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Transcript of TT21C and Safety Assessment at Unilever - Home| AXLR8axlr8.eu/workshops/fentem.pdf · TT21C and...
TT21C and Safety Assessment at Unilever
Julia Fentem, PhD FBTSVice-PresidentUnilever - Safety & Environmental Assurance Centre (SEAC)
Overview
• Safety Risk Assessment in Unilever
• Non-Animal Approaches for Consumer Safety Risk Assessment
• new technologies & risk-based approaches (exposure)
• Toxicology in the 21C (“TT21C”)• evolving (eco)toxicological risk assessment approaches for
better human health (& environmental) protection
SEAC’s Role
● Risks for consumers, workers and environment– Safety of products and supply chain technology
● Environmental impacts– Sustainability of Unilever’s brands, products & supply
chain
Provide authoritative scientific evidence and expertise so that Unilever can identify and manage:
SAFE and SUSTAINABLEDESIGN and EXECUTION ofInnovation and Technology
Characterise Hazards & Exposure, assess & manage COE Safety Risks across the Value Chain
C = Consumer safetyO = Occupational safetyE = Environmental safety
DisposalRaw materials/ ingredients
Product formulations Manufactureprocess
Transport
Consumer use
formal post-launch monitoring (if warranted)on-going monitoring & review of new data
COE safety risk assessment for market→ safety risk management decision
safety prognosis / identify key risks & datasafe by design considerations
safety risk assessment for clinical / consumer stud ies
O & E exposure scenarios
COE hazards / key safety risks
Integrated Approach to Assessing & Managing Safety Risks
C & E exposure scenarios
SAFE and SUSTAINABLEDESIGN and EXECUTION ofInnovation and Technology
Research into Alternative Non-Animal Approaches
• R&D in-house and with external partners
• work with all key stakeholders
• present & publish our scientific results
• participate in international validation studies
• since 2004 additional €3M per annum investment in:
• innovative research programme on novel consumer safety risk assessment approaches without animal testing
• new technical capabilities, e.g. “systems biology”, omics technologies� evaluating applicability for decision making on safety risks
• working with >50 external partners globally
• output shared
Embracing New Technologies
How can our consumer safety risk assessments benefit from applying new & emerging technologies being used in medical and biological research?
• “omics”• genomics, proteomics, metabolomics …• tools to interrogate biological systems at molecular level
• informatics• computational and mathematical approaches• tools to integrate, analyse, visualise and interpret data
• analytical• advanced chemical and immunological detection methods
• bioengineering• tissue constructs, stem cells …
Consumer Safety Risk Assessment
Computational Chemistry
Stem cells
US ‘Human Toxicology Project’ consortium
Advanced organ-simulating devices
Human-based cells in vitro
Computational modelling
Systems Biology and PBPK modelling
Tissue Engineering
Novel Approaches to Risk Assessment
Out-reach to Regulators
Mapping and modelling cellular circuitry controlling toxicity pathways
Pathway assays
Relationships between pathway perturbations and adverse responses
Human health risk assessments
Working with Others on New Technologies & Risk -Based Approaches
● technical collaboration with leading US scientists
– Hamner Institute, North Carolina– implement US NAS strategy (2007)
– commonalities with research strategy Unilever published in 2004
● engaging with Russian & Dubai government authoritie s– safety risk assessment approaches for consumer products– inclusion of non-animal methods in revised technical regulations
● collaborating with Chinese Academy of Sciences / La ncaster Uni., UK– environmental risk assessment of chemicals
Developing & Sharing our SafetyApproaches with Scientists Globally
EU: SCCS Opinion 2010
‘…. majority of the existing alternative methods [are] only suitable for hazard identification of cosmetic ingredients and do not give information on potency. Thus, a full human health riskassessment cannot be performed’
http://ec.europa.eu/health/scientific_committees/consumer_safety/statements/index_en.htm
Alternatives to Animal Testing (Safety Decisions)current scientific reality – 2010 expert report (EU Commission)
Source: EU Commission ‘Report on Alternative (Non-A nimal) Methods for Cosmetic Testing: Current Status and Future Prospec ts – 2010’
Human HealthToxicology Endpoint(subject to 2013 ban)
Timeline to Replace Animal Testing
[Note: regulatory acceptance would require an additional 4-8 years]
Comments
Repeated dose toxicity “no timeline could be foreseen” projects still at early research stage
(EU Comm / COLIPA partnership - SEURAT)
Carcinogenicity “no timeline could be foreseen”current in vitro tests inadequate for
generating dose-response information required for safety assessment
Skin Sensitisation “2017 – 2019 for full replacement”several non-animal approaches under
evaluation; ways to integrate & interpret data for safety assessment required
Reproductive Toxicity “no timeline could be foreseen”projects still at research stage
(EU- & US-funded programmes)
Toxicokinetics “no timeline could be foreseen”projects still at research stage
(focus for US “TT21C” research)
US NRC Report
“Advances in toxicogenomics, bioinformatics, systems biology, epigenetics, 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 biologic processes using cells, cell lines, or cellular components, preferably of human origin.”
