The Government’s Scientific Workshop On Research On OPs, 28 March 2000

The purpose of the Workshop was to consider the recommendations made in the November 99 report Organophosphates by the government’s Committee on Toxicity, and to discuss OP-related research from a wide range of interests, before deciding on overall research priorities. The COT report, which did not include any clinical examinations, concluded that ill-health due to long-term, low-dose exposure to OPs ‘must be rare’, although they acknowledge that cases held by PEX and the OP Information Network should be studied.

Chaired by Professor Anthony Newman-Taylor, the meeting accepted the COT recommendations for research:

  1. What are the most common patterns of exposure, clinical presentation and subsequent clinical course among people in the UK with chronic illnesses that they attribute to OPs?

  2. How common is dipper’s flu and what causes it?

  3. Does low-level exposure to OPs cause disabling neurological or psychiatric disease in a small sub-group of exposed persons?

  4. Do people with chronic disabling illness that is suspected of being related to OPs differ metabolically from the general population?

  5. Other then acetylcholinesterase inhibition, what mechanisms play an important role in the causation of adverse health effects by OPs?

Presentations of research:

An epidemiological study of exposure to organophosphate pesticides and neuropathy among UK sheep dippers

Adele Pilkington presented the Institute of Occupational Medicine, Edinburgh, 1999 study, which concluded that up to a fifth of sheep-dippers could suffer some degree of neurological damage after chronic exposure to OP sheep-dip, see Pesticides News 45.

The findings suggest an association between exposure to OPs, predominantly the concentrate, and sensory neurological symptoms, and to a lesser extent, sensory thresholds .This suggests that long term health effects may occur in at least some sheep dippers exposed to OPs over a working life and is consistent with results from earlier studies.

SCOPE Study into genetic variation in susceptibility to the chronic effects of OPs

Professor Nicola Cherry described the current study funded by HSE. This addresses key points:

Survey of health complaints among sheep dippers registered with sufferers’ support groups

Dr Tony Fletcher, of the Environmental Epidemiology Unit, London School of Hygiene & Tropical Medicine described the forthcoming study.

Substantial numbers of individuals with a history of repeated exposure to organophosphates used in sheep dipping, have complained of a variety of symptoms, above all neurological and neuro-psychiatric. They attribute these to their organophosphate exposure and have sought or are seeking, treatment, recognition and in some cases financial compensation for their illness. Some of them are sufficiently disabled to be unable to work. Many report frustration at the scepticism that they face, including from medical professionals, that their conditions are indeed attributable to their exposure to sheep dip chemicals.

A number of support organisations have sprung up who provide information and moral support to these sufferers, in particular OPIN, PEGS/PEX and NIOPSA (respectively the Organophosphate Pesticide Information Network, PEX Action on Pesticide Exposure, and the Northern Ireland Organophosphorous Sufferers’ Association).

Members of and subscribers to these three organisations with symptoms and OP exposure add up to approximately 1000 individuals across the UK. It is likely that individuals who have left sheep farming through ill-health and are included among these 1000, would not be picked up by cross-sectional studies of farmers such as those recently published. These registers, therefore, offer a unique route to assembling information on this potentially sizeable population. However, systematic data are not available across these populations, and so we were asked by them to design and carry out a systematic survey of these sufferers, so the scope of the potential health burden could be assessed.

This project is proposed as a collaborative exercise between London School of Hygiene and Tropical Medicine and the Institute of Occupational Medicine, and funding is being discussed with MAFF. It is proposed to undertake an interview-based survey of all the individuals in these registers, with detailed clinical examination of a sample of them to validate their answers. This latter group will be provided with a detailed diagnostic report as well as advice on treatment. As this population is self-selected, and there is no control group, it will be impossible to establish the cause of their conditions on an individual basis to the survey participants. However it was judged to be of value to gain an overview of the consistency and coherence (or not) of the patterns of exposure and symptomatology.

Once the population is surveyed and described it may well be that useful nested studies will be identified. This and other aspects of the project will be overseen by an Advisory Group including representatives of the government departments, support organisations and scientific advisers. It is expected that the main outcome will be a description of the patterns of reported ill-health and exposure history, and their inter-relationships, from which the size of the health burden which might conceivably be attributed to OPs in this population, can be given.  

