Stajich GV, Lopez GP, Harry SW, Sexson WR.

Mercer University, Southern School of Pharmacy, Atlanta, Georgia 30341, USA.

J Pediatr 2000 May;136(5):679-81

http://www.ncbi.nlm.nih.gov/entrez/query.Retrieve&db=PubMed&list_uids=10802503&dopt=Abstract

Thimerosal, a derivative of mercury, is used as a preservative in hepatitis B vaccines. We measured total mercury levels before and after the administration of this vaccine in 15 preterm and 5 term infants. Comparison of pre- and post-vaccination mercury levels showed a significant increase in both preterm and term infants after vaccination. Additionally, post-vaccination mercury levels were significantly higher in preterm infants as compared with term infants. Because mercury is known to be a potential neurotoxin to infants, further study of its pharmacodynamics is warranted.

Mercury toxicity

Journal of Pediatrics  •  March 2001 • Volume 138 • Number 3

To the Editor:

Drs Pless and Fisher¹ address mercury toxicity on exposure to fish-borne methylmercury (MeHg) or hepatitis B vaccination (thimerosal). Studies from New Zealand,^2,3 Canada,⁴ and the Faeroe Islands^5-7 suggest that gestational MeHg exposure is associated with neurologic deficits in offspring. These outcomes have not been replicated in the Republic of the Seychelles.^8-10 A number of factors have been offered for this discrepancy. (1) The neurobehavioral tests differed between the sites. (2) Children in the Seychelles were ~5.5 years old; children in the Faeroe Islands were ~7 years. (3) It is easier to perform neurocognitive testing in school-aged children. (4) Children in the Faeroe Islands are more likely to be exposed to MeHg in “bursts” as a result of periodic consumption of whale meat. Children in the Faeroe Islands may have also been simultaneously exposed to polychlorinated biphenyl-congeners (PCBs). (5) In the Faeroe Islands, mercury was measured in cord blood, potentially missing high first-trimester exposure. (6) The two populations are distinct (genetic polymorphism). 

Considerable attention in the scientific and health policy fora focuses on whether MeHg intake from fish diet is associated with aberrant central nervous system function. The unequivocal findings that the organ most sensitive to gestational MeHg exposure is the central nervous system dictate that new risk characterization should be carried out. It is incumbent upon the regulatory agencies to re-analyze these cohorts, reconsidering permissible doses of exposure. Though each agency uses a specific model of risk assessment with unique sets of assumptions, attempts should be made to derive a unified reference dose for MeHg by considering the advantages and limitations provided by each of the exposure cohorts. As suggested by Drs Pless and Risher, the public and parents of infants deserve to know the risks and benefits associated with fish consumption. 

9/35/111812 

doi:10.1067/mpd.2001.111812

Michael Aschner, PhD
Department of Physiology/Pharmacology
Wake Forest University School of Medicine
Winston-Salem, NC 27157-1083

References 

1. Pless R, Risher JF. Mercury, infant neurodevelopment, and vaccination. J Pediatr 2000;136:571-73. 

2. Kjellstrom T, Kennedy P, Wallis S, Mantell C. Physical and mental development of children with prenatal exposure to mercury from fish. Stage I: preliminary tests at age 4. Solna, Sweden. National Swedish Environmental Protection Board Report 1986;3080.

3. Kjellstrom T, Kennedy P, Wallis S, Stewart A, Friberg L, Lind B, et al. Physical and mental development of children with prenatal exposure to mercury from fish. Stage II: interviews and psychological tests at age 6. Solna, Sweden. National Swedish Environmental Protection Board Report 1989; 3642.

4. McKeown-Eyssen G, Ruedy J, Neims A. Methylmercury exposure in Northern Quebec II: neurologic findings in children. Am J Epidemiol 1983;118: 470-9. 

5. Grandjean P, Weihe P, White R, Debes F, Araki S, Yokoyama K, et al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol 1997;19:417-28. 

6. Grandjean P. Mercury risks: controversy or just uncertainty? Public Health Rep 1999;114:512-5. 

7. Steuerwald U, Weibe P, Jørgensen PJ, Bjerve K, Brock J, Heinzow B, et al. Maternal seafood diet, methylmercury exposure, and neonatal neurologic function. J Pediatr 2000;136:599-605. 

