title: 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.
authors.affiliation: *Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland ester.lovsin_barle@novartis.com.
authors.forename: Ester
authors.initials: E
authors.lastname: Lovsin Barle
authors.affiliation: Novartis Pharma AG NIBR, Postfach, CH-4002 Basel, Switzerland; and.
authors.forename: Gian Christian
authors.initials: GC
authors.lastname: Winkler
authors.affiliation: Novartis Pharma AG NIBR, Postfach, CH-4002 Basel, Switzerland; and.
authors.forename: Susanne
authors.initials: S
authors.lastname: Glowienke
authors.affiliation: Novartis Pharma AG NIBR, Postfach, CH-4002 Basel, Switzerland; and.
authors.forename: Azeddine
authors.initials: A
authors.lastname: Elhajouji
authors.affiliation: Lek Pharmaceuticals D.D, Verovškova 57, 1526 Ljubljana, Slovenia.
authors.forename: Jana
authors.initials: J
authors.lastname: Nunic
authors.affiliation: Novartis Pharma AG NIBR, Postfach, CH-4002 Basel, Switzerland; and.
authors.forename: Hans-Joerg
authors.initials: HJ
authors.lastname: Martus
mesh_terms: D000818:Animals; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004345:Drug Industry / Q000592:standards*; D006801:Humans; D019570:Inhalation Exposure / Q000009:adverse effects / Q000592:standards; D008954:Models, Biological; D009153:Mutagens / Q000009:adverse effects*; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control; D009784:Occupational Diseases / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D016273:Occupational Exposure / Q000009:adverse effects* / Q000592:standards*; D016272:Occupational Health / Q000592:standards*; D018570:Risk Assessment
chemical_list: D009153:Mutagens
keywords: TTC; acceptable risk; genotoxicity; occupational exposure limit; threshold