A framework for fit-for-purpose dose response assessment

Abstract

The NRC report Science and Decisions: Advancing Risk Assessment made several recommendations to improve chemical risk assessment, with a focus on in-depth chronic dose-response assessments conducted by the U.S. Environmental Protection Agency. The recommendations addressed two broad elements: improving technical analysis and utility for decision making. To advance the discussions in the NRC report, in three multi-stakeholder workshops organized by the Alliance for Risk Assessment, available and evolving risk assessment methodologies were considered through the development and application of case studies. A key product was a framework (http://www.allianceforrisk.org/Workshop/Framework/ProblemFormulation.html) to guide risk assessors and managers to various dose-response assessment methods relevant to a range of decision contexts ranging from priority setting to full assessment, as illustrated by case studies. It is designed to facilitate selection of appropriate methodology for a variety of problem formulations and includes a variety of methods with supporting case studies, for areas flagged specifically by the NRC committee for consideration--e.g., susceptible sub-populations, population variability and background. The framewok contributes to organization and communication about methodologies for incorporating increasingly biologically informed and chemical specific knowledge into dose-response analysis, which is considered critical in evolving fit-for-purpose assessment to address relevant problem formulations.

Evaluation of potential health effects associated with occupational and environmental exposure to styrene – an update

“…Recently, Cruzan et al 2018developed a comprehensive human relevance analysis of styrene mouse lung tumor using data integration standards promoted in multiple MOA analysis framework proposals (Meek et al 2013(Meek et al , 2014.…”

A problem formulation framework for the application of in silico toxicology methods in chemical risk assessment

“…Its importance within the field is increasingly emphasized and endorsed, not only by individual scientists (Parish et al 2020 ; Raybould 2006 ; Sauve-Ciencewicki et al 2019 ; Solomon et al 2016 ; Tepfer et al 2013 ; Wolt et al 2010 ) but also by regulatory agencies, research organizations and international bodies. Examples of these include the US EPA and the European Food Safety Authority (EFSA) (Devos et al 2019 ; US EPA 2016 ), the National Research Council of the National Academy of Sciences (NRC) (Meek et al 2013 ), and the Organization for Economic Cooperation and Development (OECD) (OECD 2019 ). Several recent studies applying in silico methods, or discussing the methods more generally, have also emphasized the need to include PF as the first step in the development and application of the methods for chemical risk assessment (Alexander-White et al 2022 ; Escher et al 2019 ; Ouedraogo et al 2022 ; Parish et al 2020 ; Raybould 2006 ; Reynolds et al 2021 ).…”

A mode of action-based probabilistic framework of dose-response assessment for nonmutagenic liver carcinogens: a case study of PCB-126

“…The dichotomized low-dose extrapolation methodology for cancer and noncancer effects ( US EPA, 2022 ) is straightforward but may be inadequate and sometimes confusing in the context of risk interpretation and decision-making. First, whether the “safe” level is sufficient to characterize overall toxicity of a chemical when only focusing on a single critical event (ie, without considering mode of action [MOA]) remains questionable ( Julien et al , 2009 ; Meek et al , 2013 ; National Research Council (NRC), 2009; Simon et al , 2014 ). Unlike a CSF, a typical RfD/RfC cannot quantitatively estimate the health risk given a certain exposure level to chemicals ( Chiu and Slob, 2015 ).…”