Overview of the Latest Scientific Developments on Animal Models and Alternatives

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Overview of the Latest Scientific Developments on
Animal Models and Alternatives

• Dr Philip A Botham
• Global Head of Human Safety
• Syngenta

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Animal Models for What ?

• Its not just about toxicology / safety evaluation

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Statistics of Scientific Procedures on Living
Animals Great Britain 2000

• Total number of Procedures 2,714,726
• Total number of animals used 2,642,993
• Total number of toxicology procedures 454,904
  (16.8)
• Total number of toxicology procedures for
  Cosmetics and Toiletries
  
  0
• Total number of acute lethal tests in the rat
  (LD50/LC50) 2292
• Total number of Procedures in Dogs
  7,632 (0.3)
• Total number of procedures in primates
  3,690 (0.1)

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• The vast majority of animals used in the European
  Union are used in
• Fundamental biological research
• Applied research in human medicine and dentistry
• Applied research in veterinary medicine
• Breeding programmes, especially for genetically
  modified animals

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The Use of Animals in Toxicology Mandatory
Tests

• For all industry sectors (pharmaceuticals,
  agrochemicals, industrial chemicals, cosmetics,
  household products)
• Regulatory requirements for conducting clinical
  trials, registration, safe manufacture, transport
• Assess hazard not risk
• Wide range of complex hazard endpoints (acute,
  chronic, reproductive system, cancer, teratogens,
  sensitisers)
• New endpoints / tests (nervous system, immune
  function, susceptible human sub-populations, e.g.
  children)

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The Use of Animals in Toxicology- Elective Tests

• Compound selection in discovery (active
  ingredient) and formulation (product) development
• Mechanistic studies are findings seen in
  mandatory tests in rodents / dogs relevant to
  man?
• Research studies understanding generic
  mechanisms, e.g. how certain chemical classes
  cause cancer

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Future Trends in Laboratory Animal Use in
Toxicology

• New toxic endpoints more testing
• More products of biotechnology / fewer
  traditional chemicals change in testing
  requirements
• Greater emphasis on understanding mechanism of
  toxicity
• Relevance of animal models
• Transgenics (humanisation of models)
• Use of in vitro and in silico technology
• Public and regulatory expectation for safer drugs
  pesticides, chemicals and food and for reduced
  animal use.

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• Toxicology offers both a threat and an
  opportunity for reduction, refinement and
  replacement alternatives to animal experimentation

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What Progress Has Been Made ?

• Replacement
• Skin corrosion
• Phototoxicity
• Skin permeability
• Refinement / Reduction
• Acute oral toxicity
• Skin sensitisation
• INVENTION TO REGULATORY ACCEPTANCE TOOK 15 20
  YEARS

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What Tests Are in Development or Validation?

• Available within 3 years
• Acute oral toxicity (in vitro
  screening/dose-setting for in vivo studies)
• Skin irritation (in vitro - replacement)
• Developmental toxicity (in vitro-screening for
  moderate to strong teratogens)
• Available within 5 10 years
• Eye irritation (in vitro replacement)
• Acute dermal and inhalation toxicity (in vivo
  refinement / reduction)
• Respiratory sensitisation (in vivo new endpoint)

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In-Vitro Replacement Tests Available Only in
Longer Term (more than 10 years)

• Acute toxicity
• Skin and respiratory sensitisation
• Kinetics and metabolism
• Target organ / system toxicity
• Developmental and reproductive toxicity
• Non-genotoxic carcinogenesis

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• Is this pessimistic or too conservative ?
• Why does it take so long to develop and validate
  alternatives ?
• Would more investment in alternatives speed up
  progress ?

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Stages in the Development of New Toxicology Test
Methods
Stage Outcome Science or Technology
Research Understanding basic toxic or biological mechanisms Science
Method Development New methods for specific applications Science
Pre Validation Optimised transferable protocol Technology
Validation Establishment of reliability and relevance Technology
Review Independent scientific peer review -
Regulatory Acceptance Regulatory agency decision on acceptability for specific application -
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• Technology can be driven to a timetable by the
  application of sufficient resources and
  management skills, while science has a pace of
  its own
• IFH Purchase, 1996
• Regulatory acceptance also has a pace of its
  own, and is perceived to be driven as much by
  politics as by science
• PA Botham, 2002

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I know, lets invent the Ames test
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Would More Investment in Alternatives Speed up
Progress ?

• Yes by giving more support for conduct and
  management of high quality validation
  studies
• Yes by encouraging test developers to better
  understand the needs for hazard and risk
  assessment in toxicology (more
  collaboration between academics and industry)
• No by funding poorly conceived or poorly -
  conducted test development

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Test Development A Current Example of
Expectation Not Matching Reality

• Genomics, Transcriptomics, Proteomics and
  Metabonomics

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Genomics, Transcriptomics, Proteomics and
Metabonomics (GTPM)

• Mechanistic toxicology improve relevance to man
• Predictive toxicology biomarkers for particular
  toxic endpoints or classes of toxiciant
• Can be used with in vitro culture systems

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The Problems with the Development of GTMP
Technology in Toxicology

• e.g. Using transcriptomics (toxicogenomics)
• Changes seen genuine adverse effects or healthy
  adaptive or repair responses?
• Effects seen at very low doses (relevance ?)
• Generic problems with the use of in vitro culture
  systems
• Transcript changes may not reflect what would
  happen in an organ in vivo
• Different microenvironment
• Lack of cellular interactions
• Inadequate or inappropriate metabolism

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• The appropriate application of these techniques
  is more demanding of careful experimental design
  than ever, as the potential to generate
  incomplete and misleading data is great.
• The attainment of common ground through
  collaboration involving the generation, sharing
  and publication of suitable, high quality, data
  should be prime goal for scientists and
  institutions engaged in researching the new
  technology and its appropriate application
  towards improving the knowledge of the
  interaction of chemicals with living things.
• B Pennie, 2001