- chemical risk
- chemical safety
- Chemical substances
- ecological risk assessment
- gene expression
- genomic science
- genomics data
- pharmaceutical industry
- Risk assessment
WR 11 : Workshop on the Application of ‘Omics in Toxicology and Ecotoxicology: Case Studies and Risk Assessment | July 2008
To review recent progress made on the application of ‘omics technologies to chemical safety and to assess their potential impact on the risk assessment of chemical substances, ECETOC organised a Workshop in Malaga, Spain (6-7 December 2007).
The workshop was limited to participation by selected industry experts, government agencies and invited external scientists (both toxicologists and ecotoxicologists), 29 people in all. Seven case studies were presented.
The general conclusion among participants was that ‘omics are now taking their place among other regular tools for hazard/risk assessment. However, the question remains whether the technology is ready to be incorporated into a regulatory setting. It was recognised that the pharmaceutical industry is more advanced at using ‘omic data in the regulatory arena (e.g. US FDA) and that mammalian models are more developed than those of environmental relevant species (e.g. US EPA). For example, genome sequence data for environmentally relevant organisms are still poorly described or non-existent.
The workshop firstly addressed the importance of using high quality study design and experimental controls (including quality controls). Good quality will improve confidence in the ?omics techniques and increase the likelihood of regulatory acceptance. Consequently, there is a need to define quality standards for the performance of ‘omic studies.
Interpretation of genomics data often proves to be a time consuming and challenging area of genomic science but is a key factor to its successful application. The further development and implementation of guidance was found to be helpful, but it was stressed that full interpretation requires a refined and appropriate characterisation of the genes in the biological system as a whole.
Participants agreed that in future, genomics will change the current paradigm of toxicology and environmental science. As regards human health, the general consensus was that toxicogenomics will have value in providing supportive evidence for toxic mechanisms but should not necessarily be expected to be a definitive endpoint in a regulatory setting of chemical/drug risk assessment. With more toxicogenomic tools becoming available and users gaining more experience, it is most likely that environmental science will increasingly witness the application of genomic tools in chemical hazard/risk assessments.
Concerning the predictability of toxicogenomics, chemical class-specific molecular signatures were identified in several of the case studies presented. Selecting the sequences that were altered in the same direction by chemical/drug with the same presumed mode of action (MoA), will identify distinct cellular pathways, indicating that the pathway associated gene expression profiles may be used to predict the genotoxic or non-genotoxic (i.e. carcinogenic) potential of a chemical/drug. Nonetheless, due caution is required when choosing a relevant biological model. Information on the toxic mechanism or mode of action of the selected biomarkers, and on their stability, will be improved by new developments, i.e. systems biology, and careful validation based on independent chemical or drug class.
For prospective ecological risk assessment, understanding species diversity is still paramount. It is necessary to discriminate the effects of chemicals in the environment from the compensatory homeostatic response at organism level in the presence of a toxicant and the compensatory dynamics of the population as a whole. High levels of gene conservation between species genomes, means that micro-organisms (e.g. Escherichia coli), nematodes, earthworms and fish could be useful as indicators for higher organisms.
Alterations in individual parameters in ‘omic studies were considered to be unsuitable to derive no observed effect levels (NOAELs). This conclusion was based on the very high probability to find random alterations, taking into account the high number of parameters assessed in such studies. To derive a meaningful NOAEL it was recommended that only specific patterns of change (in any type of ‘omics study) should be used to conclude that a potentially relevant biological effect is taking place. As changes in ‘omics pathways do not necessarily imply that changes at cellular, individual or population levels will necessarily occur, these pathways need to be correlated to observable changes at the microscopic and macroscopic level. To use changes in an ‘omics pattern for NOAEL purposes, it must be assured that the pathway identified is causally related to an adverse effect.
In all, the workshop participants concluded that the ‘omics technology is firmly established as a research tool and is also becoming less expensive. Regulators do not require ‘omic data as yet but the available data can already be included in dossiers. The efforts made to develop these techniques for risk assessment and to resolve all pending issues will benefit science and industry in the future.