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1.
J Med Virol ; 96(2): e29433, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38293900

RESUMEN

High-risk populations are the predominant populations affected by hepatitis C virus (HCV) infection, and there is an urgent need for efficient and cost-effective HCV testing strategies for high-risk populations to identify potential undiagnosed HCV-infected individuals. This study compared several commonly used testing strategies and conducted effectiveness and cost analysis to select the appropriate testing strategy for diagnosing HCV infection in high-risk populations. Among the 2093 samples from high-risk populations in this study, 1716 were HCV negative, 237 were current HCV infection, 137 were past HCV infection, and three were acute early HCV infection. It was found that out of 237 patients with HCV current infection, Strategy A could detect 225 cases, with a missed detection rate of 5.06%, and the total cost was 33 299 RMB. In addition, Strategy B could detect 237 cases of current HCV infection, and the HCV missed detection rate was 0.00%, and the total cost was 147 221 RMB. While 137 cases of past HCV infection could be distinguished by strategy C, but 14 cases with current HCV infection were missed, with an HCV-positive missed detection rate of 5.91%, and the total cost for Strategy C was 43 059 RMB. In conclusion, in high-risk populations, the HCV positivity rate is typically higher. If feasible, the preferred approach is to directly conduct HCV RNA testing, which effectively minimizes the risk of missing cases. However, in situations with limited resources, it is advisable to initially choose a highly sensitive method for anti-HCV screening, followed by HCV RNA testing on reactive samples.


Asunto(s)
Hepacivirus , Hepatitis C , Humanos , Hepacivirus/genética , Análisis Costo-Beneficio , Hepatitis C/diagnóstico , Hepatitis C/epidemiología , Factores de Riesgo , ARN
2.
J Appl Toxicol ; 44(3): 415-427, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37846211

RESUMEN

The hazards and potency of skin sensitizers are traditionally determined using animal tests such as the local lymph node assay (LLNA); however, significant progress has been made in the development of non-animal test methods addressing the first three mechanistic key events of adverse outcome pathway in skin sensitization. We developed the epidermal sensitization assay (EpiSensA), which is a reconstructed human epidermis-based assay, by measuring four genes related to critical keratinocyte responses during skin sensitization. Four in vitro skin sensitization test methods (EpiSensA, direct peptide reactivity assay [DPRA], KeratinoSens™, and human cell line activation test [h-CLAT]) were systematically evaluated using 136 chemicals including lipophilic chemicals and pre/pro-haptens, which may be related to assay-specific limitations. The constructed database included existing and newly generated data. The EpiSensA showed a broader applicability domain and predicted the hazards with 82.4% and 78.8% accuracy than LLNA and human data. The EpiSensA could detect 76 out of 88 sensitizers at lower concentrations than the LLNA, indicating that the EpiSensA has higher sensitivity for the detection of minor sensitizing constituents. These results confirmed the potential use of the EpiSensA in evaluating a mixture of unknown compositions that can be evaluated by animal tests. To combine different information sources, the reconstructed human epidermis-based testing strategy (RTS) was developed based on weighted multiple information from the EpiSensA and TImes MEtabolism Simulator platform for predicting Skin Sensitization (TIMES-SS; RTSv1) or Organization for Economic Cooperation and Development (OECD) QSAR Toolbox automated workflow (RTSv2). The predictivities of the hazards and Globally Harmonized System (GHS) subcategories were equal to or better than the defined approaches (2 out of 3, integrated testing strategy [ITS]v1, and ITSv2) adopted as OECD Guideline 497.