“TT21C” – Evolving Toxicological Risk Assessment → Better Safety Decisions “Toxicology in the 21C”
– modernisation agenda – developing & applying latest advances in S&T; transforming the toxicological hazard / risk paradigm through better understanding & interpreting effects at the cellular & molecular levels
– new scientific understanding & approaches will underpin future regulatory changes in chemical safety risk management approaches; need scientifically robust ways to integrate data from various tests & analyses
Oxidative stress response module
Developing new S&T Capability for Risk and Impact Assessments – SEAC Focus
Environmental Sustainability• Greenhouse Gas Footprint• Water Footprint
Non-Animal Approaches for Consumer Safety Risk Assessment• Skin Allergy• Exploring Risk Assessment – TT21C• New Technologies• Applying Non-Animal RA Approaches
Ecotoxicology Risk Assessment• Improving Higher Tier RAs• Improving RAs in India & China• Screening RA MethodsMicrobiological Safety Risk Assessment• Naturals & Naturalness RA• Functional Biological Agents• Water (Devices, Treatments & Ecology)
Safe and Sustainable Process Technology• Exposure Risks for Novel Ingredients• Sustainability by Design
Toxicology Risk Assessment• Functional Actives• Protein Allergy• Exposure
Chemistry• Complex Mixtures & Naturals• Proteins & Enzymes• Bioanalysis & Systemic Exposure
Cross-Domain• Risk Assessment of Nanoparticles
Non-Animal Approaches for Skin Allergy
• Current hypothesis: several non-animal hazard characterisation approaches required as inputs into risk assessments of the future
• e.g. Maxwell et al (2008) ATLA, 36, 557-568
• Understanding mechanistic basis of skin sensitisation using a mathematical modelling / systems biology approach
• This has guided selection & development of in silico and in vitroapproaches that encompass key events in Skin Sensitisation induction
• Chemical reactivity
• Peptide reactivity
• Skin disposition
• Skin bioavailability
• Skin inflammation
• Dendritic cell activation/maturation
• T cell proliferation
• Basic research still required in some areas to fill gaps in understanding
Induction Elicitation
Dendritic cell activation and migration
Calculationof net
proliferation
Chemicalexposure
Epidermal cellactivation
Dendritic cell presentation of antigen and T cell proliferation
Maxwell G. & MacKay C (2008) ATLA 36, 521-56
Modelling the Underlying Pathways
Components of the TT21C Vision
The Future of Risk Assessment?
Fast high-content information in vitro assays in human cells/models
Dose-response assessments
Computational models of the circuitry of relevant t oxicity pathways
Pharmacokinetic models supporting in vitro to in vivo extrapolations
Risk assessment focused on maintaining exposures be low the levels that significant pathway perturbations occur
CONSUMER EXPOSURE SCENARIO(S)
Biologic
Inputs
Normal
Biologic
Function
Morbidity
and
Mortality
Cell
Injury
Adaptive Stress
Responses
Early Cellular
Changes
Exposure
Tissue Dose
Biologic Interaction
Perturbation
Based on Perturbation of Toxicity Pathways
1001010.10.01
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dose
Res
pons
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i. In vitro rapidly performed toxicity pathway
test battery for n-assays in human cells , cell
lines, or tissue aggregates
ii. Computational systems biology description of
pathway circuitry for creating biologically
realistic dose response models
iii. Dose dependent transition studies for
sequential pathway activation to understand
linkage to cell and tissue level responses
(perturbations to adversity)
iv. PBPK Modules – Compound specific or QSAR-
based models for reverse dosimetry based on
adverse concentration defined in the in vitro
studies
Toxicity Pathway Results and Quantitative Risk Assessments
In Vitro to In Vivo (human exposure) Extrapolation
Exposure mg/kg/day
Target site concentration ( µM)
In vitroadaptive/adverse
threshold concentration (µM)
TT21C – Main Players
Toxicity Testing in the 21 st Century (TT21C)
Prototype Pathway Research for TT21C –Hamner/Unilever Partnership
A TT21C Prototype Toxicity Pathway: Thresholds for Genotoxic Activity
– Traditionally risk assessments of ‘genotoxins’ have been based on linear models
– At low doses, mechanisms prevent damage from becoming a permanent defect
– Defence mechanisms reach saturation; departure from the NOAEL
– Critical exposure level, below which the concentration of a compound will not produce a significant increase in mutation or chromosomal effects
Background
Dose of GenotoxinMutation
Background
Dose of GenotoxinMutation
Background
Dose of GenotoxinMutation
(Jenkins, et al., 2009, Toxicology)
Can we use mutagenicity and clastogenicity tox-path ways in TT21C paradigm to
(a) improve Genetic Toxicology RA (no animals) and
(b) provide a prototype “reason to believe” (proof of principle) for TT21C ?
