ABSTRACT
The Bone-Marrow derived Dendritic Cell (BMDC) test is a promising assay for identifying sensitizing chemicals based on the 3Rs (Replace, Reduce, Refine) principle. This study expanded the BMDC benchmarking to various in vitro, in chemico, and in silico assays targeting different key events (KE) in the skin sensitization pathway, using common substances datasets. Additionally, a Quantitative Structure-Activity Relationship (QSAR) model was developed to predict the BMDC test outcomes for sensitizing or non-sensitizing chemicals. The modeling workflow involved ISIDA (In Silico Design and Data Analysis) molecular fragment descriptors and the SVM (Support Vector Machine) machine-learning method. The BMDC model's performance was at least comparable to that of all ECVAM-validated models regardless of the KE considered. Compared with other tests targeting KE3, related to dendritic cell activation, BMDC assay was shown to have higher balanced accuracy and sensitivity concerning both the Local Lymph Node Assay (LLNA) and human labels, providing additional evidence for its reliability. The consensus QSAR model exhibits promising results, correlating well with observed sensitization potential. Integrated into a publicly available web service, the BMDC-based QSAR model may serve as a cost-effective and rapid alternative to lab experiments, providing preliminary screening for sensitization potential, compound prioritization, optimization and risk assessment.
Subject(s)
Benchmarking , Dendritic Cells , Quantitative Structure-Activity Relationship , Dendritic Cells/drug effects , Humans , Animals , Support Vector Machine , Computer Simulation , Dermatitis, Allergic Contact , Allergens/toxicity , Animal Testing Alternatives/methods , Bone Marrow Cells/drug effects , Local Lymph Node Assay , MiceABSTRACT
Exposure to environmental chemicals during early childhood is a potential health concern. At a tender age, children are exposed to fragrance chemicals used in toys and child care products. Although there are few initiatives in Europe and United States towards monitoring and regulation of fragrance chemicals in children's products, such efforts are still lacking elsewhere. Besides there has been no systematic effort to create a database compiling the surrounding knowledge on fragrance chemicals used in children's products from published literature. Here, we built a database of Fragrance Chemicals in Children's Products (FCCP) that compiles information on 153 fragrance chemicals from published literature. The fragrance chemicals in FCCP have been classified based on their chemical structure, children's product source, chemical origin and odor profile. Moreover, we have also compiled the physicochemical properties, predicted Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties, molecular descriptors and human target genes for the fragrance chemicals in FCCP. After building FCCP, we performed multiple analyses of the associated fragrance chemical space. Firstly, we assessed the regulatory status of the fragrance chemicals in FCCP through a comparative analysis with 21 chemical lists reflecting current guidelines or regulations. We find that several fragrance chemicals in children's products are potential carcinogens, endocrine disruptors, neurotoxicants, phytotoxins and skin sensitizers. Secondly, we performed a similarity network based analysis of the fragrance chemicals in children's products to reveal the high structural diversity of the associated chemical space. Lastly, we identified skin sensitizing fragrance chemicals in children's products using ToxCast assays. In a nutshell, we present a comprehensive resource and detailed analysis of fragrance chemicals in children's products highlighting the need for their better risk assessment and regulation to deliver safer products for children. FCCP is accessible at: https://cb.imsc.res.in/fccp.
Subject(s)
Endocrine Disruptors , Perfume , Child, Preschool , Endocrine Disruptors/toxicity , Humans , Odorants , Play and Playthings , Risk Assessment , United StatesABSTRACT
Objective To establish an in vitro skin sensitization test,human cell line activation test (h-CLAT),based on THP-1 cell line (a human acute monocytic leukemia cell line),and to assess the sensitizing potency of plant raw materials of chemical and cosmetic products by this in vitro skin sensitization test.Method THP-1 cells were cultured in vitro and exposed to 11 reference skin sensitization chemicals and 9 samples,by monitoring the cell viability,cell surface marker CD54 /CD86 and relative fluorescence intensity of cells surface after the cells was exposures to the substances,and to discover whether there is a positive reaction.At the same time,Buehler test was used to validate the results of samples tested by h-CLAT.Results 11 reference chemicals were distinguished correctly by h-CLAT.Among the 9 samples tested,7 samples were recognized as negative sensitizer and 2 plant extracted substances were identified as suspicious skin sensitizer.The qualitative classification of the 9 samples by h-CLAT test was consistent with the results obtained by animal test.Conclusions The h-CLAT-in vitro test can be used to replace some animal tests for the prediction of soluble skin sensitizing substances.
