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