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The Combined Effects of Aneugenic Benzimidazoles Which Act by Disrupting Microtubuli Assembly


<P>Aneuploidy can be observed in the in vitro micronucleus test as the induction of micronuclei, which consist of genetic material expelled from the cell's nucleus during cell division. The ability of the individual benzimidazoles to induce micronuclei was first investigated using a Chinese hamster ovary cell line. Micronuclei were scored with an automated imaging system using image analysis.</P>

<P>Information about their potency was then used to make predictions about their joint effects when present as multi-component mixtures. Separate predictions were made depending on whether they acted in accordance with independent action or concentration addition. A mixture experiment, using seven benzimidazoles with multiple replications, was then performed to test the predictions. The project also investigated mixtures of benzimidazoles together with aneugens which act by dissimilar mechanisms. This was to investigate whether mixtures of aneugens may act according to concentration addition even if the mechanisms are dissimilar.

<P>Finally, the project was extended to assess mixtures of benzimidazoles together with some clastogens. Clastogens also cause micronuclei, but by an entirely different mechanism, causing chromosome breaks rather than the loss of whole chromosomes from the nucleus during cell division. Current expectation was that there would be no combination effects between aneugens and clastogens. </P>

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<P>The Committee on Mutagenicity of Chemicals in Food, Consumer Products and the Environment (COM) recommended research to study the way benzimidazoles work together when present as mixtures to cause a chromosome abnormality (aneuploidy). Benzimidazoles are used as pesticides (fungicides) and veterinary medicines (anthelmintics). Most benzimidazoles are recognised to be aneugens, i.e. substances which can cause changes in the number of copies of chromosomes by affecting the segregation of chromosomes during cell division. Benzimidazoles cause aneuploidy by inhibiting microtubule formation. The COM recommended that combinations of benzimidazoles be tested to investigate whether the benzimidazoles act independently (independent action) or according to the principle of dose/concentration addition.</P>
<P>For independent dose or concentration addition, the effects of a mixture are as predicted by adding up the doses or concentrations of the individual substances after adjusting for differences in their individual potencies. A key implication of dose/concentration addition is that combined effects may occur when all mixture components are each present at low doses/concentrations at which they are ineffective on their own.
<br/>If benzimidazoles are found to:
<UL><li>act according to dose/concentration addition, then account needs to be taken of their combined exposures in dietary risk assessments </li>
<li>act independently then risk assessments can assess each benzimidazole separately</li></UL>

University of London - School of Pharmacy
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