Setting Occupational Exposure Limits for Genotoxic Substances in the Pharmaceutical Industry

Abstract

In the pharmaceutical industry, genotoxic drug substances are developed for life-threatening indications such as cancer. Healthy employees handle these substances during research, development, and manufacturing; therefore, safe handling of genotoxic substances is essential. When an adequate preclinical dataset is available, a risk-based decision related to exposure controls for manufacturing is made following a determination of safe health-based limits, such as an occupational exposure limit (OEL). OELs are calculated for substances based on a threshold dose-response once a threshold is identified. In this review, we present examples of genotoxic mechanisms where thresholds can be demonstrated and OELs can be calculated, including a holistic toxicity assessment. We also propose a novel approach for inhalation Threshold of Toxicological Concern (TTC) limit for genotoxic substances in cases where the database is not adequate to determine a threshold.

Keywords: TTC; acceptable risk; genotoxicity; occupational exposure limit; threshold.

FIG. 1

The derivation of occupational exposure limit is based on the equation published by 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. CAF = Composite Adjustment Factor.