Development of a next generation risk assessment framework for the evaluation of skin sensitisation of cosmetic ingredients

Gilmour, Nicola; Kern, Petra; Alépée, Nathalie; Boislève, Fanny; Bury, Dagmar; Clouet, Elodie; Hirota, Morihiko; Hoffmann, Sebastian; Kühnl, Jochen; Lalko, J.; Mewes, Karsten; Miyazawa, Masaaki; Nishida, Hayato; Osmani, Anne; Petersohn, Dirk; Sekine, Satoshi; Vliet, Erwin van; Klarić, Martina

doi:10.1016/j.yrtph.2020.104721

Cited by 55 publications

(38 citation statements)

References 112 publications

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“…For a qualitative judgment, testing along AOP KEs will be helpful, especially, if a prediction model can be developed that integrates the data from the assays into an overall prediction. Such a process requires many in vivo data to be available for calibration, and it is being explored at present for the skin sensitization assay (Gilmour et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors

et al. 2021

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Inhibition of complex I of the mitochondrial respiratory chain (cI) by rotenone and methyl-phenylpyridinium (MPP +) leads to the degeneration of dopaminergic neurons in man and rodents. To formally describe this mechanism of toxicity, an adverse outcome pathway (AOP:3) has been developed that implies that any inhibitor of cI, or possibly of other parts of the respiratory chain, would have the potential to trigger parkinsonian motor deficits. We used here 21 pesticides, all of which are described in the literature as mitochondrial inhibitors, to study the general applicability of AOP:3 or of in vitro assays that are assessing its activation. Five cI, three complex II (cII), and five complex III (cIII) inhibitors were characterized in detail in human dopaminergic neuronal cell cultures. The NeuriTox assay, examining neurite damage in LUHMES cells, was used as in vitro proxy of the adverse outcome (AO), i.e., of dopaminergic neurodegeneration. This test provided data on whether test compounds were unspecific cytotoxicants or specifically neurotoxic, and it yielded potency data with respect to neurite degeneration. The pesticide panel was also examined in assays for the sequential key events (KE) leading to the AO, i.e., mitochondrial respiratory chain inhibition, mitochondrial dysfunction, and disturbed proteostasis. Data from KE assays were compared to the NeuriTox data (AO). The cII-inhibitory pesticides tested here did not appear to trigger the AOP:3 at all. Some of the cI/cIII inhibitors showed a consistent AOP activation response in all assays, while others did not. In general, there was a clear hierarchy of assay sensitivity: changes of gene expression (biomarker of neuronal stress) correlated well with NeuriTox data; mitochondrial failure (measured both by a mitochondrial membrane potential-sensitive dye and a respirometric assay) was about 10–260 times more sensitive than neurite damage (AO); cI/cIII activity was sometimes affected at > 1000 times lower concentrations than the neurites. These data suggest that the use of AOP:3 for hazard assessment has a number of caveats: (i) specific parkinsonian neurodegeneration cannot be easily predicted from assays of mitochondrial dysfunction; (ii) deriving a point-of-departure for risk assessment from early KE assays may overestimate toxicant potency.

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Section: Discussionmentioning

confidence: 99%

Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors

et al. 2021

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“…3), including formal confidence assessment 47 (OECD 2014) -availability of NAMs for the AOP events, many as OECD Test Guidelines (OECD 2018a,b, 2020) -well-characterized NAMs, e.g., limitations, reproducibility, etc. (Hoffmann et al, 2018) -availability of testing strategies, so-called defined approaches (DA) (Kleinstreuer et al, 2018b) -next generation skin sensitization risk assessment (NGRA) approach of cosmetic ingredients (Gilmour et al, 2020) ficult to compare, are accumulating. We are facing this problem in more and more risk assessments, just thinking of tens of thousands of publications on bisphenol A, for example.…”

Section: Fig 2: Increasing Confidence In New Approach Methodologies (...mentioning

confidence: 99%

Probabilistic risk assessment – the keystone for the future of toxicology

Maertens

2022

ALTEX

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apparently deterministic expressions of results (classifications, labels, thresholds, etc.). It is not that we cannot know, but that our predictions have only a certain probability of being correct -not very comforting when the safety of sometimes millions of patients and consumers is at stake.The 2017 book The Illusion of Risk Control -What Does it Take to Live with Uncertainty? edited by Gilles Motet and Corinne Bieder, makes the important point of acknowledging that there is always a risk and that we can only assess and manage its probability. Consequently, safety is defined by the absence of unacceptable risk, not as the absence of all risk. Giving up on

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“…For testing of cosmetics ingredients, skin sensitisation is considered among the most relevant endpoints due to the high frequency of allergic reactions among the undesirable effects of cosmetic products. Notably, recent efforts have been made by the cosmetic industry to develop a non-animal, next generation risk assessment (NGRA) framework for the assessment of skin sensitisers (Gilmour et al 2020 ).…”

Section: Current Eu Regulatory Requirements Of Relevance For the Safety Assessment Of Chemicals And Cosmetic Productsmentioning

confidence: 99%

Current EU regulatory requirements for the assessment of chemicals and cosmetic products: challenges and opportunities for introducing new approach methodologies

et al. 2021

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The EU Directive 2010/63/EU on the protection of animals used for scientific purposes and other EU regulations, such as REACH and the Cosmetic Products Regulation advocate for a change in the way toxicity testing is conducted. Whilst the Cosmetic Products Regulation bans animal testing altogether, REACH aims for a progressive shift from in vivo testing towards quantitative in vitro and computational approaches. Several endpoints can already be addressed using non-animal approaches including skin corrosion and irritation, serious eye damage and irritation, skin sensitisation, and mutagenicity and genotoxicity. However, for systemic effects such as acute toxicity, repeated dose toxicity and reproductive and developmental toxicity, evaluation of chemicals under REACH still heavily relies on animal tests. Here we summarise current EU regulatory requirements for the human health assessment of chemicals under REACH and the Cosmetic Products Regulation, considering the more critical endpoints and identifying the main challenges in introducing alternative methods into regulatory testing practice. This supports a recent initiative taken by the International Cooperation on Alternative Test Methods (ICATM) to summarise current regulatory requirements specific for the assessment of chemicals and cosmetic products for several human health-related endpoints, with the aim of comparing different jurisdictions and coordinating the promotion and ultimately the implementation of non-animal approaches worldwide. Recent initiatives undertaken at European level to promote the 3Rs and the use of alternative methods in current regulatory practice are also discussed.

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Development of a next generation risk assessment framework for the evaluation of skin sensitisation of cosmetic ingredients

Cited by 55 publications

References 112 publications

Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors

Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors

Probabilistic risk assessment – the keystone for the future of toxicology

Current EU regulatory requirements for the assessment of chemicals and cosmetic products: challenges and opportunities for introducing new approach methodologies

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