A semiquantitative method for selection of safety factors in establishing OELs for pharmaceutical compounds

Abstract

For the purposes of establishing Occupational Exposure Limits (OELs), a conservative methodology similar to those widely used within the pharmaceutical industry for establishing such airborne limits has been developed. This methodology includes selection of the most sensitive, relevant toxicological endpoint(s), scaling for morphologic and physiologic considerations and pharmacokinetic/ pharmacodynamic parameters, and incorporation of an appropriate safety factor. This safety factor is selected to address the uncertainty and variability in extrapolating experimental data obtained in animal experimentation or clinical trials to a "healthy" worker population. Key to this OEL-setting methodology is a set of semiquantitative rules for selection of log-normally distributed safety "sub-factors." This rule set was designed to reward a robust dataset while accounting for the prevalence of response in the pivotal study or studies, species differences, study length, dose response considerations, and the significance of the pivotal effect driving the OEL. The overall, composite safety factor may then be generated as the mathematical product of these discrete, equally-weighted subfactors, and is used in calculating the final OEL.

Regulatory Cancer Risk Assessment Based on a Quick Estimate of a Benchmark Dose Derived from the Maximum Tolerated Dose

“…e Additional uncertainty factor of 10 would be considered to account for possible extra sensitivity of children per the Food Quality Protection Act of 1996 or because of the severity of cancer even from low doses (Renwick, 1995;Schwartz, 1995).…”

Setting Occupational Exposure Limits for Genotoxic Substances in the Pharmaceutical Industry

“…Subsequently, the PODs, based on critical effects, are selected and OELs calculated, provided that the data allow derivation of a threshold POD on the basis of quantitative and mechanistic information. Here we demonstrate the derivation of OELs from Galer et al (1992), Naumann and Weideman (1995), Sargent and Kirk (1988), and Schwartz (1995). Body weight (BW) of a healthy worker is set at 70 kg and volume of air (V) that a healthy worker breathes in a normal working day is 10m3.…”

Kinetic and dynamic data of analgesics and NSAIDs drugs reduce 10X uncertainty factors

“…The establishment of safe exposure levels has become a comer stone in the practice of occupational toxicology (Schwartz, 1995). Lehman and Fitzhugh of US Food Kadry et al and Drug Administration (FDA) proposed the 100-fold margin of safety for the quantitative assessment of chemical additives in 1954.…”