INDUSTRY S NEEDS FOR 21 ST CENTURY SAFETY SCIENCE & NON-ANIMAL APPROACHES: A UNILEVER PERSPECTIVE

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1 INDUSTRY S NEEDS FOR 21 ST CENTURY SAFETY SCIENCE & NON-ANIMAL APPROACHES: A UNILEVER PERSPECTIVE JULIA FENTEM & GAVIN MAXWELL UNILEVER R&D SAFETY & ENVIRONMENTAL ASSURANCE CENTRE (SEAC) CONTEXT - 1 Our aim is to protect the health of consumers, whilst facilitating innovation & new product development Replacing animal tests for complex human health effects (e.g. cancer, allergy) requires considerable long-term research investment: - fundamental biological understanding e.g. disease processes, adverse effects of chemicals at a mechanistic level - development of new (non-animal) tools & modelling approaches e.g. computational biology & chemistry, kinetic modelling 1

2 CONTEXT - 2 For many years, the EU led progress in developing non-animal methods for identifying hazardous chemicals Since 2007, the US is leading the research, innovation & public health agenda via strategic investment in 21 st Century safety science Horizon 2020 is an opportunity for EU-US transatlantic research collaboration & substantial EU research investment in safety science The research outputs will enable the EU to have a strong scientific and policy voice on chemical & product safety at the OECD and in other international fora - a priority for EU-based global companies wanting to innovate responsibly OUR CONSUMER & ENVIRONMENTAL SAFETY DECISIONS ARE BASED ON SCIENTIFIC EVIDENCE USING RISK ASSESSMENT APPROACHES Hazard-based check-list approach unnecessary (animal) testing doesn t consider how product is used Risk-based evidence- & expertise-driven essential (animal) testing only product use / exposure determines outcome To protect consumers & our environment, the key question we look to answer is: - is the use of ingredient X at concentration Y in product Z safe? 2

3 WE NEED NEW & BETTER NON-ANIMAL TOOLS TO PROVIDE THE SCIENTIFIC DATA FOR OUR SAFETY RISK ASSESSMENTS - systems biology & mathematical modelling - data mining and bioinformatic approaches - tissue engineering, human ex vivo tissues - analytical science and imaging Mathematical model of skin immune response Protein modified by skin allergen Skin section Peptide binding data heat-map Human keratinocytes treated with skin allergen Gene expression data & biological pathway analysis WE HAVE MADE GOOD PROGRESS IN REPLACING ANIMAL TESTS FOR IDENTIFYING CHEMICALS THAT CAN CAUSE SKIN EFFECTS AND DNA DAMAGE Since 1980s, EU scientists have played a leading role in development, application & regulatory acceptance (EU, OECD) of non-animal methods for identifying hazardous chemicals - skin corrosion - skin penetration - skin irritation - phototoxicity - genotoxicity ar)ficial skin models for skin irrita)on tes)ng interna)onal valida)on studies: OECD test guideline 439 adopted in

4 2007 US NATIONAL ACADEMY OF SCIENCE REPORT ON TOXICITY TESTING IN THE 21 ST CENTURY IS TRANSFORMING HUMAN HEALTH RISK ASSESSMENT - applying 21 st Century science & technology to transform human health risk assessment through better understanding effects at cellular and molecular levels ( toxicity pathways ) - significant research investment from US government authorities will underpin future regulatory changes in chemicals safety risk management approaches 2012 OECD STRATEGY ON ADVERSE OUTCOME PATHWAYS APPROACH TO CHEMICALS SAFETY RISK ASSESSMENT COULD ALIGN RESEARCH & DECISION- MAKING GLOBALLY OECD Adverse Outcome Pathway (AOP) approach provides a universal framework for: - capture & peer review of mechanistic understanding of toxic effect of interest - evaluation of non-animal methods aiming to predict key events of interest for given toxic effect - communication of data integration & mechanistic mathematical modelling approaches to decision-makers Exposure Molecular Organelle Cellular Ini1a1ng Event Effects Effects Toxicity Pathway Tissue Effects Organ Effects Organ Systems Effects Individual Popula1on Effects Effects Adverse Outcome Pathway 4

