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Scientific and Regulatory Policy Committee (SRPC) Review: Interpretation and Use of Cell Proliferation Data in Cancer Risk Assessment
Citation:
Wood, C., R. Hukkanen, R. Sura, D. Jacobson-Kram, T. Nolte, M. Odin, AND S. Cohen. Scientific and Regulatory Policy Committee (SRPC) Review: Interpretation and Use of Cell Proliferation Data in Cancer Risk Assessment. TOXICOLOGIC PATHOLOGY. Society of Toxicology, RESTON, VA, , 760-775, (2015).
Impact/Purpose:
An integrated AOP/MOA framework is being developed at EPA and elsewhere as a foundation for modeling efforts and risk assessment practices. The AOP/MOA framework is based upon development of quantitative biomarkers that can link early key events to a particular health outcome. Cell proliferation serves as a functional short-term marker in many cancer AOPs/MOAs, but greater standardization of proliferation methods and data is needed for wider application in prospective models. In this article we provide guidance for generating, using, and interpreting cell proliferation data. We also present ideas about how proliferation data may have an increasingly important role in negative predictive and prioritization models of cancer. Broadly, this information should be useful to scientists in industry, regulatory , and academic settings who generate or use cell proliferation data in cancer research and assessment. Within EPA, this information should be helpful to toxicologists in the Office of Chemical Safety and Pollution Prevention (specifically the Health Effects Division) and Office of Research and Development/National Center for Environmental Assessment involved in AOP/MOA evaluation.
Description:
Increased cell proliferation is a defining feature of carcinogenesis and a central key event in the mode of action for many non-genotoxic carcinogens. Quantitative cell proliferation data thus play an important role in the safety assessment of many pharmaceutical and environmental compounds. Currently there is limited unified information on assay standards, reference values, targeted applications, study design issues, and quality control considerations for proliferation data. Here we review issues in measuring cell proliferation indices, considerations for targeted studies, and applications within current risk assessment paradigms. As the regulatory environment moves towards more prospective evaluations based on quantitative pathway-based models, standardization of proliferation assays will become an increasingly important part of cancer risk assessment. To help address this development, we also discuss the potential role for proliferation data as a component of alternative carcinogenicity testing models. This information should improve consistency of cell proliferation methods and increase efficiency of targeted testing strategies.
