A lethal cocktail – shining a light on the relationship between alcohol use and pesticide self-poisoning

Abstract Introduction Alcohol and pesticides are toxic substances that each cause acute and chronic harm to humans. Alcohol plays an important and complex role in pesticide self-poisoning, involving toxicological, public health, and social aspects important for research, prevention, and interventions. Alcohol use disorder and social harms While the evidence on alcohol co-ingestion in the context of pesticide self-poisoning is limited, it appears that alcohol use increases complications. Even fewer studies address alcohol use disorder and dependence among pesticide self-poisoning patients. The harmful use of alcohol also impacts social life, families, and communities in several ways, including pesticide self-poisoning among individuals around the alcohol user. This, however, is vastly understudied. Outside influences Agrochemicals and alcohol are produced by industries with financial interests, and the outcome of individual acts of pesticide self-poisoning depends on the lethality of the pesticide purchased and ingested. The promotion of acutely toxic pesticides by companies must be acknowledged within this issue. Conclusion The relationship between alcohol and pesticide self-poisoning is increasingly clear, but more studies are needed to guide management. We cannot ignore that pesticide self-poisoning and harmful use of alcohol occur within the context of wider, often structural, stressors and are influenced by commercial entities.


Introduction
Fatal pesticide self-poisoning, or pesticide suicide, is a major public health issue that has resulted in an estimated 14 million premature deaths globally since the widespread introduction of highly hazardous pesticides into agricultural practice in the 1960s [1].The toxicity of pesticides varies widely -some are highly toxic, with case fatalities over 50%, while others are much less toxic, causing little harm to humans after ingestion [2,3].We recently reviewed the literature to understand the role of co-ingested alcohol in affecting outcomes as well as public health and social aspects of alcohol use interacting with pesticide self-poisoning.Our aim was to better understand the evidence base related to treatment, identification of risk factors, and prevention of pesticide suicides [4].We here aim to draw attention to the co-ingestion of alcohol and pesticides and how clinical toxicologists can play a role in addressing this complex and intertwined phenomenon.
Most pesticide self-poisoning deaths over the last 60 years have resulted from ingestion of organophosphorus insecticides [5,6].These pesticides, and the carbamate insecticides, cause their major effects by inhibiting the acetylcholinesterase enzyme in cholinergic synapses across the body.Severe toxicity includes coma, respiratory failure, and aspiration of stomach contents [7,8].Alcohol is a GABA-A agonist that can also cause coma, respiratory failure, and pulmonary aspiration of stomach contents [9].
The ingestion of organophosphorus insecticides by alcohol-intoxicated individuals is of concern, with alcohol potentiating the effect of the pesticide.This was our presumed situation in clinical practice in the resource-poor open medical wards of Sri Lanka, without intensive facilities, where the combination was a very common scenario amongst men [10,11].
A recent systematic review by Dhanarisi and colleagues [12] specifically evaluated alcohol and pesticide co-ingestion from a toxicological perspective, identifying only 14 studies.This is notable, given that current estimates suggest there are about 150,000 deaths due to pesticide self-poisoning each year [13], and alcohol is attributed to one in five selfharm deaths globally [14].The systematic review and metaanalysis concluded that pesticide self-poisoning patients who had co-ingested alcohol had a significantly increased risk of dying and a greater need for intubation [12].
A clinical study of 72 patients poisoned by a single highly toxic organophosphorus insecticide, dimethoate (designed to reduce confounding by variation between individual organophosphorus insecticides), showed that the mix of alcohol and organophosphorus insecticide markedly worsened outcome [15].Noteworthy, it was not the interaction of alcohol and organophosphorus insecticide after the poisoning that affected the outcome.Instead, it appeared that alcohol intoxication caused individuals to drink more pesticides, presumably due to a loss of restraint and perhaps taste (concentrated agricultural pesticides cannot taste good).
In contrast, a recent case series of patients with profenofos insecticide self-poisoning found that the half-life of elimination of the pesticide was prolonged more than two-fold in those who had consumed alcohol [16].Of note, the study was small; case fatality and need for intubation were, therefore, only non-significantly greater in the alcohol-using group.
It is also possible that alcohol directly inhibits acetylcholinesterase, as an in vitro study suggested a synergistic effect of the two toxins [17]; however, clinical studies have not yet been performed.The variation in dose, timing, and potency of organophosphorus insecticide and alcohol may make such studies very difficult.
A common clinical consideration for patients who have co-ingested alcohol and pesticides is withdrawal from chronic alcohol use, a particularly common problem in older men.As they started to recover from the organophosphorus insecticide poisoning, they would develop severe alcohol withdrawal.A paucity of critical care beds and ventilators meant that the medical staff were often reluctant to give therapeutic doses of diazepam, especially when patients with recovering organophosphorus poisoning commonly suffer sudden respiratory arrest due to neuromuscular junction failure (or intermediate syndrome).Another major problem was alcohol-induced cardiomyopathy; elderly patients who became atropine toxic with a fast heart rate were at major risk of tachydysrhythmias and cardiac arrest with poor outcome.This led us to advise aiming to keep the heart rate just greater than 80 beats/min to reduce the risk of inducing cardiac side effects of atropine [18].

