Paving the way for application of next generation risk assessment to safety decision-making for cosmetic ingredients

Dent, Matthew; Vaillancourt, Eric; Thomas, Russell S.; Carmichael, Paul L.; Ouédraogo, Gladys; Kojima, Hajime; Barroso, José G.; Ansell, Jay; Barton-Maclaren, Tara S.; Bennekou, Susanne Hougaard; Boekelheide, Kim; Ezendam, Janine; Field, J.G.; Fitzpatrick, Suzanne; Hatao, Masato; Kreiling, Reinhard; Lorencini, Márcio; Mahony, Catherine; Montemayor, Beta; Mazaro-Costa, Renata; Oliveira, Jonas Santana-de; Rogiers, Vera; Smegal, D.; Taalman, R. D. F. M.; Tokura, Y.; Verma, Rajeshwar P.; Willett, Catherine; Yang, Chihae

doi:10.1016/j.yrtph.2021.105026

Cited by 40 publications

(35 citation statements)

References 45 publications

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“…Regarding which methods and tools are already mature and can be implemented in the near future, it was recommended to consult the ICCR work summary on integrated strategies for the safety assessment of cosmetic ingredients (Dent, Vaillancourt et al 2021). Although, this analysis is about cosmetics, it might be relevant for food and feed as well.…”

Section: Summary Of Workhop Discussionmentioning

confidence: 99%

Development of a Roadmap for Action on New Approach Methodologies in Risk Assessment

Escher

Partosch

Konzok

et al. 2022

EFSA Supporting Publications

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While whole animal studies have their place in risk assessment of food and feed components, it is thought that more modern approaches such as human focused new approached methodologies (NAMs) would bring advantages including a greater focus to the human species, a focus on molecular mechanism and kinetics and the possibility of addressing susceptible populations. This report outlines the thinking from the authors and culminates in activity proposals in seven distinct but interacting scientific areas i.e. development of additional AOPs/AOP networks (AOPs), advanced cell culture models including Organ on a chip (OoC), toxicokinetic assessment with a focus on physiological based kinetic modelling (PBK), exposome, human susceptibility, data integration and new concepts in human risk assessment. Furthermore, the development of a Forum is proposed to facilitate the implementation of new approaches and concepts in risk assessment. The report was compiled by the project team, renowned experts in the various areas, and recommendations were discussed with EFSA and further refined following consultation with external experts via a dedicated workshop. The authors are convinced that if the recommendations are taken up, there will be a significant impact in the field, resulting in increasing the uptake and utilisation of these emerging technologies by all stakeholders involved.

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Section: Summary Of Workhop Discussionmentioning

confidence: 99%

Development of a Roadmap for Action on New Approach Methodologies in Risk Assessment

Escher

Partosch

Konzok

et al. 2022

EFSA Supporting Publications

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“…A workshop reviewing the application of the nine ICCR principles to NGRA case studies and how can these principles build confidence in safety decision making, using NAMs, identified the evaluation of the biological coverage as one of the seven areas that would help to make NGRA useful for cosmetic ingredients ( Dent et al, 2021 ). Either using a multitude of cell and tissue types or focussing on key pathways and mechanisms of concern irrespective of the origin of the cell type are two approaches that can be used alternatively or in combination to address safety concerns.…”

