Development and Application of Modelling Approaches for Realistic Assessments on Population Impacts of Endocrine Disruption in Fish.

Chemical exposures threaten the health of freshwater ecosystems worldwide. In particular, endocrine disrupting chemicals (EDCs) are of concern because of their ability to cause sub-lethal effects on organisms at low, including environmentally relevant, concentrations. The susceptibility of fish populations to the effects of these chemicals depends on exposure risk, physiological susceptibility, and population resilience. Population models can explicitly incorporate these factors into environmental risk assessments (ERAs) to improve realism and identify potentially vulnerable species. In this thesis, modelling tools were developed and evaluated for the three-spined stickleback (Gasterosteus aculeatus) to advance understanding of the ecological relevance of EDC effects.The thesis begins with a critical review of the current status of EDCs in freshwater ecosystems worldwide and their effects on individual fish and their populations. The potential for different modelling techniques to provide realistic ecological assessments for EDCs is then explored. Individual-based models (IBMs) are used throughout this thesis to provide case study specific chemical assessments. Reproductive endpoints, including disruption of breeding behaviours, are used to extrapolate EDC effects from individuals to the population level. Findings included the importance of considering behavioural endpoints within chemical assessments, since disruption of breeding behaviours caused significant reductions in population abundance. Moreover, it was identified that the breeding strategy of the stickleback makes it particularly vulnerable to chemicals which directly affect reproductive output. The chemical exposure regime and density dependent processes determined whether the population recovered post-exposure. Empirical experimental exposures were used to investigate the interactive effects of EDC exposure and food limitation on somatic growth in early life stages. An energy budget model was then developed and used to further explore the mechanisms underlying this observed effect. The combined empirical and modelling results suggested that fish can adapt their physiology (by reducing physical activity) to cope with the effects of multiple stressors. Finally, in order to explicitly incorporate environmental conditions into population level assessments, a model was developed combining the energy budget model with the stickleback IBM. This model allows analyses on direct effects of the EDC as well as the additional metabolic effects associated with the chemical exposure. The effects of two case study EDCs (an oestrogen and an androgen) on individual fecundity were simulated in low and high food availability environments in order to explore how environmental conditions affect population susceptibility. The findings illustrate that the underlying mechanism of the EDC effect and environmental conditions can affect the susceptibility of populations to EDC exposures. This thesis has developed novel models for use by both researchers and risk assessors for application in realistic population level assessments of chemical risks. The findings presented have important implications for understanding the ecological relevance of EDC exposures for fish populations

CALMS: Modelling the long-term health and economic impact of Covid-19 using agent-based simulation

Data Availability Statement: All data files are available from https://doi.org/10.17633/rd.brunel.19350518 The software is available on https://gitlab.com/anabrunel/calms.Copyright: © 2022 Mintram et al. We present our agent-based CoronAvirus Lifelong Modelling and Simulation (CALMS) model that aspires to predict the lifelong impacts of Covid-19 on the health and economy of a population. CALMS considers individual characteristics as well as comorbidities in calculating the risk of infection and severe disease. We conduct two sets of experiments aiming at demonstrating the validity and capabilities of CALMS. We run simulations retrospectively and validate the model outputs against hospitalisations, ICU admissions and fatalities in a UK population for the period between March and September 2020. We then run simulations for the lifetime of the cohort applying a variety of targeted intervention strategies and compare their effectiveness against the baseline scenario where no intervention is applied. Four scenarios are simulated with targeted vaccination programmes and periodic lockdowns. Vaccinations are targeted first at individuals based on their age and second at vulnerable individuals based on their health status. Periodic lockdowns, triggered by hospitalisations, are tested with and without vaccination programme in place. Our results demonstrate that periodic lockdowns achieve reductions in hospitalisations, ICU admissions and fatalities of 6-8% compared to the baseline scenario, with an associated intervention cost of £173 million per 1,000 people and targeted vaccination programmes achieve reductions in hospitalisations, ICU admissions and fatalities of 89-90%, compared to the baseline scenario, with an associated intervention cost of £51,924 per 1,000 people. We conclude that periodic lockdowns alone are ineffective at reducing health-related outputs over the long-term and that vaccination programmes which target only the clinically vulnerable are sufficient in providing healthcare protection for the population as a whole.EU Horizon 2020 STAMINA project No. 883441 (https://cordis.europa.eu/project/id/883441)

FACS-CHARM: A Hybrid Agent-Based and Discrete-Event Simulation Approach for Covid-19 Management at Regional Level

10.13039/100010661-EU H2020 STAMINA (Grant Number: 883441

Pharmaceutical Metabolism in Fish: Using a 3-D Hepatic In Vitro Model to Assess Clearance

