COT report on organophosphates (1999)

This report, drafted by the Working Group on Organophosphates, considers whether single, prolonged or repeated exposure to low doses of organophosphate compounds (OPs) can cause long-term adverse health effects.

Executive summary

1.1 This report of the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment considers whether single, prolonged or repeated exposure to low doses of organophosphate compounds (OPs) can cause long-term adverse health effects. Low doses were defined as those which do not produce overt acute (short-term) toxicity accompanied by recognised clinical symptoms or signs of acute toxicity. The report was drafted by a specially constituted Working Group of the Committee.

1.2 For practical reasons the Working Group concentrated on effects on human health suspected of being common to OPs in general (i.e. class effects) rather than considering compound-specific effects. In particular, they focused on neurotoxic effects. Most of the relevant scientific evidence concerned possible neurological, psychological or psychiatric effects and these were the types of illness most frequently attributed to OP exposure by those who made submissions to the Working Group. The composition of the Working Group reflected the need for a detailed investigation of this subject and the Working Group sought expert advice on psychiatric issues.

1.3 The Working Group held a total of fourteen meetings between May 1998 and September 1999 and a draft report was submitted to the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment for endorsement in October 1999. Details of the background to the establishment of the Working Group and its methods of working are given in Chapter 2 of the report.

1.4 Chapter 3 describes the nature of OPs, their chemical structures and biological properties. For the purpose of their deliberations, the Working Group defined OPs as organophosphorus compounds that inhibit the enzyme acetylcholinesterase. Their mode of action as inhibitors of this enzyme is described and consideration is then given to the various uses of OPs as pesticides and veterinary medicines, the co-formulants used in such products, and the regulatory process for approval and licensing these products in the United Kingdom.

1.5 Chapter 4 summarises the various ways in which individuals may be exposed to OPs. These include exposure to trace amounts in food and water, through the use of household or garden insecticides, and in the treatment of headlice. Consideration is also given to occupational exposure such as that during orchard spraying and, in particular, sheep dipping. The fate of OPs in the body is described, with sections on their absorption, metabolism and excretion.

1.6 The toxicology of OPs and the mechanisms involved in their acute cholinergic effects and in the induction of delayed polyneuropathy are considered in Chapter 5. The value of the hen test for screening compounds that induce delayed polyneuropathy is discussed. This chapter also examines the scope for potentiation of toxic effects through concomitant exposure to other compounds and individual variations in susceptibility to the effects of OPs.

1.7 The report then considers the sources of data that were relevant to the Working Group's remit. In Chapter 6 information provided by individuals in personal testimony, and relating to data held by the OP Information Network and the Pesticide Exposure Group of Sufferers, is described. Many individuals reported long-term illness, often severely impairing normal life, which they believed to be caused by exposure to OPs. Data available from adverse reaction schemes (the Health and Safety Executive's Pesticides Incidents Appraisal Panel; the Veterinary Medicines Directorate's Suspected Adverse Reaction Surveillance Scheme; the Medicines Control Agency's Yellow Card Scheme) and data from the National Poisons Information Service were also considered. However, these were found to be of very limited value in relation to the remit of the Working Group. The consequence was that the Working Group were unable to draw on any substantial body of clinical data. The Working Group were thus faced with a major problem. Although many of the individuals who submitted evidence reported very real, distressing illness, often distinguished by unusual combinations of symptoms, few could provide long-term medical observations or supporting clinical data. Many felt that their problems had been inadequately monitored and investigated. Individual case reports were informative but could not be used to make any assessment of cause and effect.

1.8 Chapter 7 consists of a review of the scientific evidence, largely derived from published scientific papers, describing epidemiological studies that were relevant to the deliberations of the Working Group. The Working Group identified 27 reports of such studies as being the most informative with regard to the potential toxicity of low-level exposure to OPs. These are summarised in detail in Appendix 4, with the Working Group's critique of each. Some of them concern the late sequelae of acute poisoning episodes rather than low-level exposure as defined by the Working Group. These were relevant because any chronic health effects that could be shown to result from acute poisoning might also occur with lower exposures and thus would merit special attention. The Working Group also considered the full report of a major study by the Institute of Occupational Medicine published in July 1999. In view of the importance of this study, which investigated an occupational group of particular concern, namely sheep dippers in Britain, it is summarised in detail in Appendix 5 together with a critique by the Working Group.

1.9 The review in Chapter 7 is divided into five sections covering different types of health outcome relating to the nervous system, namely: neuropsychological abnormalities, electroencephalographic abnormalities, peripheral neuropathy and neuromuscular dysfunction, psychiatric illness, and effects on the autonomic nervous system. Within each section consideration is first given to long-term effects following acute OP poisoning. This is followed by consideration of the effects of exposure to OPs in the absence of any recognised acute poisoning episode. It was, in the main, the Working Group's analysis of these studies that underlay the conclusions set out in Chapter 8.

Conclusions

1.10 Chapter 8 gives the Working Group's considered response to the question posed in their remit, namely to advise on whether prolonged or repeated low-level exposure to OPs, or acute exposure at a dose level lower than that causing overt toxicity, can cause chronic ill health. As noted earlier, the Working Group considered not only the evidence relating to low-dose exposures (i.e. those insufficient to cause overt toxicity) but also studies on the long-term sequelae of recognised acute poisoning episodes. The rationale for this is described in paragraph 1.8.

1.11 Although it has been proposed that dipper's flu is a manifestation of acute OP toxicity, the Working Group concluded that this is unproven. Thus, for the purpose of this report it was not regarded as an indicator of acute OP toxicity.

