Citation:

Kenyon, E., J. Lipscomb, R. Pegram, AND R. Hines. THE IMPACT OF SCALING FACTOR VARIABILITY ON RISK-RELEVANT TOXICOKINETIC OUTCOMES IN CHILDREN: A CASE STUDY USING BROMODICHLOROMETHANE (BDCM). Society of Toxicology, Baltimore, Maryland, March 12 - 16, 2017.

Impact/Purpose:

Our findings suggest the need to evaluate age-dependency of variation in scaling factors used for in vitro to in vivo extrapolation of biotransformation rates.

Description:

Biotransformation rates (Vmax) extrapolated from in vitro data are used increasingly in human physiologically based pharmacokinetic (PBPK) models. Extrapolation of Vmax from in vitro data requires use of scaling factors, including mg of microsomal protein/g liver (MPPGL), nmol of cytochrome P450 form/g liver (CYP) and liver mass (FVL). Our BDCM model was re-parameterized for a 10 kg child and Monte Carlo analysis was used to assess the impact of variation in pediatric scaling factors on model-derived estimates of internal dose, which was compared with findings from a similar analysis conducted using our adult BDCM PBPK model. BDCM dose metrics, including venous blood concentration (CV), area under the curve (AUCv), and amount metabolized in liver (AML) were estimated following a single 0.25 liter drink of water or a 20 minute bath, under typical (5 ppb) and plausible higher level (20 ppb) BDCM water concentrations for each exposure scenario. MPPGL, CYP and FVL values used in the pediatric analysis reflect the range of values reported for pediatric populations (3 months to 18 years). The impact of variability in scaling factors on variation in internal dose estimates was different for each exposure scenario (oral versus bathing), but similar for each BDCM water concentration. When the bathing scenario was modeled, scaling factor variability produced differences between maximum and minimum values of all dose metrics of ~ 2-fold. For oral exposure, differences were approximately 30-fold in AUCv and CV, but only1.5-fold in AML. The small change in AML is attributable to metabolism not being saturated at these exposure levels. For a similar analysis conducted using the adult PBPK model and adult scaling factor values, variation in dose metrics was less than 10% for the bathing scenario and for the oral scenario, ~15-fold for CV and AUCv, and less than 5% for AML. These findings suggest the need to evaluate age-dependency of variation in scaling factors used for in vitro to in vivo extrapolation of biotransformation rates. (This abstract does not reflect USEPA policy).

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