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Vaccines, thimerosal, and neurodevelopmental outcomes

Lawrence M. Herman, MPA, PA-C; Deborah A. Gerbert, PA-C; Lyle W. Larson, PhD, PA-C; Marie-Michèle Léger, MPH, PA-C; Robert McNellis, MPH, PA-C; Daniel L. O'Donoghue, PhD, PA-C; Cynthia Ulshafer, PA-C; Eileen M. Van Dyke, MPS, PA-C

The authors are members and staff of the Clinical and Scientific Affairs Council (CSAC) of the AAPA. This article was written by Lawrence Herman, MPA, PA-C, and edited by Sarah Zarbock, PA-C.

Considerable debate has occurred over the use of thimerosal in vaccines, especially whether a potential link exists between thimerosal and disabling neurodevelopmental childhood diseases such as autism. Publications and organizations as varied as Rolling Stone¹ and the Institute of Medicine^2,3 have provided information on the potential risks, benefits, and sequelae of thimerosal use over the past half century. In some instances, inaccurate information has been promulgated to the general population and clinicians alike—a troubling occurrence inasmuch as both groups must be able to make informed decisions. The Clinical and Scientific Affairs Council of the AAPA has reviewed the available scientific information and includes our findings in this special report.

Thimerosal and mercury

Thimerosal, first introduced by the Eli Lilly Company, is a mercury-containing preservative that has been used in some vaccines and other products for more than 70 years. It has been the most widely used vaccine preservative and meets requirements set forth by the United States Pharmacopeia and National Formulary (USP-NF).⁴ Thimerosal kills bacteria and effectively prevents bacterial contamination, particularly in opened multidose containers, and it prevents the growth of fungi, the greatest challenge to vaccine preservation.⁵ In concentrations of 0.001% (1 part in 100,000) to 0.01% (1 part in 10,000), it has been shown to be effective in clearing a broad spectrum of pathogens.⁶ It contains approximately 50% mercury by weight and is metabolized into ethylmercury and thiosalicylate. Thimerosal should not be confused with methylmercury, which is an environmental contaminant and toxin.

In 1999, several federal agencies, including the Agency for Toxic Substances and Disease Registries (ATSDR), the FDA, and the Environmental Protection Agency (EPA), established guidelines for levels of mercury exposure.⁷ Federal safety standards are based on longstanding research that has been performed on methylmercury. There are more data on methylmercury than on ethylmercury, and these more expansive data indicate that methylmercury is more toxic than ethylmercury⁸ and is of greatest public health concern.⁹ The guidelines recommend that no more than of 0.1 mcg/kg of methylmercury be injected daily in special population groups including neonates, infants, children, and pregnant women. This federal standard is frequently applied to thimerosal, giving a misleading impression of its toxicity.⁴ In reality, before thimerosal was introduced as a vaccine preservative, data were available providing evidence that it is both safe and effective.¹⁰

As federal guidelines were being established, the FDA conducted a detailed review of the mercury content within drugs and vaccines to determine their safety and efficacy. The FDA concluded that when thimerosal is used as a preservative in vaccines, a 6-month-old infant may be exposed to an amount of ethylmercury that exceeds the EPA limit for safe methylmercury exposure. However, this same amount is within the limits for safe ethylmercury intake established by the FDA, the ATSDR, and the World Health Organization.

Furthermore, the specific guideline of 0.1 mcg/kg/d of methylmercury exposure should not be construed as a “set line” below which a patient is safe and above which adverse health effects will occur. Rather, a built-in safety margin is incorporated into all acceptable methylmercury exposure limits.⁵ These guidelines are simply starting points for evaluating exposure to methylmercury.

