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In silico predictions of in vivo toxicity: are interspecies extrapolations off tangent? - CB0451

Description
Synthetic chemicals are found ubiquitously in the environment, leading to growing concerns regarding the potential health threats of exposure, for both wildlife and humans. Many of these chemicals are believed to have a disruptive effect on the endocrine system which regulates a large number of biological functions, including metabolism, growth and development, tissue function, reproductive development, sexual dimorphism and mood. Thus, disruption of the endocrine system may result in numerable adverse effects, at both the individual and population level.

As a member of the organisation for Economic Cooperation and Development (OECD) the UK has played a vital role in the adoption of chemical test guidelines for the elucidation of endocrine-mediated toxicity, which are utilised by regulatory bodies, such as defra, in the safety assessment of chemicals. These test guidelines utilise model species, such as rats, mice, fish and birds to assess risk to human health and ecological systems. The endocrine system is highly conserved throughout vertebrates, which appears to justify the common use of rodent models in estimating acute and chronic toxicity in humans. However, extrapolating in vivo (in body) health endpoints in one species to another is not without its caveats. Differences in ontogeny (origin and development) of reproductive functions, differences in metabolism and variable pollutant body burdens, can lead to significant differences in disease susceptibility. Therefore, toxicity in one species is not necessarily predictive of toxicity in another; this may compromise the extrapolation that is integral to toxicological study and regulatory risk assessment, resulting in a large amount of uncertainty regarding the efficacy of these model species in adequately assessing risk.

However, the UK is obliged to reduce the number of animals used in chemical testing strategies. As part of this aim, in vitro (in test tube) and in silico (computational) tests are being developed to replace and refine in vivo studies. This project aims to reduce the uncertainty of extrapolating between in silico, in vitro and in vivo toxicity models by further characterising the biological mechanisms and genetics that underpin endocrine toxicity. An integrated methodology of phylogenetic analysis (which maps the genetic similarity and evolutionary relationship) and protein binding analysis (in silico and in vitro) will be adopted to assess variation of endocrine function and susceptibility to perturbation both between, and within species. These findings will then be compared to data from previously conducted in vivo toxicology studies.

It is considered that this project will provide greater understanding of fundamental differences between animal models, potentially refining and reducing in vivo toxicological study by enabling greater inference from data collected. Furthermore, information gained may help regulatory bodies extrapolate toxicological findings with a greater degree of certainty.
Time-Scale and Cost
From: 2011

To: 2014

Cost: £79,439
Contractor / Funded Organisations
Cranfield University
Keywords
Endocrine Disruptors              
Fields of Study
Chemicals and Nanotechnology