The Toxicologist - Society of Toxicology

2466 CRITICAL EVALUATION OF ANIMAL ALTERNATIVE
TESTS FOR THE IDENTIFICATION OF ENDOCRINE
ACTIVE SUBSTANCES.
F. Busquet 1 , S. Belanger 2 , R. Davi 3 , B. Demeneix 4 , J. Denny 5 , M. Embry 6 , M.
Léonard 7 , M. McMaster 8 , L. Ortego 9 , P. Renner 10 , D. Villeneuve 5 and S.
Scholz 10 . 1 JRC, IHCP, ECVAM, European Commission, Ispra, Italy, 2 Procter &
Gamble, Cincinnati, OH, 3 ExxonMobil, Annandale, NJ, 4 Muséum National
d’Histoire Naturelle, CNRS, Paris, France, 5 U.S. EPA, Duluth, MN, 6 ILSI HESI,
Washington, DC, 7 L’Oréal Recherche Avancée, Aulnay sous Bois, France,
8 Environment Canada, Burlington, ON, Canada, 9 Bayer CropScience, Research
Triangle Park, NC and 10 UFZ, Leipzig, Germany.
In the past 20 years considerable progress in animal alternatives accompanied by
advances in the toxicological sciences and new emphases on aquatic vertebrates has
occurred. A significant amount of current research is targeted to evaluate alternative
test methods that may reduce, replace or refine (3Rs) the use of animals, while ensuring
human and environmental health and safety. In 2009, the US EPA began
implementation of the Endocrine Disruptor Screening Program which includes
Tier 1 screening assays in fish and frog species which are closely aligned with the
OECD test guideline series 229 and 231. However, these assays use a large number
of animals and are quite long in duration relative to an ideal screening assay. As the
Tier 1 assays screen and prioritize a large number of chemicals for possible endocrine
activity shorter-term tests would be advantageous. In order to identify potential
alternatives, a literature search was conducted and a database with alternatives
to fish and frog tests testing methodologies assembled. Data from 1995 to
present were collected related to the detection/testing of estrogen-, androgen-, and
thyroid-active chemicals in the following test systems: cell lines, primary cells,
fish/frog embryos, yeast, bacteria, cell free systems, and ‘omics technologies. A critical
analysis was performed to (1) determine the strengths and limitations of each
alternative assay identified and (2) present conclusions regarding chemical specificity,
sensitivity, and correlation with in vivo data. A summary of the most promising
alternative assays will be presented.
2467 THE OECD FISH TESTING FRAMEWORK PROJECT.
L. Touart 1 , G. Ankley 2 , M. Embry 3 , A. Gourmelon 4 , T. Iguchi 5 , G. Maack 6 , P.
Matthiessen 7 , J. Wheeler 8 and C. Willett 9 . 1 OCSPP/Office of Science Coordination
and Policy, U.S. EPA, Washington, DC, 2 Office of Research and Development,
NHEERL, Mid-Continent Ecology Division, U.S. EPA, Duluth, MN, 3 ILSI Health
and Environmental Sciences Institute, Washington, DC, 4 Organisation for Economic
Cooperation and Development (OECD), Paris, France, 5 National Institute for Basic
Biology (NIBB), Okazaki, Japan, 6 Umweltbundesamt (UBA), Dessau, Germany,
7 Consultant, Ulverston, United Kingdom, 8 Syngenta, Bracknell, United Kingdom
and 9 PETA, Norfolk, VA.
A project in the OECD Test Guidelines Programme for considering aspects of a
Fish Testing Framework was initiated in mid-2009, with the United States as the
lead country. The objectives of the project are to review the regulatory needs and
data requirements for fish testing and appraise the currency and comprehensiveness
of existing fish OECD Test Guidelines. In addition, the project aims to support animal
welfare concerns by identifying unnecessary test methods, minimizing the
number of in vivo fish tests and numbers of fish used, and ensuring the optimal use
of data derived from in vivo studies. A September 2010 workshop held at Jealott’s
Hill in the United Kingdom with participation from 50 experts was organized by
OECD with the goal of producing a Fish Testing Framework guidance document
that provides a detailed discussion of issues, relevant endpoints, and the recommendation
for a harmonized testing framework for fish. The workshop participants also
reviewed existing and proposed OECD fish-related Test Guidelines and proposed
recommendations for deleting, adding, and updating these tests. This presentation
will highlight the outcome of the September workshop and discuss the developed
framework document.
2468 DE-RISKING THE POTENTIAL FOR
CARDIOVASCULAR TOXICITY OF TYPE 2 DIABETIC
DRUGS: PRECLINICAL AND CLINICAL STRATEGIES.