The first phase of Dr Tony Fletcher’s two-year project, which may take some months, will be a telephone survey, allowing members a choice as to whether or not to participate. All information collected will be held by the study team on a strictly confidential basis. The Project Advisory Panel will include representatives from the support groups.
Progress reports on the study will be included in future PEX newsletters.

Non-cholinergic neurotoxicity induced by organophosphates: elucidation of molecular targets and mechanisms

Paul Glynn, of the Medical Research Council Toxicology Unit, University of Leicester, described this research.

Recently we have begun to identify brain proteins more sensitive to commonly-used OPs than acetylcholinesterase itself: one of these is an enzyme involved in peptide metabolism. The basic methodology in this new project, using a proteomic approach, is anupdated version of that used by our laboratory to identify Neuropathy Target Esterase (NTE), the target for OP-induced neuropathy. By cloning the NTE gene we have gained insights into the structure of this unusual protein and into the molecular consequences of its reaction with neuropathic OPs.

Studies with NTE transgenic mice are allowing an assessment of the possibility that the mechanism of OP-induced neuropathy involves not simply an inhibition of NTE’s enzyme activity, but instead a toxic gain of function in the protein. Increased mechanistic understanding is vital for hazard assessment and prediction of health risks in humans, and to provide epidemiologists with more specific indices of effect.

Use of biomarkers of exposure and effect to define exposure to organophosphates in the workplace and potential toxic effect

Richard Glass and Faith Williams described this joint project between MAFF’S Central Science Laboratory and the Neurotoxicology Unit, Newcastle University.

There is currently limited information relating exposure history to biomarkers of internal exposure, or to biomarkers of effect other than acetylcholinesterase inhibition, which is generally low and recovers soon after exposure. There is a requirement for a more sensitive biomarker of effect.

The study aims to describe: worker exposure; internal dose profile; biomarkers of effect; genotyping and phenotyping of individuals; markers of effects on neurotransmission. Parallel approaches to define organophosphate effects in man and to describe the mechanism of organophosphate toxicity that Newcastle University would propose include determining: the site and mechanism of the increase in EPP jitter in the mouse; to establish if there is any histological evidence in the mouse of nerve damage in the brain, spinal cord or peripheral axons after repeated low-level dosing with OPs; to determine the effects of repeated low-level dosing with OPs on the neuromuscular function in the mouse.

Our approach would be to genotype and phenotype a group of over 60 individuals who have been referred to Professor Peter Blain reporting adverse effects following chronic exposure to organophosphates, and compare to the control population.

Clinical experience (Professor Blain’s) of over 60 patients, referred for an expert medical opinion has failed to identify a specific set of symptoms and signs that could define a syndrome. The clinical features in these patients are not consistent nor is the causative agent easily determined, although organophosphates in sheep dips are most commonly implicated. Clinical investigation of these cases is difficult without a clear case definition or a diagnostic marker, and in most cases there are poor historical data on exposure. The aim of this study would be to compare a series of specific variables in this group of patients with a comparable control group.

Possible effects on children of exposure to OPs, either parental or direct

Elizabeth Sigmund described the following concern. In September 1998, members of OPIN, accompanied by Dr Vyvyan Howard of the Foetal and Infant ToxicoPathology Unit, Liverpool University, presented evidence to members of the HSE in London, relating to twenty two cases of severe cognitive impairment among children of families with direct occupational exposure to OP sheep dips. In each case one or other parent has been personally affected.

Members of HSE present were: Dr Stuart Smith, Senior doctor in the Health Policy Directorate of HSE; Glynn Jones, of the Health Policy Directorate; Julia O’Hara, head of Human Health Effects Section, of the HSE Pesticide Registration Section, Bootle. Also present for part of the meeting was Margaret Clare, the newly-appointed Head of Physical and Biological Agents Division of HSE Health Policy Directorate.

On October 9 1998 Dr Stuart Smith wrote to OPIN, saying that the points made at the September meeting were ‘weighty’, and that the HSE members present ‘will need to put the argument more formally to our scientific advisers, both Governmental and independent, before deciding what to do’, he said that they had found themselves ‘handicapped by our need to rely on our unaided recollection of what was said’.

What follows is a list of questions which would be the suitable basis for a formal scientific enquiry ie:

Dr Howard forwarded several scientific papers to Dr Smith, but no further action was taken.

