23-24 April 2015, Brussels, Belgium
Expert Working Group Meeting: AOP/MOA of Reproductive Health Ontology
There is no single source of information providing a comprehensive ontology of developmental toxicity linked to the molecular initiating events (MIEs) and adverse outcome pathways (AOPs) responsible for these effects. Yet there are burgeoning amounts of data increasingly available that inform us about molecular pathogenesis leading to human developmental toxicity. The time has come to organise the field of toxicology in a different way. Responding to this need, an ECETOC Expert Team made up of regulatory, academic and industry experts, met in Brussels this spring to progress its drafting of a state of science on building prenatal developmental toxicity ontology for publication in peer reviewed, open access literature. The document will first identify the challenges and approaches ― and then propose the necessary steps ― to build a prenatal mode of action (MOA) ontology framework. This work will be the basis from which to identify scientific research priorities (e.g. under Cefic LRI or Horizon 2020), and form the basis from which to plan a workshop next year.
Such an ontology will help link molecular data to traditional toxicology; elucidate whether existing high throughput or high content approaches are sufficiently inclusive of MOA and serve as an organizing structure for constructing AOPs. Thus, contributing to the universe of integrated approaches to testing and assessment (IATA), increasing efficiency and helping to reduce animal testing, whilst providing the knowledge base for industrial and regulatory scientists to use in risk assessment and decision making.
Expert Working Group : microRNA’s in toxicology and risk assessment
With an increased interest of the scientific community in microRNAs, the field is rapidly evolving but is still at an early stage with respect to (eco)toxicology. Currently microRNAs testing is not included into the regulatory process of chemicals.
MicroRNAs are highly conserved between human and animal models and regulate biological pathways by repressing target proteins. MicroRNA profiling in response to toxic compounds can provide toxicant-specific profiles in specific organs. Given microRNA’s specificity to tested compounds, the time and dose dependency, the sensitivity and simplicity of their detection in various tissues are promising tools in toxicological studies. In addition, circulating microRNAs are accessible through non-invasive protocols and thus represent ideal candidates in toxicological studies, as they may be used as biomarkers of chemical exposure for safety assessment. At the moment there is no single test available to determine microRNA effects, and there is an insufficient understanding of the normal microRNA changes and long term effects upon exposure to chemicals on human health. In addition a screening scheme for prioritising chemicals by using mircoRNA profiling has not been developed.
In order to increase our understanding of how the science of microRNAs is involved in (eco)toxicology and in turn in risk assessment, a solid understanding of the biology including the changes of microRNA profiles in response to chemical exposure is essential. In addition understanding the link between microRNA-related pharmaco-genomics and adverse reactions to chemicals/drugs will be important for risk assessment.
The Expert Group
The Expert Group is addressing the relevance of microRNA changes to the evaluation of chemicals. In particular, they will examine and reveal of the current state-of-the art scientific and technological approaches to determine and quantify microRNA effects of chemicals. This will help us to assess the potential of microRNA as biomarkers of chemical exposure for safety assessment.
‘Big data’ has become a common term to describe the large data sets that are often collected and analysed in many areas of biological and medical science. This is particularly true in molecular work where a data explosion is occurring. For toxicological science the quantity, quality and complexity of molecular variation data collected outstrips our ability to analyse or interpret in a consistent manner and this has hindered its application in the toxicological risk assessment of chemicals.
A particular challenge is in the consistent bioinformatic analysis of the data where its magnitude allows many approaches to be taken. There are many ways by which the data can be ‘sliced and diced’ that can lead to different outcomes – but no assessment as to which approach is more appropriate. Amongst many methods, all of which could be argued to be correct, the key question for regulatory purposes is:Which is most appropriate? This challenge has limited the use of high throughput molecular data in the regulatory arena.
A draft framework for best practice to ensure the univariate analysis of molecular variation data is meaningful and reliable. This could feed into the review of OECD test guidelines and help industry develop data that regulators have confidence in assessing within risk assessment dossiers.