A. S. Bass 1 and P. K. Hoffmann 2 . 1 Global Safety Assessment, Merck & Co.,
Kenilworth, NJ and 2 Preclinical Safety, Novartis, East Hanover, NJ.
Discovery of effective therapies for the treatment of Type 2 Diabetes (T2D) remains
an important and critical unmet medical need for society. As with the development
of most new pharmaceuticals, the risk of failure of a compound to achieve
marketing authorization remains high. As a result, the pharmaceutical industry has
placed a strong commitment in implementing strategies that de-risk the chance of
failure when a compound is selected for development. This commitment is reflected
in the increasing complexity of safety evaluations and dedication of resources
as a compound advances through development. Ultimately, the experiences
gained over the course of this time informs whether the de-risking strategy pursued
has been effective. As shown in the area of development of T2D drugs, the knowledgebase
upon which decisions are made is limited because scientists do not fully
understand the relationship of different therapeutics for T2D to unwanted cardiovascular
toxicities. However, standard models of cardiovascular toxicity have been
established and provide some reassurance of a compound’s safety. In those cases,
though, where there is evidence of a relationship, investigators still cannot say how
well their preclinical models and early clinical phase monitoring predict the observed
outcome when a therapy is given over a life-time. Against this backdrop a debate
of best practices in cardiovascular safety testing will ensue based on a current
understanding of the state of science in the areas of safety pharmacology, toxicology-pathology,
and clinical pharmacology. Ultimately, our panel of experts will advocate
for integration of information emerging from each of these scientific disciplines
that will lead to de-risking the potential adverse cardiovascular outcomes of
T2D drugs.
2469 ADVERSE CARDIOVASCULAR RISK ASSOCIATED
WITH THERAPEUTICS FOR TYPE 2 DIABETES:
CHALLENGES TO IDENTIFYING ACCURATE,
PREDICTIVE PRECLINICAL MODELS OF TOXICITY.
A. S. Bass. Global Safety Assessment, Merck & Co., Kenilworth, NJ.
A large comprehensive outcome trial of the cardiovascular risk posed by drugs for
the treatment of Type 2 diabetes is now required by the FDA in support of marketing
authorization. The challenges for preclinical scientists is to identify a compound’s
risk as early as possible, but no later than early clinical development, in an
effort to mitigate the high probability of attrition and focus resources on those molecules
with the best chance of success. While the adversities of certain pharmaceuticals
have been chronicled over the last several years, mechanisms for these adverse
events are not necessarily well understood. This uncertainty poses a challenge for
the scientist to identifying predictive models of cardiovascular risk. An additional
challenge is that in many cases, the investigator is to predict a cardiovascular event
that only emerges following years to decades of treatment. The fact is that not all
cardiovascular adverse events of drugs for the treatment of T2 diabetes will be
amendable to detection in preclinical assays. Accepting these challenges though, the
preclinical scientist understands many of the mechanisms of pharmacodynamic and
structural cardiovascular toxicity can be accurately modeled using sophisticated
methodologies that may also be applied to clinical monitoring for potential untoward
cardiovascular events. Thus, the issues related to the safe and expeditious progression
of drugs for the treatment of Type 2 diabetes through development have
moved the preclinical safety pharmacologist, toxicologist-pathologist and the clinical
pharmacologist to focus their efforts on developing integrated strategies that rely
on established models and technologies of monitoring for cardiovascular safety of
newly emerging molecules. The purpose of this talk is to introduce the challenges of
identifying cardiovascular risk in preclinical and clinical study of new molecules for
the treatment of Type 2 diabetes and to suggest ways of mitigating that risk, setting
the backdrop to the workshop presentations.
2470 MODELING CARDIOVASCULAR TOXICITY OF
THERAPIES FOR TYPE 2 DIABETES IN VITRO.
P. Hoffmann. Novartis, East Hanover, NJ. Sponsor: P. Bentley.
Modeling cardiovascular toxicity in vitro provides the highest capacity means of
screening molecules in an early stage of discovery and development. Furthermore,
there are several in vitro models that emulate and predict the risk of cardiovascular
toxicity in human following exposure to a new molecule. However, the lack of an
understanding of the mechanisms associated with the cardiovascular toxicity of a
life-time of therapy hinders the application of these models to predicting such a result.
The solution to this dilemma is to apply those models of cardiovascular risk
that have been established and to secondarily attempt to identify mechanisms of
toxicity specific to treatments for Type 2 diabetic drugs and to develop models that
emulate this condition as a basis for excluding those chemicals with a potential for
undesirable properties.
SOT 2011 ANNUAL MEETING 529