The Long Range Science Strategy (LRSS) of Cosmetics Europe

Transcription

1 The Long Range Science Strategy (LRSS) of Cosmetics Europe Repeated dose systemic toxicity 2016 Bas Blaauboer

2 Aim of LRSS: Development of a strategy to determine safety of cosmetic ingredients and products without the use of animal experimentation.

3 Some Initiatives on Systemic Toxicity

4 Systemic toxicity (banned in EU Cosmetic regulation EC 1233/2009) Determine the fate of chemicals after they reach the systemic circulation and evaluate their effects. Focus on: Repeated-dose systemic toxicity (sub-acute, sub-chronic, chronic): GHS definition, "specific target organ/systemic toxicity arising from a repeated exposure. (OECD TGs (non exhaustive),tgs 407, 408, 410, 411, 412, 413, 422, 452, 453) Evaluation of clinical observations, blood analysis, whole body gross necropsy, and microscopic examination of all organs and tissues (histopathology Primary studies (subacute, subchronic, chronic) Secondary studies (reproductive, developmental, cancer)

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6 RISK21 ILSI/HESI project Strategy based on problem formulation, exposure-driven, use of prior knowledge Flexible, transparent and visual framework with enough precision to make decisions. Figure 1. General conceptual framework of the RISK21 approach (Embry et al. 2014). Douglas C. Wolf; et al; Critical Reviews in Toxicology 2016, 46,

7 EU INITIATIVES ON SYSTEMIC TOXICITY: EXAMPLES Predict IV: FP7: , Improve the predictivity of in vitro systems for unwanted effects of pharmaceutical entities by applying a combination of omics technology in optimized cellular systems along with biokinetic quantification. Focused on 3 target organs of toxicity: liver, kidney and the central nervous system. etox: IMI: , Integrating bioinformatics and chemoinformatics approaches for the development of expert systems allowing the in silico prediction of toxicities Develop a drug safety database from the pharmaceutical industry legacy toxicology reports and public toxicology data; innovative in silico strategies and novel software tools to better predict the toxicological profiles of small molecules in early stages of the drug development pipeline. HeCaTos: FP7: , Hepatic and Cardiac Toxicity Systems modelling, Develop an integrated modeling framework, by combining advances in computational chemistry and systems toxicology, for modelling toxic perturbations in liver and heart across multiple scales.

8 SEURAT-1 / Safety Evaluation Ultimately Replacing Animal Testing FP7: (2016, Coach), Development a concept and a corresponding long-term research strategy for future research and development work leading to pathway based human safety assessments in the field of repeated dose systemic toxicity testing of chemicals. Integrative approach: in vitro data from human cells, from simple 2D models to sophisticated systems (liver bioreactor from Hemibio) and systems biology models (Notox)

9 ILSI-Europe paper on new strategies in food safety evaluation Blaauboer et al. Food and Chemical Toxicology 91 (2016) 19-35

10 The classical risk assessment paradigm 1 Hazard Identification 2 Dose Response In vivo animal data Dosing regime Point of departure Reference dose (NOAEL) 3 Exposure Assessment Exposure scenario Dose estimate 4 Risk Characterization Comparison: Hazard index or MoE

11 The new paradigm 1 Hazard Identification 2 Dose Response In vitro assays ADME Point of departure Reference concentration 3 Exposure Assessment PBBK modelling Target Site exposure QIVIVE 4 Risk Characterization Comparison: Hazard index or MoE

12 A general scheme for an integrated approach

13 Cosmetics Europe Long Range Science Strategy (LRSS) European trade association since 1962, personal care industry Leading role in supporting the development, scientific and political acceptance and finally the use of alternative testing methods and is dedicated to meet the challenges lying ahead Track Record Validation of 11 methods for 4 toxicological effects, applicable across industries Validation of in vitro eye irritation tests Validation of skin allergy methods Over 150 scientific publications & presentations since 2007

