title: Assessing variation in the potential susceptibility of fish to pharmaceuticals, considering evolutionary differences in their physiology and ecology.
abstract: Fish represent the planet's most diverse group of vertebrates and they can be exposed to a wide range of pharmaceuticals. For practical reasons, extrapolation of pharmaceutical effects from 'model' species to other fish species is adopted in risk assessment. Here, we critically assess this approach. First, we show that between 65% and 86% of human drug targets are evolutionarily conserved in 12 diverse fish species. Focusing on nuclear steroid hormone receptors, we further show that the sequence of the ligand binding domain that plays a key role in drug potency is highly conserved, but there is variation between species. This variation for the oestrogen receptor, however, does not obviously account for observed differences in receptor activation. Taking the synthetic oestrogen ethinyloestradiol as a test case, and using life-table-response experiments, we demonstrate significant reductions in population growth in fathead minnow and medaka, but not zebrafish, for environmentally relevant exposures. This finding contrasts with zebrafish being ranked as more ecologically susceptible, according to two independent life-history analyses. We conclude that while most drug targets are conserved in fish, evolutionary divergence in drug-target activation, physiology, behaviour and ecological life history make it difficult to predict population-level effects. This justifies the conventional use of at least a 10× assessment factor in pharmaceutical risk assessment, to account for differences in species susceptibility.
authors.affiliation: Brixham Environmental Laboratory, AstraZeneca Safety, Health & Environment, Freshwater Quarry, Brixham, UK Biosciences, College of Life and Environmental Sciences, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter, Devon, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Brown
authors.affiliation: Infectious Disease, Institute of Biomedicine, University of Gothenburg, Guldhedsgatan 10, 41346 Gothenburg, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Gunnarsson
authors.affiliation: Department of Mathematical Sciences, Chalmers University of Technology/University of Gothenburg, Chalmers Tvärgata 3, 41296 Gothenburg, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Kristiansson
authors.affiliation: Biosciences, College of Life and Environmental Sciences, University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter, Devon, UK c.r.tyler@exeter.ac.uk.
authors.forename: C R
authors.initials: CR
authors.lastname: Tyler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D017753:Ecosystem; D005399:Fishes / Q000235:genetics* / Q000502:physiology*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D010802:Phylogeny; D016415:Sequence Alignment; D013045:Species Specificity; D014874:Water Pollutants, Chemical / Q000737:chemistry / Q000633:toxicity*
chemical_list: D004364:Pharmaceutical Preparations; D014874:Water Pollutants, Chemical
keywords: drug target; orthologue; physiology; population ecology; species; susceptibility