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GRAND CHALLENGE: ENVIRONMENTAL AND HUMAN SAFETY
CAS/Unilever Workshop, 21st & 22nd November 2013
Safety Science in the 21st Century
Ian Malcomber & Paul Carmichael
Unilever Safety & Environmental Assurance Centre
IAN MALCOMBER
Graduate and post graduate studies:
Biology, Ecology, Ecotoxicology, Environmental Management
Over 18 years in Ecotoxicology:
over 15 years in Consumer products industry, over 10 years in Unilever
SEAC Leadership & Leader Environmental & Process Safety & Sustainability
Working in collaboration to progress science (examples):
http://www.oecd.org/env/ehs/testing/adverse-outcome-
pathways-molecular-screening-and-toxicogenomics.htm
UK Representative: Molecular Screening & Toxicogenomics / AOP Programme
SEAC’S ROLE – INTERNAL & EXTERNAL CENTRE OF EXCELLENCE IN SAFETY & SUSTAINABILITY SCIENCES
Provide authoritative scientific evidence & expertise so that Unilever can identify & manage:
» Risks for consumers, workers and environment • Safety of products and supply chain technology
» Environmental impacts • Sustainability of Unilever’s brands, products & supply
chain
SAFE and SUSTAINABLE
DESIGN and EXECUTION of
Innovation and Technology
SEAC SCIENTIFIC DISCIPLINES
SEAC PEOPLE & EXPERTISE
We have more than 190 people based in
Colworth, UK and Bangalore, India
Our experience – more than 50% of our people
have more than 10 years experience within
Unilever
Among our experts are more than 20
nationalities and more than 25 different spoken
languages
Our experts are recognised
internationally through Professorships, other
academic positions and memberships of
scientific bodies/advisory groups
~50 peer-reviewed scientific publications
per year
MAXIMISING EXTERNAL IMPACT GLOBALLY FROM SEAC’S SCIENTIFIC CAPABILITY
Scientific Leadership in:
• Chemical & Food Safety Risk Assessment
• Non-animal Approaches for Consumer Safety
• Environmental Impact Assessment
SEAC’s S&T Capability Publications
Presentation Externally
Scientific Conferences
Workshops
Expert Committees
Trade Associations
Posters
Oral Presn
Key Opinion Formers
Academics
Policy Makers/ Politicians
Regulators NGOs
BUILDING NETWORK IN CHINA
Colworth UK, October 2011
CAS-LEC-Unilever workshop
New chemical legislation
Research cohort ‘identify research challenges’
RESEARCH CHALLENGES IN CHINA
Research needs include:
Development of exposure models
Prioritisation tools
WORKING WITH SCIENTIFIC PARTNERS GLOBALLY
OUR LONG TERM SCIENCE GRAND CHALLENGE: NEW PARADIGM FOR SAFETY RISK ASSESSMENT
• Strategic programme: 2004-12 (non-animal approaches/ pathways)
• Unilever SEAC “2020 Research Strategy”
• Human Health (toxicology) & Environment (ecotoxicology)
• Exposure, Mechanistic Information & Mathematical Modelling
• Global Scientific Partnerships: research → science policy → scientific regulation
“HOW CAN WE ASSESS SAFETY WITHOUT ANY ANIMAL TESTING?”
SCIENTIFIC GRAND CHALLENGE: 2004 - 2012
US NATIONAL ACADEMY OF SCIENCE REPORT ON ‘TOXICITY TESTING IN THE 21ST CENTURY IS TRANSFORMING HUMAN HEALTH RISK ASSESSMENT
“Advances in toxicogenomics, bioinformatics, systems biology and computational toxicology could transform toxicity testing from a system based on whole-animal testing to one founded
primarily on in vitro methods that evaluate changes in biological processes using cells..of
human origin.”
2007
OECD STRATEGY ON ‘ADVERSE OUTCOME PATHWAYS’ APPROACH TO CHEMICALS SAFETY RISK ASSESSMENT Provides a universal (Human Health & Environmental Safety) framework for:
- Capture & peer review of mechanistic understanding of toxic effect of interest
- Evaluation of non-animal methods aiming to protect key events of interest for given toxic effect
- Communication of data integration & mechanistic mathematical modelling approaches to decision makers
- International alignment of research policy/decision-making regulation
2010
2012
Unilever’s focus during the past 10 years was on developing new non-animal scientific capabilities, e.g. mathematical
modelling, systems biology & informatics.
Unilever’s focus during the next 10 years will be on how to integrate non-animal data from applying these new capabilities within a “Adverse (Source to ) Outcome
Pathway” framework for safety & regulatory decision-making on human health & environmental safety risks.
THE FOCUS FOR UNILEVER’S RESEARCH COLLABORATIONS IS
CHANGING IN LINE WITH 21ST CENTURY SCIENTIFIC CAPABILITIES
AND US, EC-JRC & OECD STRATEGIC PLANS
http://www.alttox.org/ttrc/overarching-challenges/way-forward/westmoreland-et-al/
SHARED CHALLENGE: NEW INITIATIVES TO INVOLVE OTHERS
http://www.tt21c.org/
PAUL CARMICHAEL
• First degree in Biochemistry (Tox)
• PhD in Biochemistry
• Postdoc Cancer Biology and Genotoxicity
• Senior Lecturer Imperial College
• Toxicology Science Leader, SEAC, Unilever
• Honorary Professor Peking & Lancaster Universities
Risk-based approach: Can we use x percent of ingredient y in product z?
CAN WE USE A NEW INGREDIENT SAFELY?
