A call for action: Improve reporting of research studies to increase the scientific basis for regulatory decision-making.

This is a call for action to scientific journals to introduce reporting requirements for toxicity and ecotoxicity studies. Such reporting requirements will support the use of peer-reviewed research studies in regulatory decision-making. Moreover, this could improve the reliability and reproducibility of published studies in general and make better use of the resources spent in research.

Physiologically based pharmacokinetic modeling of hydrogen cyanide levels in human breath.

Hydrogen cyanide (HCN) is a potent and fast-acting toxin increasingly recognized as an important cause of death in fire victims. Prompt diagnosis and treatment of cyanide poisoning are essential to avoid fatalities. Unfortunately, there are at present few rapid diagnostic methods. A noninvasive methodology would be to use HCN in exhaled air as a marker for systemic exposure. To explore this possibility, we developed a preliminary physiologically based pharmacokinetic model. The model suggests that breath HCN levels following inhalation exposure at near-lethal and lethal conditions are 0.1-1 ppm, i.e., one to two orders of magnitude higher than the background breath level of about 0.01 ppm in unexposed subjects. Hence, our results imply that breath analysis may be used as a rapid diagnostic method for cyanide poisoning.

Adjustment factors for toluene, styrene and methyl chloride by population modeling of toxicokinetic variability.

The availability of experimental data suitable as a basis to quantify human variability in response to chemical exposure has increased in recent years. It has enabled scientifically based, data driven adjustment factors (AF) to be deployed in the risk assessment process. As part of this development, we derive AF for human toxicokinetic variability (HK) for three lipophilic organic solvents; toluene, styrene and methyl chloride using physiologically based pharmacokinetic (PBPK) models in a population framework. The Monte Carlo simulations cover the influence of age and gender on toxicokinetic variability in the general population, as well as workplace ventilation rates and fluctuations in exposure level and workload in adult male and female workers. The derived AFHK are below 2.2 (95th percentile) for all subpopulations, exposure scenarios and chemicals, except for markers of acute effects in workers, where the factors are up to 5.0.

Chemical-specific adjustment factors for intraspecies variability of acetone toxicokinetics using a probabilistic approach.

Human health risk assessment has begun to depart from the traditional methods by replacement of the default assessment factors by more reasonable, data-driven, so-called chemical-specific adjustment factors (CSAFs). This study illustrates a scheme for deriving CSAFs in the general and occupationally exposed populations by quantifying the intraspecies toxicokinetic variability in surrogate dose using probabilistic methods. Acetone was used as a model substance. The CSAFs were derived by Monte Carlo simulation, combining a physiologically based pharmacokinetic model for acetone, probability distributions of the model parameters from a Bayesian analysis of male volunteer experimental data, and published distributions of physiological and anatomical parameters for females and children. The simulations covered how factors such as age, gender, endogenous acetone production, and fluctuations in workplace air concentration and workload influence peak and average acetone levels in blood, used as surrogate doses. According to the simulations, CSAFs of 2.1, 2.9, and 3.8 are sufficient to cover the differences in surrogate dose at the upper 90th, 95th, and 97.5th percentile, respectively, of the general population. However, higher factors were needed to cover the same percentiles of children. The corresponding CSAFs for the occupationally exposed population were 1.6, 1.8, and 1.9. The methodology presented herein allows for derivation of CSAFs not only for populations as a whole but also for subpopulations of interest. Moreover, various types of experimental data can readily be incorporated in the model.

Bayesian population analysis of a washin-washout physiologically based pharmacokinetic model for acetone.

The aim of this study was to derive improved estimates of population variability and uncertainty of physiologically based pharmacokinetic (PBPK) model parameters, especially of those related to the washin-washout behavior of polar volatile substances. This was done by optimizing a previously published washin-washout PBPK model for acetone in a Bayesian framework using Markov chain Monte Carlo simulation. The sensitivity of the model parameters was investigated by creating four different prior sets, where the uncertainty surrounding the population variability of the physiological model parameters was given values corresponding to coefficients of variation of 1%, 25%, 50%, and 100%, respectively. The PBPK model was calibrated to toxicokinetic data from 2 previous studies where 18 volunteers were exposed to 250-550 ppm of acetone at various levels of workload. The updated PBPK model provided a good description of the concentrations in arterial, venous, and exhaled air. The precision of most of the model parameter estimates was improved. New information was particularly gained on the population distribution of the parameters governing the washin-washout effect. The results presented herein provide a good starting point to estimate the target dose of acetone in the working and general populations for risk assessment purposes.

A human physiological model describing acetone kinetics in blood and breath during various levels of physical exercise.

Physiologically based toxicokinetic (PBTK) modeling of human experimental data suggests difficulties to simultaneously describe the time courses of inhaled polar solvents in blood and breath, especially if exposures occur during physical exercise. We attribute this to the washin-washout effect in the airways. The aim was to develop a PBTK-model that explains the behavior of acetone in blood and exhaled air at different levels of physical exercise. The model includes exchange of inhaled solvent vapor with the blood flow via the mucosa and separate compartments to describe working and resting muscles. The developed model was contrasted to a traditional PBTK-model where the conducting airways were regarded as an inert tube. Our model predictions agrees well with experimentally observed acetone levels in both arterial blood and end- and mixed-exhaled air from 26 inhalation experiments conducted with 18 human volunteers at 0, 50, 100 and 150 W workload. In contrast, the inert-tube model was unable to describe the data. The developed model is to our knowledge the first which explains the toxicokinetics of acetone at such various levels of physical exercise. It may be useful in breath monitoring and to obtain more accurate estimates of absorbed dose during inhalation of polar volatiles.