At high internal doses, pharmaceuticals have the potential for inducing biological/pharmacological effects in fish. One particular concern for the environment is their potential to bioaccumulate and reach pharmacological levels; the study of these implications for environmental risk assessment has therefore gained increasing attention. To avoid unnecessary testing on animals, in vitro methods for assessment of xenobiotic metabolism could aid in the ecotoxicological evaluation. Here we report the use of a 3-D in vitro liver organoid culture system (spheroids) derived from rainbow trout to measure the metabolism of seven pharmaceuticals using a substrate depletion assay. Of the pharmaceuticals tested, propranolol, diclofenac and phenylbutazone were metabolised by trout liver spheroids; atenolol, metoprolol, diazepam and carbamazepine were not. Substrate depletion kinetics data was used to estimate intrinsic hepatic clearance by this spheroid model, which was similar for diclofenac and approximately 5 fold higher for propranolol when compared to trout liver microsomal fraction (S9) data. These results suggest that liver spheroids could be used as a relevant and metabolically competent in vitro model with which to measure the biotransformation of pharmaceuticals in fish; and propranolol acts as a reproducible positive control

STAMINA: Bioinformatics Platform for Monitoring and Mitigating Pandemic Outbreaks

Data Availability Statement: All data driven applications used the our world in data COVID-19 datasets, complimented by proprietary datasets share by the STAMINA consortium.Copyright © 2022 by the authors. This paper presents the components and integrated outcome of a system that aims to achieve early detection, monitoring and mitigation of pandemic outbreaks. The architecture of the platform aims at providing a number of pandemic-response-related services, on a modular basis, that allows for the easy customization of the platform to address user’s needs per case. This customization is achieved through its ability to deploy only the necessary, loosely coupled services and tools for each case, and by providing a common authentication, data storage and data exchange infrastructure. This way, the platform can provide the necessary services without the burden of additional services that are not of use in the current deployment (e.g., predictive models for pathogens that are not endemic to the deployment area). All the decisions taken for the communication and integration of the tools that compose the platform adhere to this basic principle. The tools presented here as well as their integration is part of the project STAMINA.The paper presented is based on research undertaken as part of the European Commission-funded project STAMINA (Grant Agreement 883441)

Applying a mechanistic model to predict interacting effects of chemical exposure and food availability on fish populations

The potential environmental impacts of chemical exposures on wildlife are of growing concern. Freshwater ecosystems are vulnerable to chemical effects and wildlife populations, including fish, can be exposed to concentrations known to cause adverse effects at the individual level. Wild fish populations are also often subjected to numerous other stressors simultaneously which in temperate climates often include sustained periods of food limitation. The potential interactive effects of chemical exposures and food limitation on fish populations are however difficult to establish in the field. Mechanistic modelling approaches can be employed to help predict how the physiological effects of chemicals and food limitation on individuals may translate to population-level effects. Here an energy budget-individual-based model was developed and the control (no chemical) model was validated for the three-spined stickleback. Findings from two endocrine active chemical (EAC) case studies, (ethinyloestradiol and trenbolone) were then used to investigate how effects on individual fecundity translated into predicted population-level effects for environmentally relevant exposures. The cumulative effects of chemical exposure and food limitation were included in these analyses. Results show that effects of each EAC on the population were dependent on energy availability, and effects on population abundance were exacerbated by food limitation. Findings suggest that chemical effects and density dependent food competition interact to determine population responses to chemical exposures. Our study illustrates how mechanistic modelling approaches might usefully be applied to account for specific chemical effects, energy budgets and density-dependent competition, to provide a more integrated evaluation of population outcomes in chemical risk assessments

Pharmaceuticals used in substrate depletion experiments using trout liver spheroids.

<p>Substrate decrease over total incubation period (%), depletion rates constant (<i>k</i>; h^-1) and half-life (t_1/2) values are shown as mean ± SD. NSD = no substrate depletion.</p

Substrate depletion kinetics of propranolol by trout liver spheroid cultures prepared from two separate fish livers.

<p>Closed circles denote cultures from fish one; open circles denote cultures from fish two (<i>n</i> = 6 at each time point). Values at each time point are mean ± SE. Substrate depletion kinetics determined using two-parameter, exponential decay curve-fit analysis (non-linear regression; Sigma Plot v12.5, Systat Software, San Jose, USA).</p

Comparison of intrinsic hepatic clearance rates (CL_{INT, HEPATIC}) of propranolol and diclofenac by trout liver spheroids with trout, human S9 and human hepatocytes.

<p>Clearance rates for human S9 and hepatocytes are shown as mean ± SD and taken from studies reviewed previously [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168837#pone.0168837.ref002" target="_blank">2</a>]. Clearance rates for trout S9 are taken from two previous fish <i>in vitro</i> studies [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168837#pone.0168837.ref002" target="_blank">2</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0168837#pone.0168837.ref020" target="_blank">20</a>]. Where no SD is provided, the data are collated from multiple studies and the figures provided for an indication of comparable rates.</p