14 AAT Strategic Roadmap 2013 Skin Irritation Eye Irritation Genotoxicity Acute Toxicity 2020 Sensitization Systemic Toxicity 2016 Eye Irritation Genotoxicity Skin sensitization Exposure / ADME Systemic Toxicity

15 Our Systematic Rationale Exposure Exposure upon use Local effects Skin, eye irritation Penetration, Metabolism, Excretion Skin penetration, metabolism Bioavailability at systemic target site Systemic Effects Sensitization, genotoxicity (Sub-) chronic toxicity Safety Assessment

16 Cosmetics Europe AAT Programme Field/Taskforce What Finalize Eye Irritation & Genotoxicity Skin Sensitization Refined testing strategies & regulatory acceptance Research, method development & evaluation Tests of mixtures & natural extracts Risk assessment including potency Regulatory acceptance Bioavailability & Metabolism ADME Systemic Toxicity, toxicodynamics Refined assays, database Refined prediction models Expansion to include systemic bioavailability / ADME / biokinetics / PBPK Consumer exposure scenarios Mechanistic understanding & testing Chemoinformatics/In silico tools Safety assessment - from low to higher exposures

17 Strategy Systemic Toxicity Exposure - Kinetics - Hazard Identification - Toxicodynamics - Systemic exposure predictions Mechanistic predictions Fusion Concentration response data Modelling - Case Studies - Safety Assessment Combined evaluation & extrapolation

18 Kinetics / ADME - Objectives Internal exposure For read-across and ab initio risk assessments Enable internal TTCs Guidance for in vitro assays (concentrations, target organs)

19 Kinetics / ADME - Way Forward Exposure In silico Skin Penetration Prediction Models ADME in vitro Toolbox intestinal absorption liver metabolism in vitro biokinetics plasma protein binding Static & Dynamic 3D Skin & Liver Models Internal TTC PBPK ADME Model Read across / ab initio concepts

20 Toxicodynamics - Objectives Discriminate between specific and non specific adversities and low toxicity Determine perturbed biological pathways for repeat dose toxicity Establish quantitative points of departure for use in risk assessment (linked to kinetics)

21 Toxicodynamics - Research Needs Chemoinformatics and data collection system First screen: transcriptomics Mode-of Action Ontology On the basis of this: choice of appropriate battery of in vitro systems Biokinetics in these in vitro systems Quantitative in vitro-in vivo extrapolation

22 Attagene Transcription Factor Profiling 22 Pentachlorophenol 22

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25 Target concentration determinants Comparing effect concentrations Differences between in vitro assays and between in vitro and in vivo assays: evaporation protein binding plastic binding free in medium MEDIUM cell binding CELL metabolism target free free in in cell cell PLASTIC (well) Concentration serum 3D matrix Exposure time Metabolic capacity Cell concentration Well plate dimensions Open vs closed systems.

26 Fusion & Safety Assessment - Case Studies / Modelling / Evaluation - Case Studies as Guiding Principle Concentration response data / modelling Quantitative in vitro-in vivo extrapolation (QIVIVE)

27 Safety assessment framework (Adapted from Berggren et al Publication in preparation) TIER 0: IDENTIFY USE SCENARIO, CHEMICAL OF CONCERN AND COLLECT EXISTING INFORMATION 1. IDENTIFY USE SCENARIO 2. IDENTIFY MOLECULAR STRUCTURE 3. COLLECT EXISTING DATA EXIT TO TTC 4. IDENTIFY ANALOGUES, SUITABILITY ASSESSMENT AND EXITING DATA EXIT TO READ ACROSS TIER 1: HYPOTHESIS FORMULATION 5. SYSTEMIC BIOAVAILABILITY (PARENT VS. METABOLITE(S), TARGET ORGANS, INTERNAL CONCENTRATION) EXIT TO INTERNAL TTC 6. MOA HYPOTHESIS GENERATION (WEIGHT OF EVIDENCE BASED ON AVAILABLE TOOLS) TIER 2: APPLICATION 7A. TARGETED TESTING 7B. BIOKINETIC REFINEMENT (IN VIVO CLEARANCE, POPULATION, IN VITRO STABILITY, PARTITION) 8. POINTS OF DEPARTURE, IN VITRO IN VIVO EXTRAPOLATION, UNCERTAINTY ESTIMATION, MARGIN OF SAFETY 9. FINAL RISK ASSESSMENT OR SUMMARY ON INSUFFICIENT INFORMATION APPROACH EXIT AB INITIO

