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

2021 ◽  
Author(s):  
Francesca Pistollato ◽  
Federica Madia ◽  
Raffaella Corvi ◽  
Sharon Munn ◽  
Elise Grignard ◽  
...  
Keyword(s):  
Human Health ◽  
Developmental Toxicity ◽  
Toxicity Testing ◽  
Alternative Methods ◽  
Cosmetic Products ◽  
Animal Testing ◽  
Regulatory Requirements ◽  
Eu Directive

AbstractThe 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.

A Study on UV Filter Chemicals from Annex VII of European Union Directive 76/768/EEC, in the In Vitro 3T3 NRU Phototoxicity Test

1998 ◽  
Vol 26 (5) ◽  
pp. 679-708 ◽  
Author(s):  
Horst Spielmann ◽  
Michael Balls ◽  
Jack Dupuis ◽  
Wolfgang J. W. Pape ◽  
Odile de Silva ◽  
...  
Keyword(s):  
Neutral Red ◽  
Optimum Concentration ◽  
Alternative Methods ◽  
Uv Filter ◽  
Eu Directive ◽  
Optimum Concentration Range ◽  
The Impact ◽  
Positive Results

In 1996, the Scientific Committee on Cosmetology of DGXXIV of the European Commission asked the European Centre for the Validation of Alternative Methods to test eight UV filter chemicals from the 1995 edition of Annex VII of Directive 76/768/EEC in a blind trial in the in vitro 3T3 cell neutral red uptake phototoxicity (3T3 NRU PT) test, which had been scientifically validated between 1992 and 1996. Since all the UV filter chemicals on the positive list of EU Directive 76/768/EEC have been shown not to be phototoxic in vivo in humans under use conditions, only negative effects would be expected in the 3T3 NRU PT test. To balance the number of positive and negative chemicals, ten phototoxic and ten non-phototoxic chemicals were tested under blind conditions in four laboratories. Moreover, to assess the optimum concentration range for testing, information was provided on appropriate solvents and on the solubility of the coded chemicals. In this study, the phototoxic potential of test chemicals was evaluated in a prediction model in which either the Photoirritation Factor (PIF) or the Mean Photo Effect (MPE) were determined. The results obtained with both PIF and MPE were highly reproducible in the four laboratories, and the correlation between in vitro and in vivo data was almost perfect. All the phototoxic test chemicals provided a positive result at concentrations of 1μg/ml, while nine of the ten non-phototoxic chemicals gave clear negative results, even at the highest test concentrations. One of the UV filter chemicals gave positive results in three of the four laboratories only at concentrations greater than 100μg/ml; the other laboratory correctly identified all 20 of the test chemicals. An analysis of the impact that exposure concentrations had on the performance of the test revealed that the optimum concentration range in the 3T3 NRU PT test for determining the phototoxic potential of chemicals is between 0.1μg/ml and 10μg/ml, and that false positive results can be obtained at concentrations greater than 100μg/ml. Therefore, the positive results obtained with some of the UV filter chemicals only at concentrations greater than 100μg/ml do not indicate a phototoxic potential in vivo. When this information was taken into account during calculation of the overall predictivity of the 3T3 NRU PT test in the present study, an almost perfect correlation of in vitro versus in vivo results was obtained (between 95% and 100%), when either PIF or MPE were used to predict the phototoxic potential. The management team and participants therefore conclude that the 3T3 NRU PT test is a valid test for correctly assessing the phototoxic potential of UV filter chemicals, if the defined concentration limits are taken into account.

scholarly journals Predicting the in vivo developmental toxicity of benzo[a]pyrene (BaP) in rats by an in vitro–in silico approach

2021 ◽  
Author(s):  
Danlei Wang ◽  
Maartje H. Rietdijk ◽  
Lenny Kamelia ◽  
Peter J. Boogaard ◽  
Ivonne M. C. M. Rietjens
Keyword(s):  
Dose Response ◽  
In Silico ◽  
Response Curve ◽  
Developmental Toxicity ◽  
Toxicity Testing ◽  
Maximal Effect ◽  
Blood Concentrations ◽  
Reverse Dosimetry

AbstractDevelopmental toxicity testing is an animal-intensive endpoints in toxicity testing and calls for animal-free alternatives. Previous studies showed the applicability of an in vitro–in silico approach for predicting developmental toxicity of a range of compounds, based on data from the mouse embryonic stem cell test (EST) combined with physiologically based kinetic (PBK) modelling facilitated reverse dosimetry. In the current study, the use of this approach for predicting developmental toxicity of polycyclic aromatic hydrocarbons (PAHs) was evaluated, using benzo[a]pyrene (BaP) as a model compound. A rat PBK model of BaP was developed to simulate the kinetics of its main metabolite 3-hydroxybenzo[a]pyrene (3-OHBaP), shown previously to be responsible for the developmental toxicity of BaP. Comparison to in vivo kinetic data showed that the model adequately predicted BaP and 3-OHBaP blood concentrations in the rat. Using this PBK model and reverse dosimetry, a concentration–response curve for 3-OHBaP obtained in the EST was translated into an in vivo dose–response curve for developmental toxicity of BaP in rats upon single or repeated dose exposure. The predicted half maximal effect doses (ED50) amounted to 67 and 45 mg/kg bw being comparable to the ED50 derived from the in vivo dose–response data reported for BaP in the literature, of 29 mg/kg bw. The present study provides a proof of principle of applying this in vitro–in silico approach for evaluating developmental toxicity of BaP and may provide a promising strategy for predicting the developmental toxicity of related PAHs, without the need for extensive animal testing.

