Dissertation/Thesis Abstract

A New Dose-Response Assessment Framework with Quantitatively Integrated Information of Mode of Action for Liver Carcinogenesis
by Chen, Qiran, Ph.D., Indiana University, 2020, 163; 28258344
Abstract (Summary)

In the framework of chemical risk assessment, dose-response assessment first quantifies the relationship between dose and critical health effects, and it then extrapolates the biologically/ statistically significant dose (i.e., point of departure [POD]) to a reference dose for regulatory use. Typically, the point of departure for chemical carcinogens is the benchmark dose (BMD) or its statistical lower bound (i.e., BMDL). From a conservative perspective, the US EPA uses linear extrapolation as a default approach to derive a cancer slope factor, which may be employed to estimate cancer risk at a given dose. If sufficient evidence of the mode of action (MOA) can support a conclusion that the dose-response relationship is nonlinear in the low-dose region (i.e., to confirm that the agent is nonmutagenic), an oral reference dose (RfD) or an inhalation reference concentration (RfC) can be calculated instead. However, calculated RfD/RfC lacks the utility to quantify the risk of adverse effects in support of a probabilistic risk assessment. Therefore, this dissertation aims to develop a new framework of dose-response assessment for chemical carcinogens with sufficient data to characterize their MOAs. There are three significant steps in the framework: (1) key quantifiable event identification and dose-response data extraction; (2) dose-response modeling and critical dose derivation for each endpoint; and (3) pathway dose-response relationship evaluation and POD calculation. Three chemical carcinogens were analyzed using the proposed framework, including TCDD and PCB 126, with the MOA of AhR, and DEHP with PPARĪ±. The results for the examples demonstrate excellent stability and flexibility of the proposed method. By quantitatively integrating human variability, the pathway POD can be used to derive a risk-specific reference dose. Rather than using a specific health effect to derive a POD in the current dose-response assessment framework, the new approach not only considers the mechanism of tumor formation but also probabilistically quantifies the dose level that may induce a defined critical key event. Linear and nonlinear methods of low-dose extrapolation can be unified before inducing to a human reference dose. The new framework of dose-response assessment will provide for more meaningful, scientifically based cancer risk assessment.

Indexing (document details)
Advisor: Klaunig, James E.
Commitee: Shao, Kan, Xun, Pengcheng, Armijos, Rodrigo X.
School: Indiana University
Department: Health and Rehabilitation Sciences
School Location: United States -- Indiana
Source: DAI-B 82/7(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Environmental Health, Toxicology
Keywords: Chemical risk assessment, Dose-response assessment, Cancer risk assessment
Publication Number: 28258344
ISBN: 9798557051927
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