bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Computer Automated Structure Evaluation Methodology as an Alternative to In Vivo Eye Irritation Testing
Authors: Klopman Gilles , Ptchelintsev Dmitri , Frierson Manton , Pennisi Stephen , Renskers Kevin , Dickens Michael 
Published: August 2020

The Multiple Computer Automated Structure Evaluation (Multi-CASE) methodology was applied to the semi-quantitative analysis of eye irritation potential of 186 organic chemicals. The resulting expert dictionary of substructural attributes indicates that the following functionalities are linked to eye irritation potential: carboxylate and sulphonate groups in anionic surfactants, phenolic moieties in non-ionic surfactants, amino groups, halogenated and unsaturated structures, anhydrides and epoxides. Ester groups were recognised as having a low irritation potential. The Multi-CASE program successfully predicted a priori the eye irritation potential of: 1) 21 individual chemicals; 2) chemical mixtures such as coconut oil, hydrogenated castor oil, rice bran, eucalyptus oils and potassium alginate; and 3) polymers,’ including polyvinyl alcohols, polyvinyl butyral, polyvinyl pyrrolidone, corn starch and nylon. It was found that the structure of the repeat units together, and not that of the individual monomers, is the best predictor of the eye irritation potential of the corresponding polymers. It appears that the repeat units of polymers dilute out the irritation potential of terminal groups normally expected to contribute significant irritation potential to chemicals of lower molecular weight. The Multi-CASE eye irritation model can be used for: 1) in vitro prescreening for eye irritation potential; and 2) design and modification of chemicals when low eye irritation potential is important.
An In Vivo/In Vitro Study of Allyl Alcohol Toxicity Using Enzyme Inhibitors
Authors: Pulci Romana , Moneta Donatella , Dostert Philippe , Brughera Marco , Scampini Giovanna , Castellino Silvana , Carminati Paolo , Mazué Guy 
Published: August 2020

The aim of this study was to verify an in vitro model of hepatotoxicity, designed to assess the production of reactive species from biologically-inert chemicals through their metabolic transformation. One example is allyl alcohol, which produces acrolein through the action of the enzyme alcohol dehydrogenase. Acrolein is a highly hepatotoxic aldehyde which is detoxified to acrylic acid by aldehyde dehydrogenase (ALDH). A deficiency of this enzyme, common in some Asian populations, can give rise to pathological conditions of hepatotoxicity. Isolated rat hepatocytes were incubated with allyl alcohol with and without cyanamide, a known inhibitor of ALDH. The toxicity of allyl alcohol, assessed on the basis of release of glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and lactate dehydrogenase (LDH) into the culture medium, was dramatically increased by the addition of cyanamide. In vivo, the same treatment scheme was used in rats treated with allyl alcohol with or without cyanamide pretreatment. It was also demonstrated that allyl alcohol toxicity is dramatically enhanced by the addition of an aldehyde dehydrogenase inhibitor, as shown by plasma levels of hepatic enzymes (GOT, GPT and LDH) and by histological findings. We believe that this in vitro model, involving the use of enzyme inhibitors, could be useful for verification of the hypothesis that hepatotoxins, such as acrolein, are produced from some pharmaceutical and other chemical compounds.
The Use of the Vitality and Chemotaxis of Human Polymorphonuclear Leukocytes for the In Vitro Estimation of the Acute Toxicity of the First Ten Chemicals from the MEIC List
Authors: Valentino Matteo , Monaco Francesca , Pizzichini Maria Antonietta , Governa Mario 
Published: August 2020

