A joint working group of the Committee on Toxicity (COT) and the Advisory Committee on Pesticides (ACP )
At the 3rd meeting, held on the 28 January 2011, the Bystander Risk Assessment Working Group discussed the following issues
Chairman: Professor J G Ayres ACP
Members: Prof A Boobis COT; Dr J Cocker ACP; Dr A Leake ACP; Prof I Morris COT; Dr A Povey ACP; Ms A Ward COT
Secretariat: Mr P Hamey CRD
Others: Dr D Basketter (present for items 1-3 only) Independent consultant
1.1 Apologies were received from: Prof C Brown (ACP) and Mrs J Wilder (CRD).
2.1 The Chairman welcomed Dr Basketter an expert with 28 years experience in sensitisation and irritation risk assessment, who had been invited to help the working group on these aspects (see Item 3).
3. Item 1. Minutes
3.1 Draft minute 8.2 - although the first sentence reflected the view that the wording in the Code of Practice was appropriate, the minute did not reflect observations on the difficulty of monitoring or controlling what was done in practice. It was agreed that the minute should be amended. Subject to this change and some minor amendments the minutes were agreed as a record of the previous meeting.
4. Item 2. Matters arising and programme [BRAWG 2 (3/2010)]
4.1 Prof Boobis informed the meeting that he was involved in initiatives with both the European Food Safety Authority and the WHO International Programme on Chemical Safety which were developing risk assessment approaches for mixtures of chemicals. Prof Boobis offered to circulate reports when they became available.
Action: Prof Boobis
4.2 No further matters arising additional to those on the Agenda were identified. The revised draft programme of work was noted. The work on drafting Working Group’s report was discussed under Item 5.
5. Item 3. Local effects of pesticide exposure
5.1 Dr Basketter gave a presentation on the “Scientific basis of the predictive identification of human sensitization thresholds”. This covered background on mechanism of allergic contact dermatitis; an outline of the Buehler and Guinea Pig maximisation tests; the Local Lymph Node Assay (LLNA); classification; before discussing the evidence for thresholds for sensitisation.
5.2 Dr Basketter reminded the group that the mechanism of sensitization involves an initial, induction, exposure where the chemical penetrates into the skin and reacts covalently with skin proteins which trigger dendritic cells to in turn trigger proliferation of chemical specific T cells. At this stage the response is asymptomatic. Further skin contact, the elicitation exposure, results in activation of the T cells and local inflammation, i.e. allergic contact dermatitis.
5.3 Dr Basketter informed that the Buehler and Guinea Pig maximisation tests score inflammation responses after elicitation. This requires judgement and is therefore difficult to use in risk assessment. The LLNA measures proliferation and is a more objective quantitative measure. The UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS) has three classes for sensitizers: strong allergens, Group 4; weak allergens, Group 3; and sensitizers that are considered too weak to classify, Group 2. Non-sensitizers are referred to as Group 1. The LLNA Groups 3 and 4 were calibrated against the guinea pig methods.
5.4 The meeting was informed the risk management decision to create Group 2, was a pragmatic response to observations, for example of some medical patients where about 10% leg ulcer suffers had reactions to long term exposures of preparations containing parabens (parabens is widely tolerated in cosmetics without adverse reactions). The working group noted that such a pragmatic approach can be problematic: it can be difficult to get authorities to look beyond a “perceived standard”, which can result in issues for those with a minority response. Dr Basketter pointed out that in reality the 4 Groups represent a continuum of responses, for example about 1/10 000 people would react to the aluminium chamber used to administer human skin tests, and about 7 individuals in the world probably react to white petroleum jelly.
5.5 Responding to questions about respiratory sensitizers Dr Basketter thought these are clearly positive in dermal tests, and it had been demonstrated in an animal model that dermal exposure could lead to respiratory sensitization. Also in the rubber industry incidents of respiratory sensitization had been observed in rubber tree “sap harvesters who wore Respiratory Protective Equipment (RPE), so the implication being they had been sensitised through dermal contact. Respiratory sensitization also occurred in the [nickel and chrome] metal plating industry, but it was difficult to exclude routes of exposure.
5.6 Dr Basketter informed the group that there was strong evidence from multiple sources for thresholds and dose-responses. He presented summary information from Guinea pig tests with p-phenylene diamine (where the induction concentration varied), and dinitrochlorobenzene (DNCB) (where the elicitation concentration varied) which showed the percentage of animals responding falling from near 100% to zero as the concentrations were lowered by four orders of magnitude (for p-phenylene diamine this assumes the trend observed over 2 orders of magnitude continues).