28 Case studies Caffeine (D. Bury, L Oreal) Benzoic Acid/Benzoate Phenoxyethanol (C. Mahony/M. Dent) Benzophenone and analogues Parabens (proposed case study with Eutoxrisk)

29 Case studies Cases selected on the basis of: - sufficient knowledge on in vivo tox data e.g.: caffeine: Is a substance of widespread use, and has the potential for direct exposure through food, medicines and consumer products. Allows us to establish a proof-of-concept for the use of TK&TD data across a range of safety assessment approaches (driven by exposure and chemical similarity) for a chemical with welldefined safety Allows us to start to seek input on incorporating the LRSS approach for safety assessment from stakeholder and interested groups to build confidence Caffeine used in cosmetics is supported by a robust safety assessment which includes in vivo data.

30 . Proposed management structure for performance of case studies Team leader Core team Small teams of experts for data collection and interpretation Experimental work carried out by contractors, where needed

31 Systemic Toxicity Long Range Science Strategy Strategic vision Strategic mission The Industry programme to innovate and defend cosmetic ingredient safety To assess safety of cosmetic ingredients after repeated exposure (replacing repeat dose toxicity animal tests) Strategic pillars Guiding Case Studies (moving increasingly away from reliance on animal data) Deliver New Solutions Leverage existing and develop new science Safeguard Output & Support Disseminate and win regulatory acceptance Secure Resources Goals Develop workflows and address uncertainty Set up read across cases(s) to leverage existing toxicological data and apply new TD and TK methods and data Set up internal TTC to leverage exposure based waiving approach and apply new method TK data (heading in direction of applying new method TD data) Set up ab initio case(s) without relying on existing animal data and to fully leverage new TD and TK methods and data Connect in vitro points of departure to equivalent systemic exposure for use in safety assessment Employ models / measure in vitro biokinetics to correlate effective concentrations across toxicity assays and perform PBPK reverse-modelling to extrapolate in vitro concentrations to in vivo dose-response relationships Invest in TD work stream to connect molecular/cellular effects to higher order outcomes (human relevant to the extent possible) Develop mode of action ontology to understand mechanisms relevant to cosmetic chemical space (and associated activity cliffs) Generate transcriptomics data (or other high throughput/content data) that broadly spans mechanisms relevant to mode of action predictions Employ Cheminformatics tool(s) to link chemistry and biological data and support toxicity alert predictions Use targeted assays when needed to derive quantitative point(s) of departure Invest in TK work stream to connect absorption, distribution, metabolism and excretion to systemic exposure predictions (starting with dermal route of exposure and route to route extrapolation) Obtain accurate external consumer exposure data as input to exposure assessment Employ in silico skin penetration & PBPK models to predict systemically available concentrations and TK profiles after topical application. Generate in vitro ADME data to enhance model(s) performance for cosmetic relevant chemicals Evaluate models for oral and inhalation routes of exposure Qualify and employ skin and liver dynamic system to measure effects of topical and systemic repeat and single doses on metabolism of cosmetic chemicals Establish Scientific Advisory Board Convene eminent scientists and stakeholders on an annual basis Publish and Present Deliver peer review publications, organise sessions and present at scientific conferences and workshops Inform via CE website and newsletter Win with Regulators Establish forum for sharing of scientific approaches and results Establish an easy process for ideas Provide outstanding management support at programme and project level Support partners to leverage and extend our program incl. protocols, guidelines Operating principles Build from available knowledge Invent where needed and reasonably feasible Work in Partnerships

32 Acknowledgement Bertrand Desprez Martina Klaric Gladys Ouédraogo Catherine Mahony Members of the Task Forces on Kinetics and Toxicodynamics