Current practice and challenges in integrating biomarkers and PBPK/PD for chemical risk assessment
The landscape of chemical risk assessment has been evolving with recent advancements in biomedical and computational sciences, as best represented respectively by biomarker discovery and physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling. The integration of epidemiological biomarkers analyses (e.g., parent chemical or its metabolites in urine) and PBPK/PD provides a promising platform to shed insight into the mechanisms of action or biological processes involved in chemical toxicity (e.g., food safety).
Despite growing interest in the use of biomarkers and PBPK/PD in chemical risk assessment, a number of challenges remain. Some biomarkers, for example, have relatively short half-lives of hours to days (e.g., urinary benzene metabolites). Thus, these biomarker levels may only reflect recent exposure, limiting their use in estimating chronic exposure via PBPK modeling. Also, one may need to take biomarker specificity into consideration. As an example, the same biomarkers such as urinary mandelic (MA) and phenylglyoxylic (PGA) can arise from either ethylbenzene or styrene. As such, it presents a key challenge in assessing chemical exposures of interest, in particular for epidemiological biomarker data collected from studies in human populations.
Of note, biological functions and pathways may also vary depending on exposure dosing levels (e.g., saturation of metabolism at higher doses). Thus, the development and validation of computational PBPK models that are able to imitate the biological mechanisms or responses over a range of exposure levels is critical for using high dose animal data to assess human health risks. This symposium will bring together experts in exposure sciences, epidemiology, food safety, biomarkers, and toxicokinetic modeling who are working on various platforms for chemical risk assessment. We will highlight key findings and topics in this symposium, such as uncertainty and variability in PBPK/PD and exposure patterns, biomarker levels, and cutting-edge technologies developed to address these issues (e.g., quantitative structure-activity relationship models, QSAR).