Dec. 3, 2002 — Editor's Note: There has been much debate about the safety of thimerosal, which is used as a preservative in childhood vaccines and also in adult influenza vaccines. Although studies generally have shown that mercury levels after vaccination are not a problem, the American Academy of Pediatrics (AAP) successfully lobbied to have thimerosal removed from all childhood vaccines. The first detailed analysis of blood, stool, and urine mercury levels in 61 infants who received vaccines containing thimerosal, published in the Nov. 30 issue of The Lancet, indicates that blood levels of mercury in children are well below current safety limits established by the Environmental Protection Agency (EPA). Surprisingly, the elimination of mercury in these children was much faster than predicted from studies of mercury toxicity from seafood. Based in part on these findings, the World Health Organization (WHO) put forth guidelines saying that thimerosal is safe and should continue to be used.

To clarify these findings and their implications, Medscape's Laurie Barclay interviews lead author and lead investigator of The Lancet article, Michael E. Pichichero, MD, a professor of microbiology, immunology, pediatrics, and medicine at the University of Rochester Medical Center in New York.

Medscape: Please summarize your Lancet study results and their implications for the safety of vaccines containing thimerosal.

Dr. Pichichero: We looked at the [blood] level of mercury in children who received thimerosal-containing vaccines. Not a single child had a blood mercury level approaching the lower safety limit established by the EPA. Former predictions of possible pediatric problems with mercury in vaccines, which led to removal of thimerosal from U.S. vaccines, were based on the notion that metabolism of ethyl mercury in the vaccine was the same as that of methyl mercury in fish. But our study showed that elimination of ethyl mercury from the vaccine was about six times as fast as that of methyl mercury. The rapid metabolism probably accounts for the very low blood levels in the children we studied.

Medscape: Could blood levels of mercury be misleading in that blood levels could be low even while mercury is accumulating in bone or in organs?

Dr. Pichichero: We accounted for virtually all the mercury contained in the vaccine in the stool of these children, with not much excretion in the urine. So there really is no evidence that there is any mercury unaccounted for which could be accumulating in bone or elsewhere, although this study was not a toxicity study and did not examine this issue directly.

Medscape: Although these results appear to be reassuring, are there any study limitations to consider in interpreting the findings?

Dr. Pichichero: This was a small study of 61 children: 20 two-month-olds who got thimerosal, 20 six-month-olds who got thimerosal, and 21 controls. Because we didn't anticipate the rapid clearance of ethyl mercury with half-life of only six to seven days, we predicted the sampling times on the basis of an assumed 45-day half-life.

Medscape: On what basis did the EPA set public safety limits for mercury levels?

Dr. Pichichero: The EPA levels were largely based on studies from the Faroe Islands which looked at the toxicity of methyl mercury ingestion from whale blubber. Mild neurodevelopmental problems occurred at blood levels of 200 to 300 ng/mL, and the mildest detectable neurodevelopmental toxicity occurred at blood levels of 58 ng/mL. So the EPA decided they'd add in a safety factor of 10, and they reasoned that levels should not exceed 5.8 ng/mL to be totally safe. In our study, most children had levels of 1 to 2 ng/mL; two had levels of 2-3 ng/mL, and one had a level of 4 ng/mL. No child approached the EPA safety limit.

Medscape: Do you think that the Faroe Islands studies form an adequate basis on which the EPA can determine safe blood levels as they pertain to infants who receive vaccines containing thimerosal?

Dr. Pichichero: Actually, it's not an adequate basis because the situations are not strictly comparable. First of all, the Faroe Islands study looked at levels of mercury in fetal cord blood when mothers ingested mercury from whale blubber. If anything, the fetus has been shown in human studies to be more susceptible to the toxic effects of mercury than are infants, because mercury easily penetrates into the fetal brain and kidneys and causes damage.

The other issue is that the Faroe Islands study looked at methyl mercury exposure, but thimerosal contains ethyl mercury. The FDA [Food and Drug Administration] assumed that metabolism of these two organic forms of mercury was closely correlated, but this was not validated by our study. We now know that the two forms are metabolized and eliminated differently. But our data are very reassuring in that the metabolism of ethyl mercury appears to be six times faster than that of methyl mercury.

An editorial accompanying the Lancet paper suggests that another study will soon be published comparing the effects of ethyl and methyl mercury. But from a toxicity point of view, once mercury is freed from its organic bonds, mercury is mercury, and it's the free form that enters the brain and kidneys and can cause damage. Our study did not examine toxicity, but we measured blood levels of free mercury, not of ethyl mercury.

Medscape: Why did the AAP urge vaccine manufacturers to remove thimerosal from U.S. vaccines? Do you think that this recommendation should be changed or updated?

Dr. Pichichero: It's very reassuring for America's children that the hypothetical concerns which led to thimerosal removal were not validated by our study. The AAP and the FDA are not likely to reverse their decision based on our findings, now that thimerosal has been replaced with other preservatives. Although this drove up the cost of vaccines, we as a wealthy nation have absorbed this cost. But the FDA and the AAP should be very pleased with our findings, which speak to the millions of children who have already received vaccines containing thimerosal. Our findings were also pivotal in the WHO's recommendation that thimerosal will remain in all vaccines provided by them to other countries.

Medscape: What are the advantages of using thimerosal in vaccines?

Dr. Pichichero: Cost is a major issue. If you don't use preservatives at all, you have to dispense vaccine in single-dose vials, which is not only more expensive but which may lead to more errors in administration. In underdeveloped countries where millions of children die of whooping cough, tetanus and measles, switching to a thimerosal-free vaccine would raise the price so high that millions of children would not be vaccinated.

The potential toxicity of using newer preservatives, as we now do in the U.S., is unknown, so we're trading the very small, known risk of thimerosal for an unknown one. The new preservatives in U.S. vaccines are presumed to be safe, but I'm not an expert on vaccine preservatives, and I don't know the extent of background research supporting this presumption.

Medscape: Is any additional research planned to clarify safety issues for thimerosal?

Dr. Pichichero: We are collaborating with a laboratory in Seattle to look at nonhuman primate models to study possible mercury accumulation and other potential toxicity of thimerosal in vaccines. We're also doing a large follow-up in Buenos Aires, Argentina, in which we'll more carefully examine and quantitate these findings in larger numbers of children.

Medscape: Please comment on the provision in the Homeland Security Bill that protects pharmaceutical manufacturers from lawsuits related to adverse effects of childhood vaccines.

Dr. Pichichero: The three major manufacturers of thimerosal-containing vaccines are GlaxoSmithKline, Aventis-Pasteur, and Wyeth. The Childhood Vaccine Protection Act is a long-standing piece of legislation which protects the pharmaceutical manufacturers against lawsuits involving vaccines recommended by the government. This legislation came into effect about a decade ago because all the lawsuits led to vaccine shortages. I'm not aware of any specific provisions in the Homeland Security Act dealing with this issue, but I haven't studied it specifically.

Lancet. 2002;360:1711-1712, 1737-1741

Reviewed by Gary D. Vogin, MD

Laurie Barclay, MD is a staff writer with WebMD. Medscape Medical News is edited by Deborah Flapan, a news coordinator at Medscape. Send press releases and comments to news@webmd.net.   Medscape Medical News 2002. © 2002 Medscape