The Cot Report: One step forward, one step back

Reproduced with kind permission of the Department of Health, UK.

The Committee on Toxicity is the scientific working group which was set up by the government in 1998 'to advise on whether prolonged or repeated low level exposure to OPs, or acute exposure to OPs at a lower dose than causing frank [overt] intoxication, can cause chronic ill-health effects'.

COT has concluded that there is insufficient proof that long-term, low-dose exposure (sheep-dipping, for example) can do so. According to them, it is not proven that dipper's flu is caused by exposure to OPs. 

COT has recommended urgent research to find out whether low-dose exposure causes 'disabling neurological or neuropsychiatric disease in a small sub-group of exposed persons'. The forthcoming epidemiological study by Dr Tony Fletcher (London School of Hygiene and Tropical Medicine) et al, (in which members of PEX, OPIN and the Northern Ireland OP Sufferers' Association will have the opportunity to participate) will include people whose ill-health means they are no longer working.

For the studies reviewed by COT leave all these sufferers out. This is the most conspicuous omission in this report, essentially a literature review of 28 papers. Another crucial point is the distinction drawn by the COT Working Group between 'acute' exposure versus 'chronic' exposure, never adequately defined.

The most serious revelation is that data from the official government monitoring schemes, including the Suspected Adverse Reaction Surveillance Scheme (SARSS), run by the Veterinary Medicines Directorate (an executive agency of MAFF), the Health & Safety Executive's Pesticide Incidents Appraisal Panel (PIAP) reports, are not worth the paper they are written on. Voluntary schemes have collected more data, both quantititatively and qualitatively, than any statutory programme, evident in the following, from the section 'Chronic toxicity of OPs: the basis for concern':

"Data from submissions made by individuals and groups

Several individuals gave personal testimony of the illnesses they had suffered following exposure to OPs, and the Working Group were informed that data are held by two organisations, the OP Information Network (OPIN) and Pesticide Exposure Group of Sufferers (PEGS) which indicated that many other people exposed to OPs suffered from similar symptoms. Many such individuals claimed long-term illness as a result of exposure to OPs during sheep dipping or other agricultural activities. A list of symptoms and signs reported by individuals who believed that they had suffered from exposure to OPs is given below. In many cases these severely impaired important aspects of normal life.

[Listed alphabetically, not in any order of priority]: anxiety, confusion, depression (including suicidal thoughts in severe cases), headache, fatigue, impaired concentration, incoordination, increased sensitivity to repeated exposure to OPs, intolerance to alcohol and other chemicals, irritability, memory loss, muscular pains, muscular spasms, nausea, nightmares, numbness of the extremities, other psychiatric disorder, respiratory disease, sleep disorders.

In addition, there were frequent references to dipper's flu being a concomitant of dipping. It was clear from enquiries made by the Working Group that there is no generally agreed definition of what constitutes dipper's flu. It is a term that has been used in common parlance in the farming community since the early 1990s. It is used to describe 'flu-like' symptoms, including runny nose, headache, aching limbs and malaise occurring shortly after the time of dipping and persisting for up to 48 hours. The cause of dipper's flu is not known. It may be related to the anticholinesterase properties of OPs. However, there is an alternative hypothesis that it arises from exposure to endotoxins that accumulate in sheep dip. The Working Group concluded that the hypothesis that dipper's flu is a manifestation of OP toxicity is not proven. Research is needed both to characterize the nature of dipper's flu more fully and to identify the mechanism involved in its causation.

The nature of exposure to OPs recalled by individuals varied, some describing particular incidents of direct contact through handling the concentrated formulation, or through being splashed and soaked by the dipwash. Others referred simply to repeated exposure during regular cycles of dipping, notably when that process was compulsory. Some individuals pointed out that sheep continued to be handled from time to time during the months of dipping. There were varying accounts given in the submissions of the care taken with regard to the use of protective clothing and other protective measures (eg changing and washing of soaked clothing and washing of exposed skin) during the period when official guidance was firt being promulgated and then later strengthened. It was excessive exposure by those who later developed more severe symptoms. It was notable that, despite the large quantities of OPs used in arable farming, relatively few cases were brought to the attention of the Working Group of long-term adverse effects from the use of OPs in that sector of farming, or in horticulture.

Data from Adverse Reaction Schemes

The Working Group also sought any relevant data that were available from the schemes for reporting adverse reactions to pesticides and veterinary medicines. These are the HSE's Pesticides Incidents Appraisal Panel (PIAP) and the Veterinary Medicines Directorate's Human Suspected Adverse Reaction Scheme (SARSS).

In the case of PIAP, data from HSE's Pesticide Incidents Reports were available, referring to the period from 1989/1990 until 1996/97. These included information on the number of incidents assessed by PIAP when at least one of the active ingredients in the pesticide product was an OP. It was noted that PIAP only assessed cases that had been brought to the attention of HSE, and had subsequently been investigated by HSE, or by a total of 69 confirmed cases over the study period, but all related to acute effects and there were no cases of chronic toxicity recorded in this process. Therefore analysis of these data was not particularly helpful to the Working Group.

See Reporting Pesticide Exposure Indicents to the Health & Safety Executive - Does it Work?

In the case of veterinary medicines, data from the reports of the Appraisal Panel for SARSS were also considered. Six hundred and fifty one reports of suspected adverse reactions due to OP sheep dips have been received since 1985. Prior to 1991 the reports each year were relatively few (ranging from 5 to 19 each year) with the greatest number being in 1991, 1992 and 1993 (127, 129 and 180 reports respectively) and then falling to 17 reports in 1998. The number of cases by reported year of onset of the adverse reaction, which may differ from the year in which the reaction was reported [have been] compared with annual sales of OP sheep dips over the same time period. In contrast to reported pesticide incidents, a substantial proportion of reported reactions to OP sheep dips involved persistent symptoms. Symptoms noted in the chronic cases were headache, fatigue, tiredness, and in a number of instances, numbness or tingling of the extremities.