The acute cytotoxicity of the first ten MEIC chemicals has been estimated by others in various cell lines. In the present investigation, isolated human polymorphonuclear leukocytes (PMN) from ten healthy non-smoking laboratory personnel were used to assess in vitro toxicity of the same chemicals. The cells were treated with different concentrations of the respective chemicals for three hours and their vitality and chemotaxis were tested. Vitality was measured by fluorescence microscopy after the addition of fluorescein diacetate and ethidium bromide. Living cells which took up and hydrolysed fluorescein diacetate, and dead cells, stained by ethidium bromide, were counted and the percentage of live cells was calculated. Locomotion stimulated by the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (F-MLP), was measured in blind-well Boyden chambers and a chemotactic index was calculated. The results were mathematically transformed to produce a linear curve, and then fitted by the linear least squares procedure, from which LC50 and IC50 values were obtained by interpolation. All the chemicals decreased the vitality and inhibited the chemotaxis of the PMN. Obviously the chemotactic test was more sensitive than the vitality one. A correlation (r = 0.933) was found between vitality and chemotaxis inhibition. Spearman rank correlation analysis revealed significant correlations between our results and those from in vitro experiments conducted in other laboratories, as well as with data concerning mouse, rat and human lethal doses.
Three-dimensional Growth of Renal Epithelial Cells in Vitro: A Tool in Toxicity Testing
Authors: Andersen Knut-Jan , Christensen Erik Ilsø , Vik Hogne 
Published: August 2020

The tissue culture of multicellular spheroids from the renal epithelial cell line LLC-PK1 (proximal tubule) is described. This represents a biological system of intermediate complexity between renal tissue in vivo and simple monolayer cultures. The multicellular structures, which show many similarities to kidney tubules in vivo, including a vectorial water transport, should prove useful for studying the potential nephrotoxicity of drugs and chemicals in vitro. In addition, the propagation of renal epithelial cells as multicellular spheroids in serum-free culture may provide information on the release of specific biological parameters, which may be suppressed or masked in serum-supplemented media.
The Galileo Data Bank on Toxicity Testing with In Vitro Alternative Methods. I. General Structure
Authors: Loprieno Nicola , Boncristiani Guido , Bosco Elena , Nieri Maria , Loprieno Gregorio 
Published: August 2020

Toxicity testing of chemicals by means of in vitro alternative methods to the use of animals has been extensively developed, as documented by a variety of studies. The interpretation of results and the comparative evaluation of data derived from various cell toxicity studies require organisation by a computerised data system, capable of handling the large number of variables included in different assays, such as cell lines, methods of treatment with the chemical, methods used to evaluate the biological effect, endpoints considered, etc. The Galileo Data Bank has been developed by the Laboratory of Genetic Toxicology at the University of Pisa, as a scientific instrument to be used in the analysis and organisation of results obtained in the toxicity testing of chemicals by means of in vitro alternative methods.
Evaluation of the EYTEX® System as a Screening Method for the Ocular Irritancy of Chemical Products
Authors: Régnier Jean-François , Imbert Christophe , Boutonnet Jean-Charles 
Published: August 2020

The EYTEX® method is an in vitro test used to predict ocular irritation, based on alterations in a protein matrix. We have evaluated this method with the aim of using it to screen chemicals. One hundred and forty-two products (commodities and specialities), having a wide range of chemical properties and ocular irritation potential in the rabbit, were tested with either the standard, MPA, AMA, KMA or UMA protocols. The results were compared with in vivo data obtained previously for each chemical and with the EEC labelling of eye irritation for dangerous substances. Intralaboratory repeatability and interlaboratory reproducibility were evaluated with seven other laboratories. Ninety-three per cent of the chemicals tested were qualified with the EYTEX method. The coefficients of the linear correlation between the EYTEX score and the maximal Draize score on the one hand and the maximal corneal score on the other hand, were 0.69 and 0.65, respectively. Compared to the EEC classification, the labelling of dangerous substances and for the prediction of severe irritants, sensitivity, specificity and equivalence were 94%, 89% and 78%, respectively. We observed nine false positives (22%) and two false negatives (2%) for the identification of R41-, R34- and R35-labelled products. The predictive values, for identifying R41, R34 and R35 products and non-irritants or R36 products were 78% and 97%, respectively. Repeatability (6.3) and reproducibility (8.9) were quite satisfactory. The EYTEX system exhibits the characteristics of a good screening method: compatibility with a large range of chemicals; a simple and rapid procedure; good intralaboratory and interlaboratory reproducibility; cost effectiveness; high sensitivity, specificity and predictive value; and a low incidence of false negative and false positive results. Based on these results, we consider the EYTEX method to be a valuable tool for the screening of eye irritancy.
Effects of Polyunsaturated Fatty Acids on Glial Cell Activation. A Study Using Primary Cultures
Authors: Grundt Inger K. , Nyland Harald 
Published: August 2020

