Michael Eddleston’s research while affiliated with University of Edinburgh and other places

Introduction: Many patients acutely self-poisoned with organophosphorus insecticides have co-ingested ethanol. Currently, profenofos 50% emulsifiable concentrate (EC50) is commonly ingested for self-harm in Sri Lanka. Clinical experience suggests that ethanol co-ingestion makes management more difficult. Therefore, we aimed to determine the relationships between plasma ethanol concentration, plasma profenofos concentration and its toxicokinetics, and clinical outcome in acute profenofos self-poisoning. Methods: Demographic and clinical data, including a history of ethanol ingestion and blood samples, were prospectively collected from all cases of acute poisoning with profenofos EC50 presenting to Teaching Hospital Peradeniya, Sri Lanka, over four years. Plasma samples were analyzed by gas chromatography-mass spectrometry to quantify the ethanol (n = 99) and profenofos (n = 30 [15 with ethanol, 15 without ethanol]) concentrations. The PKSolver program was used to calculate the toxicokinetic parameters. Results: Of 99 patients (male 78/99) with acute profenofos self-poisoning, 50 reported a history of ethanol co-ingestion. Plasma from 44 of 99 profenofos-poisoned patients had detectable ethanol concentrations. No statistical difference was observed between the mortality in the ethanol group and the no ethanol group (5/44 [11.4%] versus 3/55 [5.5%]; P = 0.461). Similarly, the median half-lives of plasma profenofos absorption in the ethanol and no ethanol groups (0.1 h and 0.1 h, respectively; time 0-24 h) were not statistically different (P = 0.6594). However, the median half-life of plasma profenofos elimination was significantly longer in the ethanol group than the no ethanol group (23.1 h and 9.9 h, respectively; time 0-24 h; P = 0.0002). According to the regression analysis, the half-life of plasma profenofos elimination was longer by 29.4 h in the ethanol group (P = 0.013). Discussion: No significant differences in outcomes, including death and endotracheal intubation rates, were found between those who did and did not co-ingest ethanol. No differences were found in toxicokinetic variables between the ethanol and no ethanol groups, but the ethanol group had a longer elimination half-life. Conclusion: The co-ingestion of ethanol leads to a slowing of the elimination kinetics of profenofos. However, the study did not reveal a significant impact of ethanol co-ingestion on clinical outcomes.

Intentional and unintentional pesticide poisoning is an important public health problem, especially in low- and middle-income countries. Individuals who have been exposed to toxic pesticides, particularly organophosphorus insecticides, need early treatment. Atropine autoinjector devices offer a potential solution, allowing storage of effective treatment near agricultural workers’ fields and homes that could be reached within minutes by the worker or fellow villagers to provide first-line emergency care. Here we present the design of a qualitative, formative study that will constitute the first phase of an implementation science study exploring the introduction of atropine autoinjectors in rural villages. This study will employ a qualitative design to investigate the feasibility and operational opportunities and challenges in providing pre-hospital emergency care with atropine autoinjectors in rural communities in Sri Lanka. We will conduct semi-structured interviews, ethnographic observations, oral history interviews, participatory mapping, and focus group discussions in villages and in hospitals. This study will allow the design of an autoinjector intervention that is tailored to specific needs of rural communities, maximise the potential benefits in the villages where they are placed, and contribute to knowledge related to biomedical technologies designed for use in LMICs. It will also contribute to social science scholarship in the context of pesticide poisoning. Study approvals have been obtained from the University of Edinburgh Medical School Research Ethics Committee (23-EMREC-039) and from Ethics Review Committee, Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka (ERC/2023/4).

