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INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

INTRODUCTION

AUTHOR/ARTICLE INFORMATION

REFERENCES

In late June of this year, the Food and Drug Administration (FDA) revealed that some infants who receive multiple doses of vaccines containing thimerosal could be exposed to total amounts of mercury that exceed some federal guidelines.¹ Thimerosal is a mercury-containing preservative used in some Haemophilus influenzae type b (Hib), diphtheria and tetanus toxoids with acellular pertussis (DTaP), hepatitis B, influenza, and other vaccines.² Federal agencies, the American Academy of Pediatrics (AAP), international agencies, and vaccine manufacturers have responded quickly to address the concern.^{1, 3, 5} However, more can be done to maintain public confidence in vaccines and to reduce childhood exposures to mercury from all sources.

Some confusion has occurred because of uncertainty regarding the applicability of guidelines for long-term exposures to methylmercury from environmental sources to intermittent exposures to ethylmercury, a breakdown product from thimerosal. Based on the limited data available, experts have concluded that the toxicity of ethylmercury may be similar to methylmercury. Guidelines for limiting exposure to methylmercury in foods (primarily fish) are based on the assumption that exposure will continue over long periods of time. The long half-life of methylmercury (average, 50 days) results in accumulation that could be harmful to the developing fetal brain, which is much more susceptible to organomercurial compounds than the adult brain.² The doses thought to be able to be consumed on a daily basis without harm vary among agencies: 0.1 µg/kg per day for the Environmental Protection Agency (EPA),⁶ 0.3 µg/kg per day for the Agency for Toxic Substances Disease Registry,⁷ and 0.4 µg/kg per day for the FDA.⁸ The World Health Organization provides a provisional tolerable weekly intake of 3.3 µg/kg for the general population, but the dose for pregnant women and infants would be smaller.⁹ The EPA estimates that 7% of women of childbearing age in the United States consume 0.1 µg/kg per day or more of mercury from fish harvested in high risk areas, and 1% of women consume 0.37 µg/kg per day or more.⁶ Mercury accumulated in these women is transferred to their children prenatally and in breast milk; subsequent exposures to organomercurials from other sources, including biologic products, are presumed to be additive to their baseline body loads.

Exposure to ethylmercury from vaccines containing thimerosal in the first 6 months of life ranges from 0 to 187 µg based on which vaccines are administered.² Since many vaccines do not contain thimerosal, most children receive less than the total amount of mercury indicated in the guidelines during the first 6 months of life. If all thimerosal-containing vaccines are given, the total exposures exceed the EPA guidelines, and possibly other guidelines, for the smallest infants. There are safety or uncertainty factors (10-fold for the EPA) built into the guidelines, and experts believe there is no evidence of harm from exposure to thimerosal in vaccines.^{1, 2} However, clinicians are uncertain as to how much mercury can be safely given at 1 time when multiple thimerosal-containing vaccines are administered simultaneously.

Data from 2 recent studies examining the relationship between methylmercury exposure and neuropsychological outcome in children suggest that intermittent large exposures may pose more risk than small daily doses. Faeroese children at age 7 years who had been exposed in utero to intermittent bolus doses of methylmercury were found to have subtle neurologic impairments based on domain-specific neuropsychological testing.¹⁰ The total exposures during pregnancy were in the range that was not associated with impairments by global IQ testing in Seychelloises children aged 5.5 years who had been exposed to smaller daily doses.¹¹ The investigators from the 2 studies disagree over what exposures are safe, but a review by a panel of independent scientists found no major methodological problems in either of the studies.^12-14 Differences in testing methods and age at evaluation might explain some of the differences; follow-up studies will provide more information. The controversy resembles that in studies of lead toxicity where sequential studies over many years provided evidence for subtle effects with progressively lower exposures and resulted in increasingly lower acceptable limits of exposure.¹⁵ Additional studies are being planned to evaluate the possible effects of mercury exposure from vaccines.

