There is no dispute about the ability of organophosphorus pesticides to produce acute toxic effects. Thus concern about reports that in the UK healthy people were being paid to ingest these compounds in tests to find out safe doses was understandable. One story was of studies of dichlorvos conducted by Medeval in Manchester for Amval Chemical Corporation in California. Dichlorvos is a pesticide used domestically, agriculturally, and industrially. The other instance was of a study being conducted by Inveresk Research in Edinburgh for the French firm Rhône-Poulenc Rorer. Here the invitation to participate in the study explains that “the aim of the study is to assess how well tolerated a pesticide called Azinphos Methyl is in humans and to determine a dose at which no side effects are observed”. Azinphos methyl is one of the most toxic of the organophosphorus insecticides and is registered in some countries for agricultural use.
The speculation, backed by a statement from the US Environmental Protection Agency in response to the revelation by an environmental pressure group about dichlorvos, was that the reason for the collection of human data was to lower the safety threshold specified by US regulators. The USA will accept as safe a dose that is only one-tenth of that deemed harmless for animals.
But could there be another reason for these studies in human beings? Medeval was making no further comment. Inveresk issued a statement carrying no reference to pesticides but saying that it conducts trials “as part of the development of potential new products, particularly medicines”. Organophosphorus agents are cholinesterase inhibitors—a class of drugs attracting much interest as potential therapy for Alzheimer's disease. Organophosphorous compounds have already been used therapeutically in human beings. Metrifonate, for instance, has been used for the treatment of schistosomiasis. The active component is its metabolite dichlorvos. Metrifonate is now undergoing phase III trials for the treatment of primary degenerative dementia.
The search for much-needed medicines is a valid reason for re-examining some of these compounds.
In the decision on the acceptability of the risk/benefit of undertaking such studies, the welfare of the participants must be paramount. Drug companies could do much to allay fear and to boost confidence in the safety of their studies by being more open about the reasons for their studies, the doses given, the information on risk given to participants, and the composition of the ethics review committees. Nevertheless, commercial pressures are such that regulatory authorities must always keep a watchful eye for ploys to weaken safety standards.
However, the difficult issue about the safety of organophosphorus agents is not acute safety but whether chronic low-dose exposure to organophosphorus compounds causes neuropsychiatric disease without producing acute cholinergic symptoms. In the further investigation of this question, direct challenge, especially of healthy people is unjustifiable in view of the uncertainty about the irreversibility of the putative effects of long-term exposure, and impracticable anyway. The bulk of the investigation will still have to be based on study of people who have been unintentionally exposed, but with attention to correction of factors that have made interpretation of completed studies difficult—eg, sampling, confounding, quantification of dose exposure, and verification that the psychological tests used are valid for toxicity studies.
An evaluation of this issue, by the Medical Research Council's Institute for Environment and Health, was published last month. Another review, limited to sheep dip, is due next month from a joint Royal College of Physicians and Royal College of Psychiatrists working party set up to hear evidence from patients, their representatives, and experts, but controversy about the membership of the working party and the closed nature of the hearings and refusals to give evidence for this reasons might cast doubt over the completeness and strength of the report. It would be a pity if resolution of this occupational health matter ended up with judicial rather than with medical assessment.