Progressing Non-Animal Approaches to Safety in India Adip Roy 1 , Gaurav Jain 1 , Paul Carmichael 2 and Andrew White 2 1 - Safety & Environmental Assurance Centre, Unilever R&D, 64 Main Road, Whitefield, Bangalore – 560066 2 - Safety & Environmental Assurance Centre, Colworth Science Park, Sharnbrook, Beds, UK – MK44 1LQ
SEAC ‘ Safety & Environmental Assurance Centre ’ Provide authoritative scientific evidence and expertise so that Unilever can identify and manage: • Risks for consumers, workers and environment • Safety of products and supply chain technology • Environmental impacts • Sustainability of Unilever’s brands, products & supply chain Colworth Science Park, UK
Ingredient Risk Assessment For any ingredient safety Risk Assessment is a function of: » Hazard – potential harmful effects • Intrinsic hazard of material • Safety concerns due to functionality » Exposure – how much will the consumer be exposed to? • Normal habits & practices • Amount of ingredient in product
Exposure Assessment Risk = Hazard x Exposure Aim is to identify Consumer Exposure Level (CEL) Initial steps in the exposure assessment are: • Determine product type/format • Amount of product per use. • Frequency of use. • Level of ingredient in product. Determination of the product type informs on the potential route(s) of exposure.
Can We Use A New Ingredient Safely? Will it be safe • For our consumers? • For our workers? • For the environment? Can we use x% of ingredient y in product z?
Toxicity Endpoints (Human Health) Relevant toxicity endpoints based on the Scientific Committee on Consumer Products guidance document “Notes of Guidance for the Testing of Cosmetic Substances and their Safety Evaluation” • Acute toxicity • Corrosivity and irritation • Skin sensitisation • Dermal/percutaneous absoprtion • Repeated dose toxicity • Reproductive toxicity • Mutagenicity/genotoxicity • Carcinogenicity • Toxicokinetic studies • Photo-induced toxicity
How Do We Assure Safety of Ingredients Legislation (in place in most countries) requires Companies to ensure that any cosmetic products they put on the market do not cause any adverse health effects when applied under normal or reasonably foreseeable conditions of use. Regardless of whether legislation exists or not, Unilever requires that all products it places on the market must be safe for use We use scientific evidence-based risk assessment methodologies to ensure that the risk of adverse health and/or environmental effects from exposure to chemicals used in our products is acceptably low . Acceptable Unacceptable risk risk
Safety Assessment Process for Ingredients in Consumer Products Consider product type and consumer habits Identify available Identify supporting toxicology data safety data (e.g. QSAR, HoSU) Determine route and amount of exposure Identify toxicological Evaluate required vs. endpoints of potential available support concern Identify critical end Conduct toxicology point(s) for risk testing as required assessment Overall safety evaluation for Conduct risk assessment product – define acceptability for each critical endpoint and risk management measures
Safety Assessment Process for Ingredients in Consumer Products Consider product type and consumer habits Identify available Identify supporting toxicology data safety data (e.g. QSAR, HoSU) Determine route and amount of exposure Identify toxicological Evaluate required vs. endpoints of potential available support concern Identify critical end Conduct toxicology point(s) for risk testing as required assessment Overall safety evaluation for Conduct risk assessment product – define acceptability for each critical endpoint and risk management measures
Available Non-animal Alternatives OECD TG438 OECD TG432 % control NRU 120 110 100 90 80 70 60 EC50 level 50 40 30 20 10 OECD TG430/431 0 0.1 1 10 100 1000 10000 OECD TG437 Concentration m g/ml OECD TG439 Eye Irritation Skin Corrosion/Irritation Phototoxicity OECD TG473 Donor Skin chamber position Receptor solution in Receptor Window chamber Receptor OECD TG471 solution OECD TG428 out OECD TG476 Genotoxicity Skin Penetration
Current Scientific Reality: Non-animal Approaches For Safety Decisions Timeline for Replacement of Animal Human Health Testing Comments Toxicology Endpoint [Note: Regulatory Acceptance would require an additional 4-8 years] Repeated dose toxicity No timeline for full replacement could Ongoing work still at research stage be foreseen Current in vitro test methods are No timeline for full replacement could inadequate for generating the dose- Carcinogenicity be foreseen response information required for safety assessment Several non-animal test methods under development & evaluation; data 2017 – 2019 for full replacement Skin Sensitisation integration approaches for safety assessment required Ongoing work still at research stage No timeline for full replacement could Reproductive Toxicity >2020 to identify key biological be foreseen pathways Ongoing work still at research stage No timeline for full replacement could Toxicokinetics 2015 – 2017: prediction of renal & be foreseen biliary excretion and lung absorption Adler et al (2011), Archives in Toxicology, 85 (5) 367-485
New Approaches to Risk Assessment Without Animals » focus on non-animal approaches for consumer safety risk assessment » data required for safety decision should be driver » dose response information is essential » understanding the underpinning human biology » we are not looking for a way to do the animal test without the animal
US NRC Report June 2007 “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.”