Thimerosal and autism

So much attention is being paid to thimerosal-containing vaccines because some much-read but nonscientific publications have postulated a link between this preservative and autism in children.^1,5 The number of children identified as having autism spectrum disorders (ASDs) has risen dramatically.¹⁰ Children with these conditions all have a degree of neurodevelopmental delay but differ as to the age when symptoms start, the speed with which they appear, and the degree of severity.¹¹ Nationally, between 1994 and 2003 the number of children classified as having an ASD increased from 22,664 to 141,022.¹¹ Although the diagnostic criteria for ASDs have evolved, the prevalence rates for ASDs using current diagnostic criteria are between 2/1,000 and 6/1,000.¹⁰

In 1991, children with ASDs became qualified for special education services. By 1994, ASDs were the 10th most common disability among children aged 6 to 21 years receiving special education services in the United States. They are now the 6th most commonly classified disability of children receiving special education. Clearly, more children are receiving these services for ASDs than ever before—possibly because the defining characteristics of ASDs are expanding and more children are therefore becoming qualified. While no one knows exactly what causes ASDs, both genetic and environmental factors are believed to play a role.¹²

Because thimerosal has been called a possible contributor to ASDs,^1,5 the Public Health Service, the American Academy of Pediatrics, and vaccine manufacturers all agreed in July 1999 that thimerosal should be reduced or eliminated in vaccines.¹³ Today, with the exception of some injectable influenza vaccines and the tetanus and diphtheria (Td) vaccine (given to children aged 7 years and older), none of the FDA-approved vaccines recommended in the US childhood immunization schedule to protect preschool children contain thimerosal as a preservative. The FDA has announced that thimerosal-free influenza vaccines are also available for use in infants, with the supply expected to have increased significantly for the 2005-2006 flu season.¹⁴

The IOM gets involved

In response to the continued allegations that thimerosal contributed to the rise in ASDs, the CDC and the National Institutes of Health requested that the National Academy of Sciences’ Institute of Medicine (IOM) establish an independent expert committee to review the risks and safety concerns associated with immunization. The Immunization Safety Review Committee (ISRC) is composed of 15 expert members from pediatrics, neurology, immunology, internal medicine, infectious diseases, genetics, epidemiology, biostatistics, communications, decision analysis, public health, nursing, and ethics.

To prove that there is no link between ASDs and a vaccine—for example, the MMR (measles, mumps, and rubella virus) vaccine—a large, randomized controlled trial powered adequately to detect the reported incidence would have to be conducted. This trial ideally would need to be randomized into three arms: a control group receiving no vaccinations, another group receiving the full CDC-recommended immunization schedule (including the MMR vaccine), and a third group receiving only the MMR vaccine. For obvious ethical reasons, this type of trial cannot be conducted. As a result, this question would have to be answered using data from other methods, such as cohort studies and/or adverse drug reaction case reports. In fact, these were the data utilized—with all of their inherent statistical limitations—to determine if an association exists between thimerosal-containing vaccines and ASDs.

In 2001, the IOM’s ISRC examined a possible link between the use of the MMR vaccine and ASDs. They noted that the epidemiologic evidence was not precise enough to detect rare idiosyncratic reactions to MMR vaccinations and that a theoretical risk remains that MMR vaccine could contribute to ASDs in a small number of children. Although the proposed biological models linking MMR vaccine to ASDs have not been firmly established, they also have not been and cannot be disproved without controlled trials.

The conclusion of the ISRC’s second report (published in 2003) on thimerosal-containing vaccines and neurodevelopmental disorders was perhaps more unsettling because the evidence linking exposure to thimerosal in vaccines with autism was inconclusive. The committee believed that the effort to remove thimerosal completely from vaccines was “a prudent measure in support of the public health goal to reduce mercury exposure of infants and children as much as possible.”¹⁰ Furthermore, the ISRC urged that “full consideration be given to removing thimerosal from any biological product to which infants, children, and pregnant women are exposed.”¹⁴ Parents found this recommendation alarming.

