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Characterisation of the nature of combined actions of chemical mixtures and estimation of dose response relationships for pesticide mixtures

Project Code: T10016

15/11/2011

Food and Environment Research Agency, Sand Hutton, York YO41 1LZ
MacNicoll, A ;
Central Science Laboratory
Hird, H;
Food and Environment Research Agency, Sand Hutton, York YO41 1LZ
Chisholm, J;
Central Science Laboratory
Lawley, W

In its report on Risk Assessment of Mixtures of Pesticides and Similar Substances, the Committee on Toxicity of Chemicals in Food Consumer Products and the Environment (COT) recommended a need for investigation of the nature and dose-response relationships for combined actions of chemical mixtures.

The general population are exposed to mixtures of low levels of pesticide residues in the diet. It has been suggested that such mixtures may interact causing responses that would not be expected from exposure to the individual residues. In order to take forward the research recommendations of the COT and to address such concerns, the Food Standards Agency funded a programme of work encompassing 17 projects including this project.

The variability of data obtained using the SH-SY5Y cell line was found to be high, which precluded distinguishing between additive, synergistic or antagonistic interactions statistically. Despite efforts at refining and adjusting the methodology, the reproducibility of the assay was sub-optimal. It was concluded that clumping of cells prevented addition of precisely the same number of cells to each assay resulting in variable amounts of AChE activity.

To address this issue, the project methodology was applied instead to AChE purified from human red blood cells. When all possible pairs of five pesticides were exposed to human red blood cell AChE, the results indicated that the mixture pairs behaved in accordance with concentration addition. The results obtained matched what is theoretically expected for compounds with similar modes of action (i.e. inhibition of the same enzyme). Human red blood cell AChE is not structurally identical to the type of AChE found in brain or at neuromuscular junctions and the refined assay with the purified enzyme could not detect interactions related to whole cells. These factors were recognised as limitations of the adjusted methodology.

The approach to the risk assessment of mixtures of substances with similar modes of action follows the advice of the COT such that such substances are considered to act additively whilst taking differences in potency into account. The balance of the evidence obtained by this project was considered to support the conclusion that mixtures of compounds with similar modes of action act in accordance with concentration/dose addition. In other words, the effect of exposure to two or more similar compounds can be estimated by simple addition of their doses after allowing for potency. There was no evidence for synergistic or antagonistic interactions.

Final report

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