All the reports received by OPIN show strikingly similar symptoms - ie cognitive impairment involving short term memory loss, language deficits, sequencing, both of numbers and letters, and lack of the ability to order information - all leading in the older child to lack of confidence and self esteem, which causes outbreaks of depression and anger.

Two young children from Cornwall have been seen by a leading London-based paediatric neurologist, who gave a written report which confirmed that both children were suffering severe neurological imbalances, but owing to the consultant knowing nothing about the possible effects of OP exposure he could not comment on the possibility that exposure to OPs might have contributed to their condition. He recommended genetic investigation, which after a three year waiting time, has not yet transpired.

None of the Government funded studies undertaken in Britain have ever considered possible damage to children, despite OPIN’s appeal to the HSE, and to the COT committee in 1998.

Early brain injury – potential risks from organophosphate compounds

David Johnson, Consultant Paediatric Neropsychologist and Julia Clarke, Consultant Clinical Neuropsychologist, submitted the following after the Workshop.

There is increasing concern that OP compounds may caused impaired neurological functioning in adults.

The foetal brain is uniquely sensitive to toxic insult by a number of mechanisms. It is particularly vulnerable because of its physiological immaturity and placental dependency. Toxic insult may occur in acute or chronic form by placental-foetal exchange, storage into fat or amniotic fluid, or immature metabolism. The effects of toxins may be transmitted via parental sperm, creating the earliest stage of insult to the foetus. Toxic substances may continue to adversely affect the child after birth, via breast transmission.

There is an urgent need for scientific investigation in this field. Neuro-developmental delays and deficits may result from underlying anomalous or absent growth. The full effects may not be seen until maturity, in the late teenage years, when the critical periods for cognitive and behavioural development have passed. There is no reasonable basis for a policy of wait and see.

Occupational Organophosphate Insecticide Exposure and Reduced Proximal Femur Bone Density

Dr Stephen Hodges’ work has been  published in The Lancet (Vol. 354 pp1791 – 1792 [1999]) and described in PEX Newsletter 4.

Autonomic features of chronic exposure to the organophosphates in sheep-dip

Dr Peter Julu and Dr Goran Jamal, of the Peripheral Nerve and Autonomic Unit, Imperial College of Science, Technology and Medicine, Department of Neurology, Central Middlesex Hospital, and the Department of Clinical Physics, Institute of Neurological Sciences, Southern General Hospital, Glasgow, presented their work. Since the Workshop, they have examined further patients using their Autonomic Function Test, and now confirm that a ‘fingerprint’ of OP damage in patients is identifiable.

We investigated 40 patients who developed chronic neurological dysfunction following clear histories of several episodes of mild to moderate acute organophosphate poisoning. Extensive failure of the cutaneous thermoregulatory vasomotor function was found in 38 patients (95%), but emotional sudomotor function was absent in only 11 patients (27%). There was failure of the cardioaccelerator function in 28 patients (70%), failure of the sympathetic control of blood vessels in the skeletal muscles was found in 18 patients (46%). Twenty patients (50%), some with clear history of oral ingestion of  organophosphates had failure of the sympathetic control of the splanchnic vascular bed. We saw disturbances of the baroreflex function in 33 patients (83%). Nearly all patients in this group had lower than normal resting cardiac vagal tones. Despite the sympathetic failures, there was either none, or very mild postural hypotension in these patients, contrary to this being the common effect of other causes of autonomic failure like diabetes mellitus and pure idiopathic autonomic failure.

Our findings support existing evidence that long-term neurological sequelae follows acute organophosphate intoxication and repetitive low level exposure to these compounds. Autonomic target-organs in the skin, large blood vessels and the heart including central parasympathetic functions are most affected. This pattern of autonomic lesions is unique to chronic organophosphate poisoning and could be diagnostic of the condition. This is the first detailed study of autonomic dysfunction in the neurological disorders associated with organophosphate exposure to our knowledge.

Neuropsychological sequelae of organophosphate poisoning

Sarah MacKenzie-Ross, of the Department of Clinical Health Psychology, University College London, described her investigations into cognitive impairment caused by exposure to OPs.

Through the course of clinical work, in-depth psychometric testing on a small number of farmers with a history of exposure to organophosphates (and ‘dippers flu’) have been carried out. These farmers show evidence of significant mental and motor slowing, impaired memory, executive dysfunction and emotional changes (anxiety and depression). Further studies are needed to determine the mechanism of damage; and whether these farmers are particularly vulnerable to the effects of organophosphates (and if so, why ?).

