COT: Stakeholder meeting: 17 April 2001

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Stakeholder meeting: 17 April 2001

Report of the Open Meeting of the Working Group on the Risk Assessment of Mixtures of Pesticides and Veterinary Medicines (WiGRAMP), Tuesday, 17 April, Aviation House, London.

This open meeting, which included consumers, academics and industry representatives, provided approximately 40 stakeholders with the chance to hear presentations from individuals and organisations who have an interest in this issue. They included the current pesticide regulatory system; whether a more precautionary approach to pesticides is needed; and current scientific knowledge of the toxicology of pesticide mixtures (including potential health problems). The final presentation drew attention to the health concerns of agricultural and industrial workers, who come into contact with pesticides on a daily basis.

Professor Frank Woods, Chair of the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) and WiGRAMP, opened the meeting. He stated that the main aim of this meeting was to allow stakeholders and other parties to contribute to the Working Group’s work towards producing a more relevant and balanced final report. It is planned that the final report will be published in spring 2002.

Presentation: 'Current Procedures for Human Risk Assessment of Pesticides and Veterinary Medicines'
The opening presentation given by Dr Ian Dewhurst (Pesticides Safety Directorate, MAFF) and Mr Andy Browning (Veterinary Medicines Directorate, MAFF) covered the evaluations currently performed to assess the risks to humans exposed to pesticides or veterinary medicines, and the derivation of operator and consumer exposure estimates, including those for children and adults. In most instances, these assessments are performed without considering what other pesticides are available.

Dr Dewhurst stated that combinations and interactions are considered under specific circumstances. For example, the acute toxicity data on the formulation as sold are compared with what is expected based on its components. Any significant discrepancies are investigated further. For residues consisting of metabolites of toxicity similar to or greater than the active substance, a combined residue definition and simple combined assessment are performed. Dr Dewhurst also explained how pesticide evaluations do not usually address the potential interactions when concurrent or sequential exposures occur to two or more pesticides having a similar mechanism of action. Initial work to develop a framework for anticholinesterase compounds has been postponed until the completion of the Working Group's final report.

Mr Browning discussed current procedures for human risk assessment of pesticides and veterinary medicines. These procedures comprise user safety and consumer safety.

User safety assessment is applicable to all individuals exposed as a result of administration of a veterinary medicine and/or contact with an animal treated with a veterinary medicine (veterinary surgeons/nurses, farmers/farm workers, animal handlers, pet owners and children). Products can be handled safely, provided that unnecessary exposure is avoided and advice is given on safe storage, handling and disposal. Mr Browning explained that the assessment is product-specific and covers the potential toxicity of the active ingredient(s), along with all other excipients present in the formulation.

Regarding consumer safety, maximum residue limits (MRLs) - the maximum concentration of a veterinary medicinal residue permitted to be present in the tissues or products of food-producing animals - must be established for each ingredient intended for use in veterinary products. In the case of new substances, MRLs have to be established before a marketing authorisation for a product containing the substance can be issued.

In order to determine MRLs, an Acceptable Daily Intake (ADI) must be set. Mr Browning stated that along with the consideration of toxicological ADI, pharmacological and, in the case of antimicrobial substances, microbiological ADIs must be examined. The overall ADI and MRLs for the substance will be based on the lowest of these three endpoints. When a marketing authorisation for a product for food-producing animals containing the active ingredient is applied for, a withdrawal period before slaughter is determined. This withdrawal period, determined from residue depletion studies, is the minimum period determined for residues in edible tissues to fall below the MRL.

In determining ADIs, a consumer risk assessment is conducted on a substance- specific basis that does not generally take into account any 'cocktail' effects. However, on the advice of its Safety Working Party, the EU Committee for Veterinary Medicinal Products restricts the theoretical maximum daily intake of residues from veterinary usage to 45 per cent of the ADI for those substances that are also used as agricultural pesticides.

The presentations were followed by questions and comments on the following:

Approval process for genotoxic compounds - The presenters noted that in the case of pesticides, one group of compounds (benzamidazoles) has a known mechanism for genotoxicity. Because the threshold has been identified, approval for the compound can be granted. For veterinary products, it was explained that no approval would be given to genotoxic substances.
Clarifying the differences between MRLs for pesticides and veterinary medicines - Mr Dewhurst noted that the MRL for pesticides is based on trials that determine what the residues are in particular crops. This information is not directly related to the ADI or any other reference value and the results from the residues feed into the over all assessment. For veterinary medicines, when the ADI has been established, a standard food basket for the average consumer is used and the tissue distribution of residues in the target is stated to set the MRL. If consumers are eating the standard food basket, they are not going to exceed the ADI.

