THEME IV – Neurotoxins and high toxicity agents

Overview

This Theme involves understanding significant chemical hazards to human health, ranging from household pollutants to toxic industrial chemicals (TICs) and chemical warfare agents (CWA). In brief, the cycle of environmental toxic agents starts from i) its presence in the environment; ii) its direct contact with humans; iii) its absorption by the body followed by the physiological process of its toxicity; and iv) its clearance from the body.

The research in this Theme focuses on elucidating the mechanisms of action, presence in the environment, impact at the cellular level, defining decontamination protocols and developing novel routes to decomposition/disruption. A key aspect is the impact of such chemicals on humans, and how to decontaminate or alleviate exposure.

Empty Blue Chemical Waste Drums Lying on an Abandoned Bank with a view on Smoking Exhaust Pipes of a Heavy Industrial Factory

Theme Leads

Theme IV Projects

Project 1: Novel screens for environmental neurotoxins – PI Nora Bourbia (UKHSA)
Researchers – Nora Bourbia (UKHSA), Leon Barron (ICL)
Project outline: Most brain disorders (including neurological and neuropsychological disorders and diseases such as Alzheimer’s Disease, Parkinson’s Disease, Bipolar disorder, depression, multiple sclerosis, chronic pain) are multifactorial involving genetic and environmental aspects. Because environmental factors have an impact on the establishment and maintenance of brain disorders, the investigation of these environmental neurotoxins will help to prevent or reverse their negative effects on brain health.
Overall objectives: This study will contribute to the overall ambition of protecting and maintaining good mental health and therefore reducing the economic burden on society. We aim to i) study the impact of nitric oxide / nitrite / nitrate on the endogenous nitric oxide pathway of brain cells; ii) study the impact of mycotoxins on brain cell activity; iii) develop an assay to screen the effect of environmental agents on the electrical properties of neurons.
Project 2: Identification and validation of novel simulants of highly toxic chemical agents – PIs Sam Collins (UKHSA), Tim Marczylo (UKHSA)
Researchers – Sam Collins (UKHSA), Tim Marczylo (UKHSA), Charlotte Hague (UKHSA), Tom Welton (ICL), Tom James (UKHSA)
Project outline: Human decontamination is critical following release of toxic chemicals and simulants are often used to assess decontamination procedure efficacy. To date, simulants employed in these studies are typically hydrophobic, volatile liquids at ambient conditions and the majority of studies have used a single chemical simulant (methyl salicylate). Another concern is the use of highly toxic powders which may require different decontamination approaches to the liquids utilised in all human decontamination studies to date.
Overall objectives: To provide evidence to support modifications to existing operational response to improve the efficacy of chemical mass casualty decontamination with respect to toxic powders and liquids. We will identify and evaluate novel simulants that address the spectrum of physicochemical properties of toxic chemicals, including novel and priority threats. This will involve a literature search for suitable low toxicity agents that have been applied to skin, are absorbed sufficiently to enable quantitation in urine and that mimic the physicochemical characteristics of toxic industrial chemicals/threat agents.
Project 3: Detection of high toxicity agents in water – PI Leon Barron (ICL)
Researchers – Leon Barron (ICL), Marc Chadeau-Hyam (ICL), Paolo Vineis (ICL), Davide Ciccarelli (ICL)
Project outline: Identification and monitoring of potentially hundreds of new highly toxic agents (HTAs) in drinking water arising from by-products of chemical treatment processes (e.g. disinfection) and contamination with chemical substances (e.g. pharmaceuticals, pesticides, organometallics, plastic-related compounds, etc.) remains a significant challenge. Analytical methods involving ion chromatography, liquid chromatography and comprehensive gas chromatography coupled to full-scan high resolution mass spectrometry (HRMS) instruments will be developed and validated for several main classes of currently known compounds including plasticisers, disinfectant by-products (haloacetic acids, oxyhalides, trihalomethanes), pesticides (herbicides, insecticides, rodenticides, etc.), pharmaceuticals and illicit drugs (focussing on those which survive wastewater treatment). Full-scan measurement data for these ‘model’ compounds will then be used to construct machine learning-based prediction models to assist in identification of new HTA substances.
Overall objectives: This project will characterise and classify new chemical HTAs in UK municipal, well and bottled drinking waters and assess their potential risks for human exposure. The objectives of the project are to i) develop AI-assisted high resolution analytical methods for screening of large numbers of suspect neurotoxins and HTA markers; ii) conduct a temporal survey of drinking water sources across the UK; iii) analyse urine samples to assess individual-level exposure and analyse wastewater from the corresponding city to extrapolate to both human population and environmental exposure; iv) evaluate public health and environmental risk of HTAs from drinking water sources.
Project 4: Clearance of neurotoxins and other highly toxic chemicals from the environment – PI Tom Welton (ICL)
Researchers – Tom Welton (ICL), Patricia Hunt (ICL/Victoria University of Wellington, NZ), Charles Romain (ICL), Gavin Smith (ICL)
Project outline: Detection of and protection from CWAs have become more urgent with recent events. Agents can be highly volatile and non-persistent (e.g. sarin) or have lower volatility and only partial water solubility creating more persistent hazards (e.g. mustard gases). New systems that can be used to safely clear CWAs from the environment are urgently required. Ionic Liquids (ILs) are efficient in detecting and absorbing gases and liquids present in low concentrations. Selected ILs also suppress solute vapour production. ILs have also been shown to accelerate the rates of chemical reactions, so providing the possibility to enhance decomposition of CWA but our understanding of these mechanisms is lacking.
Overall objectives: We will seek to understand how ionic liquid-solute interactions can be manipulated to create solutions for the detection and destruction of CWAs. We will combine computational and experimental techniques to i) identify the mechanism of solvation and decomposition of CWA in known ILs; ii) investigate solvation and decomposition of common CWA simulants, evaluate simulant fidelity against real CWA chemical structures, solvation and degradation processes, and identify better potential simulants, and their key chemical features; iii) design and test in silico novel ILs with simulants and CWA to improve containment and facilitate analytical processing; iv) design and test in silico novel ILs with simulants and CWA to enhance decomposition rates and promote generation of nontoxic degradation products.
Project 5: Identification of illegal threat manufacturing activity via wastewater markers (ThreatMARK) – PIs Keng Tiong Ng (ICL), Leon Barron (ICL)
Researchers – Keng Tiong Ng (ICL), Leon Barron (ICL), Peter Thompson (NPL)
Project outline: The early identification of illicit manufacture of threat agents is critical for protection of public safety. The aim of this work is to identify markers that exist and/or that can be added to both explosives (E) and chemical (C) threat precursors to identify synthesis via wastewater. Markers should be non-volatile, inert and not be prevalent in wastewater. The focus lies on improvised explosives (e.g., peroxides and inorganics) and nerve agents/mimics. The project integrates the latest advances in high-resolution analysis and in silico AI-assisted technologies to rapidly achieve this. Ultimately, the outcomes of this project will provide a much-needed baseline reference point for discrete monitoring of threat agent manufacturing activity on a city-wide level.
Overall objectives: i) to review and compile a list of ingredients within a range of commercially available C/E-threat precursor products; ii) to identify reactive precursor impurities under clandestine manufacturing conditions and predict their identities or chemical products; iii) to perform targeted and untargeted screening of selected precursor materials to identify common markers for manufacture of specific C/E threats; iv) to screen for the presence of all identified markers in municipal wastewater; v) to understand the stability of C/E threat markers to enable reliable back-calculation of production load in kg/day in a catchment.

Theme IV Investigators