USE OF TOXICOKINETIC AND TOXICODYNAMIC DATA TO REDUCE UNCERTAINTIES WHEN SETTING OCCUPATIONAL EXPOSURE LIMITS FOR PHARMACEUTICALS

Occupational exposure limits for pharmaceutical active ingredients sho uld be based on all of the available preclinical and clinical data gen erated during drug development, including toxicokinetic (TK) and toxic odynamic (TD) data. The framework for limit setting proposed by the In ternational Programme on Chemical Safety (IPCS) subdivides traditional 10-fold uncertainty factors (UFs) into separate partial-log default v alues based upon TK and TD considerations and allows for incorporation of compound-specific data when available. We propose an extension of this method by providing more detailed guidance on the development and use of TK and TD data to maximize the use of scientific information i n the limit setting process. Specific recommendations are made on how TK and TD parameters may be used to support replacement of default UFs with data-derived values. Proper application of TK and TD data reduce s the uncertainties when establishing limits for specific compounds an d provides better assurance that established limits are providing adeq uate protection. It also provides the scientific support for more cost -effective exposure control strategies. In time, experience with consi stent application of TK and TD data may eventually support refinements in default UFs.