Physiologically Based Modeling of n-Hexane Kinetics in Humans Following Inhalation Exposure at Rest and Under Physical Exertion: Impact on Free 2,5-Hexanedione in Urine and on n-Hexane in Alveolar Air

Abstract

We used a modified physiologically based pharmacokinetic (PBPK) to describe/predict n-hexane (HEX) alveolar air concentrations and free 2,5-HD urinary concentrations in humans exposed to n-HEX by inhalation during a typical workweek. The effect of an increase in workload intensity on these two exposure indicators was assessed and, using Monte Carlo simulation, the impact of biological variability was investigated. The model predicted HEX alveolar air concentrations at rest of 19.0 ppm (25 ppm exposure) and 38.7 ppm (50 ppm exposure) at the end of the last working day (day 5), while free 2,5-HD urinary concentrations of 3.4 μ mol/L (25 ppm) and 6.3 μ mol/L (50 ppm) were predicted for the same period (last 4.5 hours of Day 5). Monte Carlo simulations showed that the range of values expected to occur in a group of 1000 individuals exposed to 50 ppm of HEX (95% confidence interval) for free 2,5-HD (1.7–14.7 μ mol/L) is much higher compared with alveolar air HEX (33.4–46 ppm). Simulations of exposure at 50 ppm with different workloads predicted that an increase in workload intensity would not greatly affect both indicators studied. However, the alveolar air HEX concentration is more sensitive to modifications of workload intensity and time of sampling, after the end of exposure, compared with 2,5-HD. The PBPK model successfully described the HEX alveolar air concentrations and free 2,5-HD urinary concentrations measured in human volunteers and is the first, to our knowledge, to describe the excretion kinetics of free 2,5-HD in humans over a 5-day period.

Keywords:

• alveolar air concentration
• biological monitoring
• 2,5-hexanedione
• n-hexane
• toxicokinetic modeling

Notes

^A From Portier and Kaplan;⁽⁴¹⁾ type of distribution: L (lognormal); N (normal).

^B From Thomas et al.[6]

^C From Tardif et al.,[18] Thomas et al.,[6] Yu et al.[9]

^D This value corresponds to 334 L/hour (5.6 L/min) for a body weight of 65 kg: 334 (L/hour) ÷ (65 (kg)^0.7 = 18 L/hour/kg).

^E From Fisher et al.[20]

^F From Gargas et al.[19]

^G From Ali and Tardif.[10]

^H From this study.

^I From Laparé et al.[42]

^A Predicted by the PBPK model used in the present study.

^B Predicted by the PBPK model and Monte Carlo simulation (n = 1000).

^C VEI = (upper limit/lower limit; 95% confidence interval).