Those present:
Chair: Prof G Hawksworth (Chair)
Others: Prof J Ayres (Independent); Ms A Baker (Independent); Dr S Barlow (Independent); Prof T Marrs (Independent); Prof C Ockleford (Independent); Dr L Hetherington ( HPA); Mr B Maycock ( FSA); Mr M Williams ( WAG); Mr S Samuels (CRD, Secretary); Mr P Hamey (CRD); Dr N Morgan (CRD).
1. Apologies for absence:
Prof V Howard (Independent), Prof J Parry (Independent), Dr A Povey (Independent), Dr P Botham ( CPA), Dr D E Ray(Independent), Dr I Indans (HSE), Ms L George ( NAW), Mr D Renshaw, Mr Ian Pepper ( BPCA), Dr R Billington (CPA), Dr R Hartley ( NAAC), Mr J Battershill ( HPA) and Dr Cherrie (Independent).
2. Introduction
2.1 The Chair reminded Members of the confidentiality of the discussions and decisions taken at the Panel meeting. Members were asked to declare any conflicts of interest prior to the start of each agenda item.
2.2 TheChair welcomed Dr Lesley Hetherington (who was attending in place of Dr Battershill) and Mr Martin Williams as first time attendees of the Panel.
3. Minutes of the 33rd Meeting
3.1 Members were reminded that the minutes had been agreed by post.
4. Matters Arising from the 32nd Meeting
4.1 Minute 4.5 (medical advice in DARs): Members were reminded that this item was an action to find out who is responsible for checking the validity of the Medical Advice given in DARs. Since no progress had been made on this item the Chair agreed to contact the Medic on the EFSA Scientific Panel.
Action: Chair
4.2 Minute 6.8 ( ECPA review of the methodology used in epidemiology studies): Members were reminded that Dr Botham was due to give feedback on an industry working group on the methodology used in epidemiology studies. Unfortunately Dr Botham was not present so the Chair agreed to contact him on this matter.
Action: Chair
4.3 Minute 6.12 COM to investigate high numbers of positive results). Members noted the tabled paper ‘Factors affecting the incidence of genotoxicity biomarkers in peripheral blood lymphocytes: impact on design of biomonitoring studies’.
4.4 Minute 6.13 (non-Hodgkin’s lymphoma): Members noted the tabled paper ‘Non-Hodgkin’s Lymphoma: Overview Paper’ from the Department of Health’s Committee on Carcinogenicity ( CoC). It was agreed that the Secretariat would get the latest statement made by the CoC on NHL.
Action: Secretariat to contact CoC Secretariat.
4.5 Minute 8.4 (biological monitoring): Members noted that there was a progress report tabled as a main Agenda item.
4.6 Minute 9.6 (Investigation of instances where there is an acceptable risk assessment for operators but an unacceptable risk assessment for workers): The Panel was informed that due to the ongoing work on the Biomonitoring Review no time had been available for this paper. The Secretariat agreed to produce the paper for the May or more likely September 2009 meeting.
5. Matters Arising from the 33rd Meeting
- 5.1 Minute 7.15 (Critique of a review on chlorpyrifos reference doses): Members were informed that the paper had been sent on to the EPA although no additional no comments had been received by Prof Ockleford following the last panel meeting. The Chair thanked Prof. Ockleford for all his work in producing this detailed review.
- 5.2 Minute 10.1 (Review of published on pesticide induced asthma): Members heard that this review was underway.
6. Monitoring of the medical and scientific literature for epidemiological studies on pesticides published between January 2007 and December 2007
6.1 Dr Brown briefly introduced the annual review of epidemiological studies relating to pesticides.
6.2 Papers on Cancer: Members heard that Dr Povey had commented in writing. He noted that there were 7 occupational cohort studies, of which 4 came from the Agricultural Health Study (AHS) in the USA. The AHS was an important study which should have the power to detect any significant associations between pesticide exposure and health effects. However, the sheer number of potential associations that can be examined may well lead to a number of false positive results. Members heard that there were 12 case-control studies which were largely interested in residential pesticide exposure and associations with certain childhood and adult cancers. Dr Povey noted that there did not appear to be any significant advances in these studies. Some studies had small numbers of cases and controls, including the brain tumour study reference (18). None of the studies seem to have solved the problems of exposure assessment (recall bias, nature and extent of different pesticide exposures).
6.3 The Panel heard that Dr Povey had posed a number of questions in his written comments with regards to the AHS; he would like to know how they identify the associations to study e.g. whether they prioritise examining pre-existing hypotheses or look at hypothesis generation. Also do we know their publication policy, do they try and publish negative results? Dr Povey noted that this can be just as important as positive results if the study has sufficient power. Dr Brown addressed these points; the AHS investigates both pre-existing hypothesises and also undertakes new hypothesis generation. Some negative studies have been published and others only showing weak associations. Dr Brown noted negative studies are also included in MTP reviews.
