Analogy Models for Prediction of Human Toxicity

1990 ◽  
Vol 18 (1_part_1) ◽  
pp. 103-116
Author(s):  
Sven Hellberg ◽  
Lennart Eriksson ◽  
Jörgen Jonsson ◽  
Fredrik Lindgren ◽  
Michael Sjöström ◽  
...  
Keyword(s):  
Human Subjects ◽  
Toxicity Testing ◽  
In Vitro Cytotoxicity ◽  
Alternative Methods ◽  
Laboratory Animals ◽  
In Vitro Tests ◽  
Human Toxicity ◽  
Efficient Data ◽  
Basal Cytotoxicity

Estimating the toxicity to humans of chemicals by testing on human subjects is not considered to be ethically acceptable, and toxicity testing on laboratory animals is also questionable. Therefore, there is a need for alternative methods that will give estimates of various aspects of human toxicity. Batteries of in vitro tests, together with physicochemical and toxicokinetic data, analysed by efficient data analytical methods, may enable analogy models to be constructed that can predict human toxicity. It may be possible to model non-specific toxicity relating to lipophilicity, or basal cytotoxicity, for a series of diverse compounds with large variation in chemical structure and physicochemical properties. However, local models for a series of similar compounds are generally expected to be more accurate, as well as being capable of modelling more-specific interactions. Analogy models for the prediction of human toxicity are discussed and exemplified with physicochemical and cytotoxicity data from the first ten chemicals in the multicenter evaluation of in vitro cytotoxicity (MEIC) project.

Cytotoxicity Evaluation of the First Ten MEIC Chemicals: Acute Lethal Toxicity in Man Predicted by Cytotoxicity in Five Cellular Assays and by Oral LD50 Tests in Rodents

1989 ◽  
Vol 17 (2) ◽  
pp. 83-100
Author(s):  
Björn Ekwall ◽  
Inger Bondesson ◽  
José V. Castell ◽  
Maria José Gómez-Lechón ◽  
Sven Hellberg ◽  
...  
Keyword(s):  
In Vitro Cytotoxicity ◽  
In Vitro Tests ◽  
Human Toxicity ◽  
Blood Concentrations ◽  
Cell Systems ◽  
Cellular Assays ◽  
Preliminary Validation ◽  
Partial Least Squares Model ◽  
Lethal Dosage

The MEIC (multicentre evaluation of in vitro cytotoxicity) programme is a five-year programme to validate in vitro tests for general toxicity, and is organised by the Scandinavian Society for Cell Toxicology. Interested laboratories are invited, on an international basis, to test 50 published reference chemicals in their respective assays. Submitted results will then be evaluated yearly by the MEIC Committee for their relevance to various types of human toxicity, including an evaluation for the same chemicals of the prediction by animal tests of human toxicity. To establish the validation methods, a preliminary validation cycle is being performed in 1989/90 with submitted results for the first ten MEIC chemicals. The present paper is the very first step of this preliminary validation process. The prediction of human toxicity by five cytotoxicity assays (altogether 14 different cell systems/endpoints) has been evaluated, and also compared with the predictive value of rodent LD50 tests. Mouse LD50 prediction of human lethal dosage for these substances was good, while rat LD50 prediction was less satisfactory. The collective predictions by all 14 cell systems/endpoints of human toxicity in the form of a multivariate PLS (partial least squares) model of human acute lethal blood concentrations, as well as the corresponding prediction by a HeLa cell assay, were comparable to the efficiency of mouse LD50 prediction of human lethal dosage. When combined with simple toxicokinetic data (absorption of chemicals in the intestine and distribution volumes), the PLS model and the HeLa assay were able to predict human lethal dosage of the ten chemicals as accurately as the mouse LD50 value. The small number of chemicals studied to date means that general conclusions cannot be drawn from these results. Further validation of more chemicals with the in vitro methods is essential and promises to be worthwhile.