5 UNILEVER CASE STUDY: SKIN ALLERGY RISK ASSESSMENT WITHOUT ANIMAL TESTING - 1 Induction of skin allergy is a multi-stage process driven by toxicity pathways - mechanistic understanding is captured in Adverse Outcome Pathway (AOP) - non-animal test methods have been developed; each aims to predict impact of a chemical on one key event - how can we make risk assessment decisions by integrating this scientific evidence? 1. Skin Penetra)on 2. Electrophilic substance: directly or via auto- oxida)on or metabolism 3-4. Haptena)on: covalent modifica)on of epidermal proteins 5-6. Ac)va)on of epidermal kera)nocytes & Dendri)c cells 7. Presenta)on of haptenated protein by Dendri)c cell resul)ng in ac)va)on & prolifera)on of specific T cells Allergic Contact Derma))s: Epidermal inflamma)on following re- exposure to substance due to T cell- mediated cell death Key Event 1 Key Event Key Event 4 Adverse Outcome Modified from Adverse Outcome Pathway (AOP) for Skin Sensi1sa1on, OECD report UNILEVER CASE STUDY: SKIN ALLERGY RISK ASSESSMENT WITHOUT ANIMAL TESTING Skin Penetra)on 2. Electrophilic substance: directly or via auto- oxida)on or metabolism 3-4. Haptena)on: covalent modifica)on of epidermal proteins 5-6. Ac)va)on of epidermal kera)nocytes & Dendri)c cells haptenated skin protein predic)on 7. Presenta)on of haptenated protein by Dendri)c cell resul)ng in ac)va)on & prolifera)on of specific T cells No. CD8+ T cells Allergic Contact Derma))s: Epidermal inflamma)on following re- exposure to substance due to T cell- mediated cell death allergic immune response dose Y Adverse Non- Adverse dose X 1. Generate relevant non-animal data for both the chemical (hazard) and the exposure scenario 2. Use linked mathematical models to predict human allergic immune response (with non-animal data as model input parameters) 3. Apply human immune response model prediction for risk assessment decision )me 5

6 THE EU IS INVESTING IN 21 ST CENTURY NON- ANIMAL SAFETY ASSESSMENT APPROACHES EU FP7 collaboration between academic, EU Commission, NGO and industry scientists aiming to accelerate transition to toxicity pathway-based methods for chemical safety assessment EU FP7 collaboration co-funded by EU Commission & Cosmetics Europe to drive first wave of academic research required to replace need for repeatdose systemic toxicity animal data UNILEVER IS INVESTING IN NEW SCIENTIFIC CAPABILITIES TO ENABLE PATHWAYS-BASED SAFETY RISK ASSESSMENTS TOXICITY TESTING IN 21 ST CENTURY Chemistry Alerts TUBE MAP Consumer Product Exposure Assessment Current Toxicity Tes)ng High Content Assays Wet- Lab Biomarkers (Molecular Ini)a)ng Events) Computa)onal models Skin Allergy p53 NRF2/Keap1 Toxicokine)c Exposure Assessments Mitochondrial Pathways Other Pathways Interna+onal Terminus: TT21C Safety Assessment Adverse Outcome Pathways (AOPs) Quan)ta)ve In vitro to In vivo extrapola)on Dose- Response Characterisa)on Pathways- based risk assessment TT21C case study risk assessments Toxicology Exper)se for the future Acknowledgement: Dr Paul Carmichael, Unilever ~100 collaborations & partnerships (scientific network) + 6

7 REASONS TO INVEST IN NEW SAFETY SCIENCE & NON- ANIMAL APPROACHES TO PROTECT CONSUMERS & OUR ENVIRONMENT UNDER HORIZON 2020 Horizon 2020 is an opportunity for high-impact EU-US transatlantic research collaboration on 21 st Century safety science & non-animal tools requires substantial EU funding to match US investment will enable the EU to have a stronger scientific & policy voice at the OECD & in other international fora on chemical & product safety, human health & environmental risk assessment and non-animal approaches, based on new knowledge and tools high priority for EU-based global companies wanting to innovate responsibly and apply leading edge scientific tools and data in assessments of product safety 7