Leveraging comparative physiology and genomics to predict species sensitivity: A novel framework for interspecies extrapolation in ecotoxicology.

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The idiom of a 'miner's canary'A miner holds a canary as an alert for toxic gas; from experience he knows that the canary will stop singing before the gas causes lasting harm. The idiom of a 'miner's canary' is used throughout toxicological risk assessment, whether testing for potential risks to human health or for environmental impacts. A restricted range of organisms are used as 'canaries' or sentinels to assess the risk chemicals pose to entire ecosystems. However, unlike 'the canary and the miner' we often do not know the relative affect of the chemical on the sentinels in relation to other organisms. To account for this uncertainty in risk assessment, a 'safety factor', an arbitrary 100 or 1000-fold adjustment, is applied to the lowest observed toxicological effect on sentinel species in an attempt to protect more sensitive species. This extrapolation has no mechanistic grounding being itself entirely a pragmatic response to the number of chemicals entering the environment & variety of organisms present. In this application we propose to develop a novel framework that may be used to provide an objective measure of comparative species sensitivity. The framework is based on three components; i) the measurement of where a chemical goes when it enters an organism; ii) the specific interactions of the chemical with its biological receptor molecules & how this is affected by subtle differences in the receptors observed between species, & iii) the pathways that transmit the affect of the chemical from the interactions with receptor through to eventual impact on the organism.The where & the how muchTo calculate the amount of a chemical that resides in a target tissue we will use radio-labelled compounds & also detailed chemistry to determine the rates of chemical Accumulation (into the organism), Distribution (especially to the target site), Metabolism (to form more or less toxic metabolites) & Excretion (from the body). These measurements will allow us to determine the relative where & how much of a compound is present in response to a precise level of exposure.Pushing the first dominoMany chemicals affect a biological system through interaction with specific biomolecules termed receptors. In the same way as pushing on a single domino can lead to exotic patterns, a chemical-receptor interaction can act as a "Molecular Initiating Event" that ultimately produces a cascade of biological responses. This means that the precise characteristics of the chemical-receptor interaction are crucial to transmission of chemical affect. The structure of receptor molecules differs between species & this significantly influences the potency of the chemical to the organism. We will use genomics tools & modelling techniques developed for the pharmaceutical industry to predict the relative strength of the chemical-receptor interaction & therefore the effectiveness to transmit its affect.Mapping affect pathwaysChemical affect is transmitted from a molecular interaction with receptor(s) to the final observed biological effect through a complex series of biological pathways, now termed the Adverse Outcome Pathways (AOP). We will use computational approaches to derive the effective AOP for our chemical linking the exposure amount & its potency to transmit the biological impact.Case studies: Selecting chemicals & earthwormsWe have selected different earthworm species as sentinels because they are widely used for chemical risk assessment in soils, they are key ecosystem engineers & they show a significant diversity of sensitivity to a range of chemicals. The chemical we have selected to study: a) show significant differential sensitivity amongst earthworm species; b) represent a range of chemical modes-of-action; &, c) have receptors of varying complexities. Furthermore, the chemical classes selected have significant environmental relevance especially as this relates to 'non-target' impacts in terrestrial ecosystems.