Safety without animal testing: reality or fantasy

1

• Safety without animal testing reality or
  fantasy?
• Academic challenges
• Coenraad F.M.Hendriksen
• Netherlands Centre Alternatives to Animal Use
  (NCA), Utrecht University
• Netherlands Vaccine Institute

2
Safety without animal testing reality or
fantasy? Academic challenges

• What will be discussed
• hazard and risk assessment what
• does it mean in terms of animal use?
• why do we want to change from
• in vivo to non-animal safety testing?
• if so, why do we still use animals?
• what new developments might
• move risk assessment from in
• vivo to non-animal testing?
• what are the academic challenges?
• recommendations

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
3
What will be discussed

• hazard and risk assessment what
• does it mean in terms of animal use?
• why do we want to change from
• in vivo to in vitro?
• if so, why do we still use animals?
• what new developments might
• move safety assessment from in
• vivo to in vitro testing or to less
• intensive animal testing?
• what are the academic challenges?
• conclusions

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
4
Numbers of laboratory animals used in the EU-MS
Statistics of 2002 (1)
current risk assessment in terms of animal use
No. of animals used for Toxicological and other
safety evaluation (N 1.065.690
No. of animals used in EU-MS (N total
10.731.020) purposes
NCA The Netherlands Centre Alternatives to
Animal Use
Purposes
(SEC (2005) 45)
Annual European Meeting Toxicology Forum,
Brussels, 091105
5
Numbers of laboratory animals used in the EU-MS
Statistics of 2002 (2)
current risk assessment in terms of animal use
No. of animals used for Toxicological and other
safety evaluation (N 1.065.690
No. of animals used in EU-MS (N total
10.731.020) purposes
NCA The Netherlands Centre Alternatives to
Animal Use
Test Specification
(SEC (2005) 45)
Annual European Meeting Toxicology Forum,
Brussels, 091105
6
What will be discussed

• hazard and risk assessment what
• does it mean in terms of animal use?
• why do we want to do without
• animals?
• if so, why do we still use animals?
• what new developments might
• move safety assessment from in
• vivo to in vitro testing or to less
• intensive animal testing?
• what are the academic challenges?
• recommendations

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
7
Safety testing and concerns
why do we want to do without animals?
Societies acceptance of animal use for specific
purposes

• moral concerns
• economic concerns
• pragmatic concerns
• scientific concerns

NCA The Netherlands Centre Alternatives to
Animal Use
(Aldhous et al. 1999)
Annual European Meeting Toxicology Forum,
Brussels, 091105
8
Safety testing and concerns
why do we want to do without animals?

• Economic concerns
• costs of animals
• housing requirements facilities
• need for skilled staff
• labour intensive
• Pragmatic concerns
• time consuming
• rigid study design
• ethical review process

• moral concerns
• economic concerns
• pragmatic concerns
• scientific concerns

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
9
Safety testing and concerns
why do we want to do without animals?
Risk assessment hazard assessment exposure

• moral concerns
• economic concerns
• pragmatic concerns
• scientific concerns

NCA The Netherlands Centre Alternatives to
Animal Use

• Factors influencing uncertainty in extrapolation
• interspecies differences
• intraspecies differences
• differences in route and duration of exposure
• dose-response relationship
• uncertainties in exposure estimate

Annual European Meeting Toxicology Forum,
Brussels, 091105
10
Safety testing and concerns
why do we want to do without animals?
Risk assessment hazard assessment exposure
probability

• moral concerns
• economic concerns
• pragmatic concerns
• scientific concerns

NCA The Netherlands Centre Alternatives to
Animal Use

• Factors influencing uncertainty in extrapolation
• interspecies differences
• intraspecies differences
• differences in route and duration of exposure
• dose-response relationship
• uncertainties in exposure estimate

Annual European Meeting Toxicology Forum,
Brussels, 091105
11
What will be discussed

• central theme of session III
• context
• why do we want to do without animals?
• if so, why do we still use animals?
• what new developments might
• move safety assessment from in
• vivo to in vitro testing or to less
• intensive animal testing?
• what are the academic challenges?
• recommendations

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
12
Problems associated with in vitro methods
if so, why do we still use animals?

• Scientific limitations of alternatives
• Validation acceptance hurdle
• Tradition regulatory requirements
• Scientific aspects validity, extrapolation,
  risk assessment

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
13
Proposed timeframe for full replacement of animal
tests
if so, why do we still use animals?

• Human Health effects Foreseeable time
  involved
• for full replacement
• _________________ _____________________
• acute toxicity gt 2014
• skin irritation gt 2014
• skin corrosion lt 2004
• eye irritation gt 2010
• skin sensitisation gt 2019
• skin absorption/penetration gt 2006
• subacute/subchronic toxicity gtgt 2014 (not
  foreseeable)
• genotoxicity/mutagenicity gt 2016
• UV-induced effects gtgt 2019 (not foreseeable)
• Toxicokinetics and biotransformation gtgt 2014
  (not foreseeable)
• Carcinogenicity gtgt 2014 (not foreseeable)
• Reproductive toxicity gtgt 2014 (not
  foreseeable)

NCA The Netherlands Centre Alternatives to
Animal Use
(SCCNFP, 2004)
Annual European Meeting Toxicology Forum,
Brussels, 091105
14
The way to alternative methods validation
acceptance
if so, why do we still use animals?
Pre- validation 2 years
Research Development ? years





Vali- dation 1 year
Peer review 1 year
EU Re- gulatory acceptance 2 years
OECD Regulatory Acceptance 3 years
(Hartung)
Total period gt 9 years
NCA The Netherlands Centre Alternatives to
Animal Use
Scientifically validated methods for regulatory
toxicology 10 alternative tests endorsed as
scientifically valid by ECVAM skin corrosivity
(Rat TER, CORROSITEX, EpiSkin, EpiDerm),
phototoxicity (3T3NRU), embryotoxicity (EST,
MM, whole embryo assay), in vitro percutaneous
absorption. Skin sensitisation local lymph Node
Assay (LLNA) 40 in vitro models under
validation
Annual European Meeting Toxicology Forum,
Brussels, 091105
15
Tradition
if so, why do we still use animals?

