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

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.

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.

Estimated OELs ranged from 0.05 to 96 µg/m³, with 82% falling between 1 and <100 µg/³, spanning OEB 2 and OEB 3A. Developmental toxicity was regarded a class effect, while genotoxicity and carcinogenicity were less frequent and varied by target family.

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/m³ (3A) is likely protective for most SMKIs. These findings provide a quantitative, mechanism-informed framework to guide occupational risk management for SMKIs.