Introduction In overdose, a larger proportion of paracetamol (acetaminophen) is converted in the liver to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). Glutathione (GSH) is the endogenous antioxidant that protects cells from NAPQI-induced injury. In overdose, GSH stores may become depleted, leaving NAPQI free to produce liver damage. Acetylcysteine (NAC) helps prevent paracetamol toxicity by replenishing liver GSH. This protective effect of NAC produces specific metabolites in the circulation. Currently, regardless of the paracetamol dose ingested, patients in the United Kingdom receive a dose of NAC based only on their weight. Basic pharmacology, mathematical modelling and observational studies suggests that this dose may be insufficient in some patients (particularly those taking a large overdose). Methods and analysis A multi-centre trial, taking place across several hospitals in Scotland, UK, within Emergency Departments and Acute Medical Units. Recruitment commenced 19 Feb 2024, and is anticipated to run for approximately two years. This is a three-group dose finding trial, in which participants are assigned in a 1:1:1 ratio to either standard NAC (300mg/kg), or higher doses of 450mg/kg (Group 1) and 600mg/kg (Group 2). The primary outcome is the proportion of paracetamol metabolites in the circulation that are directly produced by GSH/NAC detoxification of NAPQI. A higher proportion of these metabolites will indicate that the additional NAC is reducing the amount of toxic paracetamol metabolites in the body. The study will first test the primary outcome on the HiSNAP Group 2 against Standard NAC; only if that is significant, will HiSNAP Group 1 be tested against Standard NAC. Ethics and dissemination The HiSNAP trial has been approved by East Midlands (Derby) Research Ethics Committee (reference 23/EM/0129), NHS Lothian Research and Development department, and the MHRA. Results will be disseminated by peer-reviewed publication, conferences, and linked on isrctn.com . Registration details ISRCTN 17516192 Strengths and limitations of this study The study will systematically collect data to assess the safety and efficacy of higher acetylcysteine doses and the current standard dose. The study primary endpoint is measurable in every patient, in contrast with paracetamol overdose trials examining liver injury (which only occurs in approximately 10% of patients). The study has pragmatic inclusion criteria – the decision that the patient requires acetylcysteine lies with the clinical team. The study seeks to minimise imbalances between treatment groups by stratifying randomisation according to whether a patient is at high risk of liver injury after overdose. The study is limited by the primary outcome being biomarker-based. Any benefits on clinical outcomes will still require confirmation.

Introduction: Individual researcher impact through scientific citations is carefully monitored, with little attention to the impact of individual journals through policy and patent mentions. We aimed to describe policy and patent mentions for articles published in Clinical Toxicology. Methods: Using Altmetric Explorer, we extracted mentions from 1 January 2013 to 31 December 2023, noting the citing source, Clinical Toxicology article title, and author-generated keywords. We used descriptive statistics to analyse the data. Results: We identified 165 individual policy documents (n = 139) and patents (n = 26), citing 146 articles with median of 6.4 years between publication and mention. The highest number of citing documents were by the World Health Organization (n = 45), European Monitoring Centre for Drugs and Drug Addiction (n = 22), and United States Centers for Disease Control and Prevention (n = 16). Most patents were registered in the United States (n = 17) and by the European Patent Office (n = 10), with the main classification of human necessities (n = 23). The commonest subjects of papers cited in policy and patents, from keywords, related to medical conditions and symptoms (26%) and recreational drugs (22%). The most cited article was "A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment." Discussion: Clinical Toxicology articles are cited in policy documents and patents, with a comparable number of mentions to the top-ranked journals in the field. This likely contributes to policy impact, but further work is needed to understand how cited articles are used and ripple effects through onwards citations of policy documents. Conclusions: Clinical Toxicology is a toxicology journal for which published research gets recognised within influential policy sources. The Journal can play a key role in guiding public health policy through its selection and development of submitted publications.

Objective: Socioeconomic status deprivation is known to be associated with self-harm in Western countries but there is less information about this association in Low and Middle Income Countries (LMIC). One way of investigating this is to assess the prevalence of indicators of financial stress in people who self-harm. We have assessed the prevalence and correlates of day-to-day financial hardships amongst individual presenting with non-fatal self-harm to hospitals in Sri Lanka. Methods: Data on non-fatal self-harm presentations were collected from an ongoing surveillance project in 52 hospitals in Sri Lanka. A questionnaire captured data on two forms of financial stress: unmet need (i.e., costs and bills that cannot be paid) and required support (i.e., steps taken to cover costs, such as selling belongings). Additional data on demographic, economic and clinical characteristics were also collected. Results: The sample included 2516 individuals. Both forms of financial stress were very common, with pawning/selling items (47%) and asking family or friends for money (46%) in order to pay bills or cover costs being commonly reported. Greater financial stress was associated with being aged 26-55 years, limited education, and low socioeconomic position. Financial stress was greater in women than men after adjusting for other factors. Conclusion: The results indicate that financial stress is commonly reported amongst individuals presenting to hospital with non-fatal self-harm in Sri Lanka, especially women. The research highlights a need to attend to financial stress both within self-harm prevention and aftercare.