8. Myers GJ, Davidson PW, Cox C, Shamlaye CF, Tanner MA, Choisy O, et al. Neurodevelopmental outcomes of Seychellois children sixty-six months after in utero exposure to methylmercury from a maternal fish diet: pilot study. Neurotoxicology 1995;16:639-52. 

9. Myers GJ, Davidson PW, Shamlaye CF, Axtell CD, Cemichiari E, Choisy O, et al. Effects of prenatal methylmercury exposure from a high fish diet on developmental milestones in the Seychelles Child Development Study. Neurotoxicology 1997;18:819-29. 

10. Davidson PW, Myers GJ, Cox C, Axtell C, Shamlaye C, Sloane-Reeves J, et al. Effects of prenatal and postnatal methylmercury exposure from fish consumption on neurodevelopment: outcomes at 66 months of age in the Seychelles Child Development Study. JAMA 1998;280:701-7. 

Thiomersal in vaccines

The Lancet Volume 355, Number 9211     08 April 2000

http://pdf.thelancet.com/pdfdownload?uid=llan.355.9211.correspondence.1742.1&x=x.pdf

Correspondence

Sir--Thiomersal is an organic mercurial compound that has been used for over 60 years as an antimicrobial agent in vaccines to prevent contamination. It is present in commonly used vaccines such as diphtheria-tetanus-pertussis (DTP) vaccine and tetanus toxoid (TT) as well as certain brands of hepatitis B (HB) and Haemophilus influenzae type b (Hib) vaccines, but not in live bacterial or viral vaccines. The use of thiomersal has probably prevented death or illness in countless infants by reducing the risk of contamination of for example, opened multidose vials.

There is a need to minimise exposure to mercury from all sources such as food (especially certain fish), pharmaceuticals, and biological products. In July, 1999, the US Public Health Service (USPHS) and American Academy of Pediatrics (AAP) issued a joint statement concerning thiomersal in vaccines,¹ which prompted international public debate about preservatives and their safety. At doses much higher than those used in vaccines, the preservative has been reported to cause neurotoxicity and nephrotoxicity.² However, the precise nature of toxicity from low concentrations of exposure to thiomersal remains uncertain.

Mercury exposure from thiomersal in typical immunisation schedules

Guidelines for safe exposure to methyl mercury have been used to determine whether the mercury dose from vaccines approaches a level that is of concern. Organisations such as WHO, the US Environmental Protection Agency (EPA), the US Agency for Toxic Substances and Disease Registry, and the US Food and Drug Administration provide recommendations for safe exposure to methyl mercury in the diet. Suggested safe levels range from 0·7 µg/kg bodyweight/week (EPA) to 3·3 µg/kg bodyweight/week (WHO), and have as much as a ten-fold safety margin. This works out as 34­159 µg in the birth-to-14 weeks period (when most infant vaccines are given). The table shows the exposure that would take place in a plausible scenario within a typical national immunisation schedule. While much remains to be understood about the implications of various concentrations, it seems that some infants may receive doses of mercury from vaccines that, while not obviously toxic, may be of concern and are in breach of various agency recommendations.

Removing thiomersal (and with it the risk from mercury) from vaccines is not a simple task. If the condemnation of thiomersal were to be too strong, many vital vaccines might be withdrawn from production, resulting in a global supply crisis as well as a loss of public confidence in vaccines. The risk from contamination of multidose vials would increase and lives would be put at risk from, for instance, toxic-shock syndrome.

Because of its excellent track record of safety and efficacy as a vaccine preservative over many years, WHO will continue to recommend vaccines containing thiomersal.⁴ On balance, the known risk of morbidity and mortality from vaccine-preventable diseases and the dangers posed by contaminated multidose vaccine vials far outweigh any potential risk posed by thiomersal. Nevertheless, WHO and other agencies have begun the process of reducing and removing thiomersal from vaccines. We thank M Scholtz, J Lloyd, J Herrman, P Evans, E Griffiths, J Milstien, N Dellepiane, P Duclos, L Jodar, A Padilla, for their contribution to the technical aspects of this paper. WHO gratefully acknowledges the US Food and Drug Administration, Center for Biologics Evaluation and Research, for allowing Leslie Ball, Robert Ball, and Douglas Pratt to assist with this paper.

