Use of toxicokinetic and toxicodynamic data to reduce uncertainties when setting occupational exposure limits for pharmaceuticals

Abstract

Occupational exposure limits for pharmaceutical active ingredients should be based on all of the available preclinical and clinical data generated during drug development, including toxicokinetic (TK) and toxicodynamic (TD) data. The framework for limit setting proposed by the International Programme on Chemical Safety (IPCS) subdivides traditional 10‐fold uncertainty factors (UFs) into separate partial‐log default values 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 in 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 reduces the uncertainties when establishing limits for specific compounds and provides better assurance that established limits are providing adequate protection. It also provides the scientific support for more cost‐effective exposure control strategies. In time, experience with consistent application of TK and TD data may eventually support refinements in default UFs.

Key words:

• pharmacokinetic
• pharmacodynamic
• uncertainty factors
• acceptable daily intake

Notes

Merck & Co., Inc., One Merck Drive WS2F‐45, Whitehouse Station, NJ. 08889–0100, Tel: [phone], Fax: [phone], E‐Mail: [email protected]

DuPont‐Merck, Stine‐Haskell Research Center, PO Box 30 ‐ Building 320, Newark, DE 19714–0030

Bristol‐Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543–4000