Presentation: 'Why a More Precautionary Approach is Needed to the Approval and Use of Pesticides'
Ms Sandra Bell from Friends of the Earth addressed the need for a more precautionary approach to the approval and use of pesticides. She reinforced the idea that the public are exposed to pesticides from a number of different routes, including food, water, and home and garden use, as well as the fact that pesticides are damaging to the environment. She also stated that Friends of the Earth also considered the current approval process for pesticides to be deficient in a number of aspects, notably that it was too secretive and the public was not allowed to participate in the deliberations of the approvals committees.

Other major topics of concern to Friends of the Earth were the substitution of older existing pesticides with less toxic alternatives, and the screening procedure for hormone disrupting chemicals. Ms Bell noted that a more precautionary approach should be taken to the approval of pesticides, and that this would require a radical reassessment of the approval procedure. Suggested methods for the reduction in the overall use of pesticides were also made, and it was stated that retailers should also take more action to ensure that no pesticide residues are present in produce sold to consumers. They also questioned how the government could state with such confidence that pesticides in food would not cause health effects, when it appeared that the picture of what people were actually exposed to was incomplete. Friends of the Earth were of the opinion that the current monitoring programme for pesticide residues was limited because it tested few samples and missed commonly eaten food.

The presentation was followed by questions and comments on the following:

The significance of pesticides residues in light of other public health issues: An audience member expressed the view that more lives could be saved through dietary intervention to decrease deaths from stroke and heart disease. The audience member asked Ms Bell if she could quantify the number of lives saved due to decreasing pesticide use. Ms Bell noted the importance of a precautionary approach towards pesticide use, especially in light of suggestive trends in their effects on human health. Citing examples such as increasing breast cancer incidence and declining sperm counts, Ms Bell explained that a precautionary approach in no way mutually excluded steps taken to improve dietary health.
Dose response data: Asked if there was any acceptable limit of pesticide residues, Ms Bell replied that a normal dose-response relationship did not exist for chemicals that are known hormone disruptors. As a result of these substances' ability to produce deleterious health effects at low levels, Ms Bell explained that no acceptable level exists.
Incentives for farmers to decrease pesticide use: In response to an audience member's concern that farmers have no incentive to curtail their use of pesticides, Ms Bell noted the importance of education. In many cases, she said, farmers are not being taught how to minimise pesticide use. She recommended that retailers and Government assume responsibility for training farmers. She also said Government should help farmers who want to farm organically and decrease pesticide use.

Presentation: 'Modelling Exposures to Multiple Chemicals'
David Tennant (FCRA) and Christine Chaisson (Lifeline Group USA) gave an overview of pesticide intake estimation and the fact that this has traditionally focused on one chemical at a time. It was stated that estimating exposure to a combination of residues in one food can be relatively straightforward, but exposure to multiple chemical residues is not usually restricted to incidents where residues occur in the same food item. Furthermore, food items that are consumed in different meals during the same day or perhaps over longer periods could also contain residues. The presentation discussed problems associated with making realistic estimates of consumer exposures to multiple chemicals, some current developments, and the use of probabilistic time-sequence lifetime modelling to possibly overcome these problems.

The presentation was followed by questions and comments on the following:

Children's diets: A concern was raised regarding the diets of toddlers, particularly those at the lower end of the income range. It was asked whether any studies have been conducted that target a pesticide from the particular crop it is used on through to families' dinner tables. Noting that they were unaware of any such studies, the presenters proceeded to explain how their analysis relies on models, which give, for example, an indication of the distribution of residues on potatoes and other crops. The models used take into account food consumption patterns of small children so that their potential intakes can be predicted.
The probability distributions of chemicals: It was asked on what basis the probability distributions for the same chemical, or across different chemicals, could be added in an aggregate or cumulative situation. The presenters replied that if a toxic equivalency factor approach is appropriate for combining pesticides with OP pesticides, for example, then they could account for this in the model. Each pesticide could be factored up, and corrected for its equivalency to the key pesticide.
Residue surveillance data: A question was asked regarding the adequacy of the pesticide residue surveillance data and whether the residue analysis is insufficient. The presenters concluded that enough data are not available and that due to cost limitations, the Working Party must carefully target its resources. As a result, only data 'snapshots' of a particular year are available.

Presentation: 'Concepts for the Prediction and Assessment of Mixture Effects of Pesticides/Veterinary Medicines'
This presentation by Dr Andreas Kortenkamp (School of Pharmacy, University of London, Centre of Toxicology) discussed problems associated wth making realistic estimates of consumer exposures to multiple chemicals. Dr Kortenkamp stated that the analysis of mixture effects is considered by many regulatory agencies to be an issue of very high importance, although there have been few appropriately conducted experimental studies, and within these, combinations of more than two to three chemicals were rarely analysed. The principles of synergism, antagonism and additivity were defined, and ways of calculating additivity (effect summation, concentration addition and independent action) were also explored.

