Pesticides that work in the same way

The US Environmental Protection Agency (EPA) have used specific methods to establish Common Mechanism Groups (CMGs) for organophosphate and carbamate compounds. CMGs are groups of chemicals that demonstrate a common toxic effect. The EPA approach has been reviewed by officials from the FSA and other UK Government Departments, to assess whether these groups are appropriate in assessing the cumulative (combined) risk posed by exposure to multiple residues of organophosphate and/or carbamate pesticides used in the UK.

As part of the official authorisation process for new active substances, risk assessments are usually only carried out on individual substances. The assessment process does not generally consider the potential for active substances to interact with one another when present in combination. As foods can contain a mixture of pesticides or similar substances and they are eaten in combination, consumers may be exposed to many different chemicals over time, from foods, as well as from other sources including air and water.

In the UK, the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) was asked by the Food Standards Agency to set up a Working Group for the Risk Assessment of Mixtures of Pesticides and Similar Substances (WiGRAMP). WiGRAMP concluded in its report that the risk to consumer health from mixtures of pesticides and similar substances was likely to be small. However, areas of uncertainty existed about the potential for certain substances to interact and consumer exposure to certain groups of chemicals. Therefore, an action plan was drawn up to address regulatory, surveillance and research issues. Work in these areas is overseen by inter-departmental Science and Management Groups and a paper discussing the US EPA�s methods of establishing CMGs has been written for and reviewed by the Science Group. This group consists of toxicological experts from several Government Departments.

In the US, the Food Quality Protection Act (1996) currently requires the EPA to take into account the potential human health risks from exposure to multiple pesticides that cause their toxic effects in a similar way (or mechanism) and from pesticides sources other than food. To address the uncertainty about interactions of pesticides highlighted by WiGRAMP in respect of cumulative risks, officials from the Agency, and other Government Departments evaluated the EPA�s approach to grouping pesticides together based upon a common mechanism of toxicity, with a view to applying it to pesticides in use in the UK

The paper discussed by the WiGRAMP Science Group outlines the methods used by the US EPA to establish two CMGs, for organophosphates (OPs) and carbamates. OPs have been established as a CMG on the basis of their shared ability to impair nerve functioning (by inhibiting the enzyme acetylcholinesterase (AChE) by binding a phosphorus containing group to a specific amino acid base residue). This is the critical step that leads to a common spectrum of toxic effects of OPs. N-methyl carbamate pesticides have been established as a separate CMG on the basis of their similar structural characteristics. They share the ability to inhibit the same enzyme as OPs (AChE) at the same binding site (but via a carbamate rather than phosphorus containing grouping). Both CMGs cause enzyme inhibition that leads to adverse effects known as cholinergic toxicity.

The EPA established two separate CMGs for OPs and carbamates based upon the speed at which the acetylcholinesterase enzyme regenerates following inhibition. When the enzyme is inhibited by a carbamate, it recovers its activity at a significantly more rapid rate than if it has been inhibited by an OP. The EPA concluded that the toxic effects of these two classes were unlikely to overlap.

The Pesticides Safety Directorate in the UK takes account of the potential for consumers to be exposed to mixtures of pesticides. Simple dose addition is assumed for substances that have similar toxicological action, whereas effect addition is assumed where toxicological mechanisms differ. These considerations are made when evaluating products containing more than one active substance as part of a pesticide formulation. For further information, see the Pesticides Safety Directorate report (pdf document). A similar consideration is made in the case of veterinary medicine formulation, by the Veterinary Medicines Directorate.

A scientific methodology has yet to be developed to address risks from mixtures for most CMGs. However, the Advisory Committee on Pesticides (ACP) has developed a methodology for the anticholinesterase compounds (OPs and carbamates). The ACP has also recently recommended a technique for assessing compounds (including anticholinesterase compounds) that might have combined toxicity. This includes a consideration of the proportion of the respective acute reference doses taken up by the predicted exposures to each active substance. If the overall proportion (taken by summing the individual proportions) is small, then, assuming simple dose-additivity of the individual active substances, the intake would not represent a health risk. However, if exposure to each active substance represents a high proportion of the respective reference doses and the total exceeds 100% a more detailed consideration is needed. This method may overestimate the overall risk and therefore each case also has to be specifically evaluated. The current risk assessment approach has been limited to multiple residues of OPs or carbamates. For further information, see the Pesticide Residues Committee report (pdf document).

The decision by the EPA to group the OPs and N-methyl carbamates into separate CMGs has been the subject of debate in the UK. The paper invites discussion on whether the differences between the two groups provide a scientifically valid justification for grouping the CMGs separately. At a meeting of representatives from the FSA and other government departments, it was concluded that, given that assessments of exposure to mixtures of pesticides must assume continuous / repeated exposure to OPs and carbamates in combination, and given that the toxic effects of the two groups are the same, there is no scientific justification for grouping OPs and carbamates separately. It was therefore agreed that OPs and carbamates should be placed in a single CMG, based upon their shared ability to inhibit acetylcholinesterase (either via phosphate or carbamate containing groups), eliciting a common spectrum of toxic effects. The differences in the kinetics (speed of enzyme recovery) of the two types of reaction were not considered a sufficient basis for grouping the two classes of pesticides separately because individuals are not exposed to each type of pesticide alone or in any particular order. Placing the OPs and carbamates in a single CMG represents a more precautionary approach to risk assessment as pesticides from both groups will be included in estimating a combined intake. Therefore, using a single CMG for risk assessments of OPs and carbamates would be more protective for consumers.