Scientific basis for uncertainty factors used to establish occupational exposure limits for pharmaceutical active ingredients

Abstract

The traditional “safety factor”; method has been used for years to establish occupational exposure limits (OELs) for active ingredients used in drugs. In the past, a single safety factor was used to address all sources of uncertainty in the limit setting process. The traditional 100‐fold safety factor commonly used to derive an acceptable daily intake value incorporates a default factor of 10 each to account for interindividual variability and interspecies extrapolation. Use of these defaults can lead to overly conservative health‐based limits, especially when they are combined with other (up to 10‐fold) factors to adjust for inadequacies in the available database. In recent years, attempts have been made to quantitate individual sources of uncertainty and variability to improve the scientific basis for OELs. In this paper we discuss the science supporting reductions in the traditional default uncertainty factors. A number of workplace‐specific factors also support reductions in these factors. Recently proposed alternative methodologies provide a framework to make maximum use of preclinical and clinical information, e.g., toxicokinetic and toxicodynamic data, to reduce uncertainties when establishing OELs for pharmaceutical active ingredients.

Key Words:

• drugs
• workplace
• margin of safety
• ADI
• bioavailability

Notes

To whom reprints requests should be addressed; Merck 8c Co., Inc., One Merck Drive, WS2F‐45, Whitehouse Station, NJ 08889–0100