5.7 Dr Basketter went on to state that evidence from practical experience in man, from controlled human testing and from both chemical and biological mechanistic considerations, also demonstrated thresholds for skin sensitization exist both at the level of induction as well as sensitization. He provided examples of human data for p-phenylene diamine (where the induction concentration varied), chlorobenzyl-idene malononitrile (where the elicitation concentration varied), and Neomycin (where both the induction and elicitation concentrations varied) which showed similar dose responses to the Guinea pig data. Finally, he showed the result of a 48 hour human patch test on cinnamal that showed a strong response at 1.0%, with decreasing response with lower concentrations until none was observed at 0.1% concentration. In response to a question Dr Basketter the dose-response range in an individual would be over one to two orders of magnitude.
5.8 Discussing how tests results might relate to exposure situations, Dr Basketter commented that the standard test methods often use a single occluded application as that had been demonstrated as a quick way of obtaining dose response information. However, an open application, which was repeated over a longer time could give a different view of the threshold.
5.9 The group were informed that another aspect of dose that was relevant was the dose per unit area. The first example discussed here was hydroquinone where repeated exposure over four weeks to a total dose of 168 g to the forearm sensitized 6/46 people, but a total dose of 2520 g to the whole body sensitized 0/43 individuals. The second example was DNCB where a dose of 62.5 µg applied to 1.8 cm2 sensitized 85% of subjects, but when applied to 7.1 cm2 only sensitized 8% of individuals.
5.10 The group raised questions about latency. Dr Basketter said for some skin sensitizers latency had been observed, for example for hair dye. He knew of a case where the individual for 8 years had no problem before developing symptoms. He suspected changes in physiology may be relevant, but an effect would not be observed until sufficient exposure was experienced. This added uncertainty in interpretation regarding latency. He commented that consumer products include products which contain sensitizers, but it is only a very small minority of those exposed which develop an allergy.
5.11 In response to a question about susceptibility of different body areas to sensitization, Dr Basketter said the importance of different areas was not the same as with skin penetration, and data for nickel comparing the back, top/back forearm, and hand did not show any differences. Although, there were differences between males and females and different ethnic groups.
5.12 Dr Basketter next described the “EC3” potency value of the LLNA, and its potential as in dose-response assessment. As the LLNA EC3 value increases the human potency class was reported to decrease from ‘Extreme’ to ‘Weak’. Data were also available to correlate human repeated insult patch test threshold concentrations with those in the mouse. Therefore, he suggested that to conduct a assessment for a chemical not tested in humans, one should test in the LLNA, then use the EC3 value to estimate the theoretical human threshold in µg/cm2, and apply an uncertainty factor to derive a maximum acceptable level for a single exposure.
5.13 The group noted that in reality there are a range of potencies and in the case of pesticides those most likely to be affected, i.e. users, are least likely to complain or make a connection because they perceived the benefits of using the pesticide. Dr Basketter noted EC3 values were available for some pesticides, and in terms of “thresholds” it would be possible to use consumer products as “bench marks”.
5.14 It was noted the reported pesticide incidents tend to report irritancy type symptoms which appear to be acute, and it was asked if these would be one off events. Dr Basketter commented that the time course was not obvious between exposure and sensitization reaction. Sensitization might not be observed for 24 or 48 hours after exposure. In addition, the decline of the response could be slower. It was noted that it was important to separate irritation, and intermediate and delayed sensitivity.
5.15 The Chairman, on behalf of the working thanked Dr Basketter for his informative and helpful presentation and discussions, and the meeting adjourned for a break after which Dr Basketter departed.
5.16 On reconvening, the Chairman noted the problem was that the level of bystander/resident exposure is unclear, and there is criticism of the established models used to estimate such exposures. Once exposures are known/understood the next question is what are the likely rational patterns of symptoms consequent on exposure. One component of this sequence is sensitisation and the LLNA gives a better assessment of true sensitization. He considered that the group should recommend that CRD review the LLNA information on pesticides.
5.17 The Chairman also noted that if the response to exposure is true sensitization the onset of symptoms may be timed such that the subject may be unlikely to make the link. Incident reports appear to report short term, easily attributable, subjective irritancy (involving skin, respiratory tract, eyes, or throat). He also informed the group that Dr Basketter did not consider that skin irritancy as observed in classification tests was likely to be the response in cases where individuals complain of skin irritation. This leads to the question of what is the mechanism for skin itches.