6.4 Members noted that there were a number of papers suggesting an association between pesticide use and cutaneous melanoma. A number of these papers were derived from the AHS in the USA. It was noted that sunlight would be a clear confounder. The Panel raised the question as to whether, or not, this association between pesticide use and cutaneous melanoma had be seen in previous reviews, Dr Brown agreed to investigate.
Action: Dr Brown
6.5 Members were informed that there were a number of papers looking at non-Hodgkin’s lymphoma and leukemia. There were two reviews and two case control studies, one of which showed a positive association but with small numbers of cases investigated. It was noted that Dr Battershill had requested paper 54 for detailed review.
6.6 Dr Brown informed Members that there was an increased trend to carry out genetic analysis in studies. The Chair noted that this had been done for about 20 years for common cancers but since such investigations had not produced any useful data researchers had moved away from using them, with cancer being a multifactorial condition. Prof. Ayres noted that genetic analysis was done simply because it could be done.
6.7 The Panel discussed study 18 reporting brain tumours. In his written comments Dr Povey noted that the numbers in this paper were small. Dr Brown informed the Panel that this study had been picked up in the media. The Panel were informed that one of the study’s strengths was that it employed a job exposure matrix, although only 221 cases were looked at, therefore obtaining a dose response would not be possible. Prof Marrs agreed to look at the paper in detail.
6.8 Neurotoxicity: The Panel heard from Prof. Marrs that there were a large number of positive studies involving the OPs which was typical of these yearly reviews. He drew the Panel’s attention to one paper of interest, No. 35, investigating neuropsychiatric symptoms in past users of sheep dip and other pesticides. This paper questioned the causality of the effects seen, suggesting that psychological mechanisms have a role. The Panel noted that cold had an effect on nerve phenomena. Prof. Marrs didn’t believe the paper really added anything new. Members discussed the role of mental and physical factors in Multiple Chemical Sensitivity. It was noted the knowledge that a particular profession may have a higher risk of a certain condition will lead to more cases of that condition within that group. Prof. Marrs informed Members that there was no actual syndrome associated with sheep dip. Members discussed the effects of repeated exposures as described in papers 27 and 33. Members considered that people working in below standard conditions or in high risk areas may get repeated high exposures. Members questioned whether, or not, any problems due to repeated exposures would be picked up by the Incidents Reporting Scheme. However, it was noted that the PIAP reports states that it looks at single incidences rather than chronic exposures.
6.9 Reproductive effects: Dr Barlow drew the Panel’s attention to paper 41 which investigated neural tube defects. Although she felt one paper in its self was not concerning, members heard that Dr Barlow had run a quick search and found ca 40 papers over the last 15 years (search terms pesticides and neural tube defects). She noted that mancozeb was found to be positive. However there were many studies with no association. Overall Dr Barlow considered that this area would need to need to be monitored and the Panel agreed.
6.10 Dr Barlow then drew the Panel’s attention to paper 42, a case control study investigating human exposure to endocrine-disrupting chemicals and prenatal risk factors for cryptorchidism and hypospadias. She noted that there were issues over the diagnostic criteria used for hypospadias. She was aware of another paper which demonstrated the significance of parental occupation. The study authors for paper 42 had measured the levels of 16 organochlorine pesticides in placental tissues. Dr Barlow had looked at the methods used and found them appropriate, although the pesticides found were not in use in the UK.
6.11 Dr Rees questioned whether these results showed the parents had used these pesticides. Dr Barlow explained that finding DDT in placental samples would be expected in the general population.
6.12 The Panel heard of ongoing work investigating the causes of hypospadias. An EU study had shown that while single oestrogenic pesticides had no effect, mixtures could induce hypospadias. A Spanish project still underway involved a group of studies looking across a whole range of endocrine disruptors.
6.13 Cytogenetics: Dr Povey provided the following comments; A total of 9 studies have been reviewed. Four cytogenetic studies: 3 of which are small and probably of little significance. One study (57) had examined large numbers of exposed subjects and reported statistically significant differences in chromosomal aberrations in exposed subjects. However individual pesticides are not defined. Two DNA damage studies: one examined small numbers; the other does not mention any numbers. These papers were seemingly of little significance. Three genotyping studies (Dr Povey being the author on one). Study 55 was potentially important in that it provides evidence that associations between PON1 192 polymorphisms and ill-health may also result from everyday exposures rather than specific exposures in occupationally exposed populations. If this were found to be correct then the interpretation of occupational studies would have to be revisited. However, it was unclear from the abstract whether the authors have actually examined pesticide exposures in their population or whether they have assumed that their population is unexposed or has low exposure. If the latter then it was a flaw in the study design.