A more precise study on this issue was performed in 2003 in Denmark by Hviid and colleagues, who examined the incidence of neurodevelopmental disorders (including autism) in children vaccinated with thimerosal-containing vaccines and those vaccinated with thimerosal-free vaccines from 1990 through 1996.¹⁵Because of Denmark’s unique national registry system, all children and the specific vaccines they received could be identified, as could all neurodevelopmental diagnoses made during 2,986,654 person-years of follow-up. Statistical power to draw accurate conclusions was markedly increased as well. The authors identified 440 cases of autism and 787 cases of other ASDs and found no evidence of an association between thimerosal-containing vaccines and autism.¹⁰ They concluded that there was no indication of any association between autism and amounts of ethylmercury received through thimerosal vaccines. In fact, the authors found statistically significant increased rates for ASDs and autism after thimerosal-containing vaccines were eliminated. This increase in ASD parallels the increase being seen in the United States.¹⁰

Conclusion

To summarize, the data reviewed by the ISRC do not support a relationship between thimerosal and ASDs, and other studies have specifically concluded that a causal relationship has not been demonstrated. Nevertheless, with the exception of some injectable influenza vaccines and tetanus-diphtheria vaccine, none of the vaccines sold and administered in the United States to protect preschool children against the 12 most common infectious diseases contain thimerosal as a preservative. Manufacturers are moving rapidly to remove thimerosal from these few remaining vaccines—a prudent step. While childhood immunization recommendations remain unchanged, continued vigilance is of paramount importance to ensure a safe and effective vaccine program.

REFERENCES

1.
Kennedy RF Jr. Deadly immunity. Rolling Stone. June 16, 2005. Available at: http://www.rollingstone.com/politics/story/_id/7395411. Accessed November 14, 2005.

2.
Immunization Safety Review Committee, Board on Health Promotion and Disease Prevention. Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism. Stratton K, Gable A, Shetty P, McCormick M, eds. Washington, DC: National Academies Press; 2001.

3.
Immunization Safety Review Committee. Immunization Safety Review: Influenza Vaccines and Neurological Complications. Stratton K, Alamario DA, Wizemann T, McCormick MC, eds. Washington, DC: National Academies Press; 2003.

4.
United States Pharmacopeia and National Formulary. Rockville, Md: United States Pharmacopeial Convention; 2005.

5.
Joint statement concerning removal of thimerosal from vaccines. Available at: http://www.cdc.gov/nip/vacsafe/concerns/thimerosal/joint_statement_00.htm. Accessed November 17, 2005.

6.
US Food and Drug Administration. Thimerosal in vaccines. Available at: http://www.fda.gov/cber/vaccine/thimerosal.htm#thi. Accessed November 17, 2005.

7.
Agency for Toxic Substances and Disease Registry. Toxicological profile for mercury. March 1999. Available at: http://www.atsdr.cdc.gov/toxprofiles/tp46.html. Accessed November 17, 2005.

8.
Magos L. Review on the toxicity of ethylmercury, including its presence as a preservative in biological and pharmaceutical products. J App Toxicol. 2001;21(1):1-5.

9.
Mahaffey KR. Methylmercury: a new look at the risks. Public Health Rep. 1999;114(5):396-399,402-413.

10.
Questions and Answers about the October 2001 IOM Report on Thimerosal and Neurodevelopmental Outcomes. October 2001. Available at: http://www.cdc.gov/nip/news/iom-thimQA10-1-01.htm#Thimerosal. Accessed November 11, 2005.

11.
Ball L, Ball R, Pratt RD. An assessment of thimerosal in childhood vaccines. Pediatrics. 2001;107(5):1147-1154.

12.
Autism spectrum disorders. Available at: http://www.cdc.gov/ncbddd/factsheets/asd.pdf. Accessed November 17, 2005.

13.
Joint statement concerning removal of thimerosal from vaccines. The American Academy of Family Physicians (AAFP), American Academy of Pediatrics (AAP), Advisory Committee on Immunization Practices (ACIP), and United States Public Health Service (USPHS). Approved June 22, 2000.

14.
Important immunization information. Available at: http://www.cdc.gov/nip/news/newsltrs/imwrks/2005/4-1-05_spec_imwks.htm. Accessed November 11, 2005.

15.
Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Association between thimerosal-containing vaccine and autism. JAMA. 2003;290(13):1763-1766.