Asunto(s)
Alternativas a las Pruebas en Animales , Dermatitis Alérgica por Contacto , Animales , Humanos , Alternativas a las Pruebas en Animales/métodos , Piel , Epidermis , Queratinocitos/metabolismo , Pruebas Cutáneas , Ensayo del Nódulo Linfático Local , Dermatitis Alérgica por Contacto/etiología , Dermatitis Alérgica por Contacto/metabolismo
3.
Regul Toxicol Pharmacol ; 139: 105358, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36805910

RESUMEN

Recently, due to regulatory and ethical demands, new approach methodologies (NAMs), defined approaches (DAs), and read-across (RAx) have been used in the risk assessment of skin sensitization. Integrated testing strategy (ITS)v1 DA, adopted in OECD Guideline No. 497, can be used for skin sensitization potency categorization. However, ITSv1 DA alone is not used for further refinement of the potency prediction based on EC3 (the estimated concentration that produces a stimulation index of 3 in murine local lymph node assay) values. Moreover, there is no explicit approach to incorporating NAM/DA data into RAx to fill the data gap of EC3 values with high confidence. This study developed a strategy incorporating ITSv1 DA into RAx to predict skin sensitization potency: ITSv1-based RAx. To examine the reliability of this novel strategy, a case study with lilial, a fragrance material, was performed. Based on ITSv1-based RAx, the skin sensitization potency of lilial was determined by extrapolating the EC3 value of 9.5% for the suitable analogue bourgeonal, which was close to the historical EC3 value of 8.6%. The result suggested that the strategy can refine the prediction of EC3 values with high confidence and be useful for the risk assessment of skin sensitization.


Asunto(s)
Dermatitis Alérgica por Contacto , Animales , Humanos , Ratones , Dermatitis Alérgica por Contacto/etiología , Reproducibilidad de los Resultados , Piel , Ensayo del Nódulo Linfático Local , Medición de Riesgo/métodos , Proteínas del Ojo , Factores de Transcripción , Proteínas de Homeodominio
4.
Yi Chuan ; 45(1): 29-41, 2023 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-36927636

RESUMEN

Hereditary deafness is one of the most common sensory disorders in humans, and exhibits high genetic heterogeneity. At present, the commonly used molecular diagnostic methods include gene chip, Sanger sequencing, targeted enrichment sequencing, and whole-exome sequencing, with diagnosis rates reaching 33.5%-56.67%. However, there are still a considerable number of patients who can not get a timely and definitive molecular diagnosis. Furthermore, considering the economic burden on patients' families and the relatively high cost of whole-exome or whole-genome sequencing, it is vital to provide stepwise strategies combining multiple detection methods according to the phenotypes of patients. In this review, we evaluate and discuss the utility of molecular diagnosis and the application of stepwise testing strategies in hereditary deafness to provide reference for the selection of diagnostic strategies.


Asunto(s)
Sordera , Humanos , Sordera/diagnóstico , Sordera/genética , Secuenciación Completa del Genoma , Exoma , Fenotipo , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Linaje , Pruebas Genéticas , Mutación
5.
BMC Infect Dis ; 22(1): 307, 2022 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-35351002

RESUMEN

BACKGROUND: The air borne SARS-CoV-2 poses a high threat to the elderly and people with underlying diseases. COVID-19 spread quickly in South German nursing homes and for this reason called for preventive measures by the German government. The aim of this paper is to showcase the testing strategies implemented by the Public Health Department Reutlingen to control the spread of COVID-19 in local nursing homes and to report the results thereof. METHODS: This study reports COVID-19 outbreaks in nursing homes in Reutlingen County and how they were dealt with through extensive testing, contact tracing, isolation and hygiene inspections. The testing strategy consisted of three phases: In phase 1 only suspected cases, in phase 2 all staff and residents, and in phase 3 all suspected cases and their contacts were tested. RESULTS: Nearly all residents (98%) and staff members (92%) of all nursing homes in Reutlingen County were tested for SARS-COV-2. 25 of 37 nursing homes had COVID-19 cases, 5 had 30-81 cases/home. 62% of the 395 nursing homes cases were residents, but less than half of them exhibited symptoms (41%). The cases uncovered in nursing homes represented 26% of all 1529 cases in Reutlingen County during the time of this study. CONCLUSIONS: Many COVID-19 cases were discovered through extensive testing, allowing for early interventions. The results shed light on the COVID-19 situation in nursing homes and allowed for individually designed preventive measures. The results also lead to a change in the German legislation. The outbreak management methods of the Public Health Department Reutlingen may also be applicable in other countries.


