from Nate Martin, Seinior Water Quality Scientist, Jones & Stokes:
The first flush is always the worst, especially in the lower reaches of rivers primarily due to the combination of the runoff collecting contaminants, and because of agricultural return flows. However, because agricultural operations generally don't exist above most lakes (small or large), pesticides are not much concern in Lakes. The primary concern in my opinion, would be heavy metals from acid mine drainages such as mercury or even worse methyl mercury since it is dissolved into the water column. In high concentrations heavy metals can impact the central nervous system etc.... However, most heavy metals will tend to stay attached to sediment and not be directly in the water column. Plus, since dilution is the solution to pollution, the amount of polluted runoff would have to be pretty incredible to have an impact.
In a nutshell, don't go board on a lake after the first flush event if you know that there are present or historic mining operations upstream. The Squaw Creek arm of Lake Shasta is supposed to be pretty bad but Shasta is such a large lake with such a large retention time that it can assimilate a lot of bad runoff without having too much impact. I know of others as well.