A cocktail of problems

The UK government is due to recognise concerns about the ‘cocktail’ effect of pesticide mixtures. A draft report distributed for public consultation prior to publication later in the year has confirmed a lack of understanding about the combined toxicity of mixtures of pesticides. Peter Beaumont and David Buffin report.

Pesticides are approved in the UK solely in relation to individual products. This ignores the ‘cocktail effect’ where exposure to multiple chemicals may carry uncertain risks. Additive effects are possible with some pesticides targeting similar metabolic pathways, for example organophosphate and carbamate pesticides can both target the enzyme cholinesterase, critical for nerve functioning. Synergistic effects can also occur, where the effect of multiple pesticide exposure can be greater then the sum of all the individual effects. It is difficult to predict the effects of exposure to mixtures of pesticides. 
    Research carried out by the Ministry of Agriculture, Fisheries and Food in the late 1990s demonstrated the existence of multiple residues in commonly consumed foods. Following this the Food Standards Agency requested the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) to set up the Working Group on Risk Assessment of Mixtures of Pesticides (WiGRAMP).
    In February 2002 the WiGRAMP working group released a draft report for public comments, and a finalised report will be published in June 2002.
    The terms of reference for the working group were:

• To assess the potential for multiple residues of pesticides and veterinary medicines (including sheep dips and other chemicals used to control animal parasites) in food to modify individual toxicity in humans – the so-called cocktail effect. 
• To evaluate what assumptions can be made about the toxicity of pesticides in combination. 
• To consider the potential impact of exposure to pesticides and veterinary medicines by different routes.
• To formulate advice on the standard risk assessment procedures applied to the safety evaluation of individual pesticides and veterinary medicines in the light of the above considerations.

It is important to recognise that the potential dangers exist from non-food products such as those used in the house and garden as well as food related pesticides.

Many areas of concern
In recent years a number of stakeholders have expressed concerns to PAN UK and other public interest groups about specific pesticide active ingredients over which there may be mixture-related concerns, and also the situations in which those active ingredients may give rise to exposure.
The interactive effects of mixtures has been known and indeed exploited for some time. Synergists have been important in the formulations of pesticides (particularly the synthetic pyrethroids) and are not always disclosed as part of a regulatory data package on the active substance or on labels. Regulatory assessment is usually limited to the effects on the acute toxicity of the formulation.

Specific chemical concerns
Research has highlighted pesticide impacts of endocrine disrupting chemicals (EDCs). EDCs may be responsible for adverse effects in wildlife including birth defects, reproductive failure and developmental abnormalities of the organs of reproduction, together with the growing incidence of breast cancer in women and decreasing sperm counts and increasing incidence of testicular cancer in men. Impacts on wildlife may serve as indicators of potential human health problems. More information is needed on issues such as exposure, persistence and potency of EDCs. Over 40 pesticides have been identified as possible EDCs, and users await advice on what alternatives they should use.
    The anticholinesterase group of pesticides (organophosphate and carbamates) have appreciable acute toxicity, by virtue of their neurotoxicity, and there is concern that some exposures will be additive.
    The US Environmental Protection Agency has expressed concerns about common mechanisms of toxicity for the dicarboximide group of fungicides (vinclozolin, procymidone and iprodione). There may be other groups of pesticide chemicals that have common mechanisms of action and these need to be identified.

Developing country problems
The problems of mixtures of pesticides were highlighted by a formulation of three active ingredients sold in Senegal for use on groundnuts, which resulted in over 90 poisonings and at least 20 deaths during the 2000-01 groundnut season (see p16). Two products were sold to farmers in powdered formulations containing 15% thiram, 7% benomyl and 10% carbofuran. The hazard data indicated that the most likely cause of poisoning was carbofuran. However an examination by the US EPA indicated that the toxicology of thiram is of relevance since it is a known sensitizer in humans. Developing countries do not have the capacity to regulate pesticides, and need to depend on high standards in countries like the UK for guidance.

Groups at risk
Some sub-group populations may be at more risk than others. From the exposure point of view, young children have a greater intake of food than adults on a body weight basis and have different intake patterns. Furthermore, chemicals may have permanent effects on developing systems in the foetus, neonate and young children which would be transient in the adult. Such systems may include the endocrine and developing nervous system.
    Public interest groups have also pointed to the multiplicity of sources to exposure to pesticides: food, drinking water, home and garden use, occupation exposure, public hygiene, vector control, consumer goods, timber treatments and veterinary medicines.

A lack of regulatory control
The impact of combined exposure to multiple pesticides of either toxicologically different or similar groups is rarely addressed. The impact of multiple sources of exposure is not often considered. Many of the regulation procedures concerning pesticides and veterinary medicines are being harmonized at the EU level, but the process is slow and as a result national member state legislation remains in force as a stop-gap measure.