Asunto(s)
COVID-19 , Trazado de Contacto , Anciano , COVID-19/epidemiología , Brotes de Enfermedades , Humanos , Casas de Salud , SARS-CoV-2
6.
Part Fibre Toxicol ; 19(1): 32, 2022 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-35525968

RESUMEN

The incorporation of nanomaterials (NMs) in consumer products has proven to be highly valuable in many sectors. Unfortunately, however, the same nano specific physicochemical properties, which make these material attractive, might also contribute to hazards for people exposed to these materials. The physicochemical properties of NMs will impact their interaction with biological surroundings and influence their fate and their potential adverse effects such as genotoxicity. Due to the large and expanding number of NMs produced, their availability in different nanoforms (NFs) and their utilization in various formats, it is impossible for risk assessment to be conducted on an individual NF basis. Alternative methods, such as grouping are needed for streamlining hazard assessment. The GRACIOUS Framework provides a logical and science evidenced approach to group similar NFs, allowing read-across of hazard information from source NFs (or non-NFs) with adequate hazard data to target NFs that lack such data. Here, we propose a simple three-tiered testing strategy to gather evidence to determine whether different NFs are sufficiently similar with respect to their potential to induce genotoxicity, in order to be grouped. The tiered testing strategy includes simple in vitro models as well as a number of alternative more complex multi-cellular in vitro models to allow for a better understanding of secondary NM-induced DNA damage, something that has been more appropriate in vivo until recently.


Asunto(s)
Nanoestructuras , Daño del ADN , Humanos , Nanoestructuras/química , Nanoestructuras/toxicidad , Medición de Riesgo/métodos
7.
Regul Toxicol Pharmacol ; 135: 105250, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36007800

RESUMEN

Phototoxicity testing is required by European regulations for agrochemicals with UV/visible molar extinction/absorption coefficient (MEC) higher than 10 L x mol-1 x cm-1 in the 290-700 nm wavelength range. Furthermore, regulations identify a need of considering human exposure in case of positive results. While in vitro OECD test guidelines are available for hazard characterisation, there is no guidance on how to utilise positive results in human exposure risk assessments. Our goal was to take a first step towards developing a NAM based tiered testing approach and a framework for non-dietary acute human dermal risk assessment for phototoxicity to agrochemicals. The proposed framework can be divided into a few steps: 1) use the OECD updated MEC values of 1000 L x mol-1 x cm-1 as trigger for phototoxicity testing; 2) establish a reference concentration (RfC) from in vitro phototoxicity studies using BMC approach, 3) estimate potential exposure to skin, target organ for phototoxicity, using EFSA exposure models, product specific labels and skin penetration values, and 4) phototoxicity risk assessment; 5) refinement to RfC and/or exposure estimates can be considered. Finally, case studies of a nematicide and an herbicide active substance are provided to illustrate the proposed framework.


Asunto(s)
Dermatitis Fototóxica , Herbicidas , Agroquímicos/toxicidad , Dermatitis Fototóxica/etiología , Humanos , Medición de Riesgo , Piel
8.
J Appl Toxicol ; 42(11): 1832-1842, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35792566

RESUMEN

Many defined approaches (DAs) for skin sensitization assessment based on the adverse outcome pathway (AOP) have been developed to replace animal testing because the European Union has banned animal testing for cosmetic ingredients. Several DAs have demonstrated that machine learning models are beneficial. In this study, we have developed an ensemble prediction model utilizing the graph convolutional network (GCN) and machine learning approach to assess skin sensitization. The model integrates in silico parameters and data from alternatives to animal testing of well-defined AOP to improve DA predictivity. Multiple ensemble models were created using the probability produced by the GCN with six physicochemical properties, direct peptide reactivity assay, KeratinoSens™, and human cell line activation test (h-CLAT), using a multilayer perceptron approach. Models were evaluated by predicting the testing set's human hazard class and three potency classes (strong, weak, and non-sensitizer). When the GCN feature was used, 11 models out of 16 candidates showed the same or improved accuracy in the testing set. The ensemble model with the feature set of GCN, KeratinoSens™, and h-CLAT produced the best results with an accuracy of 88% for assessing human hazards. The best three-class potency model was created with the feature set of GCN and all three assays, resulting in 64% accuracy. These results from the ensemble approach indicate that the addition of the GCN feature could provide an improved predictivity of skin sensitization hazard and potency assessment.


