What determines skin sensitization potency: Myths, maybes and realities. The 500 molecular weight cut-off: An updated analysis
Citation:
Fitzpatrick, J., D. Roberts, AND G. Patlewicz. What determines skin sensitization potency: Myths, maybes and realities. The 500 molecular weight cut-off: An updated analysis. JOURNAL OF APPLIED TOXICOLOGY. John Wiley & Sons, Ltd., Indianapolis, IN, 37(1):105-116, (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 assumption is that skin sensitizers must have a <500 molecular weight. However, this dogmas was 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 the molecular weight thresholds for skin sensitization. Of 2904 substances that had been tested for skin sensitization, 33 skin sensitizers had a MW > 500. Reaction chemistry considerations explained sensitizers with a MW > 500, refuting the misconception of a molecular weight threshold. Reaction chemistry considerations explained the sensitizers with a MW > 500, refuting the misconception of a molecular weight threshold. • 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:
It is widely considered to be a self-evident truth that substances must have a molecular weight (MW) less than 500 to effectively penetrate through the skin in order to induce sensitisation. However, Roberts et al. 2010, evaluated a data set of 699 substances taken from the TIMES-SS expert system and identified that of the 13 substances with a MW above 500, 5 were reported as skin sensitisers. This provided good evidence to refute such a MW threshold. The present study set about compiling a larger and more diverse set of substances such as those evaluated for their skin sensitisation potential under the EU REACH regulation. A dataset of 2575 substances that had been tested for skin sensitisation, using guinea pigs and/or mice was collected. The dataset contained 197 substances with a MW>500: 33 of these were categorised as skin sensitisers. Each of the 33 substances were then evaluated in turn – metal containing complexes, reaction products and mixtures were excluded from further consideration. The final set of 14 sensitisers with a MW>500 were considered on the basis of their reaction chemistry to propose likely mechanistic explanations for their sensitisation behaviour. Penetration ability is correlated with MW (and LogKow): if the MW threshold is shown to be inapplicable for skin sensitisation potency, in turn it also indicates that penetration is not a relevant parameter for skin sensitisation.
