Mode of Action Approach Supports a Lack of Carcinogenic Potential of Six Organic UV Filters

Authors: Cohen SM, Boobis AR, Jacobson-Kram D, Schoeny R, Rosol TJ, Williams GM, Kaminski NE, Eichenbaum G, Guengerich FP, Nash JF
Publication: Crit Rev Toxicol
Keywords: chemicals, gastroplus, Kp, nam, new approach methodology, partition coefficient, PBPK modeling, physiologically based pharmacokinetics, sunscreen, volume of distribution
Software: GastroPlus®
Division: PBPK

Abstract

Ultraviolet (UV) filters, the active ingredients in sunscreens, have been used for several decades to reduce the risk of acute and chronic damage to the skin from solar UV radiation, which can lead to skin cancer. Based on recent clinical studies showing that certain UV filters are absorbed systemically at low levels in humans, the US Food and Drug Administration (FDA) has requested supplementing existing safety data with preclinical studies including oral and dermal 2-year rodent carcinogenicity studies. Although the conduct of 2-year rodent carcinogenicity studies has been the standard approach for evaluating the carcinogenic potential of chemicals and new drugs for approximately 6 decades, there are multiple examples showing that such studies are not predictive of human cancer risk. Given these concerns with 2-year rodent carcinogenicity studies, we have developed and applied an alternative approach for supplementing existing data related to carcinogenic potential for six of the most commonly used UV filters in sunscreen products (i.e. avobenzone, ensulizole, homosalate, octinoxate, octisalate, and octocrylene). This approach evaluates their mode of action (MOA) based on in vivo, in vitro, and in silico data combined with an assessment of exposure margins. This approach is based on the substantial progress in understanding the MOAs that are responsible for tumor induction in humans. It is consistent with those being developed by the International Council for Harmonization (ICH) and other health authorities to replace 2-year carcinogenicity studies given their limitations and questionable biological relevance to humans. The available data for the six UV filters show that they are not genotoxic and show no evidence of biologically relevant carcinogenic MOAs. Furthermore, their systemic exposure levels in humans fall well below concentrations at which they have biologic activity. In conclusion, these data support the continued safe use of these six filters in sunscreen products

By Samuel M. Cohen, Alan R. Boobis, David Jacobson-Kram, Rita Schoeny, Thomas J. Rosol, Gary M. Williams, Norbert E. Kaminski, Gary M. Eichenbaum, F. Peter Guengerich & J. F. Nash