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The impact of variation in scaling factors on the estimation of internal dose metrics: a case study using bromodichloromethane (BDCM)
Citation:
Kenyon, E., C. Eklund, J. Lipscomb, AND R. Pegram. The impact of variation in scaling factors on the estimation of internal dose metrics: a case study using bromodichloromethane (BDCM). Toxicology Mechanisms and Methods. Taylor & Francis, Inc., Philadelphia, PA, 26(8):620-626, (2016).
Impact/Purpose:
Scaling factors used for in vitro to in vivo extrapolation (IVIVE) for metabolic rate parameters can have a significant 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.
Description:
Many physiologically based pharmacokinetic (PBPK) models include values for metabolic rate parameters extrapolated from in vitro metabolism studies using scaling factors such as mg of microsomal protein per gram of liver (MPPGL) and liver mass (FVL). Variation in scaling factor values impacts metabolic rate parameter estimates (Vmax) and hence 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 BDCM for several internal dose metrics for two exposure scenarios (single 0.25 liter drink of water or 10 minute shower) under plausible (5 micrograms/L) and high level (20 micrograms/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 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.
