The impact of variation in scaling factors on the estimation of internal dose metrics: a case study using bromodichloromethane (BDCM).
A rate for hepatic metabolism (Vmax) determined in vitro must be scaled for in vivo use in a physiologically based pharmacokinetic (PBPK) model. This requires the use of scaling factors such as mg of microsomal protein per gram of liver (MPPGL) and liver mass (FVL). Variation in MPPGL and FVL impacts variation in Vmax, and hence PBPK model-derived estimates of internal dose used in dose response analysis. The impacts of adult human variation in MPPGL and FVL on estimates of internal dose were assessed using a human PBPK model for bromodichloromethane (BDCM), a water disinfection byproduct, for multiple internal dose metrics for two exposure scenarios (single 0.25 liter drink of water or 10 min shower) under plausible (5 μg/L) and high level (20 μg/L) water concentrations. For both concentrations, all internal dose metrics were changed less than 5% for the showering scenario (combined inhalation and dermal exposure). In contrast, a 27-fold variation in area under the curve (AUC) for BDCM in venous blood was observed at both oral exposure concentrations, whereas total amount of BDCM metabolized in liver was relatively unchanged. This analysis demonstrates that variability in the scaling factors used for in vitro to in vivo extrapolation (IVIVE) for metabolic rate parameters can have a significant route-dependent impact on estimates of internal dose under environmentally relevant exposure scenarios. This indicates the need to evaluate both uncertainty and variability for scaling factors used for IVIVE.
a Integrated Systems Toxicology Division , U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory , Research Triangle Park , NC , USA.
Elaina M
EM
Kenyon
a Integrated Systems Toxicology Division , U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory , Research Triangle Park , NC , USA.
Christopher
C
Eklund
b National Homeland Security Research Center , U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory , Cincinnati , OH , USA.
John C
JC
Lipscomb
a Integrated Systems Toxicology Division , U.S. EPA, Office of Research and Development, National Health and Environmental Effects Research Laboratory , Research Triangle Park , NC , USA.
Rex A
RA
Pegram
D000279:Administration, Cutaneous; D000284:Administration, Oral; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000009:adverse effects / Q000032:analysis*; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects / Q000032:analysis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009010:Monte Carlo Method; D014018:Tissue Distribution; D022882:Trihalomethanes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D014874:Water Pollutants, Chemical / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
D022882:Trihalomethanes; D014874:Water Pollutants, Chemical; C025191:bromodichloromethane
In vitro to in vivo extrapolation (IVIVE); PBPK model; scaling factors; variation