Considerations for establishing occupational exposure limits for small molecule kinase inhibitors in drug development.

Introduction: Protein kinases regulate various cell cycle functions, and small molecule kinase inhibitors (SMKIs) represent a growing class of therapeutics. In the pharmaceutical industry, occupational toxicologists enable research and development (R&D) and manufacturing activities for SMKIs by deriving health-based exposure limits (HBELs), including occupational exposure limits (OELs) and occupational exposure bands (OEBs), often in data-limited R&D settings. Methods: The objective of this study was to evaluate health hazard data for FDA-approved SMKIs and apply a quantitative framework to estimate OELs and map them to OEBs to guide occupational health and safety practices. We compiled health hazard data for SMKIs (n = 86) from literature sources and drug labels including data on genotoxicity, carcinogenicity, developmental and reproductive toxicity (DART), minimum daily therapeutic dose, and sensitive subpopulations. For orally administered SMKIs (n = 83), we estimated OELs using a standardized dose-based approach that incorporates adjustment factors and bioavailability. Estimated OELs were then mapped to OEBs and evaluated by target family. Results: Estimated OELs ranged from 0.05 to 96 µg/m Discussion: Several target families, including JAK, FGFR, MEK, mTOR, PI3K, and VEGFR inhibitors, exhibited lower estimated OELs and may warrant more protective OEBs in data-limited R&D settings. This analysis demonstrates that a default OEB of 1 to <10 µg/m