Assessing the impact of the duration and intensity of inhalation exposure on the magnitude of the variability of internal dose metrics in children and adults

Abstract

The objective of this study was to assess the impact of the exposure duration and intensity on the human kinetic adjustment factor (HKAF). A physiologically based pharmacokinetic model was used to compute target dose metrics (i.e. maximum blood concentration (C_max) and amount metabolized/L liver/24 h (Amet)) in adults, neonates (0–30 days), toddlers (1–3 years), and pregnant women following inhalation exposure to benzene, styrene, 1,1,1-trichloroethane and 1,4-dioxane. Exposure scenarios simulated involved various concentrations based on the chemical’s reference concentration (low) and six of U.S. EPA’s Acute Exposure Guideline Levels (AEGLs) (high), for durations of 10 min, 60 min, 8 h, and 24 h, as well as at steady-state. Distributions for body weight (BW), height (H), and hepatic CYP2E1 content were obtained from the literature or from P3M software, whereas blood flows and tissue volumes were calculated from BW and H. The HKAF was computed based on distributions of dose metrics obtained by Monte Carlo simulations [95th percentile in each subpopulation/median in adults]. At low levels of exposure, ranges of C_max-based HKAF were 1–6.8 depending on the chemical, with 1,4-dioxane exhibiting the greatest values. At high levels of exposure, this range was 1.1–5.2, with styrene exhibiting the greatest value. Neonates were always the most sensitive subpopulation based on C_max, and pregnant women were most sensitive based on Amet in the majority of the cases (1.3–2.1). These results have shown that the chemical-specific HKAF varies as a function of exposure duration and intensity of inhalation exposures, and sometimes exceeds the default value used in risk assessments.

Keywords::

• AEGL
• human kinetic adjustment factor
• interindividual variability
• physiologically based pharmacokinetics (PBPK)
• risk assessment
• toxicokinetics
• VOCs