Simulation of age-dependent kinetics of volatile organic compounds using a PBPK model

Regarding the exposure to xenobiotics, children are possibly a group at risk due to possible higher external exposure (behavior, physiological needs), different kinetics (leading to higher internal exposure) and different dynamics.In order to quantify the age-dependent differences in kinetics occurring during inhalational exposure to volatile organic compounds (VOCs), a PBPK model with seven compartments (brain, liver, kidney, adipose tissue, muscle/skin, vessel rich organs and skeleton) was used. Anatomical and physiological data were derived from the literature for the ages 0 (newborn), 1, 5, 10 and 15 years as well as for the middle-aged male adult. To include the immature metabolism at the age of 0 and 1 year, 14% and 50% CYP2E1 activity per liver volume, respectively, was assumed in comparison to elder children and adults. Model calculations were made for different VOCs with high rates of alveolar absorption (low water solubility and reactivity: so-called 'category 3 gases'). Properties regarding partition coefficients (air/blood and blood/tissue) and metabolism (V max , k m ) were taken from the literature.As expected from theoretical considerations, arterial concentrations in the six age groups during simulated short-term exposures (minutes to hours, constant concentrations in ambient air) were highest in newborn, resulting mainly from the relatively high alveolar ventilation and immature metabolism. With increasing age, concentrations more and more resemble those in the middle-aged adult. Using styrene as example for a typical category 3 gas, the following concentration ratios (child/adult) were calculated following 8-hour exposure. Exposure newborn 1 year 5 years 10 years 15 years 1 ppm 1.5 1.1 1.1 1.1 1.1100 ppm 4.5 2.6 1.8 1.7 1.31000 ppm 1.5 1.2 1.3 1.2 1.2The ratios were found to be dose-dependent (maximum reached at about 80 ppm). This phenomenon is pronounced in the newborn ('immature' metabolic capacity) who reaches non-linear conditions at lower external concentrations than the adult.For the kinetics of the parent compound we conclude that at the same external exposure the newborn experiences the highest internal exposure compared to elder children and adults. This is expected to be different when considering metabolites: 5-year-old children may have the highest internal exposure (relatively high ventilation rates and metabolic activity). Regarding quantification, the ratios of the concentrations in comparison to adults depend on the compound (properties regarding partition and metabolism) and the concentration in ambient air, whereas the duration of exposure is of minor importance. For risk assessment of systemic effects resulting from inhalational exposure to VOCs, these ratios can be used to establish data-derived kinetic safety factors in order to include newborn as sensitive subpopulation.