In Vitro Toxicity Testing: Purpose, Validation and Strategy

1990 ◽  
Vol 18 (1_part_1) ◽  
pp. 11-18 ◽  
Author(s):  
Oliver P. Flint
Keyword(s):  
Cell Function ◽  
Toxicity Testing ◽  
In Vitro Toxicity ◽  
In Vitro Tests ◽  
In Vitro Test ◽  
Vitro Test ◽  
Basal Cytotoxicity ◽  
Biological Endpoint

The fullest potential for in vitro evaluation of toxicity will be realised in the context of the process of assessing the risk of human toxicity. This article is an attempt to clarify what contributions can be made by in vitro tests and what types of in vitro test can best be used. In vitro tests are clarified according to the type of biological endpoint evaluated, first into tests for general (‘basal’) cytotoxicity and, secondly, into tests for differentiated cell function. The role of each type of test is analysed and it is suggested that tests for general cytotoxicity, as opposed to differentiated function, are difficult to interpret in terms of in vivo toxicity. A general approach to evaluating in vitro tests is described, and a strategy for using these tests is proposed.

Richard Clothier: An Appreciation

2007 ◽  
Vol 35 (5) ◽  
pp. 531-537
Author(s):  
Michael Balls
Keyword(s):  
Toxicity Testing ◽  
Research Programme ◽  
In Vitro Cytotoxicity ◽  
Alternative Methods ◽  
Comparative Immunology ◽  
East Anglia ◽  
Cell Functions ◽  
Reed College ◽  
The University

The career of Richard Clothier is reviewed in the light of his long-standing collaboration with Michael Balls and Laurens Ruben at the University of East Anglia (UEA), the University of Nottingham, and Reed College, Portland, Oregon, USA. It began with work at UEA on the aetiology of the lymphosarcoma of Xenopus laevis, followed by studies on the effects of exposure to N-nitroso- N-methylurea on T-cell functions, which led to many contributions to comparative immunology. This was followed by the establishment of the FRAME Research Programme, which led to participation in extensive studies on the development of in vitro cytotoxicity tests and their application in acute and topical toxicity testing. A FRAME Trustee since 1983, Richard Clothier was a co-founder, and subsequently Director, of the FRAME Alternatives Laboratory in the University of Nottingham Medical School, where he led successful collaborations with a number of industrial partners and, in particular, with the European Centre for the Validation of Alternative Methods (ECVAM).

scholarly journals To the problems of toxicity testing of nanorized objects (Literature review)

2021 ◽  
Vol 90 (1) ◽  
pp. 75-80
Author(s):  
OB Leonenko
Keyword(s):  
Biological Effects ◽  
Chorioallantoic Membrane ◽  
Toxicity Testing ◽  
Aquatic Organisms ◽  
Alternative Methods ◽  
Laboratory Animals ◽  
Scientific Publications ◽  
Toxicological Studies ◽  
Analytical Review

Aim of the Research. To present and summarize data on the problems of assessing the toxicity and hazards of nanosized particles due to the peculiarities of their activity and variability, which prove the need to develop a vector of research in vitro. Materials and Methods. Targeted testing can provide broad coverage of nanoproducts, reduce the cost and time of research, as well as the number of animals used in experiments. Various model test systems are proposed for use, the use of which is possible to detect harmful effects of man-made nanomaterials, and also for other chemicals: cellular and subcellular elements (mitochondria, microsomes, DNA, chorioallantoic membrane vessels), organs of laboratory animals, the simplest (unicellular) organisms, microorganisms, various aquatic organisms, plants, insects, sperm of cattle. Biotesting is one of the methods of research in the field of toxicology, used to determine the degree of toxic effects of chemical, physical and biologically unfavorable factors that are potentially dangerous to humans and components of ecosystems. An analytical review of scientific publications was carried out using the abstract databases of scientific libraries Pub Med, Medline and text databases of scientific publishing houses Elsevier, Pub Med, Central, BMJ group as well as other VIP databases. Results and Conclusions. Recently, publications emphasize that the manifestations of biological effects depend on changes in the characteristics and properties of nanomaterials. These facts cannot be taken into account in standard toxicological studies. One of the ways to intensify tests and reduce their cost may be the use of accelerated toxicological studies on simple biological systems (models). In this regard, the development and implementation of alternative methods in vitro has become one of the leading areas of toxicological research of nanomaterials. Key Words: nanoparticles, toxicity, testing.

