Unilever Plc · LSE:ULVR
Unilever — Technical Presentation
31 slides from Unilever's technical presentation
Slide 1: Next generation risk assessment – principles and tools
SEAC | Unilever Next generation risk assessment – principles and tools Matt Dent, Unilever Safety and Environmental Assurance Centre, UK
Slide 2: The need for non-animal safety assessments
SEAC | Unilever 2 The need for non-animal safety assessments Societal Human Relevance Regulatory Change Attitudes/Consumer Preference
Slide 3: Cosmetic safety assessment: key safety considerations
SEAC | Unilever 3 Cosmetic safety assessment: key safety considerations Exposure data (external/applied dose and internal exposure) Corrosion/irritation (skin/eye) Phototoxicity Mutagenicity/genotoxicity Skin sensitisation Systemic toxicity (focus on repeat dose) Reproductive toxicity Carcinogenicit
Slide 4: Use of Existing OECD In Vitro Approaches
SEAC | Unilever 4 Use of Existing OECD In Vitro Approaches Skin and eye irritation; skin sensitization; phototoxicity; mutagenicity… …what about systemic effects?
Slide 5: Are non-animal safety assessments even possible for systemic toxicity?
SEAC | Unilever 5 Are non-animal safety assessments even possible for systemic toxicity? Systemic toxicity isn’t like local toxicity PoD NOAEL NOAEL ÷ 10 - 1000 ? Many possible adversities…ADME considerations…Homeostasis
Slide 6: Well-established approaches for systemic toxicity
SEAC | Unilever 6 Well-established approaches for systemic toxicity Threshold of Toxicological Concern (Yang et al 2017) https://doi.org/10.1016/j.fct.2017.08.043 Read across (Alexander-White et al 2022) https://doi.org/10.1016/j.yrtph.2021.105094 History of Safe Use (Neely et al 2011) PMID: 2202581
Slide 7: 2007 Toxicity Testing in the 21st Century (TT21C)
SEAC | Unilever 7 2007 Toxicity Testing in the 21st Century (TT21C) “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 chang
Slide 8: What is next generation risk assessment (NGRA)?
SEAC | Unilever 8 What is next generation risk assessment (NGRA)? “An exposure-led, hypothesis driven risk assessment approach that incorporates one or more NAMs to ensure that chemical exposures do not cause harm to consumers” Dent et al ., (2018) Comp Tox 7:20-26
Slide 9: One Interpretation: Tox21/ToxCast
SEAC | Unilever 9 One Interpretation: Tox21/ToxCast ~700 HTS Biological Pathways Assays National Institute of Environmental Health Sciences (NIEHS) / National Toxicology Program (NTP) National Center for Advancing Translational Sciences (NCATS) U.S. Food and Drug Administration (FDA) https://www.epa
Slide 10: The adverse outcome pathway concept (AOPs)
SEAC | Unilever 10 The adverse outcome pathway concept (AOPs) Molecular Adverse Initiating Key Event Key Event Key Event Outcome Event Nuclear Altered Cell Cell Increased Examples: receptor hormone levels proliferation transformation tumour binding incidence
Slide 11: AOP-Wiki (aopwiki.org)
SEAC | Unilever 11 AOP-Wiki (aopwiki.org)
Slide 12: AOP-Wiki (aopwiki.org)
SEAC | Unilever 12 AOP-Wiki (aopwiki.org)
Slide 13: The adverse outcome pathway concept (AOPs)
SEAC | Unilever 13 The adverse outcome pathway concept (AOPs) Molecular Adverse Initiating Key Event Key Event Key Event Outcome Event Nuclear Altered Cell Cell Increased Examples: receptor hormone levels proliferation transformation tumour binding incidence ~78 Major human organs × 5 ways a chemica
Slide 14: Paradigm shift for systemic safety - Protection not Prediction
SEAC | Unilever 14 Paradigm shift for systemic safety - Protection not Prediction Range of in vitro AC50 The hypothesis values converted to human Pyrithiobac-sodium Triclosan in vivo daily dose underpinning this type of NGRA is that if there is log (mg/kg/day) no bioactivity observed at consumer-rel
Slide 15: PBK (Physiologically Based Kinetic) Modelling
SEAC | Unilever 15 PBK (Physiologically Based Kinetic) Modelling substrate S9/Microsomes cofactor Model Input: Uptake Physiological parameters Partition coefficients Transport from arterial Kinetic constants (in vitro) to venous blood dA/dt = + KA * AGI Metabolism + QL * (CA - CV) - Vmax * CL/ (Km +
Slide 16: Principles of NGRA from ICCR
SEAC | Unilever 16 Principles of NGRA from ICCR 4 Main overriding principles: • The overall goal is a human safety risk assessment • The assessment is exposure led • The assessment is hypothesis driven • The assessment is designed to prevent harm 3 Principles describe how a NGRA should be conducted:
Slide 17: Points of Departure from NAMs can be protective
