Overview of the Latest Scientific Developments on Animal Models and Alternatives Dr Philip A Botham Global Head of Human Safety Syngenta.

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