Research on combination effects of oestrogenic pesticides and consumer chemicals was presented that suggested that multi-component mixtures of 12 chemicals could be accurately predicted by using the pharmacological model of concentration addition. Simple addition of the responses of single mixture components would have led to dramatic under-estimations of experimentally observed combination effects. Dramatic mixture effects were observed when each chemical was present at sub-threshold concentrations. These findings were said to demonstrate the limitations of single agent effect thresholds for regulatory purposes, and that ignoring the cocktail effects during risk assessment will lead to significant under-estimations of risk. Areas for future research were also identified.

The presentation was followed by questions and comments on the following:

The usefulness of PBPK modelling in assessing mixtures and combining into exposure assessments: Dr Kortenkamp noted that while aware of this concept, he had not yet seen examples where it had been applied to multi-component mixtures.

Presentation: 'Health Risks of Residues of Crop Protection Products in Food'
In the next presentation, Ms Trish Malarkey and Mr Kim Travis (Syngenta) attempted to apply a risk-based approach to the human health concerns resulting from potential exposure to multiple residues of crop protection products in the diet. A review of experimental data on combinations of chemicals at low dose levels was presented. These data demonstrated that adverse systemic effects are unlikely to occur as long as the individual components of the mixture were present at levels below their toxicity thresholds. While the data suggested that when tested at or above the toxicity threshold there was no simple additive effect, there was the theoretical possibility that the threshold level for the individual toxic effects would be reduced.

Recent exposure/residue data was used to demonstrate that the risk associated with this possibility was thought to be negligible, by illustrating the relationship of the toxicity thresholds of plant protection products to MRLs, and to residue levels on food in trade. Residue levels in food are known to be generally extremely low, and most food has no detectable residues. In the opinion of the authors, adequate safety margins exist in the risk assessment for dietary exposure to residues of single or multiple plant protection products. Therefore, further animal testing or the application of a special safety factor for combinations of residues is not warranted.

It was also stated that while existing methodology can be used to successfully assess risks to human health, more could be done to ensure that the hazard and exposure data that are generated are specifically aligned to the needs of risk assessment.

The presentation was followed by questions and comments on the following:

Tank mix data: A concern was raised that insufficient data on tank mixes are available. In particular, it was asked whether information is submitted on a whole (formulated) product as sold to the farmer, or if research is conducted only on the active ingredient. The presenters noted that data on tank mixes are not produced and that the tests performed on the formulation, consist of a battery of acute toxicity studies.
Real dietary exposure: A comment was made regarding the importance of assessing multiple pesticide exposure in all areas, including diet, household products and the garden. In particular, the audience member asked how pesticide safety should be assessed in view of the effects of hormone-disrupting chemicals. The presenters replied that this assessment is achieved using multi-generation and repeat dose studies. These would cover the developmental effects in two species with the endpoints being assessed comprehensively and functionally.

Presentation: 'The Toxicology of Mixtures'
Dr Vyvyan Howard (University of Liverpool) presented the next talk, which covered the presence of bioaccumulative compounds in virtually all animal life, along with dietary intakes of OP compounds etc. and possible links to chronic illnesses such as Parkinson's Disease. Methods for classifying the toxicity of mixtures of congeners of similar basic molecules with a similar mechanism of toxic action are available, especially PCB's and dioxins, but these tend to have limitations.

The possibility of synergistic activity of compounds in a mixture, particularly when the constituents have different modes of action, was considered. This was demonstrated using a recent study which showed that, in vitro, pesticides can act in a more than additive manner. With hormone disrupting substances, many possible mechanisms can act, from disturbance of hormone synthesis and transport to receptor expression and binding through to hormone metabolism and excretion. It was stated that with such complex systems, it is difficult to conceive reliable testing methods. For this reason, there is a strong case for following a policy that minimises the exposure of the population to synthetic chemicals that persist and bioaccumulate. If, in addition, they can disrupt hormone systems, an additional level of urgency would be needed.

The presentation was followed by questions and comments on the following:

Mixtures of pesticide formulations: An audience member noted that with the exception of glyphosate, the pesticides mentioned during the presentation were presumably applied in a relatively complex formulation. It was asked what was the relevance of exposing in vitro cell lines to formulations of pesticides which would not be encountered in vivo. It was also asked to what extent Dr Howard examined interactions between the formulants rather than the active ingredients. Dr Howard responded that each of the components was tested separately as a control in the assay. However, he noted that in vitro work can be problematic, in that it can provide a mechanism but cannot really emulate the in vivo situation. It can provide clues for further research.

