Where Is the Evidence for Treatments Used in Pesticide Poisoning? Is Clinical Toxicology Fiddling While the Developing World Burns?

Keywords :

• Poisoning
• Pesticide
• Evidence‐based medicine
• Developing countries

In 1996 an editorial explicitly stated what most clinical toxicologists already knew—that it was not possible to practice ‘evidence based medicine’ in clinical toxicology 1. This was because there was little evidence: the published data on treatment included very few randomized clinical trials (RCTs) addressing clinical end‐points, observational studies of clinical features were lacking in both quantity and quality, and diagnostic and prognostic tests were not prospectively validated. As a result, knowledge and management of many forms of poisoning was based largely on case reports, and clinicians relied on textbooks of expert opinion for guidance 1. There has subsequently been a major shift in the methods of evaluating evidence in the toxicology community 2&3.

A suggested solution was to collect prospective data and to apply the tools of clinical epidemiology to better describe the natural history of poisonings, identify high‐risk individuals, and determine the effects of treatment and the relative toxicity of drugs within therapeutic classes 4&5. However, most of these techniques are being applied for compounds of relatively low intrinsic toxicity being taken in resource rich environments. We believe that too little evidence is still being generated where it is most required.

The World Health Organization (WHO) estimates that, of the 26 million deaths a year in the developing countries of SE Asia, China, and the Western Pacific, 725,000 (2.8%) are due to injury and 552,000 of these episodes are self‐inflicted (suicides) 6.

Deliberate self‐poisoning with pesticides is the commonest method of fatal self‐harm in this region 7-9. Recent Chinese studies suggest that 175,000 deaths from pesticide self‐poisoning occur annually in that country alone 710. Assuming this data to be representative of the whole region, around 300,000 deaths from self‐poisoning with pesticides are occurring each year in SE Asia and the Western Pacific. In addition, a further 160,000 people are dying from unintentional poisoning from chemicals 6. A comparison of two WHO estimates suggests that the problem has nearly doubled in size over the last decade 611, a conclusion supported by similar or larger trends in data from individual districts 12&13. The burden of illness from pesticide poisoning is less well documented in the developing countries of Africa and South America. However from the limited data available, it is still many‐fold greater than that in the developed world 614.

Conservatively, 300–400,000 people are dying of pesticide poisoning each year in Asia and the Western Pacific. Most deaths are due to organophosphorus (OP) pesticides; other significant pesticides include paraquat and aluminium phosphide 14. While primary prevention has great potential in the long run to reduce the number of deaths, improving medical management will also reduce the death rate and probably do it much faster.

Current protocols for the management of pesticide poisoning are based on little evidence and are difficult to deliver in the resource‐poor settings in which most poisonings occur. Evidence for pesticide poisoning is at the stage that drug self‐poisoning was 15 yrs ago. Many newer pesticides have no human toxicity data at all. Even for older pesticides, there is little evidence, no systematic data collection, and low appreciation by both clinicians and textbook authors of the usefulness of clinical epidemiology research as a tool for improving the situation. The relevance of easily gathered data, such as particular agent, dose, formulation and route of exposure, initial clinical signs, symptoms and investigations, age, race and nutrition, to the course and outcome of most poisonings are often unknown. Paraquat is probably the most studied pesticide in this regard. Yet while it is clear that many of the factors outlined here are important to prognosis, the literature to support this consists mostly of small studies of selected patients with incomplete data and poorly defined associations 15.

For treatments of pesticide poisoning, there are large numbers of animal studies but few well‐conducted human studies, and even fewer RCTs [the RCTs that have been done have all been small 16-19]. Systematic reviews suggest there is no good quality human evidence that any currently used antidote, other than atropine, is of benefit 1520&21.

The need and potential for clinical research is enormous. Just for OPs, there are dozens of potential antidotes with many different mechanisms, which moreover have often shown synergistic benefit in animal models. New agents have been developed by the military and the pharmaceutical industry, and yet all have failed to progress to clinical trials. No new OP antidotes have been marketed in the last 30 yrs. Although large amounts of money are spent on antidote drug development in Western laboratories, no funding is going to conduct clinical trials.

The millions of pesticide poisonings occurring in the developing world each year offer immense opportunities for clinical research. The benefits will be shared between the people of the developed and developing worlds alike.

