model was used to simulate 14CH2Cl2 concentrations in blood and tissues, pulmonary clearance of unchanged 14CH2Cl2, and metabolic conversion to 14CO2 and 14CO as monitored by the appearances of these metabolites in expired breath. This diffusion-limited model was identified via a sequential optimization scheme using hybrid models for each compartment. Pulmonary elimination of unchanged 14CH2Cl2 was modeled as a linear process while hepatic metabolism of 14CH2Cl2 to the compounds 14CO2 and 14CO was described by a saturable metabolic rate term. The model adequately described the dose dependence in methylene chloride distribution and metabolism when simulations were compared to experimental data.