She described the limitations of earlier studies. The majority of studies have examined individuals with a history of acute poisoning. Less is known about the effects of long-term low level exposure. Agreement about the nature of ‘dippers flu’ is lacking, so it is difficult to know whether it represents acute mild poisoning. If it does then individuals with and without a history of ‘dippers flu’ should be examined separately.

Points from plenary discussions

In discussion on the meaning of low-level exposure, it was noted that COT had defined ‘low doses’ as doses lower than those causing overt acute toxicity (i.e. symptoms and signs of acute toxicity). However, this raised the question of whether exposure not sufficient to cause cholinergic symptoms should be regarded as low level. In examining the literature it was necessary to establish whether a history of cholinergic episodes was or was not relevant to case studies. It was agreed that there could be a sub-set among those reporting chronic symptoms who had experienced cholinergic symptoms which had not been ‘recognised’ at the time of the acute event. Such a sub-set would need to be distinguished in any further research for those who had not displayed any signs or symptoms of acute toxicity.

The issue of whether there was a sub-group who were particularly susceptible to OPs was linked to the issue of multiple chemical sensitivity. A possible correlation between sensitisation to very low doses of OPs and the symptoms of chronic fatigue syndrome had been suggested. In this context it was explained that sensitisation was a reaction to serial exposures to very small doses or an ‘acquired intolerance’.

The meeting noted that COT had concluded that the proposal that dippers’ flu is a manifestation of acute OP toxicity remained unproven. The Committee had not, therefore, regarded it as an indicator of acute OP toxicity. The meeting agreed that it would be important for further research into dippers’ flu to address the question of whether symptoms could be due to an acute cholinergic effect because, if it was, those reporting symptoms of dippers’ flu might develop chronic sequelae. The possibility that dippers’ flu could be caused by an allergic response to endotoxins was also raised.

There was a consensus that the possibility that chronic symptoms could be linked to low-level exposure to OPs had not been fully explored because those with symptoms sufficiently severe to take them out of work had generally not been included in previous epidemiological studies.

It was noted that previous studies had not, generally, been able to provide valid quantitative data for exposure to OPs. It was pointed out that there was no certainty that the ‘dose to insult curve’ was linear. The response could be affected by the susceptibility of individuals and the possibility that susceptibility could be changed.

It was noted that changes in the formulations of veterinary medicines and pesticides could be relevant to the question of chronic effects following low level exposure to the OP active ingredient. It was suggested that exposure to the co-formulants or additives themselves might cause or exacerbate symptoms. For example, phenols which were removed from sheep dip formulations in the early 1990s could alter the metabolic base for toxicological outcomes and this could be an important issue in relation to the possibility of sensitisation.

In turning to issues not identified by COT as those which should be addressed by further research, consideration was given to the possible immune or hormonal effects of OPs. It was noted that there had been a small number of studies including an item in the Lancet circa 1996 which had examined extensive disturbance of cellular components of immunity in a laboratory study. Reference was also made to a WHO document indicating an OP eliciting auto-immune response and, therefore, advising caution in undergoing vaccination following exposure to OPs. It was suggested that there was also a possibility of an OP impact on hormones (as endocrine disruptors) which could be synergistic or additive.

The issue of whether cholinergic conditions should be examined as a possible generic cause of Alzheimer’s disease, glaucoma, ME and related Gulf War Syndromes was raised. It was noted that this symptomology could be looked out for in the examination of data held by OPIN and PEGS to be carried out by Dr Fletcher.

Among other possibilities noted were : possible synergy between OPs and other agents; possible effects of OPs on gastro-intestinal disturbance, kidney disease, liver dysfunction and skeletal effects; cardiac conduction abnormalities; visual field defects. The meeting also noted the possibility, to be reviewed in the following session, that children as a group might be particularly vulnerable to OPs.

Ray Anderson of the Veterinary Medicines Directorate concluded the Workshop by summarising the issues which had arisen:

These questions will be drafted into a Research Requirements Document, to be placed in the public domain. Research requirements will be subject to open competition (with an independent involvement in their scrutiny); and a rapid response to these questions will be sought.

The full proceedings can be downloaded from www.maff.gov.uk/research/publications, or are available from PEX.

[Published in PEX Newsletter No.7, June 2000]