The FDA sent a letter to vaccine manufacturers on July 1, 1999, requesting plans to remove thimerosal from vaccines or justify the continued use of this preservative.¹ The AAP and the US Public Health Service issued a statement on July 7 calling for elimination or reduction of thimerosal in vaccines for children and recommending deferral of the first dose of hepatitis B vaccine for infants born to hepatitis B virus surface antigen (HBsAg) negative women until age 2 to 6 months.¹ A parallel review of these issues in Europe resulted in the European Agency for the Evaluation of Medicinal Products issuing a statement on July 8 promoting the use of vaccines without thimerosal for infants and toddlers within the shortest possible time frame.³ The AAP issued a more detailed statement on July 14⁴ that provided physicians with the mercury content in vaccines, background information on mercury toxicity, advice for reducing mercury exposures from all sources, and specific guidelines for the use of hepatitis B vaccines. The AAP also urged the FDA and manufacturers to rapidly reduce the mercury content of vaccines.² In a remarkably short time, the FDA approved a request from Merck on August 27 to market a thimerosal-free hepatitis B vaccine for use in infants. SmithKline Beecham also has submitted a request for approval of products with little or no thimerosal.⁵ The Centers for Disease Control and Prevention (CDC) and the AAP have strongly encouraged physicians to resume neonatal hepatitis B vaccination of infants born to HBsAg negative women with products that have reduced or no thimerosal.^{2, 5}

Some clinicians apparently were confused by the rapid changes in hepatitis B guidelines. Infants born to women who are HBsAg positive or whose hepatitis status is unknown should be vaccinated at birth regardless of the availability of thimerosal-free vaccines because the high risk of acquiring hepatitis B infection and increased likelihood of becoming a carrier far outweigh theoretical concerns about the amount of mercury in a single dose of this vaccine.^1-5 The CDC has emphasized the need for immunization of all newborns in populations at increased risk for hepatitis B infections from contacts early in life.⁵ Most countries have initiated programs to administer hepatitis B immunization at birth or in the first few weeks of life because this is the optimal strategy for preventing hepatitis B transmission.^{16, 17} Immunization at birth provides early and long-term protection of neonates against infection by HBsAg positive mothers who were missed by screening programs and HBsAg carriers among families, friends, and other contacts.¹⁸

In this issue of THE JOURNAL, Lauderdale and colleagues¹⁹ present evidence that neonatal hepatitis B vaccination may have additional benefits. They found that children given the first dose of vaccine in the first month of life, presumably mostly at birth, were more likely to complete the 3-dose series and to receive their first dose of DTaP vaccine at age 2 months than children who began hepatitis B immunization at an older age. Since the availability of hepatitis B vaccine in nurseries is a hospital decision, the data suggest that the birth dose helps influence parents to complete the series and seek other vaccines on time. Prospective controlled studies are needed to determine if early immunization truly increases on-time immunization at older ages or if this is a result of enrollment in a more proactive health care program.

Are preservatives like thimerosal necessary in vaccines? The FDA regulations require preservatives in multidose vials of most vaccines (with the exception of certain live viral vaccines) to protect against inadvertent contamination from repeated puncture of the seal.²⁰ Thimerosal does not prevent all bacterial contamination, as evidenced by clusters of disease from group A streptococcus infections traced to multidose diphtheria toxoid, tetanus toxoid, and pertussis (DTP) vaccine vials that were contaminated after opening.²¹ The use of single-dose vials or prefilled syringes for vaccines should be encouraged because this eliminates errors in preparation as well as the need for preservatives for most vaccines. Thimerosal is used during production of some vaccines and in many cases can be removed leaving trace amounts (<0.3 µg) of mercury that have no biologic effect.²² Such products should be considered equivalent to thimerosal-free products. Alternative preservatives are one option for multidose vials, especially in developing countries where the need to keep costs low is an essential component of the success of the World Health Organization's Expanded Program on Immunization. The use of new combination products will reduce exposure to preservatives by decreasing the number of injections needed to deliver recommended vaccines.

