Tissue dosimetry expansion and cross-validation of @entity35 and @entity19 physiologically based pharmacokinetic models for XXXX .

@entity1 @entity4966 @entity19 @entity35 @entity4965
@entity4965 ( @entity4966 ), a volatile liquid used as a degreasing agent, is a common environmental pollutant. In 2001, the EPA published a draft risk assessment for @entity4966 that incorporates dosimetry predictions of physiologically based pharmacokinetic (PBPK) models. The current modeling effort represents an expansion and extensive tissue dosimetry validation of rodent PBPK models for @entity4966 . The pharmacokinetics of @entity4966 in male Sprague-Dawley (S-D) @entity35 were characterized (1) during and after inhalation exposure to 50 or 500 ppm @entity4966 , (2) following administration of 8 mg/kg @entity4966 PO, and (3) following intra-arterial injection of 8 mg/kg @entity4966 . Blood and tissues (including liver, kidney, fat, skeletal muscle, heart, spleen, gastrointestinal tract, and brain) were collected at selected time-points from 5 min up to 24 h post initial exposure. The fat compartment was modified to be diffusion-limited to predict the observed slow release of @entity4966 from the fat. The addition of a deep liver compartment was necessary to accurately predict the slower hepatic clearance of @entity4966 for all three exposure routes. Simulations of liver concentrations following gavage of male B6C3F1 @entity19 with 300-2000 mg/kg @entity4966 were also improved with the addition of a deep liver compartment. Liver predictions were calibrated and validated using a cross-validation technique novel to PBPK modeling. Splitting of compartments did not significantly affect predictions of @entity4966 concentrations in the liver, fat, or venous blood. This model expansion and validation increases both the utility and our confidence in the current use of rodent @entity4966 PBPK models in @entity1 health risk assessment.
