TITLE

The development of response surface pathway design to reduce animal numbers in toxicity studies

AUTHOR(S)
Dewi, Sagita; Aune, Tore; Aasen Bunæs, John A.; Smith, Adrian J.; Larsen, Stig
PUB. DATE
March 2014
SOURCE
BMC Pharmacology & Toxicology;2014, Vol. 15 Issue 1, p18
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: This study describes the development of Response Surface Pathway (RSP) design, assesses its performance and effectiveness in estimating LD50, and compares RSP with Up and Down Procedures (UDPs) and Random Walk (RW) design. Methods: A basic 4-level RSP design was used on 36 male ICR mice given intraperitoneal doses of Yessotoxin. Simulations were performed to optimise the design. A k-adjustment factor was introduced to ensure coverage of the dose window and calculate the dose steps. Instead of using equal numbers of mice on all levels, the number of mice was increased at each design level. Additionally, the binomial outcome variable was changed to multinomial. The performance of the RSP designs and a comparison of UDPs and RW were assessed by simulations. The optimised 4-level RSP design was used on 24 female NMRI mice given Azaspiracid-1 intraperitoneally. Results: The in vivo experiment with basic 4-level RSP design estimated the LD50 of Yessotoxin to be 463 μg/kgBW (95% CI: 383–535). By inclusion of the k-adjustment factor with equal or increasing numbers of mice on increasing dose levels, the estimate changed to 481 μg/kgBW (95% CI: 362–566) and 447 μg/kgBW (95% CI: 378–504 μg/ kgBW), respectively. The optimised 4-level RSP estimated the LD50 to be 473 μg/kgBW (95% CI: 442–517). A similar increase in power was demonstrated using the optimised RSP design on real Azaspiracid-1 data. The simulations showed that the inclusion of the k-adjustment factor, reduction in sample size by increasing the number of mice on higher design levels and incorporation of a multinomial outcome gave estimates of the LD50 that were as good as those with the basic RSP design. Furthermore, optimised RSP design performed on just three levels reduced the number of animals from 36 to 15 without loss of information, when compared with the 4-level designs. Simulated comparison of the RSP design with UDPs and RW design demonstrated the superiority of RSP. Conclusion: Optimised RSP design reduces the number of animals needed. The design converges rapidly on the area of interest and is at least as efficient as both the UDPs and RW design.
ACCESSION #
110347058

 

Related Articles

  • Functional Toxicogenomics: Mechanism-Centered Toxicology. North, Matthew; Vulpe, Chris D. // International Journal of Molecular Sciences;Dec2010, Vol. 11 Issue 12, p4796 

    Traditional toxicity testing using animal models is slow, low capacity, expensive and assesses a limited number of endpoints. Such approaches are inadequate to deal with the increasingly large number of compounds found in the environment for which there are no toxicity data. Mechanism-centered...

  • Regulation of trichothecene biosynthesis in Fusarium: recent advances and new insights. Merhej, Jawad; Richard-Forget, Florence; Barreau, Christian // Applied Microbiology & Biotechnology;Aug2011, Vol. 91 Issue 3, p519 

    Trichothecenes are toxic secondary metabolites produced by filamentous fungi mainly belonging to the Fusarium genus. Production of these mycotoxins occurs during infection of crops and is a threat to human and animal health. Although the pathway for biosynthesis of trichothecenes is well...

  • Immunotoxicogenomics: The Potential of Genomics Technology in the Immunotoxicity Risk Assessment Process. Luebke, Robert W.; Holsapple, Michael P.; Ladics, Gregory S.; Luster, Michael I.; Selgrade, MaryJane; Smialowicz, Ralph J.; Woolhiser, Michael R.; Germoleck, Dori R. // Toxicological Sciences;Nov2006, Vol. 94 Issue 1, p22 

    Evaluation of xenobiotic-induced changes in gene expression as a method to identify and classify potential toxicants is being pursued by industry and regulatory agencies worldwide. A workshop was held at the Research Triangle Park campus of the Environmental Protection Agency to discuss the...

  • Adverse Outcome Pathways during Early Fish Development: A Conceptual Framework for Identification of Chemical Screening and Prioritization Strategies. Volz, David C.; Belanger, Scott; Embry, Michelle; Padilla, Stephanie; Sanderson, Hans; Schirmer, Kristin; Scholz, Stefan; Villeneuve, Daniel // Toxicological Sciences;Oct2011, Vol. 123 Issue 2, p349 

    The fish early life-stage (FELS) test guideline (OECD 210 or OCSPP 850.1400) is the most frequently used bioassay for predicting chronic fish toxicity and supporting aquatic ecological risk assessments around the world. For each chemical, the FELS test requires a minimum of 360 fish and 1 to 3...

  • RESEARCHES REGARDING THE EVOLUTION OF ERYTHROCYTES, HEMOGLOBIN, HEMATOCRIT AND ERYTHROCYTAR PARAMETERS IN ACRYLAMIDE CHRONIC EXPOSURE. Prisacaru, Anca-Irina; Cuciureanu, Rodica; Prisacaru, Cornelia; Andritoiu, C. V.; Hurduc, N. // Annals of the Romanian Society for Cell Biology;2011, Vol. 16 Issue 1, p205 

    The neurotoxic potential of acrylamide has been known since the very first year of production and use. Later on, the carcinogen action was reconfirmed by experimental research on laboratory animals and epidemiologic studies. Furthermore, toxic effects on the reproductive function have been...

  • Acute Stroke Therapy: Combination Drugs and Multifunctional Neuroprotectants. Callaway, Jennifer K. // Current Neuropharmacology;Jul2004, Vol. 2 Issue 3, p277 

    Ischemic stroke is responsible for about one third of all deaths in industrialized countries and is the major cause of serious, long-term disability in adults over the age of 45. It stands to reason that there is a need for pharmacotherapy to treat acute ischemic stroke. In over two decades of...

  • KINDER LAB TESTS. Stover, Dawn // Popular Science;Jul2008, Vol. 273 Issue 1, p32 

    The article discusses technology which is helping to reduce the number of animals used in laboratory experiments. Episkin, an artificial skin developed by L'Oréal, is made from human cells and is designed to replace the use of animals in laboratory tests in the cosmetic industry. By coating...

  • Invited Review: Inbred Strains Should Replace Outbred Stocks in Toxicology, Safety Testing, and Drug Development. FESTING, MICHAEL F. W. // Toxicologic Pathology;Aug2010, Vol. 38 Issue 5, p681 

    Methods of toxicity testing, barely changed for several decades, need to be improved. One way forward would be to use a small battery of inbred strains instead of the single outbred stock currently used in toxicity screening. Inbred strains are more stable, more uniform, more repeatable, and...

  • Fireflies in the Coalmine: Luciferase Technologies in Next-Generation Toxicity Testing. Simmons, Steven O. // Combinatorial Chemistry & High Throughput Screening;Sep2011, Vol. 14 Issue 8, p688 

    Whole-animal studies have been the mainstay of toxicity testing for decades. These approaches are too expensive and laborious to effectively characterize all of the chemicals currently in commercial use. In addition, there are social and ethical pressures to reduce, refine and replace animal...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics