Research and Development



Department for Environment, Food and Rural Affairs CSG 15

Research and Development

Final Project Report

(Not to be used for LINK projects)

|Two hard copies of this form should be returned to: |

|Research Policy and International Division, Final Reports Unit |

|DEFRA, Area 301 |

|Cromwell House, Dean Stanley Street, London, SW1P 3JH. |

|An electronic version should be e-mailed to resreports@defra..uk |

| |

|Project title |Investigation of possible autoimmune responses induced by organophosphate (OP) exposure      |

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|DEFRA project code |VM02116 | |

|Contractor organisation and location |Health and Safety Laboratory, Broad Lane, Sheffield S3 7HQ |

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|Total DEFRA project costs |£ 78941 | |

|Project start date |01/04/01 | |Project end date |31/12/93 |

|Executive summary (maximum 2 sides A4) |

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The hypothesis of autoimmune response causing ill health after organophosphate (OP) exposure has been discussed, but a recent review highlighted the paucity of scientific investigations to establish the validity of this hypothesis for OP or other pesticides. The possibility of an autoimmune response has been suggested as explaining the long term ill-health reported by some individuals which does not seem related to any apparent dose-response relationship. The primary aim of the study was to investigate whether OP exposure may be associated with a humoral (i.e. circulating antibody) response to the sort of organophosphorylation modification to normal proteins in the body that OP pesticides may produce or closely related ‘self’ antigens. A secondary objective was to investigate whether any characterised antibody response could be linked to either symptoms or the nature of the exposure.

Blood plasma samples from three cohorts were studied for the expression of antibodies against a number of OP-related and associated antigens. The first group consisted of 104 subjects with defined biomonitoring evidence of biologically significant OP exposure. This was defined by at least one occasion of a demonstrably depressed plasma cholinesterase (pChE) measurement carried out at our laboratory. The majority of this cohort was undergoing routine biological monitoring for occupational OP exposure. The second cohort consisted of 96 subjects with no history of occupational OP exposure. They formed the control group and were selected to reflect the sex and age distribution found in the proven-exposure cohort. A smaller third cohort of 24 individuals was also studied. These individuals had reported a history of long-term health problems involving a wide range of subjective symptoms including peripheral muscle weakness, behavioural changes which they had ascribed to OP exposure, and had undergone pChE measurements at some point in time at our laboratory. While most of this group had been potentially occupationally OP exposed, a sizeable number ascribed ill-health due to OP exposure in the house/garden or through agricultural ‘over-spray’. There were no depressed pChE measurements to substantiate OP exposure, but invariably biomonitoring investigations were not undertaken in the appropriate time-scale. Thus the third cohort is small and relatively poor in terms of case definition and may not represent those who complain of long-term OP-induced ill-health. All subjects completed a short questionnaire collecting demographic information, their employment status regarding OPs, whether and when they had ever felt ill at work, in their home or garden, which they ascribed to OPs.

All plasma samples were analysed randomised by microtitre plate based, enzyme-linked assays developed against a range of capture antigens. These antigens were developed to detect specific antibodies that may reflect OP-induced organophosphorylation of proteins or associated structures considered as ‘self’ antigens. Assay characteristics of these screening assays were investigated prior to application in the three cohorts. The table below show the prevalence of abnormal versus normal antibody results against various capture antigens for the group with proven OP exposure and the controls. The cut-off for normality was defined by the 97.5th percentile of results in the control cohort. The asterix (*) by capture antigen in the table denotes structures that have an obvious relationship with OP-induced organophosphorylation of serine residues.

| |Prevalence of normality/abnormality |P-value |

|Capture antigen | | |

| |Controls group |Exposed | |

|BSA |2/94 |1/103 |0.95 |

|Phosphoserine-BSA |2/94 |5/99 |0.51 |

|Phosphotyrosine-BSA |2/94 |14/90 |0.007 |

|Native rat neural tissue |2/90 |10/86 |0.040 |

|Dimethoxyphosphoserine-BSA* |2/90 |8/95 |0.14 |

|Diethoxyphosphoserine-BSA * |2/92 |24/80 |0.05) between abnormal antibody response towards phosphotyrosine, native rat brain, aged acetylcholinesterase and self-reporting of ‘having ever felt unwell at work considered due to pesticides’. However for the capture antigens dimethoxyphosphoserine and diethoxyphosphoserine, significant associations between self-reporting of feeling unwell at work and presence of antibody response were noted (p=0.004; p=0.025 respectively) in the cohort with evidence of OP exposure. This statistical association cannot be taken as evidence of causality between the specific antibody phenomena and ill-health. Six of the eight subjects with abnormal dimethoxyphosphoserine antibodies were employed where significant exposure to a dimethoxy-OP had occurred and concomitantly a high prevalence of respiratory and flu-like symptoms, erythrocyte acetylcholinesterase and pChE depression were found.

Correlation analysis between antibody levels expressed against capture antigens based on phosphotyrosine, dimethoxyphosphoserine, diethoxyphosphoserine and phosphoserine showed highly significant correlations (p ................
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