title: Derivation of occupational exposure limits based on target blood concentrations in humans.
abstract: An approach for deriving occupational exposure limits (OEL) for pharmaceutical compounds is the application of safety factors to the most appropriate pre-clinical toxicity endpoint or the lowest therapeutic dose (LTD) in humans. Use of this methodology can be limited when there are inadequate pre-clinical toxicity data or lack of a well-defined therapeutic dose, and does not include pharmacokinetic considerations. Although some methods have been developed that incorporate pharmacokinetics, these methods do not take into consideration variability in response. The purpose of this study was to investigate how application of compartmental pharmacokinetic modeling could be used to assist in the derivation of OELs based on target blood concentrations in humans. Quinidine was used as the sample compound for the development of this methodology though the intent was not to set an OEL for quinidine but rather to develop an alternative approach for the determination of OELs. The parameters for the model include body weight, breathing rate, and chemical-specific pharmacokinetic constants in humans, data typically available for pharmaceutical agents prior to large scale manufacturing. The model is used to simulate exposure concentrations that would result in levels below those that may result in any undesirable pharmacological effect, taking into account the variability in parameters through incorporation of Monte Carlo sampling. Application of this methodology may decrease some uncertainty that is inherent in default approaches by eliminating the use of safety factors and extrapolation from animals to humans. This methodology provides a biologically based approach by taking into consideration the pharmacokinetics in humans and reported therapeutic or toxic blood concentrations to guide in the selection of the internal dose-metric.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Lafayette, NJ, USA. gina.pastino@spcorp.com
authors.forename: G M
authors.initials: GM
authors.lastname: Pastino
authors.forename: A A
authors.initials: AA
authors.lastname: Kousba
authors.forename: L G
authors.initials: LG
authors.lastname: Sultatos
authors.forename: E J
authors.initials: EJ
authors.lastname: Flynn
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D006801:Humans; D019570:Inhalation Exposure; D016014:Linear Models; D008954:Models, Biological; D009010:Monte Carlo Method; D016273:Occupational Exposure / Q000009:adverse effects*; D010599:Pharmacokinetics; D011802:Quinidine / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D013045:Species Specificity; D013997:Time Factors
chemical_list: D000889:Anti-Arrhythmia Agents; D011802:Quinidine