A computational framework for incorporating dermal penetration and elimination pathway predictions into provisional PBPK models: A practical tool in high throughput chemical risk assessment

摘要

To further the use of non-animal hazard data into emerging risk assessment frameworks, a combination of pharmacokinetic and toxicity information is needed to calculate internal and external dose metrics. Internal dose can provide a linkage to in vitro effect data, allow for a combination of external doses to facilitate aggregate exposure assessment, maximize the ability to compare studies on related chemicals done by different dose routes and species. In this presentation, first we demonstrate the direct linkage between a dermally applied dose and the resulting internal dose and then explore methods to understand the resulting internal dosimetry when measured data to parameterize a PBPK model are missing or incomplete. We have developed an approach for rapid parameterization of dermal PBPK model based solely on in silico QSAR-derived chemical inputs. A computational model for the a priori prediction of renal and metabolic clearance mechanisms was employed in the development of this screening level model. It is anticipated that this screening level information can be used to assess the need for additional data generation when greater accuracy is required (based on projected worst case margins of safety). Importantly, being able to predict whether a compound will be renally eliminated without biotransformation will decrease the number of chemicals for which hepatic clearance will need to be measured experimentally. These concepts can be evaluated and used to help drive decisions and efficiency in safety testing of cosmetics and personal care products. A comparison of model simulations to experimental data will illustrate the approach.