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Is skin penetration a determining factor in skin sensitization potential and potency? Refuting the notion of a LogKow threshold for Skin Sensitization
Citation:
Fitzpatrick, J., D. Roberts, AND G. Patlewicz. Is skin penetration a determining factor in skin sensitization potential and potency? Refuting the notion of a LogKow threshold for Skin Sensitization. JOURNAL OF APPLIED TOXICOLOGY. John Wiley & Sons, Ltd., Indianapolis, IN, 37(1):117-127, (2017).
Impact/Purpose:
• Agency Problem: When evaluating potential chemical hazard, the Agency must consider the potential for allergic responses upon skin contact. Skin sensitization is the leading cause of occupational illness in many countries. Skin sensitization data largely comes from animal testing, which is expensive and time-consuming. With over 80,000 chemicals in commerce, the Agency needs faster and more efficient was to screen chemical for skin sensitization. EPA needs predictive, non-animal models to increase efficiency and throughput to ensure chemical safety and protect public health. • Approach: Quantitative structure-activity relationship (QSAR) models are one approach to characterize the potential for skin sensitization. QSAR models identify key chemical structure characteristics in known sensitizers chemicals and use those structural alerts to virtually screen large chemical libraries. QSAR models are based upon assumptions in chemical properties. For skin sensitization, a commonly held assumptions are that skin sensitizers must be hydrophobic (i.e., able to cross the cell membrane, with a logKow >1). However, this dogmas is unsupported by experimental evidence. Determining the veracity of these assumptions is critical for developing predictive and relevant QSAR models of skin sensitization. • Results: ORD scientists evaluated logKow threshold for skin sensitization. The available data refuted the assumption of a logKow >1 threshold. ORD scientist identified 100 skin sensitizing compounds with logKow <1, and no difference in incidence of skin sensitizers above or below logKow =1. • Impact to the Agency: The work directly impacts the Agency’s efforts to identify skin sensitizing compounds. By refuting common misconceptions, this work enables more accurate screening of chemicals, as well as the development of improved QSAR models.
Description:
Summary:Background. It is widely accepted that substances that cannot penetrate through the skin will not be sensitisers. Thresholds based on relevant physicochemical parameters such as a LogKow > 1 and a MW < 500, are assumed and widely accepted as self-evident truths. Objectives. To investigate whether LogKow >1 is a true requirement for sensitisation.Methods. A large dataset of substances that had been evaluated for their skin sensitisation potential, together with measured LogKow values was compiled from the REACH database. The incidence of skin sensitisers relative to non-skin sensitisers below and above the LogKow = 1 threshold was evaluated. Results. 1482 substances with associated skin sensitisation outcomes and measured LogKow values were identified. 305 substances had a measured LogKow < 0 and of those, 38 were sensitisers.Conclusions. There was no significant difference in the incidence of skin sensitisation above and below the LogKow = 1 threshold. Reaction chemistry considerations could explain the skin sensitisation observed for the 38 sensitisers with a LogKow < 0. The LogKow threshold is a self-evident truth borne out from the widespread misconception that the ability to efficiently penetrate the stratum corneum is a key determinant of skin sensitisation potential and potency.
URLs/Downloads:
http://onlinelibrary.wiley.com/doi/10.1002/jat.3354/abstract;jsessionid=0DE8F33CA90118EB9391C8AA460AF8D9.f01t03