TRADITIONAL RISK ASSESSMENT STRATEGY
NOAEL
NOAEL ÷ 10 - 1000
Targeted Testing Uncertainty Factors
A LONG-TERM VISION: SOURCE TO OUTCOME PATHWAY-BASED SAFETY RISK ASSESSMENT
Source Environmental Containment
Exposure Molecular Initiating
Event
Organelle Effects
Cellular Effects
Tissue Effects
Organ Effects
Organ Systems Effects
Individual Effects
Population Effects
Community Effects
Source to Outcome Pathway (S2OP)
Adverse Outcome Pathway (AOP)
Toxicity Pathway
• fully integrated exposure and hazard assessment at different levels of biological organisation
To reduce uncertainty
within our risk assessments…
...we will focus on
characterising the key
impacts…
…and replace our current reliance on
apical endpoint studies…
...of marketing any new
ingredient via:
• greater mechanistic understanding of ingredient properties to allow extrapolation from Molecular Initiating Events (MIEs) to an adverse outcome
• better communication of acceptable risk using defined protection goals (consumer, environmental)
QSPR/in vitro physicochemical
parameters
Biokinetic model
(QIVIVE)
Computational systems biology
models
In vivo human safety estimate
(mg/kg/day)
In vitro adversity, point of departure (POD)
concentration determination
Chemical ingredient with ‘significant’ human exposure
Chemical profiling (chemo-informatics) In vitro HTS (pathway inference)
Defined tox-pathway(s) of concern*
In vitro biokinetics & free concentration
In vitro concentration
response in appropriate
assays
1. Generic stress/toxicity pathways 2. Specific receptor-mediated pathways
TT21C
QSPR/in vitro physicochemical
parameters
Biokinetic model
(QIVIVE)
Computational systems biology
models
In vivo human safety estimate
(mg/kg/day)
In vitro adversity, point of departure (POD)
concentration determination
Chemical ingredient with ‘significant’ human exposure
Chemical profiling (chemo-informatics) In vitro HTS (pathway inference)
Defined tox-pathway(s) of concern*
In vitro biokinetics & free concentration
In vitro concentration
response in appropriate
assays
1. Generic stress/toxicity pathways 2. Specific receptor-mediated pathways
TT21C
BPAD Distribution
TT21C/AOP METRO
www.TT21C.org
Lung Fibrosis AR Signalling
Specific receptor targets Narcosis
A VISION FOR MORE MECHANISTIC & ECOLOGICALLY RELEVANT ENVIRONMENTAL SAFETY ASSESSMENTS
Objectives:
• assess risks of chemicals in Unilever products in the context of geographically relevant protection goals,
• assessment of chemical stress in a multi-stressed environment,
• ecologically relevant exposure and effects metrics,
• increased mechanistic understanding of chemical fate and effects to enhance predictive capability.
A VISION FOR MORE MECHANISTIC & ECOLOGICALLY RELEVANT ENVIRONMENTAL SAFETY ASSESSMENTS
Fate & bioavailability
assessment
Generalised or Specific
exposure scenarios
Same mode of action
Mechanistic effects modelling: TK/TD
for individuals
Ecosystem services
Rivers
receiving
untreated
sewage
Large slow rivers
in urban/rural
catchments
Sludge
amended
soil
Marketing regions
Product Use & disposal data
Protection goals: Key traits
representing taxa/functional
groups in ES bundle
Representative community
structures for generalised
exposure scenarios
Probabilistic exposure
•Crop production •Primary production •Nutrient cycling •Recreation •Freshwater •Wastewater treatment •Habitats •Genetic diversity
toxicity metrics: •In silico •In vitro • in vitro
Emission estimation
Population effects modelling
Adverse? Adverse?
Adaptive? Adaptive?
freshwate
r
soil
Marine
Mechanistic effects modelling: TK/TD
for individuals
Mechanistic effects modelling: TK/TD
for individuals
•In vitro
Molecular Initiating (& key) events:
•In silico •In-chemico •In vitro
Same mode of action
Same mode of action
A VISION FOR MORE MECHANISTIC & ECOLOGICALLY RELEVANT ENVIRONMENTAL SAFETY ASSESSMENTS
Fate & bioavailability
assessment
Generalised or Specific
exposure scenarios
Same mode of action
Mechanistic effects modelling: TK/TD
for individuals
Ecosystem services
Rivers
receiving
untreated
sewage
Large slow rivers
in urban/rural
catchments
Sludge
amended
soil
Marketing regions
Product Use & disposal data
Protection goals: Key traits
representing taxa/functional
groups in ES bundle
Representative community
structures for generalised
exposure scenarios
Probabilistic exposure
•Crop production •Primary production •Nutrient cycling •Recreation •Freshwater •Wastewater treatment •Habitats •Genetic diversity
toxicity metrics: •In silico •In vitro • in vitro
Emission estimation
Population effects modelling
Adverse? Adverse?
Adaptive? Adaptive?
freshwate
r
soil
Marine
Mechanistic effects modelling: TK/TD
for individuals
Mechanistic effects modelling: TK/TD
for individuals
•In vitro
Molecular Initiating (& key) events:
•In silico •In-chemico •In vitro
Same mode of action
Same mode of action
Suite of site specific
and representative
regional exposure
scenarios
Protection Goals
derived from
Ecosystem
Services Concepts
Better use of MoA
to identify toxicity
data requirements
Mechanistic models
link in-vitro to in
vivo to population
effects
Assessment of
ecologically
relevant adverse
effects including
community level
effects
OPPORTUNITIES FOR CAS/UNILEVER PARTNERSHIP:
CHEMICAL SAFETY SCIENCE FOR THE 21ST CENTURY
Long term research collaboration around a shared and enduring
science challenge with global significance
Further develop global research networks and
opportunities to collaborate wider
Contribute to and shape the scientific & policy
debate through publication/presentation
of research
Develop research scientists to meet the 21st Century Safety challenges
(e.g. through studentships, exchanges,
secondments, etc)
THANK YOU