6.14 Members discussed the papers demonstrating differences in health outcome with different (PON1) and other polymorphisms, notability sheep dippers.
6.15 Parkinson’s disease: Dr Povey’s comments - overall there were four studies reviewed. Three case control studies (two from the Geoparkinson study, one small Taiwanese study) and one cohort study from the AHS in the USA. The Geoparkinson study was an important Pan-European study with results that, in general, agree with studies linking pesticides with Parkinson’s disease. Also they report few associations with known polymorphisms. Dr Povey believed that the associations between GST, solvents and ill-health have been reported previously. He was not convinced that this was the most appropriate study design to look at whether, or not, pesticide exposure per se was linked to Parkinson’s disease, as the attributable risk in the general population was likely to be low and exposures within this population may not be that high. There was also the problem of trying to assess exposure in different countries over the same period. The paper from the AHS was potentially more valuable, given the caveats previously mentioned, in that it was examining risk in a pesticide exposed population. The numbers of cases are low, however, and there are inconsistencies within the results for incident and prevalent Parkinson’s disease. Dr Povey believed it may be a matter of waiting, unfortunately, until the numbers of cases increase to see whether any definitive associations occur.
6.16 Members discussed paper 64 from the Agricultural Health Study (AHS) which indicated that the incident Parkinson’s disease was associated with cumulative days of pesticide use, although prevalent Parkinson’s disease was not associated with overall pesticide use. Members considered that more cases were required before any firm conclusions could be drawn. Members also noted that this paper had not implicated paraquat.
6.17 Prof. Ayres drew the Panel’s attention to the Geoparkinson study, noting it was a large well conducted case control study which employed detailed individual assessments including video of patients.
6.18 Prof. Ayres noted of the four papers reviewed, three were studies from the AHS. In these three studies no measures of lung function had been made. Dr Brown told Members that he was in contact with Jane Hoppin and could speak to her about the lack of functional assessment.
Action: Dr Brown
6.19 Prof. Ayres felt that the increased odds ratio for rhinitis seen in paper 65 was not dramatic; Dr Rees noted that diagnosis of this condition was difficult. Prof. Ayres informed the Panel that although objective measurement was difficult, drug trials of nasal disease employed a robust questionnaire to get round this problem.
6.20 Prof. Ayres informed Members that asbestos does not cause chronic bronchitis, which was suggested in paper 68.
6.21 Poisoning: Members discussed the fatal case of paraquat poisoning following minimal dermal exposure. Members felt that the dermal absorption of paraquat would be low, however it was noted that the skin in this case was damaged by a burn and the subject was elderly. Therefore their skin may be more permeable than a younger subject.
6.22 Members noted the mixed cholestatic/hepatocellular liver injury induced by the herbicide quizalofop-p-ethyl reported in paper 72. Prof. Marrs questioned whether, or not, it was feasible to be exposed to a sufficient quantity quizalofop-p-ethyl to induce anything like these effects.
6.23 Patterns and Trends: Prof. Marrs noted paper 92 on hospital admission for accidental pesticide poisoning among adults of working age in England, 1998-2003, showed nothing remarkable.
6.24 Miscellaneous: Prof. Ayres informed the Panel that he would look at the nature of the airway complaints mentioned in paper 102 on airborne irritant contact dermatitis and conjunctivitis after occupational exposure to chlorothalonil in textiles. He felt it likely the paper was referring the nose and also noted that the delayed type of irritation referred to seemed unlikely, and fast and transient would be more typical.
6.25 Exposure Studies: Mr Hamey informed the Panel that paper 112 was a survey of fungicide application practices and personal protective equipment used among orchard farmers in the Agricultural Health Study (AHS). He noted that the study indicated 77% of farmers don’t wash their hands following pesticide use; he felt a similar survey in the UK would be useful. Paper 117 explored different methods of hand washing to prevent contamination being taken home. The paper stated that tape stripping was a common method which was incorrect. Mr Hamey went on to describe paper 127 on merging models and biomonitoring data to characterise sources and pathways of human exposure to organophosphorus pesticides. Members heard that in a cohort of the rural population in the US the diet was the greatest source of pesticide exposure. Dr Rees informed Members that in such a population most of the food eaten would be grown locally.