• The difficulties lies not in the new ideas, but
  in escaping from the old ones
• (John Maynard Keynes, 1883-1946)

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
16
Problems associated with in vitro methods
if so, why do we still use animals?

• Scientific limitations of alternatives
• Validation acceptance hurdle
• Tradition regulatory requirements
• Scientific aspects validity, extrapolation,
  risk assessment

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
17
What will be discussed

• central theme of session III
• context
• why do we want to do without animals?
• if so, why do we still use animals?
• what new developments might
• move safety assessment from in
• vivo to non animal testing or to
• less intensive animal testing?
• what are the academic challenges?
• recommendations

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
18
Safety without animal testing a scientific
challenge!
new developments

• Implementation of Intelligent Testing Strategies
  (ITS) and non-animal models
• Use of innovative new technologies

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
19
Safety without animal testing a scientific
challenge!
new developments

• Intelligent testing strategies
• (integrated approaches comprising multiple
  elements)
• Data mining data sharing
• Read across Expert judgement
• Tiered testing approaches
• Thresholds of toxicological concern
• Human data

• Implementation of Intelligent testing strategies
  and non-animal models
• Use of innovative new technologies

NCA The Netherlands Centre Alternatives to
Animal Use

• Non-animal methods
• (Q)SARs
• PBBK
• in vitro models

Annual European Meeting Toxicology Forum,
Brussels, 091105
20
Efficient risk assessment using ITS and non
animal models
Chemical
QSARs. TTCs, in vitro screens/tests
Existing data

• Exposure
• exposure categories
• models
• measurements

Prioritization for further testing
Read across methods
NCA The Netherlands Centre Alternatives to
Animal Use
In vivo testing
Basic hazard information
Risk assessment
(Bradbury et.al., 2004)
Risk management
Annual European Meeting Toxicology Forum,
Brussels, 091105
21
Safety without animal testing a scientific
challenge!
new developments

• Implementation of Intelligent testing strategies
  and non-animal models
• Use of innovative new technologies

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
22
Alternatives and science a scientific challenge?
New technologies
new developments

• Examples
• - omics technologies
• systems biology
• embryonic stem cells
• in silico models
• improvements in tissue
• culture techniques
• etc.

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
23
Science and Alternatives - the way to go!
new developments
NCA The Netherlands Centre Alternatives to
Animal Use
(Timo Breit)
Scientific and regulatory evolution from
what to why
Until now questions are based on what -
what is the toxicity of a chemical? - what
is the safety of a pharmaceutical?
Future why questions will dominate -
why is a chemical toxic? - why is a
pharmaceutical not safe?
Annual European Meeting Toxicology Forum,
Brussels, 091105
24
Use of omics technologies in risk assessment
process
Treatment
incubation
phenotype
minutes ? years
Advantages New biomarkers for hazard
identification Providing mechanistical
information
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Use of omics technologies in risk assessment
process
Treatment
incubation
phenotype
minutes ? years
Reduction Less animals more data per individual
animal Exchange and re-use of data possible
Refinement Shift from phenotypic analysis to
(sub)cellular analysis resulting in shorter
incubation times, no clinical signs and lower
doses. Replacement Easier translation to
non-animal in vitro assays Shift from lab.
experiments to in-silico experiments
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What will be discussed

• central theme of session III
• context
• why do we want to change from
• in vivo to in vitro?
• if so, why do we still use animals?
• what new developments might
• move safety assessment from in vivo
• to in vitro testing or to less
• intensive animal testing?
• what are the academic challenges?
• recommendations

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
27
Academia characteristics
what are the academic challenges?

• research activities generally taken place in an
  academic setting (university)
• focus of research on fundamental aspects of
  toxicology and related matters
• outside the regulatory context
• driven by specific objectives (targeted topics,
  publication-driven)

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
28
Academia challenges with regard to moving from
in vivo testing to in vitro testing or less
intensive animal testing
what are the academic challenges?

• Central is to create a 3Rs commitment based on
  the principle that working on alternatives is a
  need for animal welfare as well as for progress
  in science
• provide answers to fundamental questions in
  toxicology
• develop and optimize elements to be included in
  ITS (e.g. in silico modelling tools)
• development of new innovative technologies (e.g.
  omics)
• be a partner in interdisciplinary activities
• be involved in integration of new technologies in
  regulatory testing strategies (interaction with
  industry, regulatory field)
• be partner in validation studies

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
29
Academia concerns
what are the academic challenges?

• Limited budgets available for 3Rs activities
• Limited 3Rs training opportunities and limited
  3Rs commitment
• Focus of academic research could be too
  fundamental or too specific
• No interest in application
• No knowledge of or interest in needs of industry
  regulatory process, in particularly with regard
  to 3Rs aspects
• Language differences between academia and
  industry/regulatory area

NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
30
Academia recommendations
what are the academic challenges?

• Recommendations
• Budgets should be made available
• for 3Rs research activities
• Priorities are in education
• training with specific focus on
• 3Rs
• Intensify interactions between
• academia and industry/regulatory
• area as well as interdisciplinary
• activities

Costs development in vitro test 5
million/test (pre-)validation 0.3
million/test Total costs in vitro methods 1-8
billion
NCA The Netherlands Centre Alternatives to
Animal Use
Annual European Meeting Toxicology Forum,
Brussels, 091105
31

Thanks for your attention!!
32
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