A joint working group of the Committee on Toxicity (COT) and the Advisory Committee on Pesticides (ACP)
4th Meeting: 4 July 2011
Chairman: Prof A Boobis COT
Members: Prof C Brown ACP; Dr J Cocker ACP; Prof I Morris COT; Dr A Povey ACP; Ms A Ward COT
Secretariat: Ms J Wilder CRD
Others: Mr P Hamey CRD
1.1 Apologies were received from: Professor J G Ayres (ACP) and Dr A Leake (ACP)
2.1 The Committee noted Prof Ayres was unable to attend due to a family bereavement and sent their condolences.
3. Item 1. Minutes
3.1 The minutes were agreed subject to minor amendments
4 Item 2 matters arising
4.1 Irritation and Sensitisation:
4.1.1 CoT’s expert in immunology had provided advice. Both irritation and sensitisation occur using a common biological pathway. An acute response with an irritant is rapid and needs no prior exposure. Sensitisation however requires the immune system to be ‘primed’ at first exposure with a response occurring following further exposure after about 20 days. Thus in the absence of a detailed patient history it is not really possible to distinguish between the two for example in case reports in surveillance data. Members agreed that the relevant section of their report would clarify this aspect.
4.2 Spray fall-out data:
4.2.1 Members heard that figures 1 and 2 in the tabled paper provided a graphical representation of ground deposition from the BREAM database, figs 3 and 4 represented airborne spray in the adult zone and combined, these data resulted in figures 5 and 6. Figures 7 and 8 represented data on inhalable spray in the adult zone and figures 9 and 10 assumed an adult breathing rate. A similar set of graphs had been produced for children. Members commented that some of the data looked a little unusual. For example there was an apparent increase in figure 8, 75th percentile. Members heard that this aspect of the BREAM model works best at distances between 1 and 3 m. In reality droplets would disperse further from the sprayer, but the model doesn’t predict this well. Members sought clarification as to how realistic these data were at say 10m. The graphs presented were based on data derived from 2 passes of a 24m boom, measured as the sprayer passes. The distance given is that from the first pass of the sprayer. Members asked whether the second pass contributed to the measured spray. It was clarified that the only way to check this was to run the model separately for a single pass and then subtract the data to see the difference.
4.2.2 Members agreed that the model is probably over-estimating exposure as it assumes relatively limited dispersion from the first pass. CRD confirmed that they would probably seek more research as the model appeared OK for estimates near to the sprayer, but there were concerns about estimates at further distances. Members agreed to ask the BREAM team about the applicability of this aspect of the model.
4.2.3 Members heard that this was a stochastic model so delivers slightly different results (usually in the second decimal place) in each iteration. The graphs had been generated by running several iterations. Members commented that the ‘wobbles’ in the graph suggested relatively few iterations.
4.2.4 Members heard that the current approach relies on data generated in the 1980s. It assumes that dermal exposure at 8m is about 0.1mg, similar to the mean value presented in these graphs. For inhalation exposure, current estimates assumed inhalation of about 0.006mg, about ten times higher than the values shown in the graphs, i.e. the current estimates are more precautionary as the default assumptions made were very precautionary.
4.3 Consideration of the draft PAHES report:
4.3.1 Members heard that the PAHES working group were also preparing their report, and BRAWG asked to see this when it is available.
5 Item 3: Draft Report
5.1 Members noted that the draft report still required quite a bit of work. Whilst they would aim to draft the report as soon as possible, there were a number of constraints that suggested the final version was likely to be a little delayed. Nevertheless members were optimistic that they could complete their work by the end of the year.
5.2 Members agreed that the text should make clear their independent review of information from a range of sources in drawing together the report. Some of the sections available at present included much technical detail and it was agreed to summarise these sections and move the technical detail to appendices to aid the readability of the final report.
5.3 Members then worked through the available text in some detail.
5.4 Operators and workers definitions should include the information that they use products in accordance with approvals and that, at present in the UK, assessments for workers assume they do not use PPE. It was agreed to keep information such as this on risk mitigation within the definitions rather than surrounding text to ensure rapid readers are fully aware of these details.
5.5 Members noted that current estimates make no differentiation between adult and child exposure to spray drift, but do make a specific estimate of children’s exposure to dislodgeable residues deposited in their ‘play area’ adjacent to spraying. In comparing the adult and child estimates in the BREAM data presented under matters arising there was only a marginal difference. Child exposure estimates for airborne spray are higher next to the boom, because the boom is at about ‘child height’. The differences flatten out further away.