Perturbation of Toxicity Pathways Exposure Tissue Dose Low Dose Higher Dose Biologic Interaction Higher yet Perturbation Normal Biologic Biologic Inputs Function Early Cellular Changes Adaptive Stress Morbidity Cell Responses Injury and Mortality (From Andersen & Krewski, 2009, Tox Sci, 107 , 324)
TT21C Exposure & Consumer Use Assessment Chemistry-led alerts & in vitro High-content information in vitro screening assays in human cells & models Dose-response assessments Computational models of the circuitry of the relevant toxicity pathways PBPK models supporting in vitro to in vivo extrapolations Risk assessment based on exposures below the levels of significant pathway perturbations
Adverse Outcome Pathways (AOP) • Proposal for a template and guidance on developing and assessing the Completeness of Adverse Outcome Pathways Adapted from OECD (2012)
Adverse Outcome Pathway (AOP) • An adverse outcome pathway (AOP) is the sequence of events from the chemical structure of a target chemical through the molecular initiating event to an in vivo outcome of interest. • It is the ‘capture’ of the mechanistic processes that initiate and progress through the levels of biology to give rise to toxicity in living organisms for given chemical toxins. • Each AOP represents the existing knowledge of the linkage(s) between a molecular initiating event, intermediate events and an adverse outcome at the individual or population level.
Research on Animal Alternatives in India
Research on Animal Alternatives in India
Research on Animal Alternatives in India Identification of Drosophila-based endpoints for the assessment and understanding of xenobiotic-mediated male reproductive adversities. Misra S, Singh A, Sharma V, Reddy Mudiam MK, Ram KR. Toxicol Sci. 2014 Sep;141(1):278-91. Invertebrate Alternatives for Toxicity Testing: Hydra Stakes its Claim Vidya Patwardhan and Surendra Ghaskadbi ALTEX Proceedings 2, 1/13, Proceedings of Animal Alternatives in Teaching, Toxicity Testing and Medicine Environmental chemical mediated male reproductive toxicity: Drosophila melanogaster as an alternate animal model A.K. Tiwari, P. Pragya, K. Ravi Rama, D. Kar Chowdhuri Theriogenology 76 (2011) 197 – 216
Oxidative stress as a classical case study for Adaptive responses An existing biochemical circuit in the cell that, when sufficiently perturbed, is expected to result in an adverse health effect. Exposure Tissue Dose Biological Interaction Perturbation Normal Biological Biological Inputs Function Adaptive Stress Altered Responses and Cellular Homeostasis Responses Cell Adverse Dysfunction Health Outcomes Adapted from Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences
Oxidative stress AOP understanding complex interactions Modified network of oxidative stress as depicted by sbv improver. https://sbvimprover.com/
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