How should physicians deal with the uncertainties during the transition to the elimination or reduction of thimerosal in vaccines? On October 20, 1999, the Advisory Committee on Imunization Practices of the CDC decided not to give a general preference for thimerosal-free vaccines for administration to infants. The CDC and AAP have indicated that hepatitis B vaccines containing no or trace amounts of thimerosal should be preferentially used for infants during the first 6 months of life. I believe that this preference should be extended to Hib and DTaP vaccines for infants (especially premature infants) whenever possible. The list of mercury content in vaccines is kept up-to-date on the Institute for Vaccine Safety Web site (http://www.vaccinesafety.edu) to assist physicians in vaccine choices. If supplies are limited, exposure to no more than 1 thimerosal-containing vaccine at each visit would reduce exposures while ensuring that infants are fully protected against diseases, including influenza in high-risk infants. Elimination of thimerosal or other preservatives will be more difficult for influenza vaccines produced in eggs because a preservative helps ensure protection against contamination. The small amount of thimerosal in influenza vaccines does not constitute an undue risk for older children and adults, especially for high-risk individuals in whom complications from influenza constitute a major health burden.

The AAP encourages parents to follow local fish advisories to reduce children's exposure to mercury.² Since mercury exposures from other sources may be additive, special care should be taken not to administer additional mercury from vaccines to small infants in populations in which pregnant women may consume more than the maximum recommended amounts of mercury. Thimerosal has been eliminated from latex paints, and merthiolate, a concentrated form of thimerosal used as an antiseptic, is no longer used because of serious toxic effects from these products in infants.²³ Congress deserves credit for mandating the review of thimerosal in biological products, but needs to ensure that the agencies responsible for vaccine safety have the resources and freedom from undue regulation to allow them to carry out their mandates. The FDA needs highly qualified scientists and resources to address the increasingly complex scientific issues involved in vaccine production. Therefore, health care professionals should be concerned that the research budget for the Center for Biologics and Evaluation Research has been reduced to one third the level that it was in 1994.²⁴ Availability of the safest vaccines now and in the future requires support for scientists working at federal agencies responsible for vaccine safety. In late June and early July, when decisions needed to be made rapidly, officials from the CDC could not officially consult with the Advisory Committee on Immunization Practices because statutes prevent such meetings without posting a notice in the Federal Register.²⁵ Exceptions should be made to allow the CDC and other agencies to address urgent situations.

The public has become intolerant of unnecessary exposure to real and theoretical risks for children from all sources as evidenced by demands to make food products, toys, seat belts, and air bags as safe as possible.²⁶ Reducing or eliminating exposure to mercury from all sources, including industrial contamination of waterways that leads to accumulation of mercury in fish, should be a national priority.²⁷ Further reductions or elimination of mercury in vaccines will help maintain public confidence by demonstrating a commitment to provide the safest vaccines possible for protecting children against disease.

 
 
Author/Article Information

 
Author Affiliation: Institute for Vaccine Safety, Johns Hopkins School of Hygiene and Public Health, Baltimore, Md.
 
Corresponding Author and Reprints: Neal A. Halsey, MD, Division of Disease Control, Johns Hopkins School of Hygiene and Public Health, 615 N Wolfe St, Baltimore, MD 21205 (e-mail: nhalsey@jhsph.edu).

Editorials represent the opinions of the authors and THE JOURNAL and not those of the American Medical Association.

Acknowledgment: I am grateful to Leslie Ball and Robert Ball for comments and technical support.

Financial Disclosure: The Institute for Vaccine Safety has received research grant support from the Food and Drug Administration, the World Health Organization, and SmithKline Beecham; educational grant support from Merck & Co, SmithKline Beecham, North American Vaccine, and Pasteur Mérieux Connaught. Dr Halsey has received honoraria for a manuscript on hepatitis B vaccine from Ross Products Division, Abbott Laboratories Inc, Abbott Park, Ill.

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