developmental toxicity

/Tag:developmental toxicity

New Animal-free Concepts and Test Methods for Developmental Toxicity and Peripheral Neurotoxicity

Marcel Leist

The complex toxicological fields of repeat dose organ toxicity (RDT) and developmental and reproductive toxicity (DART) still require new concepts and approaches to achieve a fully animal-free safety assessment of chemicals. One novel approach is the generation of relevant human cell types from pluripotent stem cells, and the use of such cells for the establishment of phenotypic test methods. Due to their broad endpoints, such tests capture multiple types of toxicants, i.e. they are a readout for the activation of many adverse outcome pathways (AOPs). The 2016 Lush Science Prize was awarded for the development of one such assay, the PeriTox test, which uses human peripheral neurons generated from stem cells. The assay endpoints measure various cell functions, and these give information on the potential neurotoxicity and developmental neurotoxicity hazard of test compounds. The PeriTox test method has a high predictivity and sensitivity for peripheral neurotoxicants, and thus addresses the inherent challenges in pesticide testing and drug development. Data from the test can be obtained quickly and at a relatively high-throughput, and thus, the assay has the potential to replace animal-based safety assessment during early product development or for screening potential environmental toxicants.
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The Bioavailability of Substances Administered to Chick Embryos: The Maximum Effective Route of Administration

Drahomír Veselý, Doubravka Veselá and Richard Jelínek

Toxicokinetic studies are of key importance in both the design and the interpretation of developmental toxicity studies. The aim of this study was to determine concentrations of test substances within the chick embryo following the administration schedule recommended in the chick embryotoxicity screening test (CHEST). The concentration–time relationships were investigated by using four labelled substances with various physicochemical and embryotoxic properties ([14C] sodium acetate, [14C] palmitic acid, [3H] cortisol and [3H] cytosine arabinoside). These labelled chemicals were mixed with cold substances and singly administered at two dose levels to chick embryos on days 2, 3 and 4 of incubation. Extrachorial and subgerminal routes were used on day 2, and extrachorial and intra-amniotic applications were chosen on days 3 and 4. The concentration of labelled chemical present within the embryo was assessed at predetermined intervals by scintillation fluorimetry (from 6 minutes to 96 hours after administration), and used for estimating the concentration curves. Regardless of the substance, dose and application route, the concentration curves exhibited a characteristic pattern, reaching their peaks within the first 6 hours, and dropping down to near zero 48–96 hours after administration. The decrease followed the first order law, demonstrating that, within the CHEST system, the avian embryo does not act as a closed system. With regard to the total amount of substance entering the embryo, extrachorial administration appeared to be superior to subgerminal administration on day 2. Intra-amniotic administration was superior to extrachorial administration on days 3 and 4. These differences were most pronounced after administration of lipid-soluble palmitic acid. The concentrations within embryonic tissues were directly dosedependent. After consideration of all these findings, we concluded that the CHEST system probably has closer similarity to the toxicokinetics of exposure of mammalian embryos (i.e. reaching a peak and then a gradual decline over time) than any other in vitro test of developmental toxicity, where the chemical is simply added to culture media. Several practical recommendations for improving the CHEST system were derived.
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Integrated Decision-tree Testing Strategies for Developmental and Reproductive 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

Liverpool John Moores University and FRAME 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 the 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 the use of alternative methods (both in vitro and in silico) in developmental and reproductive toxicity testing. It considers many tests based on primary cells and cell lines, and the available expert systems and QSARs for developmental and reproductive toxicity, and also covers tests for endocrine disruption. Ways in which reduction and refinement measures can be used are also discussed, particularly the use of an enhanced one-generation reproductive study, which could potentially replace the two-generation study, and therefore considerably reduce the number of animals required in reproductive toxicity. Decision-tree style integrated testing strategies are also proposed for developmental and reproductive toxicity and for endocrine disruption, followed by a number of recommendations for the future facilitation of developmental and reproductive toxicity testing, with respect to human risk assessment.
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Integrated Decision-tree Testing Strategies for Developmental and Reproductive 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

Liverpool John Moores University and FRAME 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 the 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 the use of alternative methods (both in vitro and in silico) in developmental and reproductive toxicity testing. It considers many tests based on primary cells and cell lines, and the available expert systems and QSARs for developmental and reproductive toxicity, and also covers tests for endocrine disruption. Ways in which reduction and refinement measures can be used are also discussed, particularly the use of an enhanced one-generation reproductive study, which could potentially replace the two-generation study, and therefore considerably reduce the number of animals required in reproductive toxicity. Decision-tree style integrated testing strategies are also proposed for developmental and reproductive toxicity and for endocrine disruption, followed by a number of recommendations for the future facilitation of developmental and reproductive toxicity testing, with respect to human risk assessment.
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The Way Forward for Reproductive/Developmental Toxicity

Michael Balls et al

I was somewhat surprised when I saw Mary Moxon’s Guest Editorial, “Developmental and reproductive toxicity testing: a potted history”, in Lab Animal Europe earlier this year.1 Contrary to what I had read and heard repeatedly over several years, she clearly believed that laboratory animal tests are a sound basis for human risk assessment and will continue to be used “to protect our future generations”.
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Developmental Toxicity Testing: Protecting Future

Jarrod Bailey

A recent editorial is discussed, which implied that animal-based developmental and reproductive toxicology tests will continue to be crucial, that the thalidomide disaster could have been prevented by more animal testing, and that tests on juvenile animals would help to protect children (as developing adults) from the adverse effects of pharmaceuticals. It is argued that animal tests in these scientific areas do not provide reliable data that are predictive for human responses and, even if they did, the tests are too expensive and time-consuming for application to the very large number of substances that need to be tested. It is estimated there are already more than 100,000 man-made chemicals to which humans may be exposed on a regular basis, and it is therefore widely accepted that in vivo developmental toxicology could not possibly be used to assess all new and existing chemical substances, due to the scale of its demand upon time and resources. It is therefore imperative that alternatives such as those outlined above are embraced, further developed, accepted and used — as a matter of urgency.
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