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Integrating metabolomics, imaging and bioinformatics to develop physiology-based kinetic models for chemical safety science


Project Description

**If you are interested in this studentship, it is vital to contact Professor Mark Viant prior to application with a copy of your CV: .**

This 4-year BBSRC iCASE PhD bridges Unilever’s Safety and Environmental Assurance Centre (SEAC) and the University of Birmingham’s metabolomics team, both having state-of-the-art facilities and renowned research programmes, thereby creating an excellent environment for this impactful research project.

Project Description:

To ensure a healthy environment, a modern chemical safety assessment framework should characterise the biological impacts of a chemical before it’s allowed to enter the environment. Of major importance, yet often overlooked, is understanding the effect that organisms can have on chemicals – termed toxicokinetics, to complement the more-often studied effects that chemicals have on organisms – representing a critical element of exposure science. An understanding of the toxicokinetics will deeply influence the way we manage the potential risks of chemicals.

A revolution is now occurring in toxicology, driven by the availability of molecular technologies that can generate ‘big data’ to drive new mechanistic understanding and ultimately create quantitative models of organism function. These technologies can help us to understand the most sensitive physiological properties of organisms (and underlying molecular mechanisms) that are relevant to toxicokinetics. To achieve this prognostically within a safety assessment framework, the decision-making requires quantitative exposure and effect models, as highlighted recently in Opinion on the state-of-the-art of Toxicokinetic/Toxicodynamic effect models for regulatory risk assessment (EFSA).

The objective of this PhD is to understand the physiological properties involved in toxicokinetics, specifically chemical absorption, distribution, metabolism and excretion (ADME) processes, in an invertebrate model species. This will use state-of-the-art molecular analysis and imaging tools, and will develop physiology-based kinetic (PBK) models that can then be used to predict how chemicals are processed by this species. It is intended that these models would immediately translate into Unilever’s chemical risk assessment toolkit, highlighting the real-world impact of this PhD.

Workplan:

This project will use cutting-edge advanced technologies, including untargeted mass spectrometry (MS) and data analyses workflows, mass spectrometry imaging, genomics and mathematical modelling to address four tasks:

1. Define the physiological properties which influence the absorption of chemicals using the model invertebrate species Daphnia magna.

2. Understand the relationships between external and internal concentrations of a suite of chemicals over time and determine the properties (chemical and biological) influencing these relationships (a so-called one compartment mathematical model).

3. Understand the internal distribution of chemicals within the model organism over time to describe detoxification processes, underpinning this knowledge with genomic information on Daphnia’s ability to metabolise chemicals.

4. Develop a deployable PBK model for Daphnia magna, based on standard literature PBK model structures and parameterised and validated using the novel data generated in tasks 1-3.

Research environment:

The student training and research will take place both at the University of Birmingham and Unilever (Colworth). The Safety and Environmental Assurance Centre at Unilever houses state of the art research laboratories and ca. 180 scientists. The metabolomics team at the University of Birmingham comprises of ca. 25 PhD students and postdoctoral researchers. The School of Biosciences was ranked in 6th in the UK Russell Group in REF2014, with over 90% of research rated as world leading.

We seek an excellent, highly motivated candidate with a high quality undergraduate and preferably Masters degree (can be pending) in fields such as biochemistry, bioanalytical chemistry or (eco)toxicology. A strong interest in data analysis and modelling is required.

Funding Notes

This BBSRC studentship is for 4 years. In addition to the payment of tuition fees, the award provides an annual stipend and funds for the laboratory studies. Unilever is also providing further funding for this PhD. The funding is open to UK citizens, as well as to EU citizens who have lived in the UK for the last three years.

References

• Scientific Opinion on the state of the art of Toxicokinetic/Toxicodynamic (TKTD) effect models for regulatory risk assessment of pesticides for aquatic organisms.
EFSA Panel on Plant Protection Products and their Residues (PPR),
EFSA Journal, 2018, 16(8), p.e05377.

• Depressing antidepressant: fluoxetine affects serotonin neurons causing adverse reproductive responses in Daphnia magna.
Campos B, Rivetti C, Kress T, Barata C, Dircksen H
Environmental Science & Technology. 2016 May 11;50(11):6000-7.

• Combined mathematical modelling and experimentation to predict polymersome uptake by oral cancer cells.
Sorrell I, Shipley RJ, Hearnden V, Colley HE, Thornhill MH, Murdoch C, Webb SD. Nanomedicine: Nanotechnology, Biology and Medicine. 2014 Feb 1;10(2):339-48.

• Toxicokinetic models and related tools in environmental risk assessment of chemicals.
Grech A, Brochot C, Dorne JL, Quignot N, Bois FY, Beaudouin R.
Science of the Total Environment. 2017 Feb 1;578:1-5.

• Metabolomics Discovers Early-Response Metabolic Biomarkers that Can Predict Chronic Reproductive Fitness in Individual Daphnia magna
Nadine S. Taylor, Alex Gavin and Mark R. Viant
Metabolites. 2018 Sep; 8(3): 42-61.

• Distinguishing between the metabolome and xenobiotic exposome in environmental field samples analysed by direct-infusion mass spectrometry based metabolomics and lipidomics
Andrew D. Southam, Anke Lange, Raghad Al-Salhi, Elizabeth M. Hill, Charles R. Tyler and Mark R. Viant
Metabolomics. 2014; 10(6): 1050–1058.

How good is research at University of Birmingham in Biological Sciences?

FTE Category A staff submitted: 42.80

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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