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1.
PLoS One ; 17(9): e0274011, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36112591

RESUMO

Engineered nanomaterials pose occupational health and environmental concerns as they possess unique physical and chemical properties that can contribute to toxicity. High throughput toxicity screening methods are needed to address the increasing number of nanomaterials in production. Here we used a zebrafish photomotor response (PMR) test to evaluate a set of fifteen nanomaterials with military relevance. Automated dechorionation of zebrafish embryos was used to enhance nanomaterials bioavailability. Optimal PMR activity in zebrafish embryos was found at 30-31 hours post-fertilization (hpf). Behavioral and toxicological responses were measured at 30 and 120 hpf; behavioral responses were found for thirteen of the fifteen nanomaterials and acute toxicity (LC50) levels for nine of the fifteen nanomaterials below the maximum test concentration of 500 µg/ml. Physico-chemical characterization of the nanomaterials detected endotoxin and bacterial contamination in two of the tested samples, which may have contributed to observed toxicity and reinforces the need for physical and chemical characterization of nanomaterials use in toxicity testing. The zebrafish PMR test, together with automated dechorionation, provides an initial rapid assessment of the behavioral effects and toxicity of engineered nanomaterials that can be followed up by physico-chemical characterization if toxicity is detected, reducing the amount of time and monetary constraints of physico-chemical testing.


Assuntos
Nanoestruturas , Peixe-Zebra , Animais , Embrião não Mamífero , Endotoxinas/farmacologia , Nanoestruturas/química , Nanoestruturas/toxicidade , Testes de Toxicidade/métodos
3.
Toxicol Appl Pharmacol ; 452: 116195, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35977605

RESUMO

For decades, chemical safety assessment has been proposed to shift from animal testing to in vitro testing systems in response to the call for the 3R. In Europe, the answer was to combine various information sources in integrated testing strategies (ITS); In the US, it was in 2007 when the landmark report by the National Research Council put forward a vision of in vitro toxicity testing paradigm. Since then, efforts to develop pathway-based assessment framework have been on the track. In 2010, systems biology brought out a conceptual framework called adverse outcome pathway (AOP), which took one step further from toxicity pathway to regulatory toxicology. Computational modeling, high-throughput screening, high-content omics have all been approached to facilitate this progress. This paper briefly reviewed the achievement of pathway-based chemical assessment since 2007, discussed potential pitfalls and challenges that mechanism-driven chemical assessment may undergo, and presented future perspectives of safety assessment that is to be based on computational system biology.


Assuntos
Rotas de Resultados Adversos , Testes de Toxicidade , Animais , Simulação por Computador , Técnicas In Vitro , Medição de Risco , Biologia de Sistemas
4.
Appl Microbiol Biotechnol ; 106(18): 6317-6333, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36028635

RESUMO

Recombinant luminescent Escherichia coli strains could be used to detect the toxicity of pure or mixed contaminants as a light-off sensor. In this work, the lux operon of Photobacterium phosphoreum T3 was identified for the first time. Recombinant luminescent E. coli strains were constructed via expressing the lux operons of P. phosphoreum T3 and Vibrio qinghaiensis Q67 in E. coli MG1655, and the optimal protectant containing 10% (w/v) trehalose and 4% sucrose was used to prepare the freeze-dried recombinant luminescent E. coli cells. Then, these freeze-dried E. coli cells were subjected to acute toxicity detection. The results showed that luminescent E. coli strains displayed sensitive toxic responses to BPA, nFe2O3, Cd, Pb, As, and Hg, for example, the EC50 values of BPA and nFe2O3 to luminescent E. coli strains ranged from 1.54 to 50.19 mg/l and 17.50 to 21.52 mg/l, respectively. Indeed, luminescent E. coli strains exhibited more sensitive responses to Cd, Pb, and Hg than the natural strain Q67. The results suggested that recombinant luminescent E. coli strains could be used for the detection of acute toxicity. Furthermore, the combined toxicities of BPA and nFe2O3, Hg, and Pb were measured, and the joint effects of these mixtures were evaluated with luminescent E. coli. The results indicated that the joint effects of BPA and nFe2O3 suggested to be synergistic or additive to luminescent E. coli, while the joint effects of heavy metals and nFe2O3 exhibited additivities. The cellular endocytosis for Fe2O3 nanoparticles was not observed, which could explain the additive instead of synergistic effects between heavy metals and nFe2O3. KEY POINTS: • Sequence of the lux operon from P. phosphoreum T3 was reported for the first time. • Recombinant luminescent E. coli was more sensitive to Cd, Pb, and Hg than Q67. • Joint effects of BPA and nFe2O3 were synergistic or additive to luminescent E. coli.


