Pulmonary physiology and inhalation dosimetry in rats: development of a method and two examples

Methods were developed to measure simultaneously respiratory frequency, tidal volume, minute volume, and net uptake of an inhaled vapor in rats. During steady state, if metabolism is the only significant route of elimination, net uptake rate of the inhaled vapor is equal to its rate of metabolism. The rates of metabolism of methyl chloride in 50- and 1000-ppm-exposed rats were 0.20 and 3.3 nmol/min/g, respectively; the rates of metabolism of methylene chloride in 50- and 1500-ppm-exposed rats were 0.57 and 2.8 nmol/min/g, respectively. The uptake values obtained for both solvents were consistent with pharmacokinetic and metabolism data that were previously obtained in our laboratory. A pharmacokinetic model incorporating the metabolic rate at steady state, blood concentration versus time, and respiratory minute volume was used to describe the fate of inhaled methyl chloride in F344 rats, and to estimate the inhaled "effective" dose in 50- and 1000-ppm 6-hr-exposed rats (3.8 and 67 mg/kg, respectively). The approach used in these studies appears to be a useful method for the evaluation of metabolic rates and for inhalation dosimetry.