6.26 Ms Baker then asked a series of general questions related to the annual reviews. Firstly, at what point did the information from the reviews feed into the ‘weight of evidence on a pesticide’. She was informed that where a trend was seen linking several papers on one pesticide, or a related group of pesticides, to an adverse finding, research work can be initiated. For example, the increase in papers with evidence of DNA damage related to pesticide use led to the commissioning of a Department of Health review. Prof. Ayes pointed out that one problem with many of the papers reviewed was lack of good exposure data with the term ‘pesticides’ referred to, rather than specific named compounds.
6.27 Secondly Ms Baker asked if the reviews have identified any susceptible groups and what would be the consequence. Prof. Ayres informed her that where susceptibly was the result of a particular genetic polymorphism it would be difficult to do anything as you can’t advise workers with a specific allele not to handle pesticides. However, we can make a risk assessment for a group such as females of child bearing age and pregnant females. Dr Barlow noted that it would be impossible to label pesticides to prevent use by pregnant females, as during the first three weeks of pregnancy, during which the fetus was particularly vulnerable, the mother would be unaware of the pregnancy. She also noted that the most valuable epidemiological studies in this area were well followed up birth cohort studies.
6.28 Dr Brown pointed out that the yearly reviews look at areas of toxicology outside of the standard regulatory package and areas which the standard package may not be tailored to address, such as immunotoxicity.
6.29 The Chair concluded by reminding Members to respond to the Secretariat promptly where they had agreed to review individual papers.
7. Review of Biomonitoring Studies Progress Report
7.1 Dr Morgan summarised the progress that had been made in the review of biomonitoring literature which was ongoing at PSD. A number of steps had been taken in the selection of papers. The keywords chosen led to an initial list of ca 1600 titles. A sift of these titles produced a second list of 320 titles, for which the abstracts were obtained. After evaluation of these abstracts, 156 references were identified as possibly meeting the selection criteria identified at the outset. The full texts were acquired for evaluation. Three officers were involved in this evaluation and followed an approach agreed at an initiation meeting. The evaluation involved comparing the study reports with the established criteria for inclusion in a “selection screen” and extracting the salient information into a table format. The result of the evaluation was to produce a judgement as to whether the paper met the inclusion criteria, or not. Of the criteria, the one which has proved most crucial has been whether, or not, it was possible to establish an estimate of the systemic dose from the data provided. The decisions were highlighted with green or red accordingly; during the course of the evaluations a third group was identified, where a decision could not be made at the time. This latter group was highlighted amber to complete the “traffic light” system. The amber group included studies where crucial information might have been available from other papers, or where a second opinion was sought. Up to date, a total of 120 studies had been evaluated. A total of 39 papers were still to be received from CSL . Of those evaluated, 11 were considered to have met the criteria for inclusion and 14 were in the amber group. When all references have been evaluated and decisions made with respect to the amber group, it was the intention to record the results in a spreadsheet of bio-monitoring data; graphs will also be used to illustrate the data.
7.2 Members noted that this had been a fairly lengthy process; however given the paucity of exposure data this was not surprising. It was also felt that the REACH work on non-pesticide chemical may be of use.
8. Pesticide exposure monitoring using NPIS resources interim report (01 April – 30 June 2008)
8.1 The Secretariat informed Members that this was the interim report spanning three months, summarising returns from Electronic questionnaires, Postal questionnaires, and Telephone enquiries to NPIS Edinburgh. The Secretariat noted that nothing remarkable had been reported. The Panel were asked to comment
8.2 Members enquired if it would be possible to link the incidents data with pesticide usage. The Secretariat explained that this would be possible for professional products using Pesticides Usage Survey Group data; however, no similar surveys were carried out for Amateur products. It may be possible to obtain some data from the yearly returns provided by pesticide companies to calculate the Levy. It was noted that the majority of the incidents listed were for Amateur users.
8.3 Members discussed the data presented in the Report and noted that once the full year’s data were available trends and patterns would be more apparent. Dr Barlow pointed to the poor return rate; Members heard that this was due to a problem with software which was being addressed.
9. Tabulation of endocrine modulator characteristics in studies to show consistency of findings
9.1 The Secretariat informed Members that the paper showed a tubular format for presenting the results from a package of toxicity studies to demonstrate if the compound in question had any endocrine disrupting properties and which mechanism may be responsible. The Panel were asked to comment on the format and usefulness. In addition they were asked if there were any additions which could be made.
9.2 The Panel agree that the table would be of use, although not in a purely tick-box approach. The Secretariat informed Members that the table would be used as an aide memoire and would be useful in helpful in presenting results to ecotoxicologists. Prof Ockleford and Dr Barlow agreed to send additional endpoints which could be added to the Table.
Action: Prof Ockleford and Dr Barlow
10. Any Other Business
None was raised
11. Dates of next Meetings
May 11th 2009
October 1st 2009
