A Perspective and a New Integrated Computational Strategy for Skin Sensitization Assessment

Alves, Vinícius M.; Capuzzi, Stephen J.; Braga, Rodolpho C.; Borba, Joyce Villa Verde Bastos; Silva, Arthur C.; Luechtefeld, Thomas; Hartung, Thomas; Andrade, Carolina Horta; Muratov, Eugene; Tropsha, Alexander

doi:10.1021/acssuschemeng.7b04220

Cited by 39 publications

(55 citation statements)

References 95 publications

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“…As dermal contact is one of the ways of exposure to phthalates, we have computed their skin permeation coefficients using the SwissADME tool [51] and predicted their skin sensitization potentials using the PredSkin tool [52,53]. The values of the skin permeation coefficients are revealed in Figure 2.…”

Section: Resultsmentioning

confidence: 99%

“…Our study concerns the application of the following computational tools to envisage the possible biological effects on humans of the most commonly used phthalates: (i) the FAFDrugs4 tool [49] for producing the ADME-Tox profiles; (ii) admetSAR [50] and SwissADME [51] for envisaging pharmacokinetic profiles [50]; (iii) Pred-Skin for predicting skin sensitization [52,53]; (iv) ENDOCRINE DISRUPTOME for predicting endocrine disruption potential [54]; (v) Pred-hERG for predicting the inhibitory potential against hERGK+ channel [56]; (v) ToxTree for predicting toxicity class, carcinogenicity and mutagenicity [57]; and (vii) SwissDock [58] to assess the interactions of the cytochromes P450 (CYP) involved in xenobiotics metabolism (CYP1A2, CYP2C9, CYP2C19, CYP3A4, CYP2D6) with phthalates.…”

Section: Methodsmentioning

confidence: 99%

“…Pred-Skin is a web-based tool that uses QSAR method for determining the skin sensitization potential: the binary predictions of human skin sensitization potentials are based on human data (the prediction accuracy is between 73% and 76%), the binary and multiclass predictions of murine skin sensitization potentials are based on animal data (LLNA, the prediction accuracy is between 70% and 84%), and the binary predictions based on non-animal data, i.e. Direct Peptide Reactivity Assay (DPRA), KeratinoSens, and the human Cell Line Activation Test (h-CLAT) with an accuracy of prediction between 80% and 86% [52,53]. Usually, one positive result in one of the KeratinoSens TM or h-CLAT tests designates a potential skin sensitizer compound, and two negative results point towards a non-sensitizer compound [66].…”

Section: Methodsmentioning

confidence: 99%

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Computational assessment of the ADME-Tox profiles and harmful effects of the most common used phthalates on the human health

Crăciun¹,

Dascălu²,

Isvoran³

2019

Studia UBB Chemia

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In this study we consider 25 of the most commonly used phthalates and summarize the available data that support their effects on humans. For 15 of the 25 investigated phthalates (60%) there are no human hazard assessment data, neither from experimental nor from computational studies, which underlines the necessity of their risk assessment. Consequently, we have used various computational tools to predict their ADME-Tox profiles and assess their harmful effects on humans. The outcomes of our study reveal that the investigated phthalates have good bioavailability and skin permeability which are associated with toxicity, especially when they are inhaled. They are able to interact with important molecular targets in the human organism such as membrane receptors, cytochromes, kinases, phosphatases, transcription factors, or transporters. These interactions may conduct to predicted harmful effects of phthalates, such as toxicity and irritations of the respiratory and gastrointestinal tracts, skin and eye irritations, endocrine disruption potential, or non-genotoxic carcinogenicity. The investigated phthalates are not predicted to produce genotoxic carcinogenicity, mutagenicity and cardiotoxicity. Beside the investigated phthalates, the di(2-ethylhexyl) phthalate reflects the highest number of toxic effects, and the ditridecyl phthalate and the diisotrodecyl phthalate illustrate the smallest number of possible toxicological effects, namely skin irritation, non-genotoxic carcinogenicity and endocrine disruption potential.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Computational assessment of the ADME-Tox profiles and harmful effects of the most common used phthalates on the human health

Crăciun¹,

Dascălu²,

Isvoran³

2019

Studia UBB Chemia

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“…In recent times, there has been an increased interest in using more advanced statistical modeling techniques and sophisticated chemical descriptors, as well as leveraging the wealth of sensitization data available from multiple different in vivo and in vitro sensitization models. The Pred‐skin method utilizes multiple Naive Bayes models along with Dragon 2D chemical descriptors to generate individual assay predictions and a consensus skin sensitization prediction. The global model has a correct classification rate of between 70% to 80% for a two‐class system.…”