Assuntos
Mercúrio , Metais Pesados , Cádmio , Escherichia coli/genética , Chumbo , Medições Luminescentes , Óperon , Testes de Toxicidade
5.
Ecotoxicol Environ Saf ; 242: 113839, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35816839

RESUMO

1,2,4-triazole derivatives exhibit various biological activities, including antibacterial and antifungal properties. On the other hand, these chemicals may have unique cumulative and harmful effects on living organisms. The goal of this work is to use quantitative structure-toxicity relationship (QSTR) and interspecies quantitative toxicity-toxicity relationship (iQSTTR) models to predict the acute toxicity of 1,2,4-triazole derivatives. The QSTR models were generated by multiple linear regression (MLR) following the OECD recommendations for QSAR model development and validation. The iQSTTR models were constructed using data on acute oral toxicity in rats and mice, as well as the 2D descriptor. The application domain (AD) analysis was used to identify model outliers and determine if the forecast was credible. Six QSTR models were successfully constructed in rats and mice using various delivery methods, and the scatter plots demonstrated excellent consistency across training and test sets. According to external and internal validation criteria, all six QSTR models may be broadly accepted; however, the orally administered mice model was the optimum one among the six species. Several chemicals with leverage values above the requirements were identified as response or structural outliers in the training sets for six QSTR and two iQSTTR models. All outliers, however, fell slightly outside the threshold or had low prediction errors, which may have had little impact on the capacity to forecast and were therefore preserved in the final models. In fact, neither the QSTR nor the iQSTTR test sets contained any response outliers. Additionally, all external and internal validation results for the iQSTTR models were approved, with the iQSTTR models outperforming the comparable QSTR models, which are deemed more dependable. The QSTR and iQSTTR models performed well in predicting toxicity using test sets, which would be beneficial in evaluating and synthesizing newly discovered 1,2,4-triazoles derivatives with low toxicity and environmental hazard.


Assuntos
Relação Quantitativa Estrutura-Atividade , Triazóis , Animais , Modelos Lineares , Camundongos , Ratos , Testes de Toxicidade , Triazóis/toxicidade
6.
Ecotoxicol Environ Saf ; 242: 113907, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-35901590

RESUMO

Copper is both an essential trace element and a potent pesticide. The use of copper as an antifoulant has increased in the last decades in line with the expanding aquaculture and shipping industries. In aquatic environments, it also affects non-target taxa. One of which are copepods, which constitute the central link in the marine food web. Despite their ecological importance, there are no systematic reviews of the lethal concentration range and drivers of copper toxicity in this taxon. Here, we combined literature data from 31 peer-reviewed articles recording the Lethal Concentration 50 (LC50) for copper in copepods and the experiments' respective environmental, developmental, and taxonomic parameters. The LC50 is a traditional endpoint for toxicity testing used in standardized toxicity testing and many ecological studies. In total, we were able to extract 166 LC50 entries. The variability in the metadata allowed for a general analysis of the drivers of copper sensitivity in copepods. Using a generalized additive modeling approach, we find that temperature increases copper toxicity when above approximately 25℃. Counter to our expectations; salinity does not influence copper sensitivity across copepod species. Unsurprisingly, nauplii are more susceptible to copper exposure than adult copepods, and benthos-associated harpacticoids are less sensitive to copper than pelagic calanoids. Our final model can predict sensible specific-specific copper concentrations for future experiments, thus giving an informed analytical approach to range testing in future dose-response experiments. Our model can also potentially improve ecological risk assessment by accounting for environmental differences. The approach can be applied to other toxicants and taxa, which may reveal underlying patterns otherwise obscured by taxonomic and experimental variability.


