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1.
J Toxicol Environ Health A ; 86(13): 421-433, 2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-37203870

RESUMO

Tetrachlorvinphos (TCVP) is the pesticidal active ingredient in some collars for dogs and cats. The objective of this study was to provide a refined estimate of dermal penetration of TCVP in humans using in silico predictions as well as in vitro and in vivo data. The in vivo dermal absorption of TCVP was previously studied in the rat and shown to be saturable, ranging from 21.7% (10 µg/cm2) down to 3% (1000 µg/cm2) Subsequent in silico predictions were conducted for rats and humans to provide initial evaluations of species and dose-dependent differences in dermal absorption. A definitive comparison of TCVP systemic exposure in rat and human following dermal application was then conducted via a standard in vitro assay. TCVP dose levels of 10, 100, or 1000 µg/cm2 were applied to excised rat and human skin mounted in flow-through diffusion cells. The vehicle was 1% hydroxypropylmethylcellulose (HPMC) in water. An additional 5 µg/cm2 dose was applied to excised human skin only. The in vitro dermal absorption of TCVP was also assessed from artificial sebum at dose levels of 5, 10, or 100 µg/cm2 applied to human skin only. Utilizing the so-called triple pack approach with in vitro and in vivo rat data and in vitro human data, dermal absorption for TCVP was calculated for humans. In silico modeling indicated absorption of TCVP through human skin might be 3- to 4- fold lower than rat skin at all application levels, with a maximum dermal absorption of 9.6% at the lowest exposure of 10 µg/cm2, down to 0.1% at 1000 µg/cm2. Similar species differences were also found in the definitive in vitro absorption assays. Modeling overestimated TCVP human dermal absorption (9.6%) as compared to excised human skin results (1.7%) for the HPMC vehicle at the lowest exposure (10 µg/cm2), with better agreement at the higher exposures. Conversely, modeling accurately predicted rat dermal absorption (27.9%) as compared to in vivo rat results (21.7%) at the lowest exposure in HPMC, with diminished agreement at the higher exposures. As a first approximation, in silico estimates of dermal absorption are useful; however, these tend to be more variable than in vitro or in vivo measurements. TCVP dermal penetration measured in vitro was lower in 1% HPMC vehicle as compared to artificial sebum. For the 1% HPMC vehicle, in vitro rat dermal absorption was similar to data obtained for in vivo rats, giving confidence in the triple pack approach. In consideration of the triple pack approach, estimated human dermal absorption from 1% HPMC was ≤2%. Based upon excised human skin determinations directly, estimated human dermal absorption of TCVP from artificial sebum was ≤7%.


Assuntos
Doenças do Gato , Doenças do Cão , Humanos , Ratos , Animais , Cães , Gatos , Tetraclorvinfos/metabolismo , Doenças do Gato/metabolismo , Doenças do Cão/metabolismo , Pele/metabolismo , Absorção Cutânea
2.
Regul Toxicol Pharmacol ; 132: 105184, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35577015

RESUMO

The dermal absorption potential of 14C-Caffeine applied as a 4 mg/mL concentration (10 µL/cm2 finite dose) was investigated in six laboratories under Good Laboratory Practice conditions using an OECD TG 428-compliant in vitro assay with flow-through cells and split-thickness human skin. Potential sources of variation were reduced by a standardized protocol, test item and skin source. Particularly, skin samples from same donors were distributed over two repeats and between labs in a non-random, stratified design. Very similar recovery was achieved in the various assay compartments between laboratories, repeats and donors, demonstrating that the assay can be robustly and reliably performed. The absorption in one laboratory was 5-fold higher than in the others. This did not clearly correlate with skin integrity parameters but might be associated with an accidental COVID-19 pandemic-related interruption in sample shipment. It is possible that other factors may affect dermal absorption variation not routinely assessed or considered in the current method. The mean receptor fluid recovery, potential absorption (recovery in receptor fluid and skin except tape strips 1 and 2) and mass balance of caffeine was 6.99%, 7.14% and 99.13%, respectively, across all and 3.87%, 3.96% and 99.00% in the subset of five laboratories.


Assuntos
COVID-19 , Absorção Cutânea , Cafeína , Humanos , Organização para a Cooperação e Desenvolvimento Econômico , Pandemias , Pele/metabolismo
4.
Mutagenesis ; 26(2): 261-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20861153

RESUMO

Photosafety testing is of concern for the evaluation of personal care products and pharmaceuticals. Current regulatory guidance state that photosafety should be evaluated for compounds that absorb radiation between 290 and 700 nm with relevant exposure in the skin or eyes. However, oversensitivity and the occurrence of 'pseudo-effects' with current in vitro photo(geno)toxicity assays have become a major problem. Furthermore, at this moment, there are no relevant in vitro assays available to identify the photocarcinogenic potential of compounds, which might result in unnecessary in vivo photocarcinogenicity studies for pharmaceutical ingredients or unnecessary dropouts in the development of ingredients of personal care products. For these reasons, availability of a relevant and highly predictive in vitro model from human origin to identify the photogenotoxic and/or photocarcinogenic potential of compounds is viewed as high priority. In the present study, human skin tissue obtained from surgery was used for developing a photomicronucleus test. Prior to investigations of the photogenotoxic potential of 8-methoxypsoralen, tissue viability (lactate production and lactate dehydrogenase leakage), cell proliferation (Ki-67 expression) and the effect of ultraviolet (UV) exposure on viability (MTT test), proliferation (Ki-67 expression) and p53 expression were determined. Results of the present study indicate that ex vivo human skin seems to be a relevant method for safety evaluation of compounds that reach the skin in combination with UV exposure.


