Abstract
There is a well-defined regulatory framework governing the approval of chemicals for use as pharmaceuticals or release into the environment. Toxicity assessment is thus a major hurdle in the compound discovery pipeline, currently involving large scale animal testing. The search for alternative testing platforms is therefore an important priority. We have developed a convenient, low cost assay utilising the nematode Caenorhabditis elegans, to rapidly assess both acute toxicity and developmental and reproductive toxicity (DART). However the worm is protected by a robust cuticle that forms a barrier to chemical uptake. We assessed mutants with altered cuticle properties to identify sensitized strains optimized for toxicity assays. Evaluating the trade-off between increased permeability and reduced fitness identifies bus-5(br19) as the most suitable strain for chemical exposure. We demonstrate the applicability of this assay for a range of chemicals with differing properties, including a modified exposure protocol for volatile or less soluble compounds. This work enhances the effectiveness of C. elegans for convenient toxicity assessment, which could contribute to a reduction in the use of vertebrates particularly at the crucial early stages of product development. Strains identified in this work will also enhance the sensitivity of C. elegans based drug discovery platforms.
Highlights
There are stringent requirements for toxicity testing of chemicals involving both acute toxicity and developmental and reproductive toxicity (DART), pertinent to the petrochemical, agrochemical and cosmetics industries in which chemicals are released into the environment
The financial and ethical costs of using such large numbers of animals, together with the time taken for testing, means that alternative testing platforms are highly desirable[2]
Comparative genomic studies have revealed that C. elegans contains many genes homologous to mammals[3, 4] which make the worm a powerful biomedical tool for disease modelling, drug discovery and toxicity assessments[5,6,7,8,9]
Summary
There are stringent requirements for toxicity testing of chemicals involving both acute toxicity and developmental and reproductive toxicity (DART), pertinent to the petrochemical, agrochemical and cosmetics industries in which chemicals are released into the environment. This testing involves large numbers of animals. Animal testing has been banned within the European Union for cosmetics further driving the need for alternatives Such platforms are envisioned to give an indication of toxicity potential early in the product development pipeline in order to eliminate high-risk compounds without the need to test on vertebrates. The authors found concordance of C. elegans data with data from rats and rabbits of between 45 and 53% across a range of doses, which is only slightly lower than the concordance between rat and rabbit data (58%)
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