Asunto(s)
Cosméticos , Dermatitis Alérgica por Contacto , Alternativas a las Pruebas en Animales/métodos , Animales , Dermatitis Alérgica por Contacto/etiología , Humanos , Aprendizaje Automático , Piel
9.
Int J Mol Sci ; 23(21)2022 Oct 25.
Artículo en Inglés | MEDLINE | ID: mdl-36361632

RESUMEN

In order to assess SARS-CoV-2 real time quantitative polymerase chain reaction (RT-qPCR) results in a real-life setting, three independent laboratories in Graz (Austria) set up a continuous cross comparison schedule. The following test systems were used: The QIAGEN NeuMoDx SARS-CoV-2 Assay, the Allplex™ 2019-nCoV Assay (Seegene) on a MicroLab Nimbus (Hamilton) platform combined with RealStar SARS-CoV-2 RT-PCR Assay (Altona Diagnostics GmbH), and the cobas SARS-CoV-2 test on a fully automated cobas 6800 system (Roche). A total of 200 samples were analysed, 184 (92%) were found to be concordant with all testing platforms, 14 (7%) discordant. Two (1%) samples tested invalid on a single platform and were excluded from further analysis. Discordant results were distributed randomly across the assays. The Ct values from all assays correlated closely with each other. All discordant samples showed Ct values ≥ 26. SARS-CoV-2 RT-qPCR assays may show considerable variability, especially in samples with low viral RNA concentrations. Decision makers should thus balance the advantages and disadvantages of RT-qPCR for mass screening and adopt suitable strategies that ensure a rational management of positive samples with high Ct values.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , ARN Viral/genética , Prueba de COVID-19 , COVID-19/diagnóstico , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Sensibilidad y Especificidad
10.
J Med Virol ; 93(5): 2890-2898, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33386772

RESUMEN

Anamnestic screening of symptoms and contact history is applied to identify coronavirus disease 2019 (COVID-19) patients on admission. However, asymptomatic and presymptomatic patients remain undetected although the viral load may be high. In this retrospective cohort study, all hospitalized patients who received polymerase chain reaction (PCR) admission testing from March 26th until May 24th, 2020 were included. Data on COVID-19-specific symptoms and contact history to COVID-19 cases were retrospectively extracted from patient files and from contact tracing notes. The compliance to the universal testing protocol was high with 90%. Out of 6940 tested patients, 27 new severe acute respiratory syndrome coronavirus-2 infections (0.4%) were detected. Seven of those COVID-19 cases (26% of all new cases) were asymptomatic and had no positive contact history, but were identified through a positive PCR test. The number needed to identify an asymptomatic patient was 425 in the first wave of the epidemic, 1218 in the low incidence phase. The specificity of the method was above 99.9%. Universal PCR testing was highly accepted by staff as demonstrated by high compliance. The costs to detect one asymptomatic case in future studies need to be traded off against the costs and damage caused by potential outbreaks of COVID-19.


Asunto(s)
Prueba de Ácido Nucleico para COVID-19/métodos , COVID-19/diagnóstico , Hospitalización , Reacción en Cadena de la Polimerasa/métodos , SARS-CoV-2/aislamiento & purificación , Centros de Atención Terciaria , Adulto , Anciano , Anciano de 80 o más Años , Prueba de Ácido Nucleico para COVID-19/economía , Trazado de Contacto , Estudios de Factibilidad , Femenino , Alemania , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Estudios Retrospectivos , Carga Viral
11.
Crit Rev Toxicol ; 51(7): 600-621, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34756157

