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 micromol/L (25 ppm) and 6.3 micromol/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 micromol/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.

Urinary 2,5-hexanedione in workers exposed to n-hexane: influence of the sample treatment

“…Hamelin et al 27 determined free urinary 2,5-HD excretion and HEX in alveolar air in five volunteers exposed to HEX (25-50 ppm) for 5 consecutive days and concluded that both free urinary 2,5-HD and HEX in alveolar air are adequate indicators in the biomonitoring of exposure to HEX. Figure 2 shows the correlation between free and total 2,5-HD levels expressed in mg/g creatinine (r = 0.9127) and in mg/L (r = 0.7578).…”

The Effect of Workload on Biological Monitoring of Occupational Exposure to Toluene and N-Hexane: Contribution of Physiologically Based Toxicokinetic Modeling

“…The physiological parameters included in the PBTK model equations are shown in Table I and are the same as those used by Hamelin et al (29) Different levels of physical activity (rest, 25 W and 50 W) were simulated by varying the values of alveolar ventilation, cardiac output, and the fraction of cardiac output corresponding to each compartment. We (29) B The values in parentheses are for n-hexane model.…”

“…We (29) B The values in parentheses are for n-hexane model. C FromÅstrand (for rest and 50 W), (3) for toluene model only; blood flow for 25 W was calculated by linear interpolation between the values at rest and 50 W. D From Kumagai and Matsunaga, (35) for toluene model only.…”

“…(33) considered that rest corresponded to a level of activity of 12.5 W, as was assumed in the previous studies conducted in our laboratory. (13,14) The partition coefficients and metabolic constants for HEX and TOL were those previously used by Hamelin et al (29) and by Tardif et al (31) respectively. They are presented in Table II with their literature reference.…”

“…Physical activity of 25 W or 50 W induces less than 1.1-and 1.2-fold increases, respectively, compared with rest. To our knowledge, among the few PBTK models for HEX, the model developed by Hamelin et al (29) used in the present study, is the only one describing the kinetics of free 58 Painting 2,5-HD. The concentrations simulated by this model for 50-ppm exposure are clearly higher (0.92 mg/L at end of exposure on Day 5, at rest) than the recommended BEI value and the field data.…”