Uncertainty and variability in the exposure reconstruction of chemical incidents--the case of acrylonitrile.

The application of human physiologically based pharmacokinetic (PBPK) modeling combined with measured biomonitoring data, has a great potential to backtrack external exposure to chemicals during chemical incidents. So far, an important shortcoming of 'reversed dosimetry' is that uncertainty and variability in the model predictions are often neglected. The aim of this paper is to characterize the variation in predicted environmental air concentrations by means of reversed dosimetry as a result of uncertainty in chemical-specific input data and variability in physiological parameters. Human biomonitoring data (N-2-cyanoethylvaline in blood) from a chemical incident with acrylonitrile (ACN) combined with the BioNormtox PBPK model are used as a case to reconstruct the air concentration and uncertainty thereof at the time of the incident. The influence of uncertainty in chemical-specific properties and exposure duration, and interindividual variability in physiological parameters on the reconstructed air exposure concentrations were quantified via nested Monte Carlo simulation. The range in the reconstructed air concentrations of ACN during the incident was within a factor of 3. Uncertainty in the exact exposure duration directly after the chemical accident was found to have a dominant influence on the model outcomes. It was also shown that uncertainty can be further reduced by collecting human biomonitoring data as soon as possible after the incident. Finally, the collection of specific information about individual physiological parameters from the victims, such as body weight, may further reduce the variation by 5 to 20% in our case study. Future research should include the comparison of reversed dosimetry model outcomes with measured air and biological concentrations to further increase the confidence in the model approach and its implementation in practice.

Testing the coherence between occupational exposure limits for inhalation and their biological limit values with a generalized PBPK-model: the case of 2-propanol and acetone.

The coherence between occupational exposure limits (OELs) and their corresponding biological limit values (BLVs) was evaluated for 2-propanol and acetone. A generic human PBPK model was used to predict internal concentrations after inhalation exposure at the level of the OEL. The fraction of workers with predicted internal concentrations lower than the BLV, i.e. the 'false negatives', was taken as a measure for incoherence. The impact of variability and uncertainty in input parameters was separated by means of nested Monte Carlo simulation. Depending on the exposure scenario considered, the median fraction of the population for which the limit values were incoherent ranged from 2% to 45%. Parameter importance analysis showed that body weight was the main factor contributing to interindividual variability in blood and urine concentrations and that the metabolic parameters Vmax and Km were the most important sources of uncertainty. This study demonstrates that the OELs and BLVs for 2-propanol and acetone are not fully coherent, i.e. enforcement of BLVs may result in OELs being violated. In order to assess the acceptability of this "incoherence", a maximum population fraction at risk of exceeding the OEL should be specified as well as a minimum level of certainty in predicting this fraction.

Separating uncertainty and physiological variability in human PBPK modelling: The example of 2-propanol and its metabolite acetone.

Parameter uncertainty and interindividual variability in the predictions of a generic human physiologically based pharmacokinetic (PBPK) model were separated by means of nested Monte Carlo simulations. Separate information on uncertainty and variability can help decision makers to identify whether they should focus on identification of sensitive individuals rather than on additional research to obtain more accurate estimates for particular parameters. In this study, the concentration of acetone in human blood was simulated during and after 4h of exposure to 2-propanol via air. It was shown that the influence of interindividual variability and uncertainty varies over time, from the uptake phase, via a steady-state phase, into the elimination phase. During the uptake phase, interindividual variability played a significant role in the predicted variation of acetone concentrations in blood, with variability up to a factor of 2-3 (90th/10th percentile ratio). After exposure ceased, the parameter uncertainty increased up to a factor of 100 after 16h, whereas variability remained unchanged. Parameter importance analysis indicated that variability in human physiology had the largest influence on predicted acetone concentrations in blood during exposure. Uncertainty in the metabolic rate of acetone was most important after the exposure had ceased and overruled variability.

Hydroxypyrene in urine of football players after playing on artificial sports field with tire crumb infill.

BACKGROUND: Artificial sports fields are increasingly being used for sports. Recycled rubber from automotive and truck scrap rubber tires are used as an infill material for football grounds. There are concerns that football players may be at risk due to exposure from released compounds from rubber infill. Compounds from crumb infill may be inhaled and dermal exposure may occur. A study was performed to assess the exposure of football players to polycyclic aromatic hydrocarbons due to sporting on synthetic ground with rubber crumb infill. METHODS: In this study, football players were trained and had a match on the artificial turf pitch during 2.5 h. They had an intensive skin contact with rubber infill. All urine of seven nonsmoking football players was collected over a 3-day period, the day before sporting, the day of sporting and the day after sporting. Urine samples were analyzed for 1-hydroxypyrene. Confounding exposure from environmental sources and diet was controlled for. RESULTS: The individual increase of the amount of excretion over time was used as a measure to assess the uptake of PAH. It appeared that the baseline of excreted 1-hydroxypyrene in 4 of 7 volunteers was sufficient stable and that 1 volunteer out of 4 showed after the 2.5-h period of training and match on the playground an increase in hydroxypyrene in urine. However, concomitant dietary uptake of PAH by this volunteer was observed. CONCLUSIONS: This study provides evidence that uptake of PAH by football players active on artificial grounds with rubber crumb infill is minimal. If there is any exposure, than the uptake is very limited and within the range of uptake of PAH from environmental sources and/or diet.