RESUMEN

Traditionally, human health risk assessment focuses on defining the hazard through mammalian toxicity studies followed by exposure estimation. We have explored ways of predicting exposure based primarily on the use scenario and comparing the exposure to reference dose values derived by various regulatory agencies (US EPA, JMPR, and EU Commission) in order to identify mammalian toxicity studies that are relevant to human health risk assessment. Human dietary exposure was based on existing residue data for substances with comparable use on the same or similar crops. Human occupational exposures were based on the use scenarios and application methods. To provide a point of comparison for the exposure predictions, data were collated for acute, chronic and occupational reference dose values derived by various regulatory agencies (US EPA, JMPR, and EU Commission). The exposure predictions and range of hazard endpoints were compared using the ILSI HESI Risk21 risk matrix plots in order to visualise and contextualise the level of potential concern for the exposure prediction. In addition, an approach is proposed to categorise the likelihood of acceptability of risk based on where the exposure sits relative to the distribution of reference dose values. The approaches proposed in this study allow for exposure prediction based on the Good Agricultural Practice (GAP) in conjunction with the use of existing hazard data for crop protection products in order to make an initial determination on acceptability of risk and to identify key studies that are required for human health risk assessment and also opportunities for study waivers.


Asunto(s)
Protección de Cultivos , Exposición Profesional , Animales , Humanos , Medición de Riesgo
12.
BMC Infect Dis ; 21(1): 535, 2021 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-34098882

RESUMEN

BACKGROUND: During the SARS-CoV-2 pandemic a mass casualty incident of ambulatory patients occurred at the COVID-19 rapid response infrastructure (CRRI) facility at the University Hospital of Cologne (UHC). We report the development of a patient-centred mobile-device solution to support efficient management of the facility, triage of patients and rapid delivery of test results. METHODS: The UHC-Corona Web Tool (CWT) was developed as a web-based software useable on each patient's smartphone. It provides, among others, a self-reported medical history including type and duration of symptoms and potential risk contacts and links all retrieved information to the digital patient chart via a QR code. It provides scheduling of outpatient appointments and automated transmission of SARS-CoV-2 test results. RESULTS: The UHC-CWT was launched on 9 April 2020. It was used by 28,652 patients until 31 August 2020. Of those, 15,245 (53,2%) consulted the CRRI, representing 43,1% of all CRRI patients during the observed period. There were 8304 (29,0%) specifications concerning travel history and 17,145 (59,8%) indications of ≥1 symptom of SARS-CoV-2 infection. The most frequently indicated symptoms were sore throat (60,0%), headache (50,7%), common cold (45,1%) and cough (42,6%) while 11,057 (40,2%) patients did not report any symptoms. After implementation of the UHC-CWT, the amount of patient contacts per physician rose from 38 to 98,7 per day. The personnel for communication of test results were reduced from four on seven days to one on five days. CONCLUSION: The UHC-CWT is an effective digital solution for management of large numbers of outpatients for SARS-CoV-2 testing.


Asunto(s)
Prueba de COVID-19/métodos , COVID-19/diagnóstico , Internet , Triaje/métodos , Instituciones de Atención Ambulatoria , Registros Electrónicos de Salud , Alemania , Hospitales Universitarios , Humanos , Masculino , Anamnesis , Pandemias , Teléfono Inteligente , Encuestas y Cuestionarios , Viaje
13.
BMC Public Health ; 21(1): 1980, 2021 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-34727923

RESUMEN

BACKGROUND: The number of SARS-CoV-2 tests conversely to other factors, such as age of population or comorbidities, influencing SARS-CoV-2 morbidity and fatality rates, can be increased or decreased by decision makers depending on the development of the pandemic, operational capacity, and financial restraints. The key objective of this study is to identify and describe, within the probabilistic approach, the relationships between SARS-CoV-2 test numbers and the mortality and morbidity rates. METHODS: The study is based on a statistical analysis of 1058 monthly observations relating to 107 countries, from six different continents, in an 11-month period from March 2020 to January 2021. The variable utilised can be defined as the number of tests performed in a given country in 1 month, to the number of cases reported in a prior month and morbidities and mortalities per 1 million population. The probabilities of different mortality and morbidity rates for different test numbers were determined by moving percentiles and fitted by the power law and by the three-segment piecewise-linear approximation based on Theil Sen trend lines. RESULTS: We have identified that for a given probability the dependence of mortality and morbidity rates on SARS-CoV-2 test rates follows a power law and it is well approximated by the three Theil Sen trend lines in the three test rate ranges. In all these ranges Spearman rho and Kendall tau-b rank correlation coefficients of test numbers and morbidity with fatality rates have values between - 0.5 and - 0.12 with p-values below 0.002. CONCLUSIONS: According to the ABC classification: the most important, moderately important, and relatively unimportant ranges of test numbers for managing and control have been indicated based on the value of the Theil Sen trend line slope in the three SARS-CoV-2 test rate ranges identified. Recommendations for SARS-CoV-2 testing strategy are provided.