An Animal Protection Sponsor's View of MEIC

1997 ◽  
Vol 25 (3) ◽  
pp. 343-345
Author(s):  
Ethel Thurston
Keyword(s):  
Gold Standard ◽  
Animal Cell ◽  
Scientific Evidence ◽  
In Vitro Cytotoxicity ◽  
In Vitro Tests ◽  
Blood Concentrations ◽  
Animal Protection ◽  
Animal Tests ◽  
Lethal Blood

The Multicenter Evaluation of In Vitro Cytotoxicity programme is most important to animal protection, since it has validated 64 in vitro tests using advanced human data for 50 chemicals as the “gold standard”. Therefore, it has been able to compare animal cell tests, human cell tests and whole-animal tests fairly with unbiased scientific evidence. Added bonuses have included the identification and development of missing in vitro information (“missing tests”), publication of time-related lethal blood concentrations for all 50 chemicals, and some preliminary plans to resolve the 50,000 untested (or poorly tested) chemicals in the chemical mountain.

The Development and Evaluation of In Vitro Tests by the FRAME Alternatives Laboratory

1995 ◽  
Vol 23 (1) ◽  
pp. 75-90
Author(s):  
Richard H. Clothier ◽  
Karen A. Atkinson ◽  
Michael J. Garle ◽  
Rachel K. Ward ◽  
Angela Willshaw
Keyword(s):  
Research Programme ◽  
Neutral Red ◽  
In Vitro Cytotoxicity ◽  
In Vitro Tests ◽  
Dermal Toxicity ◽  
Mechanisms Of Toxicity ◽  
The Us ◽  
Detergent Association ◽  
Assay Methods

This review outlines the work which has been conducted in the FRAME Alternatives Laboratory during the first ten years of the FRAME Research Programme. A number of in vitro tests, including the kenacid blue, neutral red release and fluorescein leakage assay methods, have been evaluated and have subsequently been included in validation schemes organised by the US Soap and Detergent Association, the US Cosmetic, Toiletry and Fragrance Association, the European Commission and the European Cosmetic, Toiletry and Perfumery Association, as well as in the Scandinavian multicentre evaluation of in vitro cytotoxicity testing scheme. More recently, research has been undertaken in the areas of phototoxicity, immunotoxicity, dermal toxicity and intercellular communication, in addition to investigations into fundamental mechanisms of toxicity.

In Vitro Methods as a Tool in Neurotoxicity Studies

1995 ◽  
Vol 23 (4) ◽  
pp. 491-496
Author(s):  
Hanna Tähti ◽  
Leila Vaalavirta ◽  
Tarja Toimela
Keyword(s):  
Risk Evaluation ◽  
Toxicity Testing ◽  
In Vitro Models ◽  
In Vitro Tests ◽  
Industrial Chemicals ◽  
Mercury Compounds ◽  
Toxicological Data ◽  
In Vivo Tests

— There are several hundred industrial chemicals with neurotoxic potential. The neurotoxic risks of most of these chemicals are unknown. Additional methods are needed to assess the risks more effectively and to elucidate the mechanisms of neurotoxicity more accurately than is possible with the conventional methods. This paper deals with general tasks concerning the use of in vitro models in the evaluation of neurotoxic risks. It is based on our previous studies with various in vitro models and on recent literature. The induction of glial fibrillary acidic protein in astrocyte cultures after treatment with known neurotoxicants (mercury compounds and aluminium) is discussed in more detail as an important response which can be detected in vitro. When used appropriately with in vivo tests and with previous toxicological data, in vitro neurotoxicity testing considerably improves risk assessment. The incorporation of in vitro tests into the early stages of risk evaluation can reduce the number of animals used in routine toxicity testing, by identifying chemicals with high neurotoxic potential.

scholarly journals Search and evaluation of pharmacodynamic and pharmacokinetic parameters of selective blocker of TRPA 1 ion channels from the group of substituted pyrazinopyrimidinones