5.6 Members asked what factor was used to convert dermal deposition to systemic exposure estimates. CRD clarified that where no data are made available it is assumed as a default that dermal absorption is 100%. Where data were available the range was usually between 1 and 10%. Thus the dermal absorption can be a critical factor in the risk assessment. Taking both aspects into consideration, Members agreed separate scenarios for adult and child should be considered in risk assessments.
5.7 Members sought clarification of the status of the BREAM data. CRD confirmed that the draft final report had been submitted, but the contractor would not be asked to finalise the report until this working group had completed its work. However the supporting data had been published in the peer reviewed literature. Members agreed it was therefore appropriate to cite the papers in their report.
5.8 Members noted that current estimates of exposure are based on mean data, but the BREAM data provide other percentiles that could be used in risk assessment. Members agreed that different percentiles could be used for acute and longer term risk assessments. The data gathered on the high drift scenario used wind speeds at the top end of legal spraying practice. It might be possible that some specific nozzles could produce higher drift, but adequate data for the model are not available for these.
5.9 Members next sought clarification of the time period that someone might be present at the edge of the boom. It was clarified that a sprayer vehicle travelled in the region of 2.5-3.5m/second. Data indicate that the spray plume drops out in seconds. Members next considered how close to the edge of the spray boom it was reasonable to assume someone might be. Due to the boom length there are physical difficulties in bringing the machinery close to fences etc. and when the ACP had considered this they had concluded that about 2m was a close distance in terms of the uncertainties involved in practical field work. BRAWG members thought this would be quite an extreme assumption for long term exposure estimates, but would be appropriate for acute estimates. They also noted that sprayers were not allowed closer than 2m to hedges in order to protect wildlife.
5.10 Members observed that the main problem area for the longer term risk assessment is not the short term episodic exposure to the spray plume. Rather it is the deposited residue and subsequent volatilisation.
5.11 Members therefore agreed that the scenario for short term risk assessment should be someone at 2m from the edge of the spray boom using the 95th percentile data with a duration of a single pass (or about 5 mins). The longer term scenario should be considered as exposure to residues and volatilisation with a frequency of exposure of about weekly representing the intensity of spray programme as might be used for potato blight control. Thus a risk assessment for a resident should include both a short term risk assessment for exposure to the spray plume and a longer term (subchronic) risk assessment for exposure to dislodgeable residues and volatiles.
5.12 Members agreed to include a table setting out the sources of exposure and how they were considered in acute or subchronic risk assessment. The need for a lifetime exposure should be considered as the exposures were essentially episodic over a lifetime. Members noted that there had been a recent paper published considering a method of calculation to adapt the standard chronic test protocols to represent short term episodic exposure for non-genotoxic carcinogens.
5.13 An alternative approach to considering volatilisation exposure suggested in BREAM was to assume 100% loss by volatilisation of the applied compound over a day in areas where actual values were unknown. Current assessments assume a fixed concentration in air based on volatility of the active substances using highest observed values (1µg/m3 for low volatility substances based on data on parathion and 15µ/m3 for higher volatility substances based on chlorpyrifos). Thus for the current longer term risk assessment it was assumed that someone was exposed to the highest observed volatilisation each day. This was because the spatial scale for volatilisation differed from that for spray drift. Members agreed that the current assumption meant that volatilisation in a garden was more than covered by such a conservative assessment. However it was very important to ensure that such assumptions were clearly explained in the report.
5.14 Members next considered indirect exposure via produce grown in the garden. It was agreed that this could be grown right up to the fence, so again a distance of 2m from the sprayer would be appropriate for the acute risk assessment but a further distance for the longer term subchronic estimate. In terms of consistency with other aspects of the risk assessment, 5m was suggested to be appropriate.
5.15 Members agreed that at present 100% dermal absorption should be assumed in the absence of data, but when the EFSA draft dermal absorption guidance was adopted, this should be taken into account. This guidance made appropriate provision to adjust the default value based on the physical/chemical properties.
5.16 The estimated dermal exposure to dislodgeable residues was currently assumed to take place over 2 hours, based on the 90th percentile from some USA data. Members agreed that different exposure times should be assumed for acute and longer term exposures, and CRD agreed to check the detail of the US research to see whether there were any additional data available.
5.17 The current assumptions for children eating grass were again based on US data. After discussion members concluded that as spray fall out would be similar for grass and soil but the surface area would be larger for grass the single assessment would be adequate to cover both types of exposure. Members suggested that there may be some UK child behaviour data available in an Environment Agency data set used to consider risks from contaminated land CLEA, and it was suggested the current assumptions be compared to these data
5.18 Members next considered whether to include an assessment for exposure to residue on companion animals; a possible scenario might be that a pet dog rolls on grass accumulating some of the deposited residue on the grass, a child then strokes the dog and mouths contaminated hands. Members concluded that this scenario was also adequately covered by the assessment of more direct exposure to the residue on grass. Members also asked that the assumed area of 25cm2 be checked to see what this represented.