Evidence of food chain exposure 
Because residue surveillance for pesticides and veterinary residues is not random but instead targeted on products that are likely to have problems, it is extremely difficult to assess the frequency at which residues occur either below or above the statutory maximum residue limits (MRLs). A random programme of surveillance is needed to assess the frequency of dietary residues. This would require an increase in the current budget that government spends on residue analysis. 

The toxicology of mixtures
Because of complexity and variability of chemical mixtures that may occur in the environment, risk assessment of their potential toxic effects is an extremely difficult task. Most attention so far has looked at combined actions on biological targets at relatively high levels of exposure. Direct chemical reactions can occur between the components of a mixture; relatively few studies of these substances have investigated these reactions.

Implications for human health
In relation to most examples of possible human exposure to multiple residues it will be important to evaluate whether any effects are likely to occur at low levels of exposure.
    Animal toxicity studies with defined chemical mixtures have shown that the type of combined action or interaction found at clearly-toxic-effect levels do not necessarily predict what will happen at non-toxic effect levels including levels only slightly lower than the lowest observed adverse effect level (LOAEL). Even if one of the chemicals occurs at a slightly toxic-effect level, the type of combined actions of the mixtures may be different from that occurring at a clearly toxic-effect level. However, precisely what happens at non-toxic-effect levels is paramount to assessment of the potential health risk for humans exposed to mixtures of pesticides and similar substances. Generally when exposure levels of the chemical within a mixture are in the range of No Observed Adverse Effect level (NOAEL) no additivity and no potentiating interactions are found.
    On the other hand in vivo (live) studies of chemicals that exhibit the same target organ and the same mode of action suggest that additivity occurs.
    Some studies addressing the combined effects of pesticide mixtures showed clear signs of potentiation in animals exposed to effect levels of individual compounds, but direct extrapolation of these findings to lower levels may not be valid.

The working group’s draft recommendations
There are many areas in which understanding about the cocktail effects requires greater clarity. 

Research requirements include

• Changing the way in which the government estimates the range of population exposure to pesticides and veterinary residues, in order that true exposure of residues in food can be established. Dietary and food consumption surveys in the UK should continue to cover all social, age and ethnic groups within the population. The effect of processing food should also be considered.
• Methods should be developed to assess the body burdens of mixtures of pesticides and veterinary medicines from food and other sources of exposure. This work should take into account the differing responses people have to chemical exposure.
• Work should be carried out to establish the basis for a systematic framework to appraise the potential for combined actions, and to facilitate the risk assessment of exposures to mixtures of pesticides, veterinary medicines and similar substances.
• Experimentation systems are needed to assess the nature and dose-response relationships for the combined effects of these chemicals. Such studies should be performed at doses that include those potentially ingested by humans in the diet. Groups of pesticides having common targets of toxicological action should be identified. 

Regulation

• The approval of pesticides and authorisation of similar compounds used in veterinary medicines and human medicine, should include more formal analysis of the potential for combined toxic action due to the addition of other substances to the product formulation. Pesticide tank mixes also require assessment. Approval of these chemicals should consider all sources of exposure.
• When considering the risk assessment for combined exposure, the default assumptions should be that chemicals with different toxic actions will act independently, and those with the same toxic actions will act additively.

Public information

• Establish a central and accessible information resource concerning all forms of human exposure to pesticides and similar substances;
• Assess the extent of available information to the domestic pesticide user, and its ease of comprehension. 

Consumer concerns
Public interest groups have welcomed the process of public consultation initiated by the Food Standards Agency. It is unusual to allow this level of public participation, prior to final publication.
    The draft WiGRAMP report highlights how little information is available about the cocktail effects of pesticides. It is clear that huge sums of money would be required to research and assess the cocktail effects of pesticides – where will this come from? But this must not be used and as an excuse for not tackling the many complicated issues raised. The government must prioritize and produce a detailed timetable and a plan for action. 
    Environmental and consumer groups have expressed concern about the cocktail effect, but as yet evidence of the occurrence and importance of such combined action in humans remains uncertain. The focus tends to be on consumer exposure to pesticides through the diet and in the home. But what of the impacts of mixtures on farmers and others who work with pesticides, and the impacts of mixtures on the environment?
    It is unclear how the pesticide regulatory process will cope with the uncertainty of assessing the combination effects of pesticides. The government must therefore adopt a more precautionary approach to pesticide regulation, something not mentioned in the draft WiGRAMP report. Its also needs to adopt a pesticide reduction policy that progressively reduces our dependence on chemical pest control. The process of reviewing pesticides on a chemical-by-chemical basis must come to an end.

For copies of WiGRAMP’s draft consultation report contact: Keith.Butler@foodstandards.gsi.gov.uk. The final report, due to be published in June 2002, will take into account the concerns of public interest groups raised at an open meeting (held on 28 February 2002) that was organised by the Food Standards Agency. Send written comments on the draft report to Keith Butler by 31 March 2002.

Peter Beaumont, PAN UK’s former Development Director, is consumer representative on WiGRAMP Committee.

[This article first appeared in Pesticides News No. 55, March 2002, pages 10-11]