Incorporation of Acute Dynamic Ventilation Changes into a Standardized Physiologically Based Pharmacokinetic Model

Abstract

A seven-compartment physiologically based pharmacokinetic (PBPK) model incorporating a dynamic ventilation response has been developed to predict normalized internal dose from inhalation exposure to a large range of volatile gases. The model uses a common set of physiologic parameters, including standardized ventilation rates and cardiac outputs for rat and human. This standardized model is validated against experimentally measured blood and tissue concentrations for 21 gases. For each of these gases, body-mass-normalized critical internal dose (blood concentration) is established, as calculated using exposure concentration and time duration specified by the lowest observed adverse effect level (LOAEL) or the acute exposure guideline level (AEGL). The dynamic ventilation changes are obtained by combining the standardized PBPK model with the Toxic Gas Assessment Software 2.0 (TGAS-2), a validated acute ventilation response model. The combined TGAS-2P model provides a coupled, transient ventilation and pharmacokinetic response that predicts body mass normalized internal dose that is correlated with deleterious outcomes. The importance of ventilation in pharmacokinetics is illustrated in a simulation of the introduction of Halon 1301 into an environment of fire gases.

Assessing the application of acute toxic gas standards

“…TGAS addresses a number of issues that can complicate the translation of experimental results into a set of guidelines such as scaling of animal exposures to man, inclusion of physiologic response such as changes in ventilation due to gas inhalation and varying activity levels, and accounting for different target populations. TGAS also contains a physiologically based pharmacokinetic (PBPK) component that calculates tissue-specific internal doses for application to gases that are known to target and affect specific tissues (Ng et al, 2007). While implementation of internal dose is suggested for analysis of acute exposure guidelines, further exploration is needed before applying this methodology to chronic exposure guidelines.…”

“…In the second part, the standards are quantitatively compared through a calculation of body-mass-normalized internal dose using the Toxic Gas Assessment Software (TGAS), a physiologically-based toxicity evaluation model which accounts for ventilation changes as a function of species, activity, and inhaled gas (Ng et al, 2007;Stuhmiller and Stuhmilller, 2002;Stuhmiller et al, 2006). The model specifies a critical internal dose value at 50% probability (D 50 ) for incapacitation and lethality (immediate and delayed) along with the normalized log standard deviation (σ) determined by fitting incapacitation and lethality data from hundreds of toxic inhalation experiments.…”

“…To this end, many risk assessment models have been developed, along with safety standards that regulate and guide decision-making for toxic gas exposure (AIHA, 2009;CHPPM, 2002;Craig et al, 2000;Ng et al, 2007;NIOSH, 1994;NIOSH, 2006;NRC, 2001;Osha, 1992;Purser, 2008;Speitel, 1995;Stuhmiller et al, 2006). Gas toxicity standards, developed to protect certain populations, are typically expressed as exposure concentrations and durations that should not be exceeded to avoid certain health effects.…”

Simulations of exercise and brain effects of acute exposure to carbon monoxide in normal and vascular-diseased persons

“…More recently, with the advent of higher-speed computation, these organ models were combined in an interconnected human "whole"-body body model (http://physiology.umc.edu/ themodelingworkshop/). Other more specialized and limited physiological models have also been offered (e.g., Benignus, 1995;Ng et al, 2007;Smith et al, 1994;Stuhmiller and Stuhmiller, 2005). A general whole-body model called QCP (http://physiology.umc.…”