Background Suicide is one of the most common types of injuries in Nepal with recorded 6993 suicides in 2022–23, with intentional pesticide poisoning being the second most common method. Banning highly hazardous pesticides (HHPs) is a cost-effective intervention to reduce mortality from pesticide suicide. Eight mostly HHPs were banned in Nepal in 2019 with one product reformulated. Objective This talk will provide highlights from the University of Edinburgh study on the use of HHPs in suicides. HOPE GRID study (2017–2019) carried out in select hospitals and the toxicology labs identified the HHPs responsible for suicide and self-harm and provided evidence to relevant stakeholders in decision making. The current study (2021–2024) aims to monitor the impact of the 2019 pesticide bans on pesticide suicide numbers. Policy Analysis and Results The talk will present the findings of the 2017–2019 study, its impact on policy-making in Nepal, and effects on the current pesticide suicide numbers in the country. In 2021–23 study, there were 1,764 cases reported by toxicology labs in which phosphine gas (48.9%) was the most common pesticides followed by organophosphorus insecticides (29.1%). When compared the preliminary results of 2021–23 data to 2017–19, a smaller proportion of cases were the banned pesticides dichlorvos (n=70/1089; 6.4% and n=273/450; 60%, respectively) and aluminium phosphide (n=304/1089; 27.9% and n= 299/891; 33%, respectively). Policy Implications of the Study There have been hundreds of lives saved in Nepal as a result of 2019 pesticide bans. The study clearly shows that phase out and ban of key HHPs responsible for fatal poisonings is cost-effective and efficient way to reduce the numbers of deaths associated with pesticides. In the hierarchy of controls of risks associated with pesticides, elimination of hazard is by far the most effective. Based on the experience from Nepal, elimination of HHPs should be considered to reduce poisoning in agricultural LMICs. Conclusions HHPs bans 2019 in Nepal have reduced the numbers of fatal pesticide poisonings and saved lives. Our study has identified emerging pesticides now used in self-poisoning (chlorpyrifos and cypermethrin combination). The authorities should consider regulating these pesticides to further reduce poisonings and deaths.

Metal phosphides, particularly aluminium phosphide (AlP) and zinc phosphide (Zn3P2), are widely used in low- and middle-income countries (LMICs) as rodenticides in urban and domestic environments due to their low cost and high toxicity to rodent pests. However, they are also highly toxic to humans with no antidote available and have been associated with numerous fatal cases of intentional and accidental poisoning. This paper reviews alternatives to metal phosphide use for rodent pest management in urban and domestic environments, highlights case studies of effective alternative approaches, and provides recommendations for research and policy. This review identifies numerous alternative methods available for managing rodent pests in domestic/urban settings that can replace metal phosphides. These include chemical methods, i.e. rodenticides, and non-chemical methods, e.g. rodent-proofing, sanitation and trapping. However, because the majority of chemical rodenticides qualify as highly hazardous pesticides due to acute human health toxicity, environmental toxicity, and/or bioaccumulation, simply selecting substitute chemical rodenticides to replace metal phosphides are likely to replace one set of hazards with others. Thus, careful risk and hazard assessments are needed when considering substituting with other chemicals. Overall, we need to move away from current levels of rodenticide reliance towards more integrated and ecologically based approaches.

