title: Toxicokinetic and toxicodynamic considerations when deriving health-based exposure limits for pharmaceuticals.
abstract: The purpose of this paper is to describe the use of toxicokinetic (TK) and toxicodynamic (TD) data in setting acceptable daily exposure (ADE) values and occupational exposure limits (OELs). Use of TK data can provide a more robust exposure limit based on a rigorous evaluation of systemic internal dose. Bioavailability data assist in extrapolating across different routes of exposure to be protective for route-based differences of exposure. Bioaccumulation data enable extrapolation to chronic exposures when the point of departure (PoD) is from a short-term critical study. Applied in the context of chemical-specific adjustment factors (CSAFs), TK data partially replace traditional default adjustment factors for interspecies extrapolation (extrapolation from studies conducted in animals to humans) and intraspecies variability (to account for human population variability). Default adjustments of 10-fold each for interspecies and intraspecies extrapolation are recommended in several guidelines, although some organization recommend other values. Such default factors may overestimate variability for many APIs, while not being sufficiently protective for variability with other APIs. For this reason, the use of chemical specific TK and TD data are preferred. Making full use of existing TK and TD data reduces underlying uncertainties, increases transparency, and ensures that resulting ADEs reflect the best available science.
authors.affiliation: Toxicology Excellence for Risk Assessment (TERA) at the University of Cincinnati, USA. Electronic address: reichajf@ucmail.uc.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Reichard
authors.affiliation: Toxicology Excellence for Risk Assessment (TERA) at the University of Cincinnati, USA.
authors.forename: M Andrew
authors.initials: MA
authors.lastname: Maier
authors.affiliation: Merck & Co., Inc., USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Naumann
authors.affiliation: Toxicology Excellence for Risk Assessment (TERA) at the University of Cincinnati, USA.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Pecquet
authors.affiliation: F. Hoffmann-La Roche Ltd, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pfister
authors.affiliation: SafeDose Ltd, USA.
authors.forename: Reena
authors.initials: R
authors.lastname: Sandhu
authors.affiliation: Rutgers University, USA.
authors.forename: Edward V
authors.initials: EV
authors.lastname: Sargent
authors.affiliation: Johnson & Johnson, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Streeter
authors.affiliation: Genentech, Inc., USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Weideman
mesh_terms: D000818:Animals; D019540:Area Under Curve; D004345:Drug Industry / Q000331:legislation & jurisprudence / Q000592:standards; D017408:Guidelines as Topic; D006207:Half-Life; D006291:Health Policy; D006801:Humans; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D019055:No-Observed-Adverse-Effect Level; D016273:Occupational Exposure / Q000009:adverse effects / Q000331:legislation & jurisprudence / Q000517:prevention & control* / Q000592:standards; D016272:Occupational Health / Q000331:legislation & jurisprudence / Q000592:standards; D004364:Pharmaceutical Preparations / Q000145:classification / Q000592:standards; D011050:Policy Making; D018570:Risk Assessment; D013045:Species Specificity; D018675:Toxicity Tests; D066007:Toxicokinetics
chemical_list: D004364:Pharmaceutical Preparations
keywords: Area under the curve (AUC); Bioaccumulation; Bioavailability; C(max); Chemical specific adjustment factor (CSAF); Human health risk assessment; Pharmacodynamic; Pharmacokinetic; Toxicodynamic; Toxicokinetic