Balancing the nutritional benefits of fish consumption against methylmercury toxicity, and evaluating the impact of genetic polymorphisms in glutathione S-transferases on susceptibility to methylmercury in a Swedish population

............................................................................................................................................. 5 Introduction Background of the study .......................................................................................................... 6 Objectives ................................................................................................................................ 9 Hypothesis ............................................................................................................................... 9 Scope and limitations............................................................................................................. 10 Review of Literature Literature support for the hypothesis ..................................................................................... 12 Preliminary evaluation of the hypothesis............................................................................... 20 Methodology Human data set of mercury concentration and ω3 PUFA levels ........................................... 23 Simplification of the hypothesis into a working model ......................................................... 23 Implementation of the Modified Biological Model ............................................................... 23 Sensitivity testing of the Modified Biological Model............................................................ 24 Model simulation ................................................................................................................... 25 Scenario analysis.................................................................................................................... 25 Results Baseline behavior of the Modified Biological Model............................................................ 27 Scenario 1. Methylmercury exposure in the Swedish data set............................................... 28 Scenario 2: The US-EPA reference dose ............................................................................... 32 Scenario 3: Increasing fish intake .......................................................................................... 33 Scenario 4. Increasing fish intake by a smaller increment..................................................... 33 Scenario 5. Modeling the putative effect of GST polymorphisms ......................................... 34 Discussion Risks of methylmercury toxicity in the Swedish sample population ..................................... 36 Increasing fish intake ............................................................................................................. 36 Choosing between several estimates of the NOAEL ............................................................. 37 Modeling the effect of genetic polymorphisms .................................................................... 38 A systems approach to mercury toxicity................................................................................ 39 Setting a new critical limit ..................................................................................................... 40 Summary and Conclusions .............................................................................................................. 42 Literature Cited................................................................................................................................ 43 Appendix A: STELLA Diagram of the Modified Biological Model............................................... 46 Appendix B: STELLA Code of the Modified Biological Model .................................................... 47