Physiological-model-based derivation of the adult and child pharmacokinetic intraspecies uncertainty factors for volatile organic compounds

Abstract

The intraspecies uncertainty factor (UF(HH)=10x) is used in the determination of the reference dose or reference concentration and accounts for the pharmacokinetic and pharmacodynamic heterogeneity within the human population. The Food Quality Protection Act of 1996 mandated the use of an additional uncertainty factor (UF(HC)=10x) to take into account potential pre- and postnatal toxicity and lack of completeness of the data with respect to exposure and toxicity to children. There is no conclusive experimental or theoretical justification to support or refute the magnitude of the UF(HH) and UF(HC) nor any conclusive evidence to suggest that a factor of 100 is needed to account for intrahuman variability. This study presents a new chemical-specific method for estimating the pharmacokinetic (PK) component of the interspecies uncertainty factor (UF(HH-PK) and UF(HC-PK)) for volatile organic compounds (VOCs). The approach utilizes validated physiological-based pharmacokinetic (PBPK) models and simplified physiological-model-based algebraic equations to translate ambient exposure concentration to tissue dose in adults and children the ratio of which is the UF(HH-PK) and UF(HC-PK). The results suggest that: (i) the UF(HH-PK) and UF(HC-PK) are chemical specific; (ii) for the chemicals used in this study there is no significant difference between UF(HH-PK) and UF(HC-PK); (iii) the magnitude of UF(HH-PK) and UF(HC-PK) varies between 0.033 and 2.85 with respect to tissue and blood concentrations; (iv) the body weight, the rate of ventilation, the fraction of cardiac output flowing to the liver, the blood : air partition coefficient, and the hepatic extraction ratio are the only parameters that play a critical role in the variability of tissue and blood doses within species; and (v) the magnitude of the UF(HH-PK) and UF(HC-PK) obtained with the simplified steady-state equations is essentially the same with that obtained with PBPK models. Overall, this study suggests that no adult-children differences in the parent chemical concentrations of the VOCs are likely to be observed during inhalation exposures. The physiological-model-based approaches used in the present study to estimate the UF(HH-PK) and UF(HC-PK) provide a scientific basis for their magnitude. They can replace the currently used empirical default approaches to provide chemical-specific UF(HH-PK) in future risk assessments.