Slide 1: Next Generation Risk Assessment for Occupational Chemical Safety – a Real-World Example
Safety, Environmental & Regulatory Science (SERS) | Unilever Next Generation Risk Assessment for Occupational Chemical Safety – a Real-World Example with Sodium-2-hydroxyethane sulfonate Adam Wood: Safety Scientist Steve Gutsell: Head of Regulatory Science – Chemical Safety Safety, Environmental & R
Slide 2: Overview
Safety, Environmental & Regulatory Science (SERS) | Unilever 2 Overview 1. Current approaches for worker safety assessment. 2. External landscape 3. Overview of NGRA for systemic toxicity assessment. 4. Case study chemical: Sodium-2- hydroxyethane sulfonate (SI) Looking to the future: - EU roadmap t
Slide 3: Historical worker safety assessment (systemic toxicity)
Safety, Environmental & Regulatory Science (SERS) | Unilever 3 Historical worker safety assessment (systemic toxicity) Typically, risks from occupational exposures are determined via comparison with occupational limit values, e.g., occupational exposure limits (OELs) or Derived No-effect levels (DNE
Slide 4: Opportunities for improved occupational risk assessments
Safety, Environmental & Regulatory Science (SERS) | Unilever 4 Opportunities for improved occupational risk assessments Reliance on animal testing for worker safety assessment has been reduced, e.g. local toxicity, however, systemic safety assessment remains largely reliant on animal testing. In add
Slide 5: Next Generation Risk Assessment (NGRA)
Safety, Environmental & Regulatory Science (SERS) | Unilever 5 Next Generation Risk Assessment (NGRA) • Same underlying paradigm for risk assessment (hazard ID, characterisation, exposure estimation and risk characterisation). • Hazard ID/characterisation instead based on integrating non-animal meth
Slide 6: NAM development – protection vs prediction
Safety, Environmental & Regulatory Science (SERS) | Unilever 6 NAM development – protection vs prediction Rapid development of NAMs for use in risk NAMs assessment. Two alternate philosophies: Prediction Protection capturing early 1.) NAMs that measure early biological changes biological (irrespecti
Slide 7: Value of approach for large subset of chemicals
Safety, Environmental & Regulatory Science (SERS) | Unilever 7 Value of approach for large subset of chemicals Human PODs Exposure NAMs Animal Each substance was screened varied from 211 to 4557, with a median of 883 assay endpoints Case Studies Demonstrating Application of Bioactivity as a Protecti
Slide 8: Support?
Safety, Environmental & Regulatory Science (SERS) | Unilever 8 Support? “vertical dashed red lines indicate ±2 log10-mg/kg/d, between which 85% and 83% of POD ratios fall in (A) and (B), respectively” In other words, 83 or 85% of PoD ratio (PoD NAM (median)/PoD traditional (5th or 25th percentile) w
Slide 9: Unilever's NGRA journey: Case studies > toolbox evaluations > real-world use
Safety, Environmental & Regulatory Science (SERS) | Unilever 9 Unilever’s NGRA journey: Case studies > toolbox evaluations > real-world use 2020 2022 2024 2025 Toolbox and Conceptual Evaluation of Toolbox and First NGRA case workflow for DART toolbox toolbox, workflow workflow for DART study on cond
Slide 10: Translating principles to practice with case studies
Safety, Environmental & Regulatory Science (SERS) | Unilever 10 Translating principles to practice with case studies • Principles around using high-throughput test batteries translated to case study in 2020. • Demonstrated feasibility of approach based on realistic test battery. • In recent years, f
Slide 11: Unilever's NGRA journey: Case studies > toolbox evaluations > real-world use
Safety, Environmental & Regulatory Science (SERS) | Unilever 11 Unilever’s NGRA journey: Case studies > toolbox evaluations > real-world use 2020 2022 2024 2025 Toolbox and Conceptual Evaluation of Toolbox and First NGRA case workflow for DART toolbox toolbox, workflow workflow for DART study on con
Slide 12: Unilever systemic toolbox evaluations
Safety, Environmental & Regulatory Science (SERS) | Unilever 12 Unilever systemic toolbox evaluations To evaluate the value of a pragmatic suite of NAMs for making protective safety decisions, a ‘toolbox’ and ‘workflow’ has been established and evaluated, entailing: ✓ Toolbox of NAMs established ✓ E
Slide 13: Unilever's NGRA journey: Case studies > toolbox evaluations > real-world use
Safety, Environmental & Regulatory Science (SERS) | Unilever 13 Unilever’s NGRA journey: Case studies > toolbox evaluations > real-world use 2020 2022 2024 2025 Toolbox and Conceptual Evaluation of Toolbox and First NGRA case workflow for DART toolbox toolbox, workflow workflow for DART study on con
Slide 14: Integrating DART Safety Assessment into Existing NGRA Framework
