Development of an inhalation physiologically based pharmacokinetic (PBPK) model for 2,2, 4-trimethylpentane (TMP) in male Long-Evans rats using gas uptake experiments

Abstract

2,2,4-Trimethylpentane (TMP) is a volatile colorless liquid used primarily to increase the octane rating of combustible fuels. TMP is released in the environment through the manufacture, use, and disposal of products associated with the gasoline and petroleum industry. Short-term inhalation exposure to TMP (< 4 h; > 1000 ppm) caused sensory and motor irritations in rats and mice. Like many volatile hydrocarbons, acute exposure to TMP may also be expected to alter neurological functions. To estimate in vivo metabolic kinetics of TMP and to predict its target tissue dosimetry during inhalation exposures, a physiologically based pharmacokinetic (PBPK) model was developed for the chemical in Long-Evans male rats using closed-chamber gas-uptake experiments. Gas-uptake experiments were conducted in which rats (80–90 days old) were exposed to targeted initial TMP concentrations of 50, 100, 500, and 1000 ppm. The model consisted of compartments for the closed uptake chamber, lung, fat, kidney, liver, brain, and rapidly and slowly perfused tissues. Physiological parameters were obtained from literature. Partition coefficients for the model were experimentally determined for air/blood, fat, liver, kidney, muscle, and brain using vial equilibration methods. Common to other hydrocarbons, metabolism of TMP via oxidative reactions is assumed to mainly occur in the liver. The PBPK model simulations of the closed chamber data were used to estimate in vivo metabolic parameters for TMP in male Long-Evans rats.

Keywords::

• Gas uptake inhalation
• isooctane
• PBPK
• sensitivity analysis
• TMP

Acknowledgments

This article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. EPA, and approved for publication. The authors thank Drs. Mike DeVito, Elaina Kenyon, and William Boyes for helpful comments during the preparation of this article. The authors also thank Brenda Edwards for help in preparing and conducting gas-uptake experiments.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Appendix

A_CH = amount of TMP in chamber (mg)

C_A = arterial blood TMP concentration (mg/L)

A_LI = amount of TMP in liver

C_CH = chamber concentration (mg/L)

V_CH = chamber volume (L)

C_R = rapidly perfused tissue TMP concentration (mg/L)

V_R = rapidly perfused tissue volume (L)

P_R = rapidly-perfused tissue/blood partition coefficient

Q_R = rapidly-perfused blood flow (L/h)

C_s = slowly-perfused tissue TMP concentration (mg/L)

V_S = slowly-perfused tissue volume (L)

P_s = slowly-perfused tissue/blood partition coefficient

Q_s = slowly-perfused tissue blood flow (L/h)

C_F = fat tissue TMP concentration (mg/L)

V_F = fat tissue volume (L)

P_F = fat tissue/blood partition coefficient

Q_F = fat tissue blood flow (L/h)

C_K = kidney tissue TMP concentration (mg/L)

V_K = kidney tissue volume (L)

P_K = kidney tissue/blood partition coefficient

Q_K = kidney tissue blood flow (L/h)

C_Br = brain tissue TMP concentration (mg/L)

V_Br = brain tissue volume (L)

P_Br = brain tissue/blood partition coefficient

Q_Br = brain tissue blood flow (L/h)

C_LI = liver tissue TMP concentration (mg/L)

V_LI = liver tissue volume (L)

P_LI = liver tissue/blood partition coefficient

Q_LI = liver tissue blood flow (L/h)

P_B = blood/air partition coefficient

Q_p = ventilation rate (L/h)

Q_c = cardiac output (L/h)

k_loss = chamber loss (h⁻¹)

k_met = metabolism first-order constant (h⁻¹)

R_v = rate of transport of TMP to lung via venous blood (mg/h)