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Show 157 THE UNIVERSITY OF UTAH RESEARCH POSTERS ON THE HILL 2012 WE ARE ALL TOXICITY ASSESSMENT TEST SUBJECTS: REDUCING HEALTH RISKS WITH ORGANISMAL PERFOR MANCE ASSAYS OPAS Joseph Cauceglia, Ruth Tanner (Wayne Potts) Department of Biology University of Utah We are all toxicity assessment test subjects: reducing health risks with organismal performance assays (OPAs) Joseph Cauceglia, Ruth Tanner, Shannon Gaukler, James Ruff and Wayne Potts Department of Biology OPAs use seminatural populations to directly compete exposed and unexposed house mice. OPA end points: Territoriality, Survival, Reproduction, Fitness Criteria for an ideal toxicity assay: Be sensitive Be broad Provide measures of adversity Identify mechanisms Ruth Tanner Joseph Cauceglia Examples of substances whose toxicity were only discovered after Humans were exposed: Asbestos Bisphenol A (BPA) Lead 42% of pharmaceuticals fail during clinical testing after investing 100s of millions dollars. 10% fail after public release! The OPA is the only current assay capable of fulfilling the first three criteria. These three are the critical criteria required for avoiding public harm. OPA fitness comparisons of eight suspected causes of health adversity Fructose dietary levels required for detecting adversity using various assays 0 20 40 60 80 Insulin Resistance Obesity Fatty Liver Disease OPA % Fructose (Kcal) 0.0 0.2 0.4 0.6 0.8 1.0 Full Sibling Inbreeding 25% Gluc/Fruc T-compex Heterozygotes Cousin Inbreeding Hox A3D3 Hox A1B1 Hox B1A1 G7 PAMAM dendrimers Male Fitness Compared to Controls Wayne Potts PhD. Too often, after years of clinical use or environmental exposure, pharmaceuticals and other agents once considered safe are found to have adverse conse-quences. To prevent such experimentation on our-selves, there is a great need for broad, sensitive assays able to detect toxicity at exposure levels relevant to humans. We have developed an assay that shows both unparalleled sensitivity and breadth compared to conventional assays. This assay uses house mice in seminatural populations where experimental mice treated with a potential toxicant compete directly with control animals. This model achieves its sensitivity and breadth because high performance from most physiological systems is required for individual success, as determined by survival, social dominance, and reproduction. Consequently, any toxicity that reduces performance of any physiological system is likely to be detected by this assay and no a priori assumption about the target organ or mechanism of toxicity has to be made because the endpoint measures integrate across most physiological systems. We refer to this methodology as Organismal Performance Assays (OPAs). Here we evaluate the e cacy of OPAs using published and unpublished data and show that OPAs: 1) have proven 50 times more sensitive than previ-ous methods in detecting the adverse consequences of inbreeding, 2) have captured the lowest observed adverse e ect level of dietary fructose at doses considered safe and experienced by 20% of Americans, and 3) have revealed previously undetected adverse e ects of two pharmaceuticals that have been either recalled (Vioxx) or black labeled (Paxil). OPAs are unrivaled at determining if mouse health has declined due to an experimental exposure and could be used as a simple safety screen for toxicity from pharmaceu-ticals, chemicals and other potential toxicants. It is important to use sensitive and broad toxicity assess-ment methodologies to test potential toxicants; otherwise we use humans as the experimental subjects. |
