Lack of evidence linking thimerosal with autism

October 2005

Despite significant evidence for the public health benefits of pediatric immunization, controversy and skepticism from parents about vaccines are not uncommon.

Thimerosal, a mercury-based preservative previously found in many pediatric vaccines, has created significant concern for many caregivers, as blame has been given to mercury and thimerosal as a potential cause of autism and autistic spectrum disorders. Since 2001, all vaccine products of the childhood immunization schedule (for children 6 and younger) are thimerosal free (or contain only trace amounts, <1 µg per dose). Prior to its removal from vaccines, thimerosal was typically present as a 0.01% concentration, with amounts of mercury ranging from 12.5 to 25 µg per dose. Parenthetically, this can be compared to 11.5 µg of mercury found in a can of tuna. Several influenza virus vaccines, however, continue to contain thimerosal. This month’s column will review the current status of thimerosal use as a preservative in pediatric vaccines, with an assessment of data describing a purported link to autism spectrum disorders.

Thimerosal is metabolized to ethylmercury and thiosalicylate and contains mercury 50% by weight. Ethylmercury is considered an organomercurial, as opposed to inorganic mercury. Although the majority of mercury in nature is in an inorganic state, mercury accumulates in animals as methylmercury, also an organomercurial. Organomercurials disperse and stay in the human body more readily than inorganic mercury, with seafood as the primary source.

Methylmercury is known to be neurotoxic, and fetuses appear to be more sensitive to its neurotoxic effects than infants or adults. Several organizations (eg, FDA, WHO) have established guidelines for safe exposure to methylmercury (0.1 to 0.47 mg/kg/day), although these guidelines were not developed to define toxic doses.

In 1999, the FDA assessed mercury content of regulated products, including vaccines, as required by the 1997 FDA Modernization Act. It was determined in this review that the possibility existed for some infants, depending upon weight, to be exposed to a cumulative amount of mercury (based upon guidelines for methylmercury, not ethylmercury) in the first six months of life through routine pediatric immunization, which exceeded the above dosing guidelines. Pharmaceutical manufacturers were urged to reformulate vaccine products to be thimerosal free.

It is important to distinguish between the two organomercurials described above, ethylmercury and methylmercury. Concerns over potential toxicity of mercury, as methylmercury, have been applied to thimerosal, as ethylmercury. However, it may not be appropriate to equate the potential for toxicity with these two organomercurials. Some evidence from animal studies indicate that ethylmercury is less neurotoxic than methylmercury (Magos, et al). The pharmacokinetic profiles of methylmercury and ethylmercury may also differ. Published data indicate that ethylmercury is more rapidly eliminated from the body than methylmercury.

Thimerosal and autism

Concern exists among some parents and caregivers that thimerosal, as a form of mercury, is a cause of autistic spectrum disorders. Published hypotheses of this link have raised this concern. The Institute of Medicine (Immunization Safety Review Committee) reviewed data describing the potential for an association between thimerosal and autistic spectrum disorders (www.iom.edu). The Institute of Medicine, in its 2004 final report, concluded that evidence to date favors rejection of a casual relationship between thimerosal and autism, and the suggestion for a physiologic link between mercury and thimerosal is theoretical only.

An additional analysis of data relating thimerosal with the potential for development of autistic spectrum disorders was published last year. Parker and colleagues reviewed original published data linking thimerosal-containing vaccines and autistic spectrum and neurodevelopmental disorders, and studies of ethylmercury pharmacokinetics (10 epidemiologic and two pharmacokinetic studies). Of the 10 epidemiologic studies, four studies concluded a link between thimerosal exposure and autism exists. These studies, from the same researchers and using overlapping data, were criticized by Parker and colleagues to have significant methodologic deficiencies, thus allowing a link between thimerosal and autism to be doubtful. The remaining studies did not report an association with thimerosal and autism, and were described as methodologically appropriate.

Current vaccine products

As stated above, nearly all vaccine products used in the recommended pediatric immunization schedule (for children 6 and younger) contain no thimerosal or only trace amounts. Trace amounts are defined as 1 µg or less of mercury per dose, resulting from manufacturing processes. These vaccine products have been reformulated with other preservatives or reformulated as single-dose products only.

Products containing only trace amounts of mercury include Tripedia (DTaP, Sanofi Pasteur) with <0.3 µg per 0.5 mL dose; Pediarix (DTaP-HepB-IVP, GlaxoSmithKline) with <0.0125 µg per 0.5 mL dose; Engerix B (hepatitis B, GSK) with <0.5 µg per 0.5 mL dose; and Fluvirin Preservative-Free (inactivated influenza, Chiron Evans) with <1 µg per 0.5 mL dose.

Only two products for use in infants and children, both inactivated influenza vaccines, contain thimerosal: FluZone (Sanofi Pasteur) with 12.5 µg per 0.25 mL dose and Fluvirin (Chiron Evans) with 25 µg per 0.5 mL dose. FluZone with thimerosal is available as a multidose vial and is labeled for use in children aged 6 months and older. FluZone is also available as a thimerosal-free product, as 0.25 mL unit dose syringes for use in infants 6 to 35 months of age and 0.5 mL unit dose syringes for children 3 and older. Fluvirin, also available thimerosal free (containing trace amounts), is available as 0.5 mL unit dose syringes and is labeled for use in children aged 4 and older. Both of these thimerosal-free inactivated influenza vaccine products may be less available this year than the similar product containing thimerosal. Live-attenuated influenza virus vaccine (FluMist, MedImmune) is thimerosal free. The FDA maintains an Internet site listing all vaccine products and thimerosal content (www.fda.gov/cber/vaccine/thimerosal.htm).

Conclusions

Despite a lack of strong data linking mercury and thimerosal with neurodevelopmental disorders and statements by expert panels or published data analysis, thimerosal has been removed from nearly all pediatric vaccine products. Some parents or caregivers may continue to express concerns about thimerosal. With the availability of thimerosal-free products, immunization should not be withheld because of these concerns. For parents who may continue to harbor concerns over even trace amounts of thimerosal contained in some vaccine products, clinicians should discuss the lack of evidence linking thimerosal with autism, including differences among the forms of organic mercury.

For more information:

• Parker SK, Schwartz B, Todd S, et al. Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data. Pediatrics. 2004;114:793-804.
• Pichichero ME, Cernichiarie, Lopreiato J, et al. Mercury concentrations and metabolism in infants receiving vaccines containing thimerosal: a descriptive study. Lancet. 2002;360:1737-1741.
• Magos L, Brown AW, Sparrow S, et al. The comparative toxicology of ethyl- and methylmercury. Arch Toxicol. 1985;57:260-267.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.