Alcohol use disorder and social harms
One notable limitation of the existing literature is the lack of reporting and assessment of chronic alcohol use within the context of acute alcohol consumption and pesticide poisoning [4,12].In the few studies that reported on chronic alcohol use, alcohol dependence (as per DSM-IV or ICD-10) was common among poisoned patients [4], yet this was not addressed in studies looking at acute alcohol consumption.Accounting for chronic alcohol use, however, is important because tolerance impacts the clinical effects of alcohol and, as Dhanarisi and colleagues [12] noted, 'chronic exposure to alcohol, [is] a likely confounder in understanding the relationship between acute alcohol use and pesticide poisoning.' Our scoping review expanded the perspective by including qualitative studies on chronic alcohol use -highlighting how alcohol use (almost exclusively by men), and importantly, its impact on families, is an underlying factor in many cases of pesticide self-poisoning.This also includes acts of pesticide self-poisoning by family members of individuals with alcohol use disorder [4].The World Health Organization (WHO) has acknowledged the need to address harm to individuals other than the actual alcohol user, as noted in the Global strategy to reduce the harmful use of alcohol in 2010 [19].This has led to the development of the term 'alcohol's harm to others', which has been explored within different cultural contexts, including in work led by the WHO [20].
The harm alcohol poses to others includes pesticide selfpoisoning; however, this is under-researched [21].There is, therefore, a need for more research within communities where pesticide self-poisoning is an issue to explore the harm of alcohol to others through a public health framework to inform preventative actions.Especially, there is a need to understand how harmful alcohol use is rooted in much wider societal issues, acknowledging the need for a broad public health approach addressing socio-economic, community, and family factors, as well as factors specifically related to harmful alcohol use (such as availability, price, and treatment options) [22].

Outside influences
Beyond the need to explore ways of reducing harmful alcohol use in communities with easy access to toxic pesticides [4], we need to look past individual patients or communities.There are greater forces at play when toxic products like agrochemicals and alcohol are produced by industries with financial interests, sometimes organized as multinational corporations, particularly in low-and -middle-income countries [23,24].We recently highlighted the need for the suicide prevention research community to study how industries (for example, alcohol, pesticides, gambling, or firearms) influence suicide prevention agendas in the context of competing commercial interests and health outcomes [25].
For example, the pesticide industry and its international federations (CropLife and AgroCare) lobby international bodies and national regulators to influence policy and regulations aiming to reduce or prevent the use of pesticides [26].The outcome of individual acts of pesticide self-poisoning depends on the lethality of the pesticide purchased and ingested.The availability of lethal pesticides depends on national regulations, which are influenced by industry.Of note, multinational corporations based in Europe, where highly hazardous pesticides are highly restricted, continue to export their products to low-and middle-income countries [27], where pesticide self-poisoning is an identified public health issue causing way too many deaths.

Conclusion
In conclusion, while we have identified a gap in toxicological studies that can aid in understanding the toxic effects of coingestion of alcohol and pesticides, there is a need to also pay attention to the context in which this occurs.We cannot ignore that pesticide self-poisoning and harmful use of alcohol occur within the context of wider social and structural stressors and are influenced by commercial entities.