Thimerosal and animal brains: new data for assessing human ethylmercury risk.

Since the 1950s, vaccines have contained thimerosal, a mercury-based preservative that breaks down to ethylmercury and thio-salicylate in the body. By some calculations, children given the usual schedule of vaccines containing thimerosal receive ethylmercury in doses exceeding the U.S. Environmental Protection Agency's guidelines for methylmercury, a known neurotoxicant. Because of the lack of pharmacokinetic and toxicity data for ethylmercury, methylmercury has been used as a reference for ethylmercury toxicity based on the assumption that the two compounds share similar toxicokinetic profiles. However, a new animal study shows that methylmercury is an inadequate reference for ethylmercury due to significant differences in tissue distribution, clearance rates, and ratios of organic to inorganic mercury in the brain [EHP 113:1015-1021].

During their first two years, children in the United States may receive more than 20 routine vaccinations. The rise in childhood autism has sparked concerns that thimerosal-derived ethylmercury may be at least partly to blame for some of these cases--concerns that are largely driven by awareness of methylmercury's neurotoxicity. Beginning in 1999 thimerosal-free versions of routine vaccines for children under age 6 started becoming available. However, as of winter 2005, the flu vaccine still contained thimerosal, and the preservative continues to be used in vaccines in other countries.

In the current study, researchers assigned 41 newborn monkeys to one of three exposure groups. Seventeen of the monkeys were injected with vaccines spiked with thimerosal for a total mercury dose of 20 micrograms per kilogram ([micro]g/kg) at ages 0, 7, 14, and 21 days, mimicking the typical schedule of vaccines for human infants. At the same ages, another 17 monkeys received 20 [micro]g/kg methylmercury by stomach tube to mimic typical methylmercury exposure. A third group of 7 monkeys served as unexposed controls.

The researchers drew blood from all monkeys prior to any exposure and at other points prior to sacrifice, which occurred 2, 4, 7, or 28 days after the last dosing on day 21. Total mercury concentrations were measured in blood samples, and total and inorganic mercury concentrations were measured in brain samples. Organic mercury concentrations were calculated from those values.

The initial absorption rate and tissue distribution of mercury was similar in both exposed groups. However, total mercury progressively accumulated in the blood of methylmercury-exposed monkeys and remained detectable 28 days after the last dose. Among thimerosal-exposed monkeys, total mercury in blood declined rapidly between doses, and the researchers estimated clearance to be 5.4-fold higher than in the methylmercury group. In the thimerosal group, the half-life of total mercury in blood was 6.9 days, compared to 19.1 days for the methylmercury group.

Brain concentrations of total mercury were approximately 3-4 times lower in the thimerosal group than in the methylmercury group, and total mercury cleared more rapidly in the thimerosal group (with a half-life of 24.2 days versus 59.5 days). However, the proportion of inorganic mercury in the brain was much higher in the thimerosal group (21-86% of total mercury) compared to the methylmercury group (6-10%). Brain concentrations of inorganic mercury were approximately twice as high in the thimerosal group compared to the methylmercury group. Inorganic mercury remains in the brain much longer than organic mercury, with an estimated half-life of more than a year. It's not currently known whether inorganic mercury presents any risk to the developing brain.

Given these findings, the researchers caution that risk assessments for thimerosal based on studies using blood mercury measurements may not be valid, depending on the design of the study. Further, the observed differences in distribution and breakdown of mercury compounds between exposed groups indicate that methylmercury is not a suitable model for thimerosal toxicity.

The researchers emphasize, however, that the risks associated with low-level exposures to inorganic mercury in the developing brain are unknown, and they describe other research linking persistent inorganic mercury exposure with increased activation of microglia in the brain, an effect recently reported in children with autism. They recommend further research focused specifically on the biotransformation of thimerosal and its neurotoxic potential.