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

The intraspecies uncertainty factor (UFHH =10x) is used in the determinatio n of the reference dose or reference concentration and accounts for the pha rmacokinetic and pharmacodynamic heterogeneity within the human population. The Food Quality Protection Act of 1996 mandated the use of an additional uncertainty factor (UFHC =10x) to take into account potential pre- and post natal toxicity and lack of completeness of the data with respect to exposur e and toxicity to children. There is no conclusive experimental or theoreti cal justification to support or refute the magnitude of the UFHH and UFHC n or any conclusive evidence to suggest that a factor of 100 is needed to acc ount for intrahuman variability. This study presents a new chemical-specifi c method for estimating the pharmacokinetic (PK) component of the interspec ies uncertainty factor (UFHH-PK and UFHC-PK) for volatile organic compounds (VOCs), The approach utilizes validated physiological-based pharmacokineti c (PBPK) models and simplified physiological-model-based algebraic equation s to translate ambient exposure concentration to tissue dose in adults and children the ratio of which is the UFHH-PK and UFHC-PK The results suggest that: (1) the UFHH-PK and UFHC-PK are chemical specific; (ii) for the chemi cals used in this study there is no significant difference between UFHH-PK and UFHC-PK; (iii) the magnitude of UFHH-PK and UFHC-PK varies between 0.03 3 and 2.85 with respect to tissue and blood concentrations; (iv) the body w eight, the rate of ventilation, the fraction of cardiac output flowing to t he liver, the blood:air partition coefficient, and the hepatic extraction r atio are the only parameters that play a critical role in the variability o f tissue and blood doses within species; and (v) the magnitude of the UFHH- PK and UFHC-PK obtained with the simplified steady-state equations is essen tially the same with that obtained with PBPK models. Overall, this study su ggests that no adult-children differences in the parent chemical concentrat ions of the VOCs are likely to be observed during inhalation exposures. The physiological-model-based approaches used in the present study to estimate the UFHH-PK and UFHC-PK provide a scientific basis for their magnitude. Th ey can replace the currently used empirical default approaches to provide c hemical-specific UFHH-PK in future risk assessments. (C) 2001 Academic Pres s.