Presentation: 'Pesticides, Endocrine Disruption and Potential Human Health Effects: Range Of Endpoints and Mixture and Combined Exposure Considerations'

The next scientific presentation was by Dr Philip Harvey (National Centre for Environmental Toxicology, Medmenham, Marlow). Dr Harvey's presentation focused almost exclusively on endocrine disrupting compounds. An overview of the endocrine system, along with the function of individual hormones was given as an introduction to the subject. Examples of known and suspected endocrine disrupting chemicals and the range of effects they may induce were also provided. It was stated that this is still a relatively new field, and most of the work done thusfar has been on oestrogenicity in vitro, but combined effects on other endpoints are beginning to be studied. This work can probably only be assessed in vivo and should particularly examine effects on development. It is clear that the number of pesticides and endocrine endpoints, together with the types of interactions that can occur between the various compounds in the test systems (antagonism, additivity, synergism), is extremely large and requires a co-ordinated approach.

The presentation was followed by questions and comments on the following:

Oestrogen mimickers: It was asked why oestrogen mimics are more common than the other classes of hormone disrupters mentioned during the presentation. Dr Harvey replied that many organochlorine compounds have very similar chemistry. He also noted that many of these compounds have weak oestrogen activity and that anything that has a phenol input seems to confer oestrogenicity.

Presentation: 'Working with Pesticides'
The final presentation of the day was given by Mrs Maureen Dennis, a farm-worker in Lincolnshire for many years. She had a worrying tale to tell regarding exposure on arable farms almost half a century ago. At that time, there was no monitoring for health effects, and none have been performed since. In the intervening years, there have been a large number of incidents of cancer, and now heart disease, around the area in question. It was stated that farmers tended to seek advice on spraying from the chemical companies supplying the pesticides they are using - a situation that is far from ideal.

Mrs Dennis was also of the opinion that if the farmers were not concerned for their employees, they will not be concerned about the consumers. It was also mentioned that it may be that GPs do not wish to link pesticides to the diseases they are seeing for fear of 'rocking the boat'. Furthermore, adverse reactions may not be reported because people believe the reporting procedure is ineffectual and sufferers could jeopardise their jobs by doing so.

The presentation was followed by questions and comments on the following:

Workers having better protective equipment: It was asked how farmers could be persuaded to give their workers better protective equipment when using pesticides. In Mrs Dennis’s opinion, improving the situation was difficult, as personal protective equipment can be expensive and many worker do not wish to say anything that may result in them losing their jobs.
The frequency of visits of Health and Safety Inspectors: Mrs Dennis stated that these used to be extremely infrequent or even non-existent, and contacting the Inspector carried the unspoken threat of dismissal.

General discussion
At the conclusion of the presentations, a general discussion took place. The main points covered were as follows:

The need to devise clear definitions and adhere to them: The meeting was assured that there would be an agreed set of definitions and that the text of the report with be consistent throughout in relation to them.
Concern over the strength of current pesticide regulations: The meeting was reminded that although the group had no direct powers to influence regulatory procedures. However part of the group’s terms of reference was to make suggestions in relation to regulation.
There was a concern that not enough foods are currently being monitored for pesticide residues, in particular, imported food products: It was noted that the ideal situation would be to monitor all pesticides and all foods. However,given the size of the UK market this be impracticable due the enormous cost and so a balance had to be struck. Currently, targeted monitoring programmes are in place across the country, that assess a wide variety of foods (and a wide variety within specific food types, eg imported and UK-grown). The use of multi-residue methods enables a wide range of compounds to be detected and more specific monitoring could be carried out if this were necessary.
Other routes of exposure: The Chairman was able to confirm that the working group would be looking at routes of exposure other than food.
Sharing of residue data by retailers: A question was raised as to whether the results of residue monitoring carried out by retailers was being made available to the working group. In response, one of the retailers present noted that the results of extensive monitoring programmes had been made available and that there was a common interest in reducing pesticide residues.
Pressure on producers: The meeting was reminded of the real problems faced by growers/producers in producing 'perfect' products to meet consumer demands. In seeking to meet this demand there was a real danger of increased pesticide usage and wastage of 'health' produce.
How will this review impact on current EU activity: It was the intention of the Agency to forward the conclusions of the working group via the COT to the EU. If in the light of the group's considerations it was felt that some amendment to existing regulations any tightening of the rules would have to be initiated at EU level.

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Stakeholder meeting: 17 April 2001