The aim of this study was to examine the effects of essential fatty acids (gammalinolenic acid [18:3 n-6; GLA] and alpha-linolenic acid [18:3 n-3; Lin]) on the activation of glial cells, using lipopolysaccharides as the activating agent. Primary cultures of mixed glial cells from rat brain were used as the model. The morphological activation of microglia was the most significant response to the exposure. This activation was followed by an increase in 5’-nucleotidase (5’-NT) activity. The 5’-NT activity was increased by GLA or Lin alone to 250–350% of the control value and further increased by co-incubation with lipoteichoic acid (a lipopolysaccharide) to 500–600% of the control value. The lipopolysaccharide-induced activation of glial cells was also followed by an augmented release of prostaglandin E2. GLA increased the release of prostaglandin E2 in a dose-dependent manner, whereas Lin had no effect on its release. The results show that this model system is useful for studies on factors affecting the activation of glial cells. GLA and Lin did not reverse glial activation induced by lipopolysaccharides under these experimental conditions.
Induction of Sister-chromatid Exchanges, Micronuclei and Gene Mutations by Indirectly Acting Promutagens Using Human Hepatoma Cells as an Activation System
Authors: Darroudi Firouz , Natarajan Adayapalam T. 
Published: August 2020

An established human hepatoma cell strain (designated Hep G2) was used in sister-chromatid exchange (SCE) and micronuclei (MN) assays to study, in vitro, the genotoxic potentials of indirectly acting promutagenic carcinogens, such as 2-acetylaminofluorene (2-AAF) and hexamethylphosphoramide (HMPA), and a non-carcinogen, 4-acetylaminofluorene (4-AAF). In addition, Hep G2 S9-fractions were isolated and used to activate the same chemicals using Chinese hamster ovary (CHO) cells as target cells in vitro. The percentage survival and the frequencies of MN, SCEs and point mutations (at the HPRT locus) were used as biological endpoints. A dose-dependent increase in the frequencies of SCEs, MN, cytotoxicity, and/or point mutations was found in Hep G2 cells, and in CHO cells in the presence of Hep G2 S9-fractions, with 2-AAF and HMPA, but with 4-AAF no increase was found. The results obtained demonstrate that the Hep G2 cells and their S9-fractions are capable of activating different classes of mutagens to form biologically active metabolites.
The Use of Porcine Proximal Tubular Cells for Studying Nephrotoxicity In Vitro: Validation of the Effects of Culturing and Cryopreservation
Authors: Kruidering Marieke , Maasdam Diedka H. , Leeman Winfried R. , de Heer Emile , Nagelkerke J. Fred 
Published: August 2020

The susceptibility to nephrotoxins of freshly isolated porcine proximal tubular cells (PPTC) and cultured PPTC in suspension were compared, with a view to using PPTC as in vitro models for studying nephrotoxicity. In a previous paper, we described how, in freshly isolated PPTC, well-known nephrotoxins such as mercury (II) chloride, cisplatin, p-aminophenol and halogenated hydrocarbons caused a dose-dependent decrease in the viability and mitochondrial membrane potential of the PPTC. In this paper, we show that suspensions of cultured PPTC, harvested by trypsinisation, are less susceptible to nephrotoxins, possibly due to the synthesis of extracellular matrix components. PPTC in primary culture are suitable for relatively long-term nephrotoxicity studies. This was demonstrated by incubation with mercury (II) chloride for 24 hours, resulting in a dose-dependent loss of viability. Freshly isolated PPTC can be cryopreserved by computer-controlled freezing. The cryopreserved PPTC displayed an increased susceptibility to mercury (II) chloride and a decreased susceptibility to cisplatin and 1,1-dichloro-2,2-difluoroethylene-cysteine, the toxicity of the latter indicating that the renal enzyme β-lyase remains active during cryopreservation.
The Role of Structure-activity Relationships and Expert Systems in Alternative Strategies for the Determination of Skin Sensitisation, Skin Corrosivity and Eye Irritation
Authors: Barratt Martin D. 
Published: August 2020