Assuntos
Copépodes , Poluentes Químicos da Água , Animais , Copépodes/fisiologia , Cobre/toxicidade , Dose Letal Mediana , Testes de Toxicidade , Poluentes Químicos da Água/toxicidade
7.
Aquat Toxicol ; 249: 106220, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35777163

RESUMO

Risk assessment of hydrophobic organic compounds (HOCs) is difficult because maintaining a well-defined exposure during aquatic toxicity testing is challenging due to the limited water solubility and various loss processes such as volatilization, biodegradation and sorption. Passive dosing techniques help to overcome these challenges by providing a well-controlled and solvent-free exposure. In this study, the algal growth inhibition test (DIN EN ISO 8692) was converted into a miniaturized passive dosing setting. For this purpose, biocompatible O-rings were used as substance reservoirs and loaded with polycyclic aromatic hydrocarbons (PAHs). The growth inhibition of the microalgae Raphidocelis subcapitata induced by single PAHs (log KOW 3.24-5.91) was investigated. In addition, recreated PAH mixtures were tested representing field compositions of the pore water North Sea sediments. Some of the single PAHs revealed strong growth inhibiting effects on the algal growth, while the recreated mixture compositions had slightly lower effect on the growth inhibition in the highest concentrations. Overall, the toxicity of the PAHs generally increased with the maximum chemical activities (amax) of the PAHs and the inhibition data could be fitted with one maximum chemical activity response curve. Therefore, the miniaturized passive dosing approach appears as a promising practical and economical method that can be used for toxicity testing of the different trophic levels to improve comprehensive risk assessment.


Assuntos
Microalgas , Hidrocarbonetos Policíclicos Aromáticos , Poluentes Químicos da Água , Hidrocarbonetos Policíclicos Aromáticos/química , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Testes de Toxicidade/métodos , Água/química , Poluentes Químicos da Água/toxicidade
8.
Reprod Toxicol ; 112: 100-108, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35788364

RESUMO

103 novel drugs were approved by the FDA in 2020-2021. Embryofetal development (EFD) studies were conducted for 76 % of these approvals. For the majority of drugs, EFD studies were conducted in rats and rabbits. Both species were equally sensitive to developmental toxicity, but the rabbit was slightly more sensitive to maternal toxicity at the same systemic exposure level. Nonetheless, 68 % of drugs showed more than a 2-fold difference in the low adverse effect level for developmental toxicity between the rat and rabbit. Previous reviews in this series compiled information on EFD studies for all small molecule pharmaceuticals approved since 2014 and for all therapeutic monoclonal antibodies approved to date. The use of non-human primates for the developmental toxicity testing of biopharmaceuticals has fallen over recent years (22 % of biologics license applications (BLAs) for 2020-2021, compared with 62 % for 2002-2015), with more biopharmaceuticals now tested in rodents (37 % of BLAs for 2020-2021). While the Pregnancy and Lactation Labeling Rule (PLLR), adopted in 2014, has brought consistency to the presentation of EFD data in drug labels, prescribers complain that the pregnancy section of current drug labels is neither concise nor clear. The FDA has pledged to address the concerns of clinicians in a future revision of the PLLR rule. The recommendations on risk assessment in the recently revised ICHS5(R3) guideline could be incorporated into the PLLR rule to remove extraneous nonclinical details from the label with the aim of facilitating rapid understanding by the practitioner.


Assuntos
Produtos Biológicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Animais , Rotulagem de Medicamentos , Feminino , Preparações Farmacêuticas , Gravidez , Coelhos , Ratos , Testes de Toxicidade
9.
Environ Toxicol Pharmacol ; 94: 103917, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35779704

RESUMO

A previous acute toxicity study of binary mixtures showed that the combined toxicity can be predicted with the parameter k∙ECx. To systematically investigate the ability of k∙ECx to predict the chronic combined toxicity of binary mixtures, the toxicity of six contaminants and five binary mixtures was determined by long-term microplate toxicity analysis (L-MTA) using Aliivibrio fischeri as the test organism. The independent action model (IA) and the relative model deviation ratio (rMDR) were employed to determine the relationship between the Δ(k∙ECx)% and rMDRx. The results showed that these two factors conformed to the exponential function in long-term toxicity. Owing to the time-dependence of toxicity, the mixture type of chronic toxicity changes to the relative type of acute toxicity. If the acute toxicity of binary mixtures changes their mode of joint action throughout the concentration range, the chronic toxicity will also change their mode of joint action, and vice versa. This study clarified the change rules of the joint action of binary mixtures in acute and chronic toxicity which can promote research on chronic toxicity of binary mixtures.


