title: Rofecoxib-Induced Deleterious Effects Escape Detection by Organismal Performance Assays.
abstract: BACKGROUND
  Organismal Performance Assays (OPAs) are a unique toxicity quantification method used to assess the safety of potentially toxic compounds, such as pharmaceuticals. OPAs utilize genetically diverse wild mice (Mus musculus) housed in semi-natural enclosures wherein exposed individuals compete directly with controls for resources. Previously, OPAs have been successful in detecting adverse effects in mice that were exposed to paroxetine. Here, we further test OPAs utility in pharmaceutical safety assessment by testing OPAs with rofecoxib, a drug with known adverse effects in humans.
  
  
  METHODS
  We exposed mice to rofecoxib (~37.5 mg/kg/day) during gestation and into early adulthood. Exposure ceased when individuals were released into enclosures. Five independent populations were established and rofecoxib-exposed individuals (n= 58) competed directly with control individuals (n= 58) over 28 weeks. Organismal performance was determined by quantifying reproduction, survival and male competitive ability.
  
  
  RESULTS
  In enclosures, rofecoxib-exposed males had equal reproduction, survival and competitive ability. Rofecoxib-exposed females had equal survival compared to controls but experienced 40% higher reproductive output.
  
  
  CONCLUSIONS
  The adverse health effects of rofecoxib seen in humans escaped detection by OPAs, just as they had during traditional preclinical assays. These results may be explained by the exposure design (in enclosures, all animals were on the control diet), the relatively short duration of exposure, species differences, or because the health benefits of the drug negated the side effects. Similarly to numerous assays used in preclinical trials, OPAs cannot reveal all maladies, despite their demonstrated sensitivity in detecting cryptic toxicity from numerous exposures.
authors.affiliation: Department of Biology, University of Utah, 257 S. 1400 E., Room 201, Salt Lake City, Utah 84112.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Gaukler
authors.affiliation: Department of Biology, University of Utah, 257 S. 1400 E., Room 201, Salt Lake City, Utah 84112.
authors.forename: James S
authors.initials: JS
authors.lastname: Ruff
authors.affiliation: Department of Biology, University of Utah, 257 S. 1400 E., Room 201, Salt Lake City, Utah 84112.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Morrison
authors.affiliation: Department of Biology, University of Utah, 257 S. 1400 E., Room 201, Salt Lake City, Utah 84112.
authors.forename: Wayne
authors.initials: W
authors.lastname: Potts
keywords: coxib; intra-specific competition; pharmacodynamics; reproductive success; semi-natural enclosures; toxicity assessment