A historical database containing the results of 294 defined single substances tested in the guinea-pig maximisation test, carried out according to a single protocol, was used to derive a set of structural alerts for skin sensitisation, which have been incorporated into the expert system, DEREK. Together with an assessment of percutaneous absorption, this system forms an integral part of a strategic approach to the identification of contact allergens. Quantitative structure-activity relationships (QSARs) were derived for the skin corrosivity of organic acids and bases, and for the eye irritation potential of neutral organic chemicals. The independent variables used for these analyses were selected on the basis of the putative mechanisms for skin irritation or corrosivity and for eye irritation, respectively. Data sets were analysed using principal components analysis; plots of the first two principal components for each data set showed that the analyses were able to discriminate well between chemicals with different classifications of toxicological activity. The derived QSARs are expected to give useful predictions of skin corrosivity and eye irritancy for new or untested chemicals in these classes. Although the development of these techniques is still at a very early stage, they are already able to play an important part in proposed strategies for the reduction of experimental animal usage. In the long term, it should be possible to conduct safety evaluations using fewer experimental animals or no animals at all. However, acceptance by regulatory authorities will be a key factor in realising the full benefits of the approach.
Application of Statistical Classification Methods to the Evaluation of In Vitro Tests
Authors: Glaser Sabine 
Published: August 2020

The first Amden Report defines validation as “The process by which the reliability and relevance of a test are established”. The recommendations of the Amden conference mention the need for biometric methods, but, unfortunately, most publications on alternatives to animal testing procedures do not pay much attention to statistical problems in the validation process. The biometric repertoire consists mainly of scatterplots, correlation coefficients and linear regression. In the evaluation of an interlaboratory study, we applied multivariate statistical methods to analyse the ability of two in vitro tests to identify severely irritating substances. In this study, conducted by the German Bundesgesundheitsamt, two alternatives to the well-known Draize eye irritancy test — the neutral red uptake test and the HET-CAM test — were investigated. The statistical methods applied were discriminant analysis and the Classification and Regression Trees (CART) method. The results presented here show that the combination of the endpoints of the in vitro tests, analysed by using the CART method, can give a sensitivity of about 67% with 76% specificity. Discriminant analysis models only achieve a sensitivity of 55%. The results obtained with the data presented here show that these statistical methods are very suitable and useful for this type of problem. This was confirmed by further analyses with discriminant analysis models, which gave a sensitivity of about 80%.
In Vitro Toxicology Methods in Risk Assessment
Authors: Purchase Iain F. H. 
Published: August 2020

The title of this paper is challenging, because the question of how in vitro methods and results contribute to human health risk assessment is rarely considered. The process of risk assessment usually begins with hazard assessment, which provides a description of the inherent toxicological properties of the chemical. The next step is to assess the relevance of this to humans, i.e. the human hazard assessment. Finally, information on exposure is examined, and risk can then be assessed. In vitro methods have a limited, but important, role to play in risk assessment. The results can be used for classification and labelling; these are methods of controlling exposure, analogous to risk assessment, but without considering exposure. The Ames Salmonella test is the only in vitro method which is incorporated into regulations and used widely. Data from this test can, at best, lead to classification of a chemical with regard to genotoxicity, but cannot be used for classification and labelling on their own. Several in vitro test systems which assess the topical irritancy and corrosivity of chemicals have been reasonably well validated, and the results from these tests can be used for classification. The future development of in vitro methods is likely to be slow, as it depends on the development of new concepts and ideas. The in vivo methods which currently have reasonably developed in vitro alternatives will be the easiest to replace. The remaining in vivo methods, which provide toxicological information from repeated chronic dosing, with varied endpoints and by mechanisms which are not understood, will be more difficult to replace.
Nicotinic Receptors of Different Species Exhibit Differential Sensitivities to Nitromethylene and Organophosphate Insecticides
Authors: Oortgiesen Marga , van Kleef Regina G.D.M. , Zwart Ruud , van den Beukel Ingeborg , Vijverberg Henk P.M. 
Published: August 2020

