ToxSci Advance Access originally published online on August 21, 2009
Toxicological Sciences 2009 112(1):175-184; doi:10.1093/toxsci/kfp178
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Effects of Methyl Mercury in Combination with Polychlorinated Biphenyls and Brominated Flame Retardants on the Uptake of Glutamate in Rat Brain Synaptosomes: A Mathematical Approach for the Study of Mixtures
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* University of Oslo, Department of Biochemistry, Institute of Basic Medical Sciences, NO-0317 Oslo, Norway
Norwegian Defence Research Establishment, NO-2027 Kjeller, Norway
1 To whom correspondence should be addressed at Norwegian Defence Research Establishment, P.O. Box 25, N-2027 Kjeller, Norway. Fax: +47-63807115. E-mail: espen.mariussen{at}ffi.no.
Received June 8, 2009; revision received July 28, 2009; accepted July 28, 2009
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Abstract |
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Regulatory limit values for toxicants are in general determined by the toxicology of the single compounds. However, little is known about their combined effects. Methyl mercury (MeHg), polychlorinated biphenyls (PCBs), and brominated flame retardants (BFRs) are dominant contaminants in the environment and food. MeHg is a well known neurotoxicant, especially affecting the developing brain. There is increasing evidence that PCB and BFRs also have neurotoxic effects. An enhanced effect of these toxicants, due to either synergistic or additive effects, would be considered as a risk for the fetal development. Here we studied the combinatorial effects of MeHg in combination with PCB or BFR on the reuptake of glutamate in synaptosomes. To provide the optimal conclusion regarding type of interaction, we have analyzed the data using two mathematical models, the Löewe model of additivity and Bliss’ model of independent action. Binary and ternary mixtures in different proportions were made. The toxicants had primarily additive effects, as shown with both models, although tendencies towards synergism were observed. MeHg was by far the most potent inhibitor of uptake with an EC50 value of 0.33µM. A reconstituted mixture from a relevant fish sample was made in order to elucidate which chemical was responsible for the observed effect. Some interaction was experienced between PCB and MeHg, but in general MeHg seemed to explain the observed effect. We also show that mixture effects should not be assessed by effect addition.
Key Words: neurotransmitter; predictive toxicology; polychlorinated biphenyls; methyl mercury; brominated flame retardants; ecotoxicology.