Assuntos
Indústria Farmacêutica/métodos , Pele , Adulto , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Feminino , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Antígeno Ki-67/metabolismo , Masculino , Metoxaleno/toxicidade , Micronúcleos com Defeito Cromossômico , Testes para Micronúcleos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Fatores de Tempo , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta
5.
Mutagenesis ; 25(4): 407-16, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20460329

RESUMO

For pharmaceuticals, current regulatory guidance for photosafety testing states that studies are warranted for drug candidates that both absorb light in the range of 290-700 nm and that are either applied topically or reach the skin or eyes by systemic exposure. In contrast to standard genotoxicity evaluations, where a positive (or equivocal) result in vitro can be placed into context with additional testing in vivo, there are no equivalent short-term in vivo photogenotoxicity assays in the current photosafety test battery. Therefore, a short-term in vivo assay for the evaluation of a photogenotoxic potential in the skin, the target organ for photocarcinogenicity, was developed in rats. After oral 8-methoxypsoralen administration, rats were exposed to ultraviolet radiation and sacrificed 3 days after treatment to isolate epidermal cells for subsequent micronucleus (MN) evaluation. Optimal conditions were determined to obtain maximal induction of MN, followed by demonstrating feasibility and reproducibility of the method. The results of the present study indicate that the in vivo rat skin photomicronucleus test may be a promising tool for detection of photoclastogenicity. Given the association between MN induction and cancer, the assay may also provide a promising tool for the early detection of photocarcinogenesis and help bridge the gap in the existing photosafety testing paradigm.


Assuntos
Testes para Micronúcleos/métodos , Pele/efeitos da radiação , Animais , Relação Dose-Resposta à Radiação , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/efeitos da radiação , Masculino , Metoxaleno/administração & dosagem , Metoxaleno/toxicidade , Ratos , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/metabolismo
6.
Regul Toxicol Pharmacol ; 57(2-3): 200-9, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20178823

RESUMO

Most QSARs for dermal absorption predict the permeability coefficient, K(p), of a molecule, which is valid for infinite dose conditions. In practice, dermal exposure mostly occurs under finite dose conditions. Therefore, a simple model to predict finite dose dermal absorption from infinite dose data (K(p) and lag time) and the stratum corneum/water partition coefficient (K(SC,W)) was developed. To test the model, a series of in vitro dermal absorption experiments was performed under both infinite and finite dose conditions using acetic acid, benzoic acid, bis(2-ethylhexyl)phthalate, butoxyethanol, cortisone, decanol, diazinone, 2,4-dichlorophenol, ethacrynic acid, linolenic acid, octylparaben, oleic acid, propylparaben, salicylic acid and testosterone. For six substances, the predicted relative dermal absorption was not statistically different from the measured value. For all other substances, measured absorption was overpredicted by the model, but most of the overpredictions were still below the European default absorption value. In conclusion, our finite dose prediction model provides a useful and cost-effective estimate of dermal absorption, to be used in risk assessment for non-volatile substances dissolved in water at non-irritating concentrations.


Assuntos
Bases de Dados Factuais , Modelos Biológicos , Absorção Cutânea/fisiologia , Pele/metabolismo , Adulto , Relação Dose-Resposta a Droga , Feminino , Hormônios/química , Hormônios/farmacocinética , Humanos , Técnicas In Vitro , Lipídeos/química , Lipídeos/farmacocinética , Pessoa de Meia-Idade , Compostos Orgânicos/química , Compostos Orgânicos/farmacocinética , Prognóstico , Relação Quantitativa Estrutura-Atividade , Medição de Risco
7.
Toxicol In Vitro ; 29(1): 81-4, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25236440

RESUMO

The skin sensitizing potential of chemicals is mainly assessed using animal methods, such as the murine local lymph node assay. Recently, an in vitro assay based on a gene expression signature in the HaCaT keratinocyte cell line was proposed as an alternative to these animal methods. Here, the human relevance of this gene signature is assessed through exposure of freshly isolated human skin to the chemical allergens dinitrochlorobenzene (DNCB) and diphenylcyclopropenone (DCP). In human skin, the gene signature shows similar direction of regulation as was previously observed in vitro, suggesting that the molecular processes that drive expression of these genes are similar between the HaCaT cell line and freshly isolated skin, providing evidence for the human relevance of the gene signature.