The effects of nitromethylene heterocycle (NMH) and organophosphate (OP) insecticides were studied on nicotinic acetylcholine receptors (nAChR) in cultured cells of different species origin, in order to examine the selectivity of these compounds at the level of the target sites. In mouse muscle BC3H1, mouse NIE-115 and human SH-SY5Y neuroblastoma, and locust thoracic ganglion cells, the neurotransmitter, acetylcholine (ACh), induces a similar transient inward current. Dependent on the cell type, the six NMHs acted as agonists and/or antagonists on nAChR. Distinct agonistic effects of NMHs on nAChR are observed on insect neurons only. Further, NMHs potently block nicotinic responses in insects, while mammalian cells are only moderately affected. In all cases, the neuronal type nAChR was more sensitive to blocking than the endplate type nAChR in mammalian cells. Parathion and paraoxon at micromolar concentrations inhibit ACh-induced nicotinic inward currents. The insecticide, parathion, is a 50-fold more potent inhibitor than its acetyl-cholinesterase-inhibiting metabolite, paraoxon. Moderate differences in sensitivity to the blocking action of the OPs appear to exist among cells of different species. The results demonstrate that the experimental approach of fundamental electrophysiology and the use of cell lines are relevant tools for investigating the species specificity of neurotoxic compounds.
Association between the interferon-γ +874T/A polymorphism and susceptibility to hepatitis B virus infection: a meta-analysis
Authors: Li Liang 
Published: August 2020

Objective This study investigated the correlation between the interferon (IFN)-γ +874T/A polymorphism and hepatitis B virus (HBV) susceptibility using meta-analysis. Methods PubMed, EMBASE, Web of Science, CNKI, and China Wanfang databases were searched for case–control studies investigating the IFN-γ +874T/A polymorphism and HBV susceptibility from the time of database establishment to April 2020. Stata 15.0 software was used, and the subgroups of ethnicity and Hardy–Weinberg equilibrium were analyzed. Results Thirteen articles were included in this study. Significant differences were seen in the allelic model, dominant model, homozygous model, and heterozygous model, but heterogeneity was high. Analysis of the East Asian population revealed combined odds ratios of the allelic model (T vs. A), dominant model (TT + TA vs. AA), homozygous model (TT vs. AA), and heterozygous model (TA vs. AA) of 0.61, 0.56, 0.50, and 0.59, respectively. The difference was significant and the heterogeneity low. The recessive model showed no significance in the overall comparison, or in East Asian and Caucasian populations. Conclusions The IFN-γ +874T/A polymorphism is associated with the risk of HBV, especially in the East Asian population. Individuals with the T allele and TT and TA genotypes have a reduced risk of HBV infection.
A Pilot Study of An Intervention to Increase Family Member Involvement in Nursing Home Care Plan Meetings
Authors: Oliver Debra Parker , Rolbiecki Abigail J. , Washington Karla , Kruse Robin L. , Popejoy Lori , Smith Jamie B. , Demiris George 
Published: August 2020

Background and Objectives: Many family members struggle to negotiate their aging relative’s care with nursing home staff, potentially leading to depression and other negative outcomes for residents’ families. This pilot study tested an intervention designed to empower residents’ family members to attend and participate in nursing home care plan meetings. Research Design and Methods: We conducted a small, randomized, controlled trial of the Families Involved in Nursing home Decision-making (FIND) intervention, which used web conferencing to facilitate family participation in care plan meetings. Results: Overall, FIND was feasible and acceptable. Family members who received the FIND intervention were more likely to experience decreased depressive symptoms than those who did not. Discussion and Implications: FIND is a promising approach to reduce depression among family members of nursing home residents. Findings support the need for a follow-up clinical trial.