Integrated Decision-tree Testing Strategies for Environmental Toxicity with Respect to the Requirements of the EU REACH Legislation

2008 ◽  
Vol 36 (1_suppl) ◽  
pp. 29-42 ◽  
Author(s):  
Christina Grindon ◽  
Robert Combes ◽  
Mark T.D. Cronin ◽  
David W. Roberts ◽  
John F. Garrod
Keyword(s):  
Risk Assessment ◽  
Decision Tree ◽  
Aquatic Toxicity ◽  
Toxicity Testing ◽  
Threshold Concentration ◽  
Alternative Methods ◽  
The European Union ◽  
Animal Testing ◽  
Testing Strategies

Liverpool John Moores University and FRAME recently conducted a research project sponsored by Defra on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This paper focuses on the prospects for using alternative methods (both in vitro and in silico) for environmental (aquatic) toxicity testing. The manuscript reviews tests based on fish cells and cell lines, fish embryos, lower organisms, and the many expert systems and QSARs for aquatic toxicity testing. Ways in which reduction and refinement measures can be used are also discussed, including the Upper Threshold Concentration — Step Down (UTC) approach, which has recently been retrospectively validated by ECVAM and subsequently endorsed by the ECVAM Scientific Advisory Committee (ESAC). It is hoped that the application of this approach could reduce the number of fish used in acute toxicity studies by around 65–70%. Decision-tree style integrated testing strategies are also proposed for acute aquatic toxicity and chronic toxicity (including bioaccumulation), followed by a number of recommendations for the future facilitation of aquatic toxicity testing with respect to environmental risk assessment.

Workshop Proceedings

2013 ◽  
Vol 32 (1) ◽  
pp. 4-10 ◽  
Author(s):  
Nicola J. Stagg ◽  
Hanan N. Ghantous ◽  
Gregory S. Ladics ◽  
Robert V. House ◽  
Steven M. Gendel ◽  
...  
Keyword(s):  
San Francisco ◽  
Immunoglobulin E ◽  
The Novel ◽  
Animal Testing ◽  
Regulatory Requirements ◽  
Challenges And Opportunities ◽  
Protein Allergenicity ◽  
Regulate Protein

A workshop entitled “Challenges and Opportunities in Evaluating Protein Allergenicity across Biotechnology Industries” was held at the 51st Annual Meeting of the Society of Toxicology (SOT) in San Francisco, California. The workshop was sponsored by the Biotechnology Specialty Section of SOT and was designed to present the science-based approaches used in biotechnology industries to evaluate and regulate protein allergenicity. A panel of experts from industry and government highlighted the allergenicity testing requirements and research in the agricultural, pharmaceutical/biopharma, and vaccine biotechnology industries and addressed challenges and opportunities for advancing the science of protein allergenicity. The main learning from the workshop was that immunoglobulin E-mediated allergenicity of biotechnology-derived products is difficult to assess without human data. The approaches currently being used to evaluate potential for allergenicity across biotechnology industries are very different and range from bioinformatics, in vitro serology, in vivo animal testing, in vitro and in vivo functional assays, and “biosimilar” assessments (ie, biotherapeutic equivalents to innovator products). The challenge remains with regard to the different or lack of regulatory requirements for allergenicity testing across industries, but the novel approaches being used with bioinformatics and biosimilars may lead to opportunities in the future to collaborate across biotechnology industries.

Integrated Decision-tree Testing Strategies for Developmental and Reproductive Toxicity with Respect to the Requirements of the EU REACH Legislation

2008 ◽  
Vol 36 (1) ◽  
pp. 65-80 ◽  
Author(s):  
Christina Grindon ◽  
Robert Combes ◽  
Mark T.D. Cronin ◽  
David W. Roberts ◽  
John F. Garrod
Keyword(s):  
Risk Assessment ◽  
Decision Tree ◽  
Endocrine Disruption ◽  
Reproductive Toxicity ◽  
Toxicity Testing ◽  
Alternative Methods ◽  
The European Union ◽  
Animal Testing ◽  
Testing Strategies

Liverpool John Moores University and FRAME conducted a research project, sponsored by Defra, on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This paper focuses on the prospects for the use of alternative methods (both in vitro and in silico) in developmental and reproductive toxicity testing. It considers many tests based on primary cells and cell lines, and the available expert systems and QSARs for developmental and reproductive toxicity, and also covers tests for endocrine disruption. Ways in which reduction and refinement measures can be used are also discussed, particularly the use of an enhanced one-generation reproductive study, which could potentially replace the two-generation study, and therefore considerably reduce the number of animals required in reproductive toxicity. Decision-tree style integrated testing strategies are also proposed for developmental and reproductive toxicity and for endocrine disruption, followed by a number of recommendations for the future facilitation of developmental and reproductive toxicity testing, with respect to human risk assessment.