SEAC | Unilever 17 Points of Departure from NAMs can be protective …PODECHA Case Studies Demonstrating Application of Bioactivity as a Protective POD Paul-Friedman et al., 2020
Slide 18: First workflow for ab initio NGRA
SEAC | Unilever 18 First workflow for ab initio NGRA Continue through tiers until enough information to make a decision: assessment may be complete at any tier Berggren et al., (2017) Computational Toxicology 4: 31-44. https://doi.org/10.1016/j .comtox.2017.10.001 18
Slide 19: From principles to application
SEAC | Unilever 19 From principles to application Read across Exposure-based waiving In silico tools Metabolism and metabolite identification Physiologically-based kinetic modelling In chemico assays ‘Omics Reporter gene assays In vitro pharmacological profiling 3D culture systems Organ-on-chip Zebr
Slide 20: From principles to application
SEAC | Unilever 20 From principles to application Readiness judged by ICCR in 2018: (ICCR IS JWG Part 2 FINAL (iccr-cosmetics.org) Read across Exposure-based waiving In silico tools Metabolism and metabolite identification Physiologically-based kinetic modelling In chemico assays ‘Omics Reporter gen
Slide 21: Bioactivity NAMs in our core toolbox 1/4
SEAC | Unilever 21 Bioactivity NAMs in our core toolbox 1/4 In vitro pharmacological profiling ~79 targets Bowes et al. 2012. Nat Rev Drug Discov 11(12): 909-22 High-Throughput transcriptomics (HTTr) Cell stress panel (CSP) • TempO-seek technology – full gene panel • 36 biomarkers covering • 24hr ex
Slide 22: Bioactivity NAMs in our core toolbox 2/4
SEAC | Unilever 22 Bioactivity NAMs in our core toolbox 2/4 In vitro pharmacological profiling To investigate possible interactions with key targets known to be associated with adversity Experiment in 2 phases: ~79 targets Screening at a fixed concentration (10 or 100 µM) Dose-response assays on pos
Slide 23: Bioactivity NAMs in our core toolbox 3/4
SEAC | Unilever 23 Bioactivity NAMs in our core toolbox 3/4 Cell stress panel (CSP) • 36 biomarkers covering 10 cell stress pathways • HepG2 • 24hr exposure • 8 concentrations • Dose-response analysis using BIFROST model Image kindly provided by Paul Walker (Cyprotex) Hatherell et al. 2020. Toxicol
Slide 24: Bioactivity NAMs in our core toolbox 4/4
SEAC | Unilever 24 Bioactivity NAMs in our core toolbox 4/4 High-Throughput transcriptomics (HTTr) • TempO-seq technology – full gene panel • 24hr exposure • 7 concentrations • Various cell models (e.g. HepG2, MCF7, HepaRG) • Dose-response analysis using BMDExpress2 and BIFROST model Reynolds et al.
Slide 25: Risk Assessment Outcome
SEAC | Unilever 25 Risk Assessment Outcome BIOACTIVITY EXPOSURE Face cream Body lotion Identify lowest (most sensitive) point of departure, Identify realistic worst-case plasma exposure (Cmax) expressed in µM expressed as µM BIOACTIVITY The bigger the BER, the greater the BIOACTIVITY EXPOSURE RATIO
Slide 26: What do we still need to do?
SEAC | Unilever 26 What do we still need to do? 1. Increase confidence in exposure predictions (including metabolites) 2. Determine whether tools give us enough biological coverage 3. Be explicit about the level of confidence in the assessment 4. Develop agreed standards for using tools and reportin
Slide 27: What do we still need to do?
SEAC | Unilever 27 What do we still need to do? 1. Increase confidence in exposure predictions (including metabolites) 2. Determine whether tools give us enough biological coverage 3. Be explicit about the level of confidence in the assessment 4. Develop agreed standards for using tools and reportin
Slide 28: Tiered, exposure-led NGRA means we can make robust safety decisions today
SEAC | Unilever 28 Tiered, exposure-led NGRA means we can make robust safety decisions today • Increasing recognition that in vitro bioactivity can inform decision making (e.g. Health Canada, SCCS) • Our knowledge will never be complete, but we know enough to start, and to ensure animal testing is o
Slide 29: Conclusions
SEAC | Unilever 29 CONCLUSIONS • The 9 ICCR Principles underpin the use of novel data in Next Generation Risk Assessment • The Principles can be applied to improve safety decision making • Use of tiered approaches means that gaps in some of the higher tier tools does not prevent risk assessments fro
Slide 30: Acknowledgements
SEAC | Unilever 30 Acknowledgements Maria Baltazar Alistair Middleton Sophie Cable Ruth Pendlington Paul Carmichael Katie Przybylak Richard Cubberley Georgia Reynolds Sharon Scott Julia Fentem Sandrine Spriggs Sarah Hatherell Carl Westmoreland Jade Houghton Andrew White Predrag Kukic Hequn Li Beate
Slide 31: Thank You
Thank You seac.unilever.com