2018 ◽  
Vol 4 (3) ◽  
pp. 49-62
Author(s):  
Evgeniya А. Beskhmelnitsyna ◽  
Dmitriy V. Kravchenko ◽  
Lev N. Sernov ◽  
Irina N. Dolzhikova ◽  
Tatyana V. Avtina ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Laboratory Animals ◽  
Absolute Bioavailability ◽  
Organ Distribution ◽  
Pharmacokinetic Parameters ◽  
In Vitro Tests ◽  
Activity Levels ◽  
General Locomotor Activity ◽  
Anti Inflammatory

Introduction. Doctors of almost all specialties have to deal with the problem of pain and its relief. According to the literature, almost 30 million people daily take analgesics from the group of non-opioid analgesics, but in more than half of them 4-6 hours after taking the medication, the severity of pain is unchanged. Objective. to search for the most active molecules potential selective inhibitors of the TRPA1 ion channel with further investigation of their pharmacodynamic effects, toxicological safety, pharmacokinetic parameters and organ distribution, as well as to assess their impact on the psychoemotional state, general locomotor activity levels and anxiety in laboratory animals. Materials and methods. According to the results of in vitro tests, the most active molecule under code ZC02-0012 was selected from the pool of candidates. Further its analgesic activity was evaluated using an acetic acid-induced writhing test and a hot plate test; its anti-inflammatory activity was studied in the acute exudative paw edema model; in the open field and elevated plus-maze tests the influence of ZC02-0012 on the general locomotor activity levels and the anxiety of the laboratory animals was studied. The pharmacokinetic parameters and organ distribution of the substance ZC02-0012 were studied using a liquid chromatograph with an operating pressure range of 0-60 mPa (Thermo Scientific Dionex UltiMate 3000). Results and discussion. According to the results of in vitro tests, it was found that IC50 of the TRPA1 selective inhibitor under laboratory code ZC02-0012 was 91.3 nmol. The preclinical studies showed that ZC02-0012 possessed pronounced analgesic and anti-inflammatory activities and absence of the influence on the behavior and anxiety of the laboratory animals. Absolute bioavailability of ZC02-0012 in rabbits was 47%, while ZC02-0012 was intensely distributed into organs and tissues with a high level of blood circulation. The highest content of ZC02-0012 is typical of liver, kidneys and lungs, the lowest – for muscle tissue. Most of the substance is undergone rapid biotransformation and excreted as metabolites.

Integrated Decision-tree Testing Strategies for Environmental Toxicity with Respect to the Requirements of the EU REACH Legislation

2008 ◽  
Vol 36 (1_suppl) ◽  
pp. 29-42 ◽  
Author(s):  
Christina Grindon ◽  
Robert Combes ◽  
Mark T.D. Cronin ◽  
David W. Roberts ◽  
John F. Garrod
Keyword(s):  
Risk Assessment ◽  
Decision Tree ◽  
Aquatic Toxicity ◽  
Toxicity Testing ◽  
Threshold Concentration ◽  
Alternative Methods ◽  
The European Union ◽  
Animal Testing ◽  
Testing Strategies

Liverpool John Moores University and FRAME recently conducted a research project sponsored by Defra on the status of alternatives to animal testing with regard to the European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with the REACH system. This paper focuses on the prospects for using alternative methods (both in vitro and in silico) for environmental (aquatic) toxicity testing. The manuscript reviews tests based on fish cells and cell lines, fish embryos, lower organisms, and the many expert systems and QSARs for aquatic toxicity testing. Ways in which reduction and refinement measures can be used are also discussed, including the Upper Threshold Concentration — Step Down (UTC) approach, which has recently been retrospectively validated by ECVAM and subsequently endorsed by the ECVAM Scientific Advisory Committee (ESAC). It is hoped that the application of this approach could reduce the number of fish used in acute toxicity studies by around 65–70%. Decision-tree style integrated testing strategies are also proposed for acute aquatic toxicity and chronic toxicity (including bioaccumulation), followed by a number of recommendations for the future facilitation of aquatic toxicity testing with respect to environmental risk assessment.

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