Importance Deliberate self-poisoning using pesticides as a means of suicide is an important public health problem in low- and middle-income countries. Three highly toxic pesticides—dimethoate, fenthion, and paraquat—were removed from the market in Sri Lanka between 2008 and 2011. In 2015, less toxic pesticides (chlorpyrifos, glyphosate, carbofuran, and carbaryl) were restricted. Subsequent outcomes have not been well described. Objective To explore the association of pesticide bans with pesticide self-poisonings and in-hospital deaths. Design, Setting, and Participants In this cross-sectional study with an interrupted time series design, data were prospectively collected on all patients with deliberate self-poisonings presenting to 10 Sri Lankan hospitals between March 31, 2002, and December 31, 2019, and analyzed by aggregated types of poisoning. The correlates of pesticide bans were estimated within the pesticide group and on self-poisonings within other substance groups. The data analysis was performed between April 1, 2002, and December 31, 2019. Exposures Implementation of 2 sets of pesticide bans. Main Outcomes and Measures The main outcomes were changes in hospital presentations and in-hospital deaths related to pesticide self-poisoning as measured using segmented Poisson regression. Results A total of 79 780 patients (median [IQR] age, 24 [18-34] years; 50.1% male) with self-poisoning from all causes were admitted to the study hospitals, with 29 389 poisonings (36.8%) due to pesticides. A total of 2859 patients died, 2084 (72.9%) of whom had ingested a pesticide. The first restrictions that targeted acutely toxic, highly hazardous pesticides were associated with an abrupt and sustained decline of the proportion of poisonings with pesticides (rate ratio [RR], 0.85; 95% CI, 0.78-0.92) over the study period and increases in poisonings with medications (RR, 1.11; 95% CI, 1.02-1.21) and household and industrial chemicals (RR, 1.20; 95% CI, 1.05-1.36). The overall case fatality of pesticides significantly decreased (RR, 0.33; 95% CI, 0.26-0.42) following the implementation of the 2008 to 2011 restrictions of highly hazardous pesticides. Following the 2015 restrictions of low-toxicity pesticides, hospitalizations were unchanged, and the number of deaths increased (RR, 1.98; 95% CI, 1.39-2.83). Conclusions and Relevance These findings support the restriction of acutely toxic pesticides in resource-poor countries to help reduce hospitalization for and deaths from deliberate self-poisonings and caution against arbitrary bans of less toxic pesticides while more toxic pesticides remain available.

Modern agriculture relies on pesticides to maximise outputs. While many highly hazardous pesticides (HHPs) are banned in places like the European Union due to concerns about harm to the environment and human health, their use continues in many low- and middle-income counties (LMICs). Pesticide suicide is a public health problem unique to countries where HHPs are used, and Sri Lanka has successfully implemented several HHP bans as part of a suicide prevention strategy. On 27 April 2021, the Sri Lankan government announced an imminent import ban of all fertilizers and pesticides which was later revoked in November 2021. The aim of this article was to explore the media framing of the import ban as it pertained to pesticides. Guided by Entman’s typology of frame functions, we analysed newspaper articles from nine Sri Lankan newspapers (N = 102) between 20 April to 31 October 2021. Overall, most framings were supportive of the ban, captured by framings that articulated the ban through a health, environment, and organic farming narrative. Framings that foregrounded farmer or industry livelihoods and the pesticide market were primarily adopted to express opposition to the ban. The presence of frames opposing the ban within media articles increased over time during the study period. There was a greater proportion of opposing frames in private newspapers compared to government (78% vs 22%). Many of the articles analysed described the widespread impact of the ban, but only 11% of articles represented the voices of policy end users. This study adds understanding to the ways communication via outlets like mainstream newspapers may shape public support or opposition to pesticide bans in a LMIC. Mass media is an under-recognised factor in policy implementation and this study may inform planning to implement pesticide bans in other countries.

Introduction Pesticide self-poisoning causes severe health and socioeconomic hardship in low- and middle-income countries, including Sri Lanka. A stepped-wedge cluster randomised controlled trial (cRCT) has been designed to test whether ‘gatekeeper’ training for pesticide vendors reduces pesticide self-poisoning in rural Sri Lanka (Vendor cRCT). Ensuring intervention fidelity in RCTs is essential for consistently replicating interventions, accurately assessing their impact and improving outcomes. Thus, the overarching goal of this proposed study is to explore to what extent the pesticide vendors use the ‘gatekeeper’ strategies. Methods and analysis A multimethod qualitative research design is being used to explore the pesticide-selling behaviours of vendors after the ‘gatekeeper’ training. A subsample of the Vendor cRCT Study population is being recruited using a stratified purposive sampling method in all six intervention districts in Sri Lanka to ensure that the sample is representative of the pesticide vendors in the study area. Participant diaries, observations and focus group discussions are being adopted to collect data. Data triangulation will be performed and data will be analysed thematically. Ethics and dissemination The study was approved by the Ethics and Research Committee, Faculty of Medicine and Allied Sciences, at the Rajarata University of Sri Lanka (ERC/2023/09). All participants will provide informed consent. Findings will be disseminated in scientific peer-reviewed journals and conference presentations.