overview of the latest scientific developments on animal models and alternatives dr philip a botham...
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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
Animal Models for What ?
It’s not just about toxicology / safety evaluation
Statistics of Scientific Procedures on Living Animals : Great Britain 2000
Total number of Procedures 2,714,726Total 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%)
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
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, transportAssess hazard not riskWide 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)
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
Future Trends in Laboratory Animal Use in Toxicology
New toxic endpoints – more testingMore products of biotechnology / fewer
“traditional” chemicals – change in testing requirements
Greater emphasis on understanding mechanism of toxicityRelevance of animal modelsTransgenics (“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.
Toxicology offers both a threat and an opportunity for reduction, refinement and replacement
alternatives to animal experimentation
What Progress Has Been Made ?
ReplacementSkin corrosionPhototoxicitySkin permeability
Refinement / ReductionAcute oral toxicitySkin sensitisation
“INVENTION” TO REGULATORY ACCEPTANCE TOOK 15 – 20 YEARS
What Tests Are in Development or Validation?
Available within 3 yearsAcute 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 yearsEye irritation (in vitro – replacement)Acute dermal and inhalation toxicity (in vivo – refinement /
reduction)Respiratory sensitisation (in vivo – new endpoint)
In-Vitro Replacement Tests Available Only in Longer Term (more than 10
years)
Acute toxicitySkin and respiratory sensitisationKinetics and metabolismTarget organ / system toxicityDevelopmental and reproductive toxicityNon-genotoxic carcinogenesis
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 ?
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
-
“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
“I know, let’s inventthe Ames test”
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
Test Development – A Current Example of Expectation
Not Matching Reality
Genomics, Transcriptomics, Proteomics and Metabonomics
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
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
systemsTranscript changes may not reflect what would happen in an
organ in vivo Different microenvironment Lack of cellular interactions Inadequate or inappropriate metabolism
“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
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