Section: Introductionmentioning

confidence: 99%

“…This is equivalent to the concordance between different experimental approaches. We refer readers to three recent reviews that discuss the current state of the art in QSAR modeling, read‐across, and rule‐based prediction for skin sensitization data …”

Section: Introductionmentioning

confidence: 99%

Theoretical studies to estimate the skin sensitization potential of chemicals of the Schiff base domain

Gleeson

2020

Int J of Quantum Chemistry

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Skin sensitization occurs when an exogenous chemical substance forms a covalent adduct with a dermal protein electrophile or nucleophile. This instigates an immune response which leads to inflammation. The local lymph node assay is an in vivo model used in the assessment of relative skin sensitizing potency of chemicals. The method is time consuming and expensive, as well as poses ethical questions given that a number of mice must be sacrificed for each compound assessed. In this work, we investigate the use of an inexpensive, rapid, and ethical method to predict the skin sensitization potential of Schiff base chemicals. We employ quantum chemical methods to rationalize the sensitization potential of 22 compounds with a diverse range of activities. To this end, we have evaluated the mechanistic profile associated with this type of reaction using gas-phase models. We subsequently use the predicted rate determining barriers and key physico-chemical parameters (such as logP) to establish stucture activity relationship (SAR) guidelines to predict the skin sensitization potential for new chemicals. We find that the predicted rate determining barriers for aldehydes, ketone, and 1,2 and 1,3 diones generally decrease in the given order, which concurs with the overall trends in sensitization. We find that lipophilicity also plays a role, with those chemicals displaying both low barriers to reaction, and lower lipophilicity (ie, diones), being more likely to display undesirable skin sensitization effects. These findings are in line with experiment-based observations in the literature and point to the value 3D quantum chemical calculations could have if combined with other orthogonal approaches to estimate skin sensitization potential of chemicals. K E Y W O R D S DFT, EC3, QM calculation, Schiff base, LLNA, skin sensitization

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Insights into the Photodegradation of the Contact Allergen Fragrance Cinnamyl Alcohol: Kinetics, Mechanism, and Toxicity

Gao

Luo

et al. 2021

Enviro Toxic and Chemistry

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Fragrances can cause general health issues, and special concerns exist surrounding the issue of skin safety. Cinnamyl alcohol (CAL) is a frequent fragrance contact allergen that has various toxic effects on indiscriminate animals. In the present study, the photodegradation transformation mechanism of CAL and toxicity evolution during this process were examined. The results showed that CAL (50 μM) can be completely degraded after 90-min ultraviolet (UV) irradiation with a degradation rate of 0.086 min -1 . Increased toxicity on bioluminescent bacteria was observed during this process, with lethality increasing from 10.6% (0 min) to 50.2% (90 min) under UV light irradiation. Further, the photodegradation mechanisms of CAL were explored to find the reason behind the increased toxicity observed. Laser flash photolysis and quenching experiments showed that O 2•-, 1 O 2 , and • OH were mainly responsible for CAL photodegradation, together with 3 CAL* and e aq -. The 5 main photodegradation products were cinnamyl aldehyde, benzaldehyde, benzenepropanal, cinnamic acid, and toluene, as identified using gas chromatography-mass spectrometry and liquid chromatography-quadrupole-time-offlight-mass spectrometry. Once exposed to air, CAL was found to be easily oxidized to cinnamyl aldehyde and subsequently to cinnamic acid by O 2 •-or 1 O 2 -mediated pathways, leading to increased toxicity. Benzaldehyde exhibited bioreactive toxicity, increasing the toxicity through • OH-mediated pathways. Theoretical prediction of skin irritation indicated that cinnamyl aldehyde (0.83), benzenepropanal (0.69), cinnamyl aldehyde (0.69), and benzaldehyde (0.70) were higher than CAL (0.63), which may cause a profound impact on an individual's health and well-being. Overall, the present study advances the understanding of the photodegradation processes and health impacts of fragrance ingredients.

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A Perspective and a New Integrated Computational Strategy for Skin Sensitization Assessment

Cited by 39 publications

References 95 publications

Computational assessment of the ADME-Tox profiles and harmful effects of the most common used phthalates on the human health

Computational assessment of the ADME-Tox profiles and harmful effects of the most common used phthalates on the human health

Theoretical studies to estimate the skin sensitization potential of chemicals of the Schiff base domain

Insights into the Photodegradation of the Contact Allergen Fragrance Cinnamyl Alcohol: Kinetics, Mechanism, and Toxicity

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