|Home | About | Journals | Submit | Contact Us | Français|
Some years ago, we explicitly stated what most clinical toxicologists already knew – that it was not possible to practice ‘evidence based medicine’ in clinical toxicology.(1) This was simply because there was next to no evidence: the published data on treatment included very few randomised 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)
We suggested that the 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.(2;3) There has subsequently been a major shift in the methods of evaluating evidence in the toxicology community.(4;5) However, we believe that too little evidence is still being generated where it is most required.
The World Health Organization (WHO) estimate that, of the 26 million deaths a year in the developing countries of SE Asia, China and the Western Pacific, 725,000 (2.8% of total) are due to ‘injury’ and 552,000 of these episodes are self-inflicted (i.e. suicides).(6)
Deliberate self-poisoning with pesticides is the commonest method of fatal self-harm in this region.(7-9) + Sri Lankan studies (see added refs)). A recent Chinese study suggested that 175,000 deaths from pesticide self-poisoning occur annually in that country alone.(10) 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.(6) A comparison of two WHO estimates suggests that the problem has nearly doubled in size over the last decade,(6;11) a conclusion supported by similar or larger trends in data from individual districts.(12;13)
Conservatively, half a million 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 drug self-poisoning was 15 years ago. Some new 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. 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 (15-18)) Systematic reviews suggest there is no good quality human evidence that any currently used antidote, other than atropine, is of benefit.(19-21)
The 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 years. 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.
We believe that clinical toxicologists in the developed world should set up collaborations with developing world colleagues to establish centres 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 centre does not exist anywhere.
The broad aims of such a centre would be:
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. 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 (20). 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 which has been a very successful policy mechanism promoting rational drug use).(22) 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 on 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. Yet they are probably managed sub-optimally 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 USA, Australia and the UK. 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 centre 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.