title: Use of acute and chronic ecotoxicity data in environmental risk assessment of pharmaceuticals.
abstract: For many older pharmaceuticals, chronic aquatic toxicity data are limited. To assess risk during development, scale-up, and manufacturing processes, acute data and physicochemical properties need to be leveraged to reduce potential long-term impacts to the environment. Aquatic toxicity data were pooled from daphnid, fish, and algae studies for 102 active pharmaceutical ingredients (APIs) to evaluate the relationship between predicted no-effect concentrations (PNECs) derived from acute and chronic tests. The relationships between acute and chronic aquatic toxicity and the n-octanol/water distribution coefficient (D(OW)) were also characterized. Statistically significant but weak correlations were observed between toxicity and log D(OW), indicating that D(OW) is not the only contributor to toxicity. Both acute and chronic PNEC values could be calculated for 60 of the 102 APIs. For most compounds, PNECs derived from acute data were lower than PNECs derived from chronic data, with the exception of steroid estrogens. Seven percent of the PNECs derived from acute data were below the European Union action limit of 0.01 μg/L and all were anti-infectives affecting algal species. Eight percent of available PNECs derived from chronic data were below the European Union action limit, and fish were the most sensitive species for all but 1 API. These analyses suggest that the use of acute data may be acceptable if chronic data are unavailable, unless specific mode of action concerns suggest otherwise.
authors.affiliation: Merck, Kenilworth, New Jersey, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Vestel
authors.affiliation: Johnson & Johnson, New Brunswick, New Jersey, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Caldwell
authors.affiliation: Pfizer Global Research and Development, Pfizer, Groton, Connecticut, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Constantine
authors.affiliation: Quantum Management Group, Clifton, New Jersey, USA.
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: D'Aco
authors.affiliation: Bristol-Myers Squibb, New Brunswick, New Jersey, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Davidson
authors.affiliation: Amgen, Thousand Oaks, California, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Dolan
authors.affiliation: Probability, Statistics & Information, Seattle, Washington, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Millard
authors.affiliation: AstraZeneca, Brixham, Devon, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Murray-Smith
authors.affiliation: Eli Lilly, Indianapolis, Indiana, USA.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Parke
authors.affiliation: GlaxoSmithKline, Hertfordshire, United Kingdom.
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Ryan
authors.affiliation: F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Jürg Oliver
authors.initials: JO
authors.lastname: Straub
authors.affiliation: Sanofi, Bridgewater, New Jersey, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Wilson
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D000818:Animals; D000460:Chlorophyta / Q000187:drug effects; D000458:Cyanobacteria / Q000187:drug effects; D003621:Daphnia / Q000187:drug effects; D064420:Drug-Related Side Effects and Adverse Reactions; D005399:Fishes; D018570:Risk Assessment; D023382:Toxicity Tests, Acute; D036401:Toxicity Tests, Chronic; D014867:Water / Q000737:chemistry; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D014874:Water Pollutants, Chemical; D014867:Water; D020003:1-Octanol
keywords: Acute-to-chronic ratio; Aquatic toxicity; Environmental risk assessment; Pharmaceuticals; Predicted no-effect concentration (PNEC)