5.19 Members then considered the possible exposure for someone walking in the treated crop and noted that if this was added to an assumption of continuous exposure for a resident this would represent a potential duplication of time (or a day longer than 24 hours!). Members agreed that this meant there was a need to work carefully through the detail of each calculation in considering if and how they should be combined to consider aggregate exposure.
5.20 Members next considered whether, if all routes of exposure were to be considered the standard dietary exposure estimates should also be included. They heard that there are tools in development for undertaking such aggregate exposure estimates.
5.21 As each estimate of exposure is based on conservative assumptions it would be inappropriate to simply add them up as this would result in a super conservative estimate of exposure based on overall unrealistic assumptions. The USA had completed some probabilistic estimates, but these required suitable input data. Members considered whether to recommend a very worst case super-conservative approach or to recommend that tools to complete a more realistic estimate be developed. They agreed that ideally data on a range of exposures from consumer intakes could be obtained. If these contributed say 10% or less to the estimated exposures they would be well within the range of other exposure estimates any way and hence could be ignored for these purposes.
5.22 Members heard that writing the toxicology section was in progress, and a draft was expected to be ready by the end of the month. Members drafting this section sought a steer from the working group as to how much information to include about long term low dose exposures and whether the standard toxicology package covers the concerns. The concerns were primarily whether low dose exposures in utero or early life stages had consequences in later life. The current package could be said to miss testing the fetal origins of diseases of old age such as cancers and diabetes. Studies in epigenetics suggested this was a possibility. The US National Toxicology Program (NTP) had suggested a protocol that started exposure in the long term study in utero and continued with a single generation for a 2 year period. However there are significant problems with the study design. There are as yet no good data confirming that the standard test package is missing information, but the concern is that it might be. It is unclear what diseases should be considered. Overall the group agreed that it was not yet a mature enough field for the working group to be able to suggest a valid way forward.
5.23 Members recalled that one point made by the RCEP report was that there are health endpoints that cannot be picked up in animal models. However toxicology members of the group agreed that standard tests include behavioural changes in the animals and these are ways of picking up on some of these end points. Overall they did not think that that standard toxicology package would miss important end points.
5.24 Members heard that a paper by Barton et al outlined a testing strategy designed to make better use of the 2 year study by taking further blood samples and testing basic kinetics. The paper also suggested further work during the existing dog and rat studies to consider systemic exposures and to get better data on metabolism. Such additions would be relatively easy to do and would provide information that could be useful in post approval surveillance. However members suggested that further work would be better in humans than lab animals as systemic exposure and metabolism were complex and variable.
5.25 Turning to the section on local effects it was noted that sensitisation and allergy were both terms used. It was confirmed that sensitisation was a subset of allergy. The section title currently referred to skin only – but respiratory allergy was also a possibility. This section was to be updated to include the information from the previous meeting. Members noted that there were new in vitro test protocols available in this area eg OECD ‘episkin’. This had been validated by ECVAN, but it was unclear whether it had been included in the standard data requirements. This was important in addressing the wider policy to replace animal testing where possible. Members noted the table with cut-off points drawn from classification rules. One aspect not addressed in this section was whether human effects are adequately covered by the LLNA test. This test considers a single mechanism pathway. Members were unsure whether the reported adverse effects in humans would all be due to this mechanism. It was suggested that advice be sought from a clinical immunologist.
Action: Dr Povey
5.26 Members agreed the timetable for the next stage:
Prof Brown, Dr Cocker and Dr Povey would redraft their sections in line with this discussion, Prof Boobis would prepare his section all by the last Friday in July. These were to be sent to the secretary to forward to Prof Morris and Prof Ayres. Once a compete draft was available it would be sent to Ms Ward to edit.
6. Items 4 and 5: Plans for stakeholder discussion and date of next meeting
6.1 Members agreed that if necessary they would hold a further meeting to finalise the report for discussion. As such it was likely the stakeholder consideration would be held late in the year.
7. Item 6: Any other business
7.1 Members noted the comments that had been provided on the EFSA scientific opinion and agreed to consider the comments received late before the meeting at a future date.
8. Item 7: Items for information
8.1 Members noted these papers and commented that it would be useful to have an analysis of the USA data of relevance to the UK.