Assuntos
Aliivibrio fischeri , Testes de Toxicidade , Bioensaio
10.
ACS Appl Mater Interfaces ; 14(28): 31667-31676, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35791814

RESUMO

At present, microscale high-throughput screening (HTS) for drug toxicity has drawn increased attention. Reported methods are often constrained by the inability to execute rapid fusion over diverse droplets or the inflexibility of relying on rigid customized templates. Herein, a light-responsive candle-soot-hybridized lubricant-infused slippery surface (CS-LISS) was reported by one-step femtosecond laser cross-scanning to realize highly effective and flexible drug HTS. Due to its low-hysteresis merits, the CS-LISS can readily steer diverse droplets toward arbitrary directions at a velocity over 1.0 mm/s with the help of tracing lateral near-infrared irradiation; additionally, it has the capability of self-cleaning and self-deicing. Significantly, by integrating the CS-LISS with a GFP HeLa cell chip, high-efficiency drug toxicity screening can be successfully achieved with the aid of fluorescence imaging. This work provides insights into the design of microscale high-throughput drug screening.


Assuntos
Pró-Fármacos , Testes de Toxicidade , Avaliação Pré-Clínica de Medicamentos , Excipientes/química , Células HeLa , Humanos , Lubrificantes/química , Imagem Óptica , Pró-Fármacos/química , Pró-Fármacos/toxicidade , Fuligem
11.
Biologicals ; 78: 17-26, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35840492

RESUMO

This online workshop Accelerating Global Deletion of the Abnormal Toxicity Test for vaccines and biologicals. Planning common next steps was organized on October 14th, 2021, by the Animal Free Safety Assessment Collaboration (AFSA), the Humane Society International (HSI), the European Federation of Pharmaceutical Industries and Associations (EFPIA), in collaboration with the International Alliance of Biological Standardization (IABS). The workshop saw a participation of over a hundred representatives from international organizations, pharmaceutical industries and associations, and regulatory authorities of 28 countries. Participants reported on country- and region-specific regulatory requirements and, where present, on the perspectives on the waiving and elimination of the Abnormal Toxicity Test. With AFSA, HSI, EFPIA and IABS representatives as facilitators, the participants also discussed specific country/global actions to further secure the deletion of ATT from all regulatory requirements worldwide.


Assuntos
Testes de Toxicidade , Vacinas , Indústria Farmacêutica , Humanos , Padrões de Referência , Vacinas/efeitos adversos
12.
Part Fibre Toxicol ; 19(1): 50, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35854357

RESUMO

BACKGROUND: The EU-project GRACIOUS developed an Integrated Approach to Testing and Assessment (IATA) to support grouping high aspect ratio nanomaterials (HARNs) presenting a similar inhalation hazard. Application of grouping reduces the need to assess toxicity on a case-by-case basis and supports read-across of hazard data from substances that have the data required for risk assessment (source) to those that lack such data (target). The HARN IATA, based on the fibre paradigm for pathogenic fibres, facilitates structured data gathering to propose groups of similar HARN and to support read-across by prompting users to address relevant questions regarding HARN morphology, biopersistence and inflammatory potential. The IATA is structured in tiers, allowing grouping decisions to be made using simple in vitro or in silico methods in Tier1 progressing to in vivo approaches at the highest Tier3. Here we present a case-study testing the applicability of GRACIOUS IATA to form an evidence-based group of multiwalled carbon nanotubes (MWCNT) posing a similar predicted fibre-hazard, to support read-across and reduce the burden of toxicity testing. RESULTS: The case-study uses data on 15 different MWCNT, obtained from the published literature. By following the IATA, a group of 2 MWCNT was identified (NRCWE006 and NM-401) based on a high degree of similarity. A pairwise similarity assessment was subsequently conducted between the grouped MWCNT to evaluate the potential to conduct read-across and fill data gaps required for regulatory hazard assessment. The similarity assessment, based on expert judgement of Tier 1 assay results, predicts both MWCNT are likely to cause a similar acute in vivo hazard. This result supports the possibility for read-across of sub-chronic and chronic hazard endpoint data for lung fibrosis and carcinogenicity between the 2 grouped MWCNT. The implications of accepting the similarity assessment based on expert judgement of the MWCNT group are considered to stimulate future discussion on the level of similarity between group members considered sufficient to allow regulatory acceptance of a read-across argument. CONCLUSION: This proof-of-concept case-study demonstrates how a grouping hypothesis and IATA may be used to support a nuanced and evidence-based grouping of 'similar' MWCNT and the subsequent interpolation of data between group members to streamline the hazard assessment process.