Following the recommendations from a review of the procedures for monitoring and investigating human suspected adverse reactions to veterinary reactions to veterinary medicines, the Appraisal panel no longer classifies individual cases according to likely causation. In the years up to 1997, after which this change in practice took place, the Appraisal Panel classified none of the chronic cases as showing strong evidence for an exposure to the cited sheep dip product.

Data from the National Poisons Information Service (NPIS)

In addition to considering information from the specific adverse reaction schemes relating to pesticides and veterinary medicines, the Working Group sought data from all the NPIS centres in the UK. The extent and format of the data varied from centre to centre. The emphasis of the Working Group was on incidents due to inhalation or dermal exposure rather than deliberate ingestion, because the main concern of the Working Group was with low-level exposure. Although there were a number of reports of such incidents, in nearly all cases the individuals were asymptomatic or suffered only mild, transient poisoning incidents and that follow-up data were available for only a few cases.

Data from the Medicines Control Agency (MCA)

It was noted that within the data held by the NPIS there were a number of reports of incidents relating to use of malathion in preparations to treat headlice, although in most cases these were due to accidental ingestion (100% of cases reported from one NPIS Centre involved ingestion); in all cases individuals were asymptomatic or suffered transient effects. These data were consistent with those provided by MCA from their yellow card adverse reaction reporting scheme for human medicines. The data related to the period January 1990 to September 1998. Only a small number of cases had been reported and there was no consistent pattern. The Working Group noted, however, that any delayed effects would be unlikely to be detected by this system, particularly for over-the-counter products such as shampoos for the treatment of headlice.

Conclusions

The substantial number of individuals with disabling illness that has been reported as following exposure to OPs is a major cause for concern. As a means of assessing the extent of the problem, the data considered from the various reporting schemes (PIAP, SARSS, MCA) and from the NPIS were of limited value to the Working Group. All of the long-term consequences of prolonged or repeated low-level exposure, particularly if the illness produced was not specific to OPs. It was not possible, therefore, to draw any conclusions from these schemes regarding the frequency of possible delayed (or chronic) effects.

It also became clear from individual submissions that there were barriers to full reporting, such as consequences for employment, the large numbers in self-employment, and a culture of stoicism among agricultural workers. These would all reduce the number of cases reported. In addition, there was no means of gauging the overlap between the official reporting data, the case reports collected by OPIN, and the case reports collected by PEGS.

The Working Group was thus faced with a major problem regarding the data available. The sufferers reported very real, and for both them and their families, distressing illness, often distinguished by unusual combinations of symptoms. For these people, the illness is palpable and because their symptoms have developed since exposure they believe the cause to be exposure to OPs. But few had long-term medical observations or results of tests to present with their accounts. Many individuals felt that their problems had been poorly recognised, inadequately monitored and investigated, and exacerbated by lack of appropriate medical advice. It was claimed that only one or two individual practitioners recognised and addressed their problems. It is to be hoped that the situation will be improved following the report of the Royal College of Physicians of London and the Royal College of Psychiatrists. This report, and the recommendations it contains on diagnosis and management of patients, were drawn to the attention of doctors by an article in CMO's Update [Chief Medical Officer], a quarterly publication sent to all doctors in England and CMOs in Wales, Scotland and Northern Ireland.

The consequence was that the Working Group was unable to draw on any substantial body of clinical data. The inquiry of the Working Group would have been helped greatly by a systematic description of the clinical features of a large case series, such as might have been provided by the clinical database proposed by the British Medical Association [13 January 1997]. The individual case reports were informative, but were inadequate to define the syndrome, if it existed.
[PEX emphasis]

OVERALL CONCLUSIONS

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.

In reviewing the scientific evidence the Working Group focused on five different health outcomes relating to the nervous system. These were: neuropsychological abnormalities, electroencephalography (EEG) abnormalities, peripheral neuropathy and neuromuscular dysfunctin, psychiatric illness and effects on the autonomic nervous system. Of these, the data on EEG abnormalites and effects on the autonomic nervous system were insufficient to allow any firm conclusions to be drawn. Conclusions regarding the other endpoints are given below.

Long-term sequelae [consequent disorder] of acute poisoning 

Neuropsychological outcomes
The balance of evidence supports the view that neuropsychological abnormalities can occur as a long-term complication of 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
Peripheral neuropathy, as one feature of OP-induced delayed neuropathy, is a well-established complication of poisoning of OPs that inhibit the enzyme NTE [neuropathy target esterase]. The neuropathy is predominantly motor but possibly also sensory. Compounds that produce more than 70% inhibition of NTE give positive results in the hen test. Compounds evaluated as giving a positive response in the hen test are not used in the UK and have not been approved or licensed by regulatory agencies.

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

Psychiatric illness
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

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 acute toxicity, is less convincing.

Neuropsychological outcome
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
The balance of evidence indicates that low-level of 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
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 to psychiatric illness to OPs is insufficient to allow useful conclusions.

Acute exposure to OPs at a lower dose than causes frank [overt] toxicity
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 of such exposure must be small.

Monitoring of human adverse effects
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."

Reproduced with kind permission of the Department of Health
Organophosphates, Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment, Department of Health, available free from The Department of Health, PO Box 777, London SE1 6XH Fax 01623 724 524 doh@prologistics.co.uk  Also available on the internet.

[Published in PEX Newsletter No.5, December 1999]