5.18 In discussion the group had some questions regarding the time course of responses to elicitation. It was agreed that it was important to clarify these aspects and it was agreed to consult with CoT’s expert in this area at the coming COT meeting.
Action: Prof Morris
5.19 It was also agreed that the group would recommend that further information on sensitizers: information on particularly those used in plant protection products, and their scale of use should be considered (it was suggested it could be useful to focus on products used on wheat). It is necessary to understand the routes to symptoms, have a better idea of what exposures might be and to understand if acute exposure results in long term effects.
6. Item 4. Derivation of appropriate toxicological comparators
6.1 The Working Group accepted the concept of an Acute AOEL as recommended by the EFSA Plant Protection Products and their Residues (PPR) Panel in 2010 and being included in the European Commission’s draft revised data requirements for active substances.
6.2 It was observed that if operator exposure was not long term and it was therefore considered appropriate to base the AOEL on a 90 day study, it was necessary to consider the nature of resident exposures. The Chairman considered the evidence for long term exposures and health outcomes was nowhere near as secure as it was for acute exposures. He offered that if acute exposures were controlled then long term exposures would be by implication. Members also noted the duration of exposure would be important; acute over a couple of minutes compared to long term over a lifetime. Arguments for having to address long term exposures remained, but it was noted if acute exposures are reduced longer term exposures would be too, although it was noted that compounds that were not acutely toxic would not be included in this approach.
6.3 It was also noted that accumulation of exposure was unlikely given the metabolic and excretion profiles of current pesticides. However, accumulation of response was an issue where there was no information. It was possible to consider a hypothetical example of neurone degeneration, where single exposure might disrupt individual neurones, and overtime no effect might be observed until a critical level of damage was reached.
6.4 The issue of mixtures was discussed. There were three possibilities for combined toxicological effects: dose-addition; independent action; combined action with enhanced effect greater than dose-addition (synergy). Exposure of residents was low compared to toxicological effect levels and additive toxicity was considered to be the most likely worst case and is beginning to be assessed internationally. A review of 150 papers, found synergy with maximum increase of 3½ times and that there was no scientific basis for the “cocktail effect”. Members heard that systemic exposures may be separated in time by toxicokinetics (eg different rates of dermal absorption) even when pesticides were applied in the same tank mix. However, it was necessary for assessments to state what worst cases and time intervals were considered.
6.5 The Chairman noted that WIGRAMP and the ACP Med Tox panel had considered papers on tank mixes.
6.6 Returning to the issue of the basis of determination of the AOEL, the relevant question is, if exposure is seasonal and a 90 Day study is used on that basis, are there effects in the study that would persist to the next year? It was also noted that it might be appropriate to use the chronic studies for the risk assessment, with amortisation for the periodic offsets when there would be no exposure.
6.7 The Chairman indicated that it should be recommended that it is necessary to understand what people near fields do, and how what information they receive may affect their behaviour.
6.8 Thus far the discussion had been on biological effects especially acute ones. The COT was considering acute anxiety syndrome. There was convincing discussion on how individuals interpret information and develop psychological and physiological symptoms. CoT offered to bring this information into the report.
Action: Prof Morris
6.9 The group noted the uncertainty factors currently used to set AOELs were appropriate and saw no grounds to move away from the present approach. However, additional areas where uncertainty factors would need to be addressed would be in a risk assessment for sensitization, if it was recommended to use the LLNA in a semi quantitative approach. However, drawing on information for food allergens it was considered that there was much uncertainty in response and it was unknown how the response varies in the population.
7. Item 5. Draft report
7.1 The Chairman reminded members they should be drafting their contributions for the next meeting. He asked for initial contributions, written as numbered paragraphs using bullet points as appropriate, to be sent to him by the end of March and said he would combine these before circulating for comments. He had in mind something that was concise and readable, but suitably scientific.
7.2 The outline of the structure, with indicative page sizes and responsibilities was discussed as:
- Introduction, Terms of Reference, Background (possibly 4 pages) + definitions, – Prof Ayres
- Exposures (possibly 6 pages) – Dr Cocker with Volatility from Prof Brown
- Toxicology (possibly 6-10 pages) – talking through current registration package, including acute AOEL, ADI, irritation, and sensitization – Dr Povey and Profs Boobis and Morris
- Issues, gaps, and recommendations - Prof Ayres
8. Item 6. Plans for stakeholder meeting
8.1 It was noted meeting should be publicised on the ACP website
9. Item 7. Date of next meeting
9.1 The Chair suggested the next meeting should be end of May or early June 2011