chronic toxicity

/Tag:chronic toxicity

EDIT: A New International Multicentre Programme to Develop and Evaluate Batteries of In Vitro Tests for Acute and Chronic Systemic Toxicity

Björn Ekwall, Cecilia Clemedson, Barbro Ekwall, Patrik Ring and Lennart Romert

The Multicenter Evaluation of In Vitro Cytotoxicity (MEIC) programme provided a battery of three basal cytotoxicity tests with a good (R2 = 0.77) prediction of human acute lethal blood concentrations. The predictive power of this battery would be considerably improved by the addition of new supplementary in vitro tests. The development of these new tests will be facilitated by a close coupling of test development to evaluation. The Cytotoxicology Laboratory, Uppsala (CTLU), is therefore inviting all interested in vitro toxicologists to take part in the Evaluation-guided Development of In Vitro Toxicity and Toxicokinetic Tests (EDIT). All EDIT activities (subprojects) will be designed on a case-by-case basis, but will follow a common pattern. The CTLU will use the accumulated MEIC/EDIT data, and its experience from the previous MEIC evaluation, to suggest priority areas, i.e. the need for certain in vitro toxicity data/tests as supplements to existing in vitro models/batteries on human systemic toxicity. Detailed research programmes corresponding to these areas will be published on the Internet. The CTLU will also try to raise funds for some projects and will coordinate multilaboratory studies. Interested laboratories developing or already using priority tests are encouraged to join the subprojects and to test specific sets of substances (usually sets of MEIC reference chemicals) in their new assays. The CTLU will provide adequate human reference data and will also evaluate results as single components of complex models, together with the laboratory conducting the test. At present, ten priority areas have been identified: a) repeat dose toxicity in vitro; b) urgent mechanistic information from in vitro studies of protein denaturation, morphology of cell injury, differential toxicity between various rapidly measured endpoints (10–60 minutes) and 24-hour cytotoxicity, toxicity to aerobic cells, and discrimination between rapid and slow cytotoxic mechanisms; c) in vitro tests on vitally important, specific receptor toxicity in humans; d) excitatory cytotoxicity; e) reversibility of cell toxicity; f) in vitro tests on passage across the blood–brain barrier; g) in vitro tests on absorption in the gut; h) protein binding in vitro; i) in vitro tests on distribution volumes (Vd); and j) in vitro tests on biotransformation to more-toxic metabolites (hepatocytes plus target cells). This paper gives a short presentation of the rationale for each subproject and reports on ongoing activities.
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An Integrated Decision-tree Testing Strategy for Repeat Dose Toxicity with Respect to the Requirements of the EU REACH Legislation

Christina Grindon, Robert Combes, Mark T.D. Cronin, David W. Roberts and John F. Garrod

This paper presents some results of a joint research project conducted by FRAME and Liverpool John Moores University, and 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 the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and (in silico) for repeat dose (sub-acute, sub-chronic and chronic) toxicity testing. It reviews the limited number of in silico and in vitro tests available for this endpoint, and outlines new technologies which
could be used in the future, e.g. the use of biomarkers and the ‘omics’ technologies. An integrated testing strategy is proposed, which makes use of as much non-animal data as possible, before any essential in vivostudies are performed. Although none of the non-animal tests are currently undergoing validation, their results could help to reduce the number of animals required for testing for repeat dose toxicity.
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Long-term, Repeated Dose In Vitro Neurotoxicity of the Glutamate Receptor Antagonist L-AP3, Demonstrated in Rat Hippocampal Slice Cultures by Using Continuous Propidium Iodide Incubation

Bjarne W. Kristensen, Morten Blaabjerg, Jens Noraberg and Jens Zimmer

Most in vitro models are only used to assess the short-term effects of test compounds. However, as demonstrated here, hippocampal slice cultures can be used for long-term studies. The test compound used was the metabotropic glutamate receptor antagonist, L(+)-2-amino-3-phosphonopropionic acid (L-AP3), which is known to be toxic in vivo after subchronic, but not acute, administration. Degenerative effects were monitored by measuring the cellular uptake of propidium iodide (PI; continuously present in the medium) and lactate dehydrogenase (LDH) leakage, and by using a panel of histological stains. Hippocampal slices, derived from 2–3 day old rats and grown for 3 weeks, were subsequently exposed for the next 3 weeks to 0, 10 or 100μM L-AP3, with PI (2μM) in the culture medium. Exposure to 100μM L-AP3 induced severe toxicity after 4–6 days, as shown by massive PI uptake, LDH leakage, and changes in MAP2 and GFAP immunostaining and in Nissl and Timm staining. In contrast, 10μM L-AP3 did not induce detectable neuronal degeneration. Treatment with the NMDA receptor antagonist, MK-801, or the AMPA/KA receptor antagonist, NBQX, together with 100μM L-AP3, reduced neurodegeneration to close to control values. It is concluded that the continuous incubation of hippocampal slice cultures with PI is technically feasible for use in studies on inducible neuronal degeneration over time.
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An Integrated Decision-tree Testing Strategy for Repeat Dose Toxicity with Respect to the Requirements of the EU REACH Legislation

Christina Grindon, Robert Combes, Mark T.D. Cronin, David W. Roberts and John F. Garrod

This paper presents some results of a joint research project conducted by FRAME and Liverpool John Moores University, and 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 the safety testing and risk assessment of chemicals. The project covered all the main toxicity endpoints associated with REACH. This paper focuses on the use of alternative (non-animal) methods (both in vitro and in silico) for repeat dose (sub-acute, sub-chronic and chronic) toxicity testing. It reviews the limited number of in silico and in vitro tests available for this endpoint, and outlines new technologies which
could be used in the future, e.g. the use of biomarkers and the ‘omics’ technologies. An integrated testing strategy is proposed, which makes use of as much non-animal data as possible, before any essential in vivostudies are performed. Although none of the non-animal tests are currently undergoing validation, their results could help to reduce the number of animals required for testing for repeat dose toxicity.
You need to register (for free) to download this article. Please log in/register here.