Safety, Environmental & Regulatory Science (SERS) | Unilever 14 Integrating DART Safety Assessment into Existing NGRA Framework: Plasma Cmax PoDin vitro Systemic In Vitro Determination Sufficient Exposure Estimates YES Risk Biological of Bioactivity- Data & Use Scenario Assessment Activity exposure
Slide 15: The DART framework is protective for most high-risk scenarios when using a BER threshold of 1
Safety, Environmental & Regulatory Science (SERS) | Unilever 15 The DART framework is protective for most high-risk scenarios when using a BER threshold of 1 Adult Pregnant Foetal ➢ 16 of the 17 high risk exposure scenarios, as determined by traditional risk assessment methods, are identified as unc
Slide 16: Application of NGRA to occupational safety assessment – challenges
Safety, Environmental & Regulatory Science (SERS) | Unilever 16 Application of NGRA to occupational safety assessment – challenges… • Simultaneous exposure over multiple routes (dermal and inhalation) and limited biomonitoring data to Perceived industry challenges for calibrate PBK models. uptake of
Slide 17: Problem formulation
Safety, Environmental & Regulatory Science (SERS) | Unilever 17 Problem formulation Wood et al., (2024)
Slide 18: Problem formulation, in silico predictions and literature data
Safety, Environmental & Regulatory Science (SERS) | Unilever 18 Problem formulation, in silico predictions and literature data • Sodium-2- hydroxyethane ToxTree sulfonate (SI) is widely used in the manufacture of alkyl isethionate surfactants. • Historical toxicology studies: 90-day oral (NOAEL: 200
Slide 19: Exposure assessment – external
Safety, Environmental & Regulatory Science (SERS) | Unilever 19 Exposure assessment – external:
Slide 20: External exposure assessment
Safety, Environmental & Regulatory Science (SERS) | Unilever 20 External exposure assessment: PROC number: Description: - Life cycle assessment performed to identify relevant Chemical production or refinery in closed process PROC 1 without likelihood of exposure or processes with equivalent containm
Slide 21: Exposure assessment – internal
Safety, Environmental & Regulatory Science (SERS) | Unilever 21 Exposure assessment – internal:
Slide 22: Internal exposure assessment - PBK
Safety, Environmental & Regulatory Science (SERS) | Unilever 22 Internal exposure assessment - PBK • Worst-case Rate of Rate of exposures were systemic Total Worker Dermal Inhalation Max total Duration Exposure Exposure systemic GastroPlus exposure systemic Total contributing exposure exposure time
Slide 23: Internal exposure assessment - PBK
Safety, Environmental & Regulatory Science (SERS) | Unilever 23 Internal exposure assessment - PBK • 3 PBK simulation types – pregnant individual, Cmax 95th percentile Cmax worker and pregnant population. PBK simulation (µM) Mean Cmax (µM) (µM) Single person, deterministic 0.62 - - • Models built us
Slide 24: In Vitro Biological Activity Characterisation
Safety, Environmental & Regulatory Science (SERS) | Unilever 24 In Vitro Biological Activity Characterisation
Slide 25: Limited bioactivity across NAM assays
Safety, Environmental & Regulatory Science (SERS) | Unilever 25 Limited bioactivity across 5 NAM assays: • SI showed limited bioactivity across all Workflow for in vitro disposition data needs assays. • Lowest PoD - transcriptomics (MCF-7 cell line), based on a single probe significantly more sensit
Slide 26: Bioactivity Exposure Ratio Determination and Safety Decision
Safety, Environmental & Regulatory Science (SERS) | Unilever 26 Bioactivity Exposure Ratio Determination and Safety Decision
Slide 27: Bioactivity Exposure Ratio Determination and Safety Decision
Safety, Environmental & Regulatory Science (SERS) | Unilever 27 Bioactivity Exposure Ratio Determination and Safety Decision • Lowest PoD compared with exposure estimates. • Most conservative BER BER BER (calculated from lowest PoD and 95th percentile pregnant population Cmax) was 130. • In combinat
Slide 28: Wrap up
Safety, Environmental & Regulatory Science (SERS) | Unilever 28 Wrap up • Current lack of published examples of application of NGRA to worker safety. • Framework developed here includes multiple options for refinement and is applicable to large subset of substances to which worker exposure occurs. •
Slide 29: Looking to the future…
Safety, Environmental & Regulatory Science (SERS) | Unilever 29 Looking to the future… • EU roadmap towards phasing out animal testing is targeting all relevant pieces of legislation, including worker safety. Greater emphasis of non-animal methods (in guidance and legislation) expected as a result o
Slide 30: Acknowledgements
Safety, Environmental & Regulatory Science (SERS) | Unilever 30 Acknowledgements: NGRA (especially this one) is a multidisciplinary exercise requiring the involvement of a multitude of individuals across a broad range of expertise areas. • SEAC safety scientists: Richard Cubberley, Matt Dent, Jade H