Considerations For Establishing Health-Based Exposure Limits (HBELs) For Small Molecule Protein Kinase Inhibitors (P211)

Protein kinases are involved in various cell cycle functions such as cell growth, differentiation, and development. Consequently, dysregulation of these kinases is frequent in many diseases and small molecule kinase inhibitors (SMKIs) are a growing class of therapeutics. Research and development activities for SMKIs require speculative health-based exposure limits (HBELs) (including occupational exposure limits [OELs]) and an understanding of the health hazards presented by this class of molecules; information which is supplied by occupational toxicologists. Since molecules in early research often lack data, it is imperative to understand the common hazards presented by SMKIs to properly assess the potential risk of new molecules. This work presents a consolidated overview of the health hazard data (nonclinical and clinical) for FDA approved (n=80) SMKIs, their common health hazards from an occupational standpoint, and guidance for establishing OELs for this chemical class. The majority of SMKIs are compounds with oncology indications (88%; 70/80) and administered orally (96%; 77/80). In line with their indirect anticancer activity, most approved SMKIs are not mutagenic (98%; 78/80). However, 13% (10/79) were positive in an in vivo micronucleus or chromosome aberration assay and 99% (79/80) caused developmental toxicity in animal studies. Overall, this information assists in understanding the potential human health hazards associated with SMKIs that can be leveraged when establishing speculative HBELs for SMKIs lacking compound-specific data.