Asunto(s)
COVID-19 , SARS-CoV-2 , Prueba de COVID-19 , Humanos , Morbilidad , Pandemias
14.
Public Health ; 190: 147-151, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33386140

RESUMEN

OBJECTIVES: The objective of this study was to inform public health practitioners who are designing, adapting and implementing testing and tracing strategies for Coronavirus disease (COVID-19) control. STUDY DESIGN: The study design is monitoring and evaluation of a national public health protection programme. METHODS: All close contacts of laboratory-confirmed cases of COVID-19 identified between the 19th May and 2nd August were included; secondary attack rates and numbers needed to test were estimated. RESULTS: Four thousand five hundred eighty six of 7272 (63%) close contacts of cases were tested with at least one test. The secondary attack rate in close contacts who were tested was 7% (95% Confidence Interval [CI]: 6.3 - 7.8%). At the 'day 0' test, 14.6% (95% CI: 11.6-17.6%) of symptomatic close contacts tested positive compared with 5.2% (95% CI: 4.4-5.9%) of asymptomatic close contacts. CONCLUSIONS: The application of additional symptom-based criteria for testing in this high-incidence population (close contacts) is of limited utility because of the low negative predictive value of absence of symptoms.


Asunto(s)
Prueba de COVID-19/estadística & datos numéricos , COVID-19/prevención & control , Trazado de Contacto/estadística & datos numéricos , SARS-CoV-2 , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Infecciones Asintomáticas , Portador Sano , Niño , Preescolar , Trazado de Contacto/métodos , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Irlanda/epidemiología , Masculino , Persona de Mediana Edad
15.
Crit Rev Toxicol ; 50(1): 72-95, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-32133908

RESUMEN

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) organized a workshop "Hazard Identification, Classification and Risk Assessment of Carcinogens: Too Much or Too Little?" to explore the scientific limitations of the current binary carcinogenicity classification scheme that classifies substances as either carcinogenic or not. Classification is often based upon the rodent 2-year bioassay, which has scientific limitations and is not necessary to predict whether substances are likely human carcinogens. By contrast, tiered testing strategies founded on new approach methodologies (NAMs) followed by subchronic toxicity testing, as necessary, are useful to determine if a substance is likely carcinogenic, by which mode-of-action effects would occur and, for non-genotoxic carcinogens, the dose levels below which the key events leading to carcinogenicity are not affected. Importantly, the objective is not for NAMs to mimic high-dose effects recorded in vivo, as these are not relevant to human risk assessment. Carcinogenicity testing at the "maximum tolerated dose" does not reflect human exposure conditions, but causes major disturbances of homeostasis, which are very unlikely to occur at relevant human exposure levels. The evaluation of findings should consider biological relevance and not just statistical significance. Using this approach, safe exposures to non-genotoxic substances can be established.


Asunto(s)
Pruebas de Carcinogenicidad/métodos , Carcinógenos/toxicidad , Carcinógenos/clasificación , Ecotoxicología , Humanos , Medición de Riesgo/métodos
16.
Int J Mol Sci ; 21(7)2020 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-32235610