1.12 In reviewing the scientific evidence the Working Group focused on the five different health outcomes relating to the nervous system that are listed in paragraph 1.9. Of these, the data on EEG abnormalities and effects on the autonomic nervous system were insufficient to allow any firm conclusions to be drawn. The conclusions, which are those of the Committee, regarding the other endpoints are given below.

Long-term sequelae of acute poisoning

Neuropsychological outcomes
1.13 The balance of evidence supports the view that neuropsychological abnormalities can occur as a long-term complication of acute OP poisoning, particularly if the poisoning is severe. Such abnormalities have been most evident in neuropsychological tests involving sustained attention and speeded flexible cognitive processing ("mental agility"). In contrast, current evidence suggests that long-term memory is not affected after acute poisoning.

Peripheral neuropathy
1.14 Peripheral neuropathy, as one feature of OP-induced delayed polyneuropathy, is a well-established complication of poisoning by OPs that inhibit the enzyme neuropathy target esterase. The neuropathy is predominantly motor but possibly also sensory. Compounds that produce more than 70% inhibition of neuropathy target esterase give positive results in the hen test. Compounds evaluated as giving a positive response in the hen test are not used in the United Kingdom and have not been approved or licensed by regulatory agencies (i.e. the Veterinary Medicines Directorate or the Pesticides Safety Directorate).

1.15 The balance of evidence indicates that acute poisoning by other OPs, which do not inhibit neuropathy target esterase, can also lead to persistent peripheral neuropathy detectable by neurophysiological tests. If this occurs, most cases are not at a level that would give rise to symptoms.

Psychiatric illness
1.16 The limited evidence available does not allow any firm conclusions to be drawn regarding the risk of developing psychiatric illness in the long term as a consequence of acute poisoning by OPs.

Prolonged low-level exposure

1.17 In comparison with the positive neurological and neuropsychological findings following recognised poisoning incidents, the evidence relating to chronic low-level exposure to OPs, insufficient to cause overt acute toxicity, is less convincing.

Neuropsychological outcomes
1.18 Although some studies suggest impairment in the same tests that are affected after acute poisoning, others do not. The balance of evidence does not support the existence of clinically significant effects on performance in neuropsychological tests from low-level exposures to OPs. If such effects do occur, they must either be relatively uncommon or so small that they are not consistently detectable by standard methods of testing.

Peripheral neuropathy
1.19 The balance of evidence indicates that low-level exposure to OPs does not cause peripheral neuropathy. If effects on peripheral nerve function sufficient to cause severe disability do occur, they must be rare.

Psychiatric illness
1.20 The available data indicate that exposure to OP sheep dips is not a major factor in the excess mortality from suicide among British farmers. However, in general, the evidence relating psychiatric illness to OPs is insufficient to allow useful conclusions.

Acute exposure to OPs at a lower dose than causes frank toxicity

1.21 No studies have examined the long-term effects of a single exposure to OPs insufficient to cause acute toxicity. However, the findings in individuals with prolonged and repeated low-dose exposures, and in those who have suffered recognised acute poisoning, together indicate that any risk of serious health effects from such limited exposure must be small.

Questions posed to the Working Group by the Official Group on OPs

1.22 In addition to addressing the central question stated in the remit of the Working Group, consideration was given to the specific questions (listed in Appendix 2) posed to the Working Group by the Official Group on OPs. These were modified for clarity and as a result of the evolution of the thinking of the Group over time. Answers to these questions, as modified, are given in Appendix 3.

Monitoring of human adverse effects

1.23 It was a matter of particular concern to some members of the Working Group that the present schemes for monitoring human adverse effects had yielded so few relevant data and that little progress had been made in establishing a relevant clinical database.

Outstanding issues

1.24 In addition to drawing the above conclusions the Working Group identified outstanding issues, which need to be addressed by further research.

1.25 The major gap in current knowledge relates to the possibility that OPs cause disabling neurological or neuropsychiatric disease in a small sub-group of exposed persons. Most research has focused on people who were in work at the time of investigation, and therefore by definition were sufficiently fit for employment. Moreover, the available published studies have generally been designed to look for effects on the mean level of quantitative health indices in the exposed population, rather than exploring the possibility that only a small proportion of subjects may be at increased risk of clinically significant disease. Thus, although the substantial body of evidence that has now accumulated gives little support to the hypothesis that low-level exposure to OPs can cause chronic disease of the nervous system, it does not exclude the possibility that at least some of the illnesses that were described to the Working Group as following such exposure are indeed a manifestation of toxicity.

1.26 Further investigation, using suitably designed studies, is needed to establish whether the risk of more severe neurological or neuropsychiatric disease is increased by low-level exposure to OPs.

1.27 In view of the widespread public concern about OPs, evident from the response to the Working Group's inquiry, there is an urgent need for further research targeted at the issues set out above.

Recommendations for further research

1.28 The Working Group recommended further research to address the outstanding issues. These were grouped around the following questions, the answers to which would help to clarify the remaining uncertainties:

  • What are the most common patterns of exposure, clinical presentation and subsequent clinical course among people in the United Kingdom with chronic illnesses that they attribute to OPs?
  • How common is dipper's flu, and what causes it?
  • Does low-level exposure to OPs cause disabling neurological or psychiatric disease in a small subgroup of exposed persons?
  • Do people with chronic disabling illness that is suspected of being related to OPs differ metabolically from the general population?
  • Other than acetylcholinesterase inhibition, what mechanisms play an important role in the causation of adverse health effects by OPs?