Setting occupational exposure limits (OELs) for genotoxic substances in pharmaceutical industry

Pharmaceutical drug substances (DS) and intermediates (IM) with positive results in genotoxicity tests, indicatethat they induce directly or indirectly damage to the genetic material. The basic assumption for the shape of the dose-response relationship of genotoxic substances is that it is linear, meaning that there is no health based lower limit below which there is no risk, so that an occupational exposure limit (OEL) cannot be readily calculated. However, it has been accepted recently that threshold-like mechanisms may apply under certain conditions, indicating that in such cases an OEL can be calculated, instead of applying a limit associated with an acceptable excess cancer risk. We have investigated the possibility to determine the conditions that need to be encountered in order to define the threshold and therefore calculate an OEL. In addition we investigated the inhalatory toxicological threshold concentration (iTTC) which would provide acceptable level of protection for those substances for which the threshold cannot be determined such as mutagenic IM, in line with hypotheses applied in other areas of cancer risk assessment. The availability of thresholds for the substances must be determined on a case-by-case basis including detailed evaluation of the mode of action (MOA) based on convincing experimental evidence for possible threshold-like mechanisms. Several examples for threshold and non-threshold mechanism are presented and calculations of OEL for those substances, as well as an argument for iTTC of 1.6 ug/m3 sufficiently protective against the unacceptable risks.