Use of novel inhalation kinetic studies to refine physiologically-based pharmacokinetic models for ethanol in non-pregnant and pregnant rats

Abstract

Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and developmental effects in the rat. Physiologically-based pharmacokinetic (PBPK) models have been used to predict the inhalation exposure concentrations necessary to produce blood EtOH concentrations (BEC) in the range associated with these effects. Previous laboratory reports often lacked sufficient detail to adequately simulate reported exposure scenarios associated with BECs in this range, or lacked data on the time-course of EtOH in target tissues (e.g. brain, liver, eye, fetus). To address these data gaps, inhalation studies were performed at 5000, 10 000, and 21 000 ppm (6 h/d) in non-pregnant female Long-Evans (LE) rats and at 21 000 ppm (6.33 h/d) for 12 d of gestation in pregnant LE rats to evaluate our previously published PBPK models at toxicologically-relevant blood and tissue concentrations. Additionally, nose-only and whole-body plethysmography studies were conducted to refine model descriptions of respiration and uptake within the respiratory tract. The resulting time-course and plethysmography data from these in vivo studies were compared to simulations from our previously published models, after which the models were recalibrated to improve descriptions of tissue dosimetry by accounting for dose-dependencies in pharmacokinetic behavior. Simulations using the recalibrated models reproduced these data from non-pregnant, pregnant, and fetal rats to within a factor of 2 or better across datasets, resulting in a suite of model structures suitable for simulation of a broad range of EtOH exposure scenarios.

Application of Biologically Based Lumping To Investigate the Toxicokinetic Interactions of a Complex Gasoline Mixture

“…Rats were maintained in groups of two per polycarbonate cage (18780, Maryland Plastics, Inc., Federalsburg, MD Exposure System. The vapor condensates of gasoline were generated for this project by Chevron USA, Inc. (Richmond, CA) under contract with the EPA as described by Bushnell et al 30 Rats were exposed using a nose-only chamber described by Martin et al 31 Briefly, a 52-port Cannon-style directed flow N− O exposure system was used to expose rats and enable rapid removal for sacrifice and collection of kinetic time points. Liquid vapor condensates were first expressed from pressurized storage containers into a heated J-tube, according to Bushnell et al 30 Once volatilized, the vapors were passed into the inner plenum of the exposure chamber and expressed into the breathing zones of the rats via jets within the N−O ports.…”

“…The blood and tissue samples were collected, prepared, and stored as previously described for nonpregnant rats. 31 The complexities of analyzing a fuel mixture in blood necessitated that a subgroup of chemicals be The solution of standards described above was dissolved in cumene (4-isopropylbenzene). A "standard mix" was recreated every 14 days during the analysis to maintain the desired concentrations of these volatile hydrocarbons.…”

“…The vapor condensates of gasoline were generated for this project by Chevron USA, Inc. (Richmond, CA) under contract with the EPA as described by Bushnell et al Rats were exposed using a nose-only chamber described by Martin et al Briefly, a 52-port Cannon-style directed flow N–O exposure system was used to expose rats and enable rapid removal for sacrifice and collection of kinetic time points. Liquid vapor condensates were first expressed from pressurized storage containers into a heated J-tube, according to Bushnell et al .…”

“…The blood and tissue samples were collected, prepared, and stored as previously described for nonpregnant rats . The complexities of analyzing a fuel mixture in blood necessitated that a subgroup of chemicals be tracked, rather than attempting to quantify every measurable chemical in the mixture.…”

An Overview of Physiologically-Based Pharmacokinetic Models for Forensic Science

“…Ethanol exposure as an occupational hazard, through either accidental inhalation or dermal exposure from hand sanitizers, has been explored by multiple research groups through various PBPK models [ 95 , 96 , 97 , 98 ]. Environmental exposure to alcohol from a variety of sources such as fuel or non-occupation hand sanitizer use has been published by multiple groups as well [ 99 , 100 , 101 , 102 ]. Intentional exposure, either through common social consumption routes or healthy volunteer research cohorts, were also modeled by multiple groups [ 103 , 104 ].…”