RESUMEN

Nanotechnology has rapidly promoted the development of a new generation of industrial and commercial products; however, it has also raised some concerns about human health and safety. To evaluate the toxicity of the great diversity of nanomaterials (NMs) in the traditional manner, a tremendous number of safety assessments and a very large number of animals would be required. For this reason, it is necessary to consider the use of alternative testing strategies or methods that reduce, refine, or replace (3Rs) the use of animals for assessing the toxicity of NMs. Autophagy is considered an early indicator of NM interactions with cells and has been recently recognized as an important form of cell death in nanoparticle-induced toxicity. Impairment of autophagy is related to the accelerated pathogenesis of diseases. By using mechanism-based high-throughput screening in vitro, we can predict the NMs that may lead to the generation of disease outcomes in vivo. Thus, a tiered testing strategy is suggested that includes a set of standardized assays in relevant human cell lines followed by critical validation studies carried out in animals or whole organism models such as C. elegans (Caenorhabditis elegans), zebrafish (Danio rerio), and Drosophila (Drosophila melanogaster)for improved screening of NM safety. A thorough understanding of the mechanisms by which NMs perturb biological systems, including autophagy induction, is critical for a more comprehensive elucidation of nanotoxicity. A more profound understanding of toxicity mechanisms will also facilitate the development of prevention and intervention policies against adverse outcomes induced by NMs. The development of a tiered testing strategy for NM hazard assessment not only promotes a more widespread adoption of non-rodent or 3R principles but also makes nanotoxicology testing more ethical, relevant, and cost- and time-efficient.


Asunto(s)
Autofagia , Nanoestructuras/toxicidad , Pruebas de Toxicidad/métodos , Animales , Autofagia/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos
17.
Regul Toxicol Pharmacol ; 101: 35-47, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30439387

RESUMEN

A decision tree-based defined approach (DA) has been designed using exclusion criteria based on applicability domain knowledge of in chemico/in vitro information sources covering key events 1-3 in the skin sensitisation adverse outcome pathway and an in silico tool predicting the adverse outcome (Derek Nexus). The hypothesis is that using exclusion criteria to de-prioritise less applicable assays and/or in silico outcomes produces a rational, transparent, and reliable DA for the prediction of skin sensitisation potential. Five exclusion criteria have been established: Derek Nexus reasoning level, Derek Nexus negative prediction, metabolism, lipophilicity, and lysine-reactivity. These are used to prioritise the most suitable information sources for a given chemical and results from which are used in a '2 out of 3' approach to provide a prediction of hazard. A potency category (and corresponding GHS classification) is then assigned using a k-Nearest Neighbours model containing human and LLNA data. The DA correctly identified the hazard (sensitiser/non-sensitiser) for 85% and 86% of a dataset with reference LLNA and human data. The correct potency category was identified for 59% and 68% of chemicals, and the GHS classification accurately predicted for 73% and 76% with reference LLNA and human data, respectively.


Asunto(s)
Haptenos/toxicidad , Alternativas a las Pruebas en Animales , Animales , Simulación por Computador , Árboles de Decisión , Dermatitis Alérgica por Contacto , Haptenos/clasificación , Humanos , Bases del Conocimiento , Ensayo del Nódulo Linfático Local , Ratones , Medición de Riesgo
18.
Ecotoxicol Environ Saf ; 167: 513-519, 2019 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-30384058

RESUMEN

The Amphibian Metamorphosis Assay (AMA) is a screening test for detecting chemicals with thyroid activity. There is little experience in data interpretation and in using AMA data for screening, testing and identifying endocrine disruptors. To investigate the sensitivity of different endpoints of the AMA, the publically available data for 57 thyroid active and inactive chemicals were compiled and analyzed. Endpoints body weight and length appeared as sensitive as apical thyroid responsive endpoints hind limb length (HLL) and developmental stage (DS) for 12 thyroid active chemicals. The sensitivity of body weight, length and HLL was comparable, which is higher than that of DS for 45 thyroid inactive chemicals. The decision logic of the AMA suggests that an advanced development alone indicates thyroid activity. The analysis here showed that advanced development at day 7 could indicate thyroid activity of a chemical. However, advanced development at day 21 may be influenced by thyroid inactive chemicals. Among 39 thyroid inactive chemicals, which affected one or more endpoints, 33% and 77% induced changes in HLL and/or DS at day 7 and 21, respectively; only 10% influenced thyroid histology. These results showed that apical thyroid responsive endpoints HLL and DS are influenced by thyroid active chemicals as well as thyroid inactive chemical. Both endpoints should be combined with thyroid histology for the identification of thyroid active chemicals. The use of the AMA in a testing strategy to identify chemicals with thyroid activity is discussed.


