Impact of stressors in the aviation environment on xenobiotic dosimetry in humans: physiologically based prediction of the effect of barometric pressure or altitude

ABSTRACT

Standard health risks from volatile organic compounds (VOCs) are generally interpreted at ambient environmental conditions. The aim of this study was to develop a strategy for using physiologically based pharmacokinetic (PBPK) modeling to compare known risks in the general population to calculated risks in pilots experiencing pressure-based stressors. PBPK models facilitate these comparisons by prediction of how target-tissue specific doses are altered when a stressor, such as high altitude, produces changes in physiological parameters. Cardiac output, regional blood flow, and alveolar ventilation rate following acute exposure to altitude ranging from moderate to extremely high were estimated from published data from 52 groups of human subjects. Scenarios where pilots might inhale toluene, 1,2,4-trimethylbenzene (1,2,4-TMB), or cyclohexane during routine military flight training were simulated. At the recommended Threshold Limit Values (TLV), arterial blood concentrations were predicted to be higher for exposure at 15000 ft (4572 m) than at sea level. The differences were greater for toluene and TMB, which have higher blood: air and fat: blood partition coefficients than less lipophilic cyclohexane. In summary, quantitative approaches to internal dosimetry prediction that take advantage of existing knowledge of physiological changes induced by occupational stressors possess potential as tools in performing a human health risk assessment.

KEYWORDS:

• Aviation
• health risk assessment
• altitude
• barometric pressure
• cardiac output
• regional blood flow
• pulmonary ventilation
• physiologically based pharmacokinetic modeling

Acknowledgments

The author thanks Drs. Corey Hart and Matt Linakis, 711^th Human Performance Wing, and Dr. Jeff Gearhart, Henry M. Jackson for the Advancement of Military Medicine, Wright-Patterson Air Force Base, OH, and anonymous reviewers for helpful comments. This study was supported by the Defense Health Program. The views expressed in the article are those of the author and do not necessarily reflect the official policy or position of the Air Force, the Department of Defense, or the U.S. Government.

Declarations of interest

The author has no competing interests to declare.

Ethics declaration

No human studies were conducted for the purpose of completing the work described herein.

Data availability

Data supporting the findings in this study are provided within the article and in the Supplementary Material.

Supplementary materials

Supplemental data for this article can be accessed on publisher’s website.

Additional information

Funding

This work was supported by the US Air Force Defense Health Program [2018-217].