Molecular Targets and Early Response Biomarkers for the Prediction of Developmental Toxicity In Vitro

2007 ◽  
Vol 35 (3) ◽  
pp. 335-342 ◽  
Author(s):  
Michael Stigson ◽  
Kim Kultima ◽  
Måns Jergil ◽  
Birger Scholz ◽  
Henrik Alm ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Developmental Toxicity ◽  
Molecular Targets ◽  
Toxicity Testing ◽  
Early Response ◽  
In Vitro Tests ◽  
In Vivo Models ◽  
Response Biomarkers

There is an urgent need for new in vitro methods to predict the potential developmental toxicity of candidate drugs in the early lead identification and optimisation process. This would lead to a reduction in the total number of animals required in full-scale developmental toxicology studies, and would improve the efficiency of drug development. However, suitable in vitro systems permitting robust high-throughput screening for this purpose, for the most part, remain to be designed. An understanding of the mechanisms involved in developmental toxicity may be essential for the validation of in vitro tests. Early response biomarkers — even a single one — could contribute to reducing assay time and facilitating automation. The use of toxicogenomics approaches to study in vitro and in vivo models in parallel may be a powerful tool in defining such mechanisms of action and the molecular targets of toxicity, and also for use in finding possible biomarkers of early response. Using valproic acid as a model substance, the use of DNA microarrays to identify teratogen-responsive genes in cell models is discussed. It is concluded that gene expression in P19 mouse embryocarcinoma cells represents a potentially suitable assay system, which could be readily used in a tiered testing system for developmental toxicity testing.

Recent Progress in the Eye Irritation Test

1993 ◽  
Vol 9 (6) ◽  
pp. 1017-1025 ◽  
Author(s):  
Ih Chu ◽  
Peter Toft
Keyword(s):  
Animal Studies ◽  
In Vitro Tests ◽  
Animal Testing ◽  
Regulatory Requirements ◽  
Eye Irritation ◽  
Significant Development ◽  
In Vivo Test ◽  
Irritation Test

The rabbit eye irritation test based on the Draize method is required for the hazard assessment of chemicals and products that may come into contact with the eye. Due to the potential for the suffering of animals and subjectivity of the test, many modifications of the method have been made that involved a reduction in the number of animals and a refinement of techniques. Additionally, there has been significant development of in vitro alternatives. This paper reviews recent advances in the in vivo test and in vitro alternatives, as well as regulatory requirements. While the refinement of in vivo protocols has resulted in a reduction in the number and discomfort on animals, the development of in vitro alternatives could lead to an eventual replacement of animal studies. In view of the inherent simplicity of many in vitro methods, some of which comprise cell cultures, further research into the relevance/mechanism of effects is required. Batteries of in vitro tests, when properly validated, may be considered as replacements for animal testing.

A New Bioassay Including a Small Scale Hepatocyte Bioreactor for Hepato-Mediated Toxicity Testing in a Target Cell Line

2002 ◽  
Vol 25 (10) ◽  
pp. 975-984 ◽  
Author(s):  
C.J. Deglmann ◽  
R. Metzger ◽  
M. Stickel ◽  
S. Hoerrlein ◽  
F.W. Schildberg ◽  
...  
Keyword(s):  
Cell Line ◽  
Toxicity Testing ◽  
Small Scale ◽  
Animal Testing ◽  
Target Cell Line ◽  
Set Up ◽  
New Bioassay ◽  
Hepatocyte Bioreactor

New approaches for in vitro testing of hepato-mediated toxicity are undertaken to offer alternatives to in vivo animal testing. The described bioassay for hepato-mediated toxicity testing is based on a small scale hepatocyte-bioreactor with pig hepatocytes connected to a silicon sensor based microphysiometer system for monitoring of the extracellular acidification rate (EAR) of cells and the microphysiometer alone. EAR represents the metabolic activity of tested cells (hepatocytes and ZR 751 cells) under the influence of perfused media, compared to controls, which were set to 100%. Cyclophosphamide (CYCL), whose cytostatic effect is dependent on CYP 450 biotransformation was used as a model substrate. CYCL showed decrease of EAR in hepatocytes, but not in ZR 751 cells. Bioreactor supernatant including CYCL was pumped into the microphysiometer and EARs of the target ZR 751 cell line were recorded. After 7 h of bioreactor supernatant perfusion the ZR 751 cell line showed an EAR decrease of 18.68% ± 10.18, as compared to controls (bioreactor supernatant from the identical set-up without CYCL). Thus the presented model of hepato-activated toxicity showed an EAR decrease in the ZR 751 cell line that reflected the toxic activation of CYCL by the bioreactor. This new bioassay serves as an example of future applications for hepatocyte bioreactors in automated toxicity testing devices, e.g. in preclinical drug studies or evaluation of hepato-mediated toxicity, not depending on cell destruction or further assays.

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