Assuntos
Nanotubos de Carbono , Fibrose Pulmonar , Administração por Inalação , Humanos , Pulmão , Nanotubos de Carbono/toxicidade , Testes de Toxicidade/métodos
14.
Chemosphere ; 303(Pt 3): 135197, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35691390

RESUMO

In spite of the sensitivity of amphibians to contamination, data from fish have been commonly used to predict the effects of chemicals on aquatic life stages. However, recent studies have highlighted that toxicity data derived from fish species may not protect all the aquatic life stages of amphibians. For pesticide toxicity assessment (PTA), EFSA has highlighted that more information on lethal toxicity for the aquatic life stages of amphibians is still needed to reduce uncertainties. The current review aims to propose a test with amphibians based on spatial avoidance, as a more humane alternative method to the lethality tests for chemicals. A review of lethal toxicity tests carried out with amphibians in the period between 2018 and 2021 is presented, then we discuss the suitability of using fish toxicity data as a surrogate to predict the effects on more sensitive amphibian groups. The possible differences in sensitivity to chemicals may justify the need to develop further tests with amphibian embryos and larvae in order to reduce uncertainties. A new test is proposed focused on the avoidance behaviour of organisms fleeing from contamination to replace lethal tests. As avoidance indicates the threshold at which organisms will flee from contamination, a reduction in the population density, or its disappearance, at the local scale due to emigration is expected, with ecological consequences analogous to mortality. Avoidance tests provide an ethical advantage over lethal tests as they respect the concepts of the 3 Rs (mainly Refinement), reducing the suffering of the organisms.


Assuntos
Anfíbios , Poluentes Químicos da Água , Animais , Peixes , Larva , Medição de Risco/métodos , Testes de Toxicidade , Poluentes Químicos da Água/toxicidade
15.
Lab Chip ; 22(14): 2600-2623, 2022 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-35678285

RESUMO

Microtoxicology is concerned with the toxic effects of small amounts of substances. This review paper discusses the application of small amounts of noxious substances for toxicological investigation in small volumes. The vigorous development of miniaturized methods in microfluidics over the last two decades involves chip-based devices, micro droplet-based procedures, and the use of micro-segmented flow for microtoxicological studies. The studies have shown that the microfluidic approach is particularly valuable for highly parallelized and combinatorial dose-response screenings. Accurate dosing and mixing of effector substances in large numbers of microcompartments supplies detailed data of dose-response functions by highly concentration-resolved assays and allows evaluation of stochastic responses in case of small separated cell ensembles and single cell experiments. The investigations demonstrate that very different biological targets can be studied using miniaturized approaches, among them bacteria, eukaryotic microorganisms, cell cultures from tissues of multicellular organisms, stem cells, and early embryonic states. Cultivation and effector exposure tests can be performed in small volumes over weeks and months, confirming that the microfluicial strategy is also applicable for slow-growing organisms. Here, the state of the art of miniaturized toxicology, particularly for studying antibiotic susceptibility, drug toxicity testing in the miniaturized system like organ-on-chip, environmental toxicology, and the characterization of combinatorial effects by two and multi-dimensional screenings, is discussed. Additionally, this review points out the practical limitations of the microtoxicology platform and discusses perspectives on future opportunities and challenges.