Assuntos
Dermatite Alérgica de Contato/genética , Queratinócitos/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Adulto , Alérgenos/efeitos adversos , Ciclopropanos/efeitos adversos , Dermatite Alérgica de Contato/metabolismo , Dinitroclorobenzeno/efeitos adversos , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Técnicas In Vitro , Queratinócitos/metabolismo , Pessoa de Meia-Idade , Pele/efeitos dos fármacos , Pele/metabolismo , Adulto Jovem
8.
Toxicol In Vitro ; 28(2): 258-64, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24216300

RESUMO

The respiratory route is an important portal for human exposure to a large variety of substances. Consequently, there is an urgent need for realistic in vitro strategies for evaluation of the absorption of airborne substances with regard to safety and efficacy assessment. The present study investigated feasibility of a 3D human airway epithelial model to study respiratory absorption, in particular to differentiate between low and high absorption of substances. Bronchial epithelial models (MucilAir™), cultured at the air-liquid interface, were exposed to eight radiolabeled model substances via the apical epithelial surface. Absorption was evaluated by measuring radioactivity in the apical compartment, the epithelial cells and the basolateral culture medium. Antipyrine, caffeine, naproxen and propranolol were highly transported across the epithelial cell layer (>5%), whereas atenolol, mannitol, PEG-400 and insulin were limitedly transported (<5%). Results indicate that the 3D human airway epithelial model used in this study is able to differentiate between substances with low and high absorption. The intra-experimental reproducibility of the results was considered adequate based on an average coefficient of variation (CV) of 15%. The inter-experimental reproducibility of highly absorbed compounds was in a similar range (CV of 15%), but this value was considerably higher for those compounds that were limitedly absorbed. No statistical significant differences between different donors and experiments were observed. The present study provides a simple method transposable in any lab, which can be used to rank the absorption of chemicals and pharmaceuticals, and is ready for further validation with respect to reproducibility and capacity of the method to predict respiratory transport in humans.


Assuntos
Modelos Anatômicos , Mucosa Respiratória/fisiologia , Absorção , Adulto , Idoso , Algoritmos , Asma/metabolismo , Asma/patologia , Brônquios/metabolismo , Brônquios/fisiologia , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Preparações Farmacêuticas/metabolismo , Mucosa Respiratória/metabolismo , Doenças Respiratórias/metabolismo , Doenças Respiratórias/patologia
10.
Int Arch Occup Environ Health ; 79(5): 405-13, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16435152

RESUMO

OBJECTIVES: To determine the effect of skin thickness on the percutaneous penetration and distribution of test compounds with varying physicochemical properties using in vitro systems. Studies were carried out in accordance with OECD guidelines on skin absorption tests. METHODS: Percutaneous penetration of caffeine (log P -0.01), testosterone (log P 3.32), propoxur (log P 1.52) (finite dose in ethanol to water vehicle ratio) and butoxyethanol (log P 0.83) (undiluted finite dose or as an infinite dose 50% [v/v] aqueous solution) through skin of varying thicknesses under occluded conditions was measured using flow through cells for 8-24 h. Saline (adjusted to pH 7.4) was used as receptor fluid, with BSA added for studies with testosterone and propoxur. Following exposure, the remaining surface dose was removed by swabbing and the skin digested prior to scintillation counting. RESULTS: The maximum flux of caffeine was increased with decreasing skin thickness, although these differences were found to be non-significant. The presence of caffeine in the skin membrane was not altered by skin thickness. Maximum flux and cumulative dose absorbed of testosterone and butoxyethanol (in both finite and infinite doses) were markedly reduced with full thickness (about 1 mm thick) skin compared with split thickness skin (about 0.5 mm). Maximum flux of propoxur (dissolved in 60% ethanol) was clearly higher through skin of 0.71 mm than through skin of 1.36 mm, but no difference was found between 0.56 and 0.71 mm. The proportion of propoxur present in the membrane after 24 h increased significantly over the complete range of thicknesses tested (0.56-1.36 mm). CONCLUSIONS: A complex relationship exists between skin thickness, lipophilicity and percutaneous penetration and distribution. This has implications for risk assessment studies and for the validation of models with data from different sources.


Assuntos
Ácido 2,4-Diclorofenoxiacético/análogos & derivados , Cafeína/farmacocinética , Propoxur/farmacocinética , Absorção Cutânea , Fenômenos Fisiológicos da Pele , Testosterona/farmacocinética , Ácido 2,4-Diclorofenoxiacético/administração & dosagem , Ácido 2,4-Diclorofenoxiacético/farmacocinética , Cafeína/administração & dosagem , Relação Dose-Resposta a Droga , Europa (Continente) , Humanos , Técnicas In Vitro , Propoxur/administração & dosagem , Testosterona/administração & dosagem
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