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.

Preliminary toxicological assessment of heated tobacco products: A review of the literature and proposed strategy

“…Alternatively, a threshold of toxicological concern approach adapted to inhalation exposure may be applied. In reviewing the available related publications [11] , [18] , [40] , [9] , it appears acceptable to consider the following thresholds, i.e ., 1800 µg/day for Cramer Class I compounds, 90 µg/day for Cramer Class II and III compounds, 18 µg/day for organophosphates, and 0.15 µg/day for substances presenting structural alerts for genotoxicity. The outcome of this risk assessment is a decision on the acceptability of the substance, along with the maximum use level at which the substance is deemed acceptable.…”

Use of the benchmark‐dose (BMD) approach to derive occupational exposure limits (OELs) for genotoxic carcinogens: N‐nitrosamines

“…Nevertheless, using 1.5 μg/day for a lifetime exposure and correcting it by WLT exposure duration (approx. 12.5% of lifetime, Equation 1) and a volume of 10 m 3 of air inhaled in an 8‐hour period equate to an TTC OEL of 1.2 μg/m 3 (1.5 μg/day: 0.125*10m 3 = 1.2 μg/m 3 ) (Lovsin Barle et al, 2016; SWA, 2018). The oral equivalent of this TTC OEL inhalation dose is 12 μg/day (assuming 100% BA) (Equation 6).…”

“…Here, an estimated cancer risk of 1 in 100,000 will be used for the linear extrapolation method. However, there is sufficient data to follow "a biologically plausible (practical) threshold" for nitrosamines in accordance with relevant guidelines and recommendations for threshold genotoxic carcinogens in setting OEL limits (COC, 2020;ECHA, 2017;ECHA, 2019;Lovsin Barle et al, 2016).…”

Approaches for setting occupational exposure limits in the pharmaceutical industry

“…Lovsin Barle and coworkers proposed an exposure limit of 2 μg/m 3 (TTC limit), which can be assumed as generically sufficiently protective for all substances with unknown toxicological properties, including genotoxic effects (Lovsin Barle et al, 2016). The value was derived from a permissible daily exposure level of 1.5 μg/day for mutagenic impurities (EMA, 2014).…”