impact of human variability on the biological monitoring of exposure

Impact Of Human Variability On The Biological Monitoring Of Exposure To Toluene:
I. Physiologically Based Toxicokinetic Modelling
R Tardif 1, P Droz 3, G Charest-Tardif 1, G Pierrehumbert 3, G Truchon 2
1) Département de santé environnementale et santé au travail, Université de
Montréal, Canada,
2) Institut de recherche Robert-Sauvé en santé et sécurité du travail (IRSST),
Montréal, Canada,
3) Institut universitaire Romand de santé au travail, Lausanne, Suisse.
Human variability results in broad range of differences in chemical kinetics and as such is likely
to affect the level of exposure indicators (EIs) used to assess worker's exposure. The present
study was aimed at the evaluation of the impact of human variability on EIs of toluene (TOL).
Using an approach involving physiologically based toxicokinetic (PBTK) modelling and Monte
Carlo simulation (MCS), we investigated the impact of the biological variability affecting the
parameters (e.g., physiological, physicochemical, biochemical) which determine toluene (TOL)
kinetics on two EIs: urinary excretion of o-cresol (o-CR) measured at the end of an 8-hr exposure
at 50 ppm and, unchanged TOL in blood (B-TOL) sampled prior to the last shift of a 5-day
workweek. Physiological parameter values were set to consider a physical workload of 50 W.
Sensivity analysis showed that o-CR values depend mainly on alveolar ventilation (AV) and
cardiac output, fraction of TOL converted to o-CR and factors governing urine output whereas
B-TOL values depend primarily on AV, blood: air partition coefficient and TOL kinetics in
adipose tissue compartment. For MCS, population variance was described by assuming normal
or lognormal distribution of parameter values and assigning to each one ± 2 SD (or ± 2 GSD) or,
a fixed value of coefficient of variation (CV). PBTK-MCS (n = 1000) resulted in a geometric
mean (GM) of 0.635mmol/mol creatinine for urinary o-CR [upper and lower limits (95%)
ranging from 0.23 to 1.75), whereas GM for B-TOL was 120.6 µg/l (95% limits: 64.5 –225.7).
Overall the results showed that this approach predicted relatively wide range of EI values for
TOL and that the range for B-TOL is about one-half of the one predicted for o-CR. (Supported
by IRSST, Québec).