Assuntos
Técnicas de Cultura de Células , Microfluídica , Bactérias , Dispositivos Lab-On-A-Chip , Testes de Toxicidade
16.
Environ Toxicol Chem ; 41(8): 2003-2007, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35661245

RESUMO

Long-chain per- and poly-fluoroalkyl substances (PFAS) have been the active ingredients in firefighting foams for more than 50 years. Due to their extreme persistence, regulatory agencies are concerned about their potential adverse environmental and health impacts. Recently, nonfluorinated chemical constituents have been proposed for use in fire-fighting foams in an effort to reduce the potential negative impacts of PFAS on terrestrial and aquatic flora and fauna. However, it is important to also determine the potential ecotoxicity of these nonfluorinated foam products, because we have little toxicological information for many of them. In preparation for a chronic study, we conducted an acute (24-h) oral toxicity test in northern bobwhite quail (Colinus virginianus) using six different fluorine-free foams; five were commercial foams (BioEx ECOPOL A, Fomtec Enviro USP, National Foam Avio Green KHC, National Foam NFD 20-391, and Solberg Re-Healing Foam), and one was an experimental foam (NRL 502W). A short-chain PFAS-based foam (Buckeye Platinum Plus C6) was also evaluated for comparative purposes. Groups of five birds were initially pseudogavaged with a volume of each product corresponding to a "limit" (the highest exposure concentration expected to occur environmentally). Only one bird (1 of 35) died during the limit test, indicating that all seven products have an acute median lethal dose in adult quail at or above the limit (~1500 mg/kg body wt). Environ Toxicol Chem 2022;41:2003-2007. © 2022 SETAC.


Assuntos
Colinus , Fluorcarbonetos , Animais , Fluorcarbonetos/toxicidade , Dose Letal Mediana , Codorniz , Testes de Toxicidade
17.
Environ Toxicol Chem ; 41(9): 2285-2304, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35723421

RESUMO

When assessing the environmental risks of offshore produced water discharges, it is key to properly assess the toxicity of this complex mixture. Toxicity can be assessed either through the application of whole-effluent toxicity (WET) testing or based on its substance-based chemical composition or both. In the present study, the toxicity assessed based on WET and substance-based was compared for 25 offshore produced water effluents collected for the Norwegian implementation of the Oslo-Paris convention risk-based assessment program. The objectives were, firstly, to examine the concurrence between toxicity estimates derived from these two lines of evidence; and, secondly, to evaluate whether toxicity of produced water discharges predicted from substance-based data is adequately addressed in comparison with ground truth reflected by WET. For both approaches, 50% hazardous concentrations (HC50s) were calculated. For at least 80% of the effluents the HC50s for the two approaches differed by less than a factor of 5. Differences found between the two approaches can be attributed to the uncertainty in the estimation of the concentration of production chemicals that strongly influences the substance-based estimated toxicity. By evaluating effluents on a case-by-case basis, additional causes were hypothesized. Risk management will particularly benefit from the strength of risk endpoints from both approaches by monitoring them periodically in conjunction over time. This way (in)consistencies in trends of both indicators can be evaluated and addressed. Environ Toxicol Chem 2022;41:2285-2304. © 2022 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.


Assuntos
Monitoramento Ambiental , Poluentes Químicos da Água , Ecotoxicologia , Gases , Óleos , Testes de Toxicidade , Água , Poluentes Químicos da Água/análise
18.
Reprod Toxicol ; 112: 14-22, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35714935

