A holistic approach to chemical risk assessment

Traditionally, toxicology has been a field dominated by in vivo animal testing. However, with society moving forward, rapid, low-cost, sustainable alternatives to animal testing are very much in demand. Density functional theory has long been in use to examine covalent bond forming/breaking reactions in organic chemistry. However, it's use in toxicology remains strikingly underdeveloped. Work by Townsend and Grayson developed a fast, low-cost framework for assessing the mutagenic risk of pharmaceutically important organic electrophiles (J. Chem. Inf. Model. 2019, DOI: 10.1021/acs.jcim.9b00966). Building on this work, the same methodology will be applied and developed towards aquatic toxicity.
Increased global industrialisation has led to a plethora of organic pollutants entering the environment, and chemical reactivity plays a vital role in their ecotoxicology. It is therefore vital that new in silico methods are developed to reduce the use of animals in toxicological testing protocols. Covalent modification of proteins, DNA, RNA and other biological nucleophiles is responsible for many deleterious end points in toxicology. Electrophile LUMO energies and activation barriers for reaction between a model for glutathione, and a series of electrophiles will be calculated using DFT to assess the ability of these parameters to predict aquatic toxicity data. Hydrophobicity also contributes to the toxicological profile of these organic electrophiles. We will therefore explore DFT and machine learning approaches to calculating hydrophobicity. This work will lead to a new protocol for computationally assessing the toxicity of pollutants through the combined calculation of reactivity and hydrophobicity. Other work in this project could focus on expanding the DFT approach to respiratory and skin sensitization prediction; these endpoints can be caused by covalent bond-forming reactions as part of the adverse outcome pathway. Furthermore, electrophile classes known to react with DNA which have yet to be studied include SN1 and SN2 electrophiles, Schiff base formers and acylating agents. Studying these reaction classes will provide the opportunity to broadly expand our work in predictive computational toxicology.
Collaboration with Dr Bryant, as co-supervisor for the project, will focus on the mass-transport mechanisms by which organic compounds enter aquatic environments on catchment and system scales, using a local drinking-water-supply reservoir (Blagdon Lake, managed by Bristol Water) as a project study site. Dr Bryant will also support the investigation of the transport and distribution of organic compounds within the water and sediment components of an aquatic system (i.e., Blagdon Lake).

The Centre for Doctoral Training (CDT) in Sustainable Chemical Technologies (SCT) at the University of Bath will place fundamental concepts of sustainability at the core of a broad spectrum of research and training at the interface of chemical science and engineering. It will train over 60 PhD students in 5 cohorts within four themes (Energy and Water, Renewable Resources and Biotechnology, Processes and Manufacturing and Healthcare Technologies) and its activities and graduates will have potential economic, environmental and social impact across a wide range of beneficiaries from academia, public sector and government, to industry, schools and the general public.

The primary impact of the CDT will be in providing a pool of highly skilled and talented graduates as tomorrow's leaders in industry, academia, and policy-making, who are committed to all aspects of sustainability. The economic need for such graduates is well-established and CDT graduates will enhance the economic competitiveness of the UK chemistry-using sector, which accounts for 6m jobs (RSC 2010), contributing £25b to the UK economy in 2010 (RSC 2013). The Industrial Biotechnology (IB) Innovation and Growth Team (2009) estimated the value of the IB market in 2025 between £4b and £12b, and CIKTN (BIS) found that "chemistry, chemical engineering and biology taken together underpin some £800b of activity in the UK economy".

UK industry will also gain through collaborative research and training proposed in the Centre. At this stage, the CDT has 24 partners including companies from across the chemistry- and biotechnology-using sectors. As well as direct involvement in collaborative CDT projects, the Centre will provide an excellent mechanism to engage with industrial and manufacturing partners via the industrial forum and the Summer Showcase, providing many opportunities to address economic, environmental and societal challenges, thereby achieving significant economic and environmental impact.

Many of the issues and topics covered by the centre (e.g., sustainable energy, renewable feedstocks, water, infection control) are of broad societal interest, providing excellent opportunities for engagement of a wide range of publics in broader technical and scientific aspects of sustainability. Social impact will be achieved through participation of Centre students and staff in science cafés, science fairs (Cheltenham Science Festival, British Science Festival, Royal Society Summer Science Exhibition) and other events (e.g., Famelab, I'm a Scientist Get Me Out of Here). Engagement with schools and schoolteachers will help stimulate the next generation of scientists and engineers through enthusing young minds in relevant topics such as biofuels, solar conversion, climate change and degradable plastics.

The activities of the CDT have potential to have impact on policy and to shape the future landscape of sustainable chemical technologies and manufacturing. The CDT will work with Bath's new Institute for Policy Research, through seminars, joint publication of policy briefs to shape and inform policy relevant to SCT. Internship opportunities with stakeholder partners and, for example, the Parliamentary Office of Science and Technology will provide further impact in this context.