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Mercury
The Truckee River, a source water for Pyramid Lake, has previously been affected with mercury through Steamboat Creek by legacy mining of the Comstock Lode. Mercury is highly bioaccumulative, and tissue concentrations of mercury have been observed several times greater than mercury concentrations found in water. Mercury in water is transformed to methylmercury by microorganisms and bioaccumulates up trophic levels, usually then found attached to the amino acid cysteine. Methylmercury toxicity symptoms in humans include paresthesia, deafness, and dysarthria among others, like the destruction of neurons in cases of severe exposure. Several other effects of methylmercury have been studied, such as genotoxic effects like aneuploidy, polyploidy, and hyperdiploidy, immunotoxic effects like lymphocyte apoptosis, and developmental effects like cerebral palsy.

Although much of the research on mercury has been done on human effects, it may also affect other organisms as well. In particular, one study was conducted on the effects of mercury on American white pelicans at Pyramid Lake, but the mercury was found to be relatively harmless to the birds. Mercury concentrations were below known effect levels, no impact was reported on hatching success, no microscopic lesions characteristic of mercury toxicity were found, and high levels of mercury in adult livers of the birds suggested demethylation as a detoxification mechanism against mercury toxicity.

Other contaminants
The United States Geological Survey (USGS) analyzed water samples from the Truckee River for 258 analytes, a list greater in breadth than the U.S. Environmental Protection Agency's DSSAM Model. Among 8 water samples, the USGS detected camphor, galaxolide, limonene, benzene, ethylbenzene, naphthalene, o-xylene, styrene, toluene, xylene, 1,2,4-trimethylbenzene, dichloromethane, bromoform, chloroform, and the wastewater disinfection byproducts bromodichloromethane, dibromochloromethane, and 1,4-dichlorobenzene. The concentrations of these analytes are below the EPA's maximum contaminant levels and the USGS's health-based screening levels.

Trihalomethanes are often studied for carcinogenicity to humans, via animal cancer bioassays. The cumulative concentration of the detected disinfection byproducts bromodichloromethane, dibromochloromethane, and 1,4-dichlorobenzene is within a factor of 10 of the EPA's maximum contaminant level for trihalomethanes. The trihalomethane levels noted are below human health limits, but its toxicity to other organisms via transgenic mice and fish models remain areas to be studied further. However, further research may not be immediately crucial, as a recent study on wastewater treatment plant effluents from five cities in East China noted that trihalomethanes were only minorly responsible for cytotoxic effects, despite their dominance in the fraction of disinfection byproducts. This study suggests that haloacetonitriles and nitrosamines are of greater concern in wastewater treatment plant effluents.