• Develop tools to assess dose response for DNA-damage stress pathways, linking HCA, gene expression and mutation, to assess dose-dependent transitions for case-study mutagenic compounds
• Applying data to develop a computational systems biology model of the p53-mdm2 network to examine the basis of the dose-dependent transitions in mutational efficiency� providing a TT21C risk assessment approach
Joint Research Programme
Joint Research Programme
• Protein response to DNA damage• phos-p53, total-p53, p21, MDM2, Chk2, p-ATM, H2AX• Localization of Mn & DNA repair proteins in single cells
• Alterations in gene expression following DNA damage• Time and dose-dependent changes • Full-genome arrays
• Computational modeling of dose response for DNA damage pathway activation
Integrate Data into Models
� Basal function
� Response to small
perturbations
� Response to larger
perturbations
� Assess threshold level of
damage to increase
mutation
Some Challenges ...
Scientific
• Increase collaborative research (EU – US – China ....) – common roadmap(s)
• New research ideas linked to understanding pathways & outcomes critical for human health and environmental risk assessments
Key Question: is use of ingredient X at concentration Y in product Z safe –
for consumers?– for the environment?
Some More Challenges ...
Regulatory Acceptance• Traditionally, in vitro alternative tests validated as 1 for 1 replacements for
existing animal tests• ECVAM / ICCVAM validation
• OECD guidelines
• Regulatory acceptance
• Likely that a pathways-based approach will involve a ‘toolbox’ of several different non animal-based methodologies, none of which (by themselves) will be a ‘replacement’ for a current animal test
• Tests based on understanding toxicity pathways for use in risk assessments will need a new approach to gaining acceptance
• Understanding robustness and transferability of the tests themselves
• Acceptance of new paradigms for use of new data in risk assessments
2007-2008: education, discussion of
content and rational
2009-2010: synthesis and discussion of issues
and challenges
Into the future: moving forward with
implementation – a pilot project approach
Implementation of
TT21C for Testing
and Risk
Assessment
Profiling &
Prioritizing
with HTS
Testing
Systems
Toxicology for
Pathway
Identification
and New
Methods
Pilot Projects
emphasizing
application to
risk assessment
Different Opportunities for Implementation
And, others –
public-private
partnerships
The TT21C
Report
Exposuretissue
dose
Apical
Endpoint
(cancer)
intermediate
responses
“likely to be
a high dose
toxicant”
concentration
in vitro
pathway
assays
Evaluation of ‘adverse’ degree of
system perturbation from panel of
assays and computational systems
for d-r modeling
Value of Prototypes
Mode of Action
Framework
TT21C
Approaches
p53-mdm-2 DNA damage pathway –
Unilever & Exxon-Mobil
PPAR-α α α α receptor pathway mapping and
modeling - Dow Chemical
Rat/human tissue surrogates, in vitro-
in vivo extrapolation and genomics –
ACC
Oxidative stress pathway – Dow
Chemical and Sumitomo
Extend on-going
work
Expand group of
pathways
Develop training
component
Plan use in
safety/risk
assessment
Status
http://www.tt21c.org
With special thanks to ...
• Mel Andersen• Director, Institute for Chemical Safety Sciences, Hamner Institutes
• Paul Carmichael• Cameron MacKay• Gavin Maxwell• Carl Westmoreland