Asunto(s)
Determinación de Punto Final , Metamorfosis Biológica/efectos de los fármacos , Pruebas de Toxicidad , Acetanilidas/toxicidad , Anfibios , Animales , Benzotiazoles/toxicidad , Bioensayo , Disruptores Endocrinos/toxicidad , Tiocarbamatos/toxicidad , Glándula Tiroides/efectos de los fármacos , Triazinas/toxicidad , Xenopus laevis
19.
Crit Rev Toxicol ; 48(5): 344-358, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29474128

RESUMEN

Cosmetics Europe, the European Trade Association for the cosmetics and personal care industry, is conducting a multi-phase program to develop regulatory accepted, animal-free testing strategies enabling the cosmetics industry to conduct safety assessments. Based on a systematic evaluation of test methods for skin sensitization, five non-animal test methods (DPRA (Direct Peptide Reactivity Assay), KeratinoSensTM, h-CLAT (human cell line activation test), U-SENSTM, SENS-IS) were selected for inclusion in a comprehensive database of 128 substances. Existing data were compiled and completed with newly generated data, the latter amounting to one-third of all data. The database was complemented with human and local lymph node assay (LLNA) reference data, physicochemical properties and use categories, and thoroughly curated. Focused on the availability of human data, the substance selection resulted nevertheless resulted in a high diversity of chemistries in terms of physico-chemical property ranges and use categories. Predictivities of skin sensitization potential and potency, where applicable, were calculated for the LLNA as compared to human data and for the individual test methods compared to both human and LLNA reference data. In addition, various aspects of applicability of the test methods were analyzed. Due to its high level of curation, comprehensiveness, and completeness, we propose our database as a point of reference for the evaluation and development of testing strategies, as done for example in the associated work of Kleinstreuer et al. We encourage the community to use it to meet the challenge of conducting skin sensitization safety assessment without generating new animal data.


Asunto(s)
Cosméticos/efectos adversos , Bases de Datos Factuales , Dermatitis Alérgica por Contacto/inmunología , Piel/inmunología , Alternativas a las Pruebas en Animales/métodos , Cosméticos/farmacología , Dermatitis Alérgica por Contacto/etiología , Humanos , Piel/efectos de los fármacos
20.
Crit Rev Toxicol ; 48(5): 359-374, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29474122

RESUMEN

Skin sensitization is a toxicity endpoint of widespread concern, for which the mechanistic understanding and concurrent necessity for non-animal testing approaches have evolved to a critical juncture, with many available options for predicting sensitization without using animals. Cosmetics Europe and the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods collaborated to analyze the performance of multiple non-animal data integration approaches for the skin sensitization safety assessment of cosmetics ingredients. The Cosmetics Europe Skin Tolerance Task Force (STTF) collected and generated data on 128 substances in multiple in vitro and in chemico skin sensitization assays selected based on a systematic assessment by the STTF. These assays, together with certain in silico predictions, are key components of various non-animal testing strategies that have been submitted to the Organization for Economic Cooperation and Development as case studies for skin sensitization. Curated murine local lymph node assay (LLNA) and human skin sensitization data were used to evaluate the performance of six defined approaches, comprising eight non-animal testing strategies, for both hazard and potency characterization. Defined approaches examined included consensus methods, artificial neural networks, support vector machine models, Bayesian networks, and decision trees, most of which were reproduced using open source software tools. Multiple non-animal testing strategies incorporating in vitro, in chemico, and in silico inputs demonstrated equivalent or superior performance to the LLNA when compared to both animal and human data for skin sensitization.


Asunto(s)
Alternativas a las Pruebas en Animales/métodos , Biología Computacional/métodos , Simulación por Computador , Cosméticos/efectos adversos , Dermatitis Alérgica por Contacto/inmunología , Piel/inmunología , Animales , Cosméticos/farmacología , Dermatitis Alérgica por Contacto/etiología , Humanos , Ratones , Piel/efectos de los fármacos
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