RESUMO

The Extended-One-Generation Study [EOGRTS, OECD 443] is a study in which the toxic effects of test substances on reproduction (Cohort 1), neurodevelopment (Cohort 2), and development of the immune system (Cohort 3) in rats are evaluated. The latter two Cohorts are not always required according to the European Chemicals Agency (ECHA) based on data from previously performed toxicity studies. Although the Cohorts for developmental neurotoxicity (DNT) and developmental immunotoxicity (DIT) are often omitted, the F1-animals normally required for these Cohorts are still maintained for evaluation of sexual maturation since three F1-animals/sex/litter/group are required according to OECD Guidance Document (GD) No. 151. This review investigates whether two F1-animals/sex/litter/group would suffice for this endpoint by investigating the rationale provided by the GD and by comparing results of eighteen EOGRTSs in which three versus two F1-animals/sex/litter/group were evaluated. After a comprehensive literature research, we concluded that the rationale in the GD does not substantiate the decision to use three F1-animals/sex/litter/group. The scientific papers provided as rationale focused on male observations and the observations discussed do not match the observations for sexual maturation mentioned by the guidelines. The investigation using data from eighteen EOGRTSs showed that the toxicological conclusions, whether the test substance affected sexual maturation or not, matched when comparing data of two F1-animals/sex/litter/group to three F1-animals/sex/litter/group. To conclude, two F1-animals/sex/litter/group would suffice for the evaluation of sexual maturation, which negates the requirement for a so called "Cohort 1 C" (i.e. 160 animals (80 males and 80 females)) per EOGRTS, as well as the number of regulated procedures that need to be performed.


Assuntos
Reprodução , Maturidade Sexual , Animais , Estudos de Coortes , Feminino , Humanos , Sistema Imunitário , Masculino , Ratos , Testes de Toxicidade/métodos
19.
Toxicol Pathol ; 50(4): 432-465, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35730663

RESUMO

Beagle dogs are a key nonrodent species in nonclinical safety evaluation of new biomedical products. The Society of Toxicologic Pathology (STP) has published "best practices" recommendations for nervous system sampling in nonrodents during general toxicity studies (Toxicol Pathol 41[7]: 1028-1048, 2013), but their adaptation to the Beagle dog has not been defined specifically. Here we provide 2 trimming schemes suitable for evaluating the unique neuroanatomic features of the dog brain in nonclinical toxicity studies. The first scheme is intended for general toxicity studies (Tier 1) to screen test articles with unknown or no anticipated neurotoxic potential; this plan using at least 7 coronal hemisections matches the STP "best practices" recommendations. The second trimming scheme for neurotoxicity studies (Tier 2) uses up to 14 coronal levels to investigate test articles where the brain is a suspected or known target organ. Collection of spinal cord, ganglia (somatic and autonomic), and nerves for dogs during nonclinical studies should follow published STP "best practices" recommendations for sampling the central (Toxicol Pathol 41[7]: 1028-1048, 2013) and peripheral (Toxicol Pathol 46[4]: 372-402, 2018) nervous systems. This technical guide also demonstrates the locations and approaches to collecting uncommonly sampled peripheral nervous system sites.


Assuntos
Síndromes Neurotóxicas , Testes de Toxicidade , Animais , Cães , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/veterinária , Sistema Nervoso Periférico , Manejo de Espécimes , Medula Espinal
20.
Artigo em Inglês | MEDLINE | ID: mdl-35589063

RESUMO

Early-life stage (ELS) avian toxicity tests have been proposed as a more ethical alternative to traditional standardized tests with adult birds. At the same time, 'omics approaches are gaining traction in the field of avian toxicology, but little has been done to characterize the metabolome and transcriptome at different life stages. The present study uses 'omics data from toxicity tests of 8 environmental chemicals in ELS and adult Japanese quail (Coturnix japonica) to address this data gap. Previous analyses of these data focused on responses to each of the individual chemicals. Here, we consider data from all studies to describe variation in the metabolome and transcriptome between life stages and across independent experiments, irrespective of chemical treatment. Of the 230 metabolites detected in liver, 163 were shared between the two life stages. However, many of the targeted bile acids that were present in the adult liver were absent from ELS samples. For the transcriptome, >90% of the 18,364 detected transcripts were common to both life stages. Based on the 213 genes solely detected in ELS liver, the neuroactive ligand-receptor interaction pathway was significantly enriched. Multivariate and hierarchical clustering analyses revealed that variability among independent experiments was higher for the adult than the ELS studies at both the metabolomic and transcriptomic levels. Our results indicate concordance of the two approaches, with less variation between independent experiments in the ELS metabolome and transcriptome than in adults, lending support for the use of ELS as an alternative toxicity testing strategy.


Assuntos
Coturnix , Transcriptoma , Animais , Coturnix/genética , Metaboloma , Metabolômica , Testes de Toxicidade
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