Why toxicogenomics?

We are at the brink of major changes in chemical safety testing in the EU. Where still patients are at risk of toxic effects of pharamceutics, drugs having less adverse side-effects, are on demand. The 7th Amendment of the Cosmetics Directive will necessitate developing new risk assessment paradigms that do not need input of data generated by animal experiments. the EU Chemicals Regulation (REACH; Registration, Evaluation, Authorisation and Registration of Chemicals) will increase the need for generating safety data of functional foods, fortified foods, nutraceuticals, etc. are currently under development. The arrival of 'omics technologies will change traditional regulatory toxicology because it will generate more insight in molecular mechanisms underlying toxic mode of actions and in dose-response relationships, and will therefore impact on assessing no-effect levels and thus the basis of current approaches to establishing chemical safety.

Toxicogenomics is thus expected to achieve considerable societal value through profound improvements in human and environmental health and substantial reductions in the use of animal based tests, as related to:

  • Pharmaceuticals: Bringing innovative and safer medicines to patients faster and cheaper
  • Industrial Chemicals: Improved and more quantitive understanding of chemical risks to both human and environmental health, enabling more rational use and regulation of chemical substances
  • Cosmetics: The elimination of animal tests in ensuring the safety of personal care products
  • Foods: Increased safety from "Farm-to-fork", including safer foods additives and fillers, nutraceuticals, animal feeds, and even food storage.

Chemical safety testing mainly involves studies in vivo with animals since till now, no adequate and thoroughly validated alternatives are available. Annually, ca. 63,000 animals are used for toxicity testing in the Netherlands, and about 708,000 in the EU, ranging from 1-day acute toxicity tests to 2-years carcinogenicity studies.

In general, the initial screening of chemical compounds for hazardous properties and human health risks relies on acute and sub-chronic studies with animal models. Depending on production levels, results from the initial screenings and likelihood of human exposure, additional long-term chronic in vivo bioassays may be required (EC and OECD guidelines). These routine toxicology studies are focused to describe the no-observed adverse effect level (NOAEL) in most cases in a population of 20-100 test animals, using a range of toxicopathological determinants (e.g. histopathology, clinical chemistry, etc). However, the mode of action of the compound under study may still be unknown and hence the relevance for humans is questionable. Moreover, data are frequently confounded by experimental insensitivity (extremely high dose levels are applied to observe toxic effects), lack of mechanistic information (pathology is the only end-point analyzed), and the existence of marked species differences. So, despite their frequent use, the reliability, relevance and effectiveness of these animal testing-based risk assessment methodologies are subjected to many uncertainties with regard to the extrapolation from hazard to risk.

Clearly, toxicogenomics is increasingly being recognized for its potential to innovate and improve the specificity and range of methods used to predict chemical hazards and inform and overcome a number of uncertainties involved in chemical-related risk assessment, thereby improving human health and customer’s safety.

The development of new, mechanism-based, assays with a high predicitve value for the induction of adverse health reactions in humans is now feasible through the availibility of powerful technologies from monitoring genetic sequences, genetic variations, amd global functional gene expressions, as well as proteome expressions and metabolite formation. This enables high troughput and multi-endpoints analysis of effects of chemicals, thus presenting exciting human toxicants, and for monitoring the effects of human exposure to toxicants.

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