Section: Discussionmentioning

confidence: 99%

Beyond AOPs: A Mechanistic Evaluation of NAMs in DART Testing

et al. 2022

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New Approach Methodologies (NAMs) promise to offer a unique opportunity to enable human-relevant safety decisions to be made without the need for animal testing in the context of exposure-driven Next Generation Risk Assessment (NGRA). Protecting human health against the potential effects a chemical may have on embryo-foetal development and/or aspects of reproductive biology using NGRA is particularly challenging. These are not single endpoint or health effects and risk assessments have traditionally relied on data from Developmental and Reproductive Toxicity (DART) tests in animals. There are numerous Adverse Outcome Pathways (AOPs) that can lead to DART, which means defining and developing strict testing strategies for every AOP, to predict apical outcomes, is neither a tenable goal nor a necessity to ensure NAM-based safety assessments are fit-for-purpose. Instead, a pragmatic approach is needed that uses the available knowledge and data to ensure NAM-based exposure-led safety assessments are sufficiently protective. To this end, the mechanistic and biological coverage of existing NAMs for DART were assessed and gaps to be addressed were identified, allowing the development of an approach that relies on generating data relevant to the overall mechanisms involved in human reproduction and embryo-foetal development. Using the knowledge of cellular processes and signalling pathways underlying the key stages in reproduction and development, we have developed a broad outline of endpoints informative of DART. When the existing NAMs were compared against this outline to determine whether they provide comprehensive coverage when integrated in a framework, we found them to generally cover the reproductive and developmental processes underlying the traditionally evaluated apical endpoint studies. The application of this safety assessment framework is illustrated using an exposure-led case study.

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“…The industry has decades of commitment in promoting the use of alternatives to animal testing for safety assessment of cosmetics and has been at the forefront of the development and use of non-animal testing methods for safety assessment. One approach to allow animal-free decision-making is “Next generation risk assessment” (NGRA), which is an exposure-led and hypothesis-driven tiered workflow designed to prevent harm to humans ( Dent et al, 2021 ). One of the principles underpinning the NGRA of cosmetic ingredients is that it is only conducted following an appraisal of all existing information, which may already be sufficient to make a safety decision.…”

Section: Discussionmentioning

confidence: 99%

Use of Physiologically-Based Kinetics Modelling to Reliably Predict Internal Concentrations of the UV Filter, Homosalate, After Repeated Oral and Topical Application

et al. 2022

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Ethical and legal considerations have led to increased use of non-animal methods to evaluate the safety of chemicals for human use. We describe the development and qualification of a physiologically-based kinetics (PBK) model for the cosmetic UV filter ingredient, homosalate, to support its safety without the need of generating further animal data. The intravenous (IV) rat PBK model, using PK-Sim®, was developed and validated using legacy in vivo data generated prior to the 2013 EU animal-testing ban. Input data included literature or predicted physicochemical and pharmacokinetic properties. The refined IV rat PBK model was subject to sensitivity analysis to identify homosalate-specific sensitive parameters impacting the prediction of Cmax (more sensitive than AUC(0-∞)). These were then considered, together with population modeling, to calculate the confidence interval (CI) 95% Cmax and AUC(0-∞). Final model parameters were established by visual inspection of the simulations and biological plausibility. The IV rat model was extrapolated to oral administration, and used to estimate internal exposures to doses tested in an oral repeated dose toxicity study. Next, a human PBK dermal model was developed using measured human in vitro ADME data and a module to represent the dermal route. Model performance was confirmed by comparing predicted and measured values from a US-FDA clinical trial (Identifier: NCT03582215, https://clinicaltrials.gov/). Final exposure estimations were obtained in a virtual population and considering the in vitro and input parameter uncertainty. This model was then used to estimate the Cmax and AUC(0–24 h) of homosalate according to consumer use in a sunscreen. The developed rat and human PBK models had a good biological basis and reproduced in vivo legacy rat and human clinical kinetics data. They also complied with the most recent WHO and OECD recommendations for assessing the confidence level. In conclusion, we have developed a PBK model which predicted reasonably well the internal exposure of homosalate according to different exposure scenarios with a medium to high level of confidence. In the absence of in vivo data, such human PBK models will be the heart of future completely non-animal risk assessments; therefore, valid approaches will be key in gaining their regulatory acceptance.Clinical Trial Registration: https://clinicaltrials.gov/, identifier, NCT03582215

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Paving the way for application of next generation risk assessment to safety decision-making for cosmetic ingredients

Cited by 40 publications

References 45 publications

Development of a Roadmap for Action on New Approach Methodologies in Risk Assessment

Development of a Roadmap for Action on New Approach Methodologies in Risk Assessment

Beyond AOPs: A Mechanistic Evaluation of NAMs in DART Testing

Use of Physiologically-Based Kinetics Modelling to Reliably Predict Internal Concentrations of the UV Filter, Homosalate, After Repeated Oral and Topical Application

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