The logical way forward is for developed world clinical toxicologists to collaborate with developing world colleagues in establishing centers of excellence in clinical toxicology research. Combining developed world laboratory resources and expertise in research methodology with developing world clinical experience of pesticide poisoning could answer many questions rapidly. At present, such a center does not exist anywhere.

The broad aims of such a centre would be

• To expand the evidence base in clinical toxicology of pesticides and management of deliberate self harm

• To develop methods that ensure that this evidence moves rapidly into clinical practice

• To explore models for prevention of poisoning, including pesticide regulation

• To provide descriptive human toxicology data for different pesticides to allow comparisons of human toxicity

• To support and provide training in clinical management and research

The most important and direct outcome of such collaborations will be a reduction in the number of people dying from pesticide poisoning in developing countries. The reasons for the extremely high number of deaths in the developing world are not well studied but are almost certainly multifactorial. The most important are likely to include the wide availability of toxic pesticides, the lack of effective antidotes for many pesticides, and, in many areas, a shortage of resources or training. By tackling the problem on a number of synergistic fronts (antidote development, research into relative toxicity, preventive strategies, and improved delivery of evidence‐based clinical care), the number of deaths could be more than halved.

Pesticide regulation is an area where the developed world may stand to benefit greatly from research in developing countries. Most toxicological evaluation of safe exposure levels relies largely or solely on extrapolation from animal data. Human clinical and toxicokinetic data would determine if the assumptions used in these extrapolations are warranted and may also identify toxic effects that are specific to humans.

Furthermore, the WHO has recommended that access to highly toxic pesticides be globally restricted. The few studies performed have shown that where this has been done for specific poisons, suicide rates have fallen 22. We have suggested that one means of achieving this is to have a WHO and FAO‐endorsed Minimum Pesticides List (analogous to the WHO Essential Drugs List that has been a very successful policy mechanism promoting rational drug use) 23. Such a list would lead to an easily adopted strategy to assess all pesticides on the basis of indications, human and environmental toxicity, and cost. However, to convince all governments of the benefits will require much firmer evidence of the health outcomes that can be expected from regulatory approaches.

Although pesticide poisoning is relatively uncommon in the developed world, it remains an important clinical problem for two reasons. First, it is one of the more common causes of in‐hospital death from poisoning. Each patient uses up a great deal of resources, often spending weeks in intensive care. Many are left with long‐term disabilities. Despite the much better resources available in the west, the case‐fatality ratios for pesticide poisoning are similar to those reported from the developing world 16&1724&25. Perhaps they are managed suboptimally due to lack of good clinical data on treatment and prognosis.

Second, throughout the world there is a growing concern about chemical weapons. The most commonly used weapons in recent years have been nerve agents, which are in essence OPs with relatively higher mammalian toxicity. The neurotoxicological complications reported in animals and the antidotes proposed are the same as those used for the pesticides. The antidotes were used in the Tokyo subway incident, were given to troops in the 1991 Gulf War, and are now being purchased in very large quantities and stockpiled at great expense by many countries including the United States, Australia, and the United Kingdom. It is not known whether these antidotes are the most effective way of treating anticholinesterase poisoning or indeed if they are effective at all.

Animal studies suggest a large number of promising antidotes for OPs, paraquat, and other pesticides that deserve further evaluation. The establishment of a center that develops a track record of doing clinical trials of OP antidotes to a high standard may well serve to overcome the drug‐development impasse.

The developed world has a great deal to gain from more effective, safer, cheaper, and more easily administered antidotes to deal with mass casualty situations resulting from terrorist use of OP nerve agents. Conditions in terms of resources and manpower in the case of such an event are likely to be similar to those that prevail in rural hospitals in the developing world. Both humanitarian concern and self‐interest suggest we should make a concerted effort to improve these conditions.

The in‐hospital case fatality rate in developing world poisonings is 10–20% or more, while in the developed world it is well under 0.5%. Clinical toxicologists aiming to make a real impact should put their efforts where they will make the most difference.

Acknowledgments

The SACTRC research program is primarily supported by two large grants: A Wellcome Trust/National Health and Medical Research Council (NHMRC) International Collaborative Research Grant GR071669MA and grant GR063560MA from the Wellcome Trust's Tropical Interest Group to Michael Eddleston.