A Mode of Action-Based Probabilistic Framework of Dose-Response Assessment for Non-mutagenic Liver Carcinogens: A Case Study of PCB-126

Abstract

A main function of dose-response assessment is to estimate a “safe” dose in the target population to support chemical risk assessment. Typically, a “safe” dose is developed differently for cancer and non-cancer effects based on a two-step procedure, i.e., point of departure (POD) derivation and low-dose extrapolation. However, the current dose-response assessment framework is criticized for its dichotomized strategy without integrating the mode of action (MOA) information. The objective of this study was, based on our previous work, to develop a MOA-based probabilistic dose-response framework that quantitatively synthesizes a biological pathway in a dose-response modeling process to estimate the risk of chemicals that have carcinogenic potential. 3,3′,4,4′,5-Pentachlorobiphenyl (PCB-126) was exemplified to demonstrate our proposed approach. There were four major steps in the new modeling framework, including (1) key quantifiable events (KQEs) identification and extraction, (2) essential dose calculation, (3) MOA-based POD derivation, and (4) MOA-based probabilistic reference dose (RfD) estimation. Compared to reported PODs and traditional RfDs, the MOA-based estimates derived from our approach were comparable and plausible. One key feature of our approach was the use of overall MOA information to build the dose-response relationship on the entire dose continuum including the low-dose region. On the other hand, by adjusting uncertainty and variability in a probabilistic manner, the MOA-based probabilistic RfDs can provide useful insights of health protection for the specific proportion of population. Moreover, the proposed framework had important potential to be generalized to assess different types of chemicals other than non-mutagenic carcinogens, highlighting its utility to improve current chemical risk assessment.