*C J Clements, L K Ball, R Ball, D Pratt

References

2 Pfab R, Muckter H, Roider G, Zilker T. Clinical course of severe poisoning with thiomersal.  Clin Toxicol  1996; 34: 453­60. [PubMed]

3 Ball L, Evans G, Bostrom A. Risky business: challenges in vaccine risk communication.  Pediatrics  1998; 101: 453­58. [PubMed]

4 Children's vaccines--safety first. Note to the press No 18, 9 July 1999. World Health Organization, Geneva, Switzerland.

Mercury, infant neurodevelopment, and vaccination

Journal of Pediatrics  •May 2000 • Volume 136 • Number 5

See related articles, p. 599 and p. 679.

In this issue of The Journal, 2 studies examine mercury exposure among newborns. Steuerwald et al¹ estimated fetal exposure to mercury resulting from maternal seafood consumption during pregnancy and examined subsequent neurologic function of newborns by using a standardized scale. Stajich et al² examined the impact of a birth dose of hepatitis B vaccine containing thimerosal (an organic mercury compound) on the acute blood mercury levels of premature versus term newborns.

Research on mercury exposure dates to the 1950s, when the tragic effects of mercury poisoning were recognized—first, in Japan from consumption of contaminated fish and later in Iraq from consumption of mercury-containing fungicide in seed grain. These episodes led to the confirmation of mercury as a neurotoxicant and to the derivation of early exposure guidelines.³ Follow-up studies involving inhabitants of the Faeroe and Seychelles islands,^4-6 who consume frequent seafood meals and are thus regularly exposed to methylmercury, are leading to more sophisticated outcome evaluations.⁷ The field of mercury toxicology continues to progress. Policymakers, in the meantime, work with the most current information to recommend action and examine the applicability of exposure guidelines, and each new study published adds to the existing database on mercury exposure.

At the root of the scientific interest in mercury over these last decades is the story of mercury itself, an element that cycles through several different chemical forms throughout the environment, exposing living organisms to its potential effects in the process. Modern industrial activity, especially fossil fuel combustion and waste incineration, is responsible for an estimated threefold increase in environmental mercury levels in this century alone.⁸ As a result, a number of concerted efforts have been implemented to reduce mercury release from industrial processes. The major source of non-occupational exposure is dietary intake of methylmercury, with fish and seafood the main culprits because of their propensity to concentrate mercury from the water. Through dietary intake and other sources, mercury is present at low concentrations in many tissues. Contributing to such exposures are pharmaceutical products including some vaccines that contain thimerosal, a mercury-derived preservative in use since the 1930s, which is composed of 49.6% mercury by weight in the form of ethylmercury. Although there are currently no health guidance values for ethylmercury, existing pharmacokinetic and toxicologic data suggest that ethylmercury behaves similarly to methylmercury, and experts therefore consider the methylmercury exposure guidelines appropriate. Attention in the medical community and among federal agencies has focused on how to interpret and apply current federal guidelines for exposure with regard to mercury in vaccines. Both the Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products have undertaken a comprehensive review of all mercury-containing pharmaceuticals. The addition of a number of important vaccines over the years has increased exposure to mercury among infants. When assumptions are made about the form of mercury, its route of exposure by injection, and the dosing intervals involved in administration of vaccines, some infants may now be exposed to cumulative doses of mercury in the first 6 months that exceed the US Environmental Protection Agency limit of 0.1 µg/kg/d for chronic (ie, long-term) daily exposure to methylmercury. However, this maximum cumulative exposure does not exceed either the Food and Drug Administration acceptable daily intake of 0.4 µ/kg or the Agency for Toxic Substances and Disease Registry health guidance values of 0.3 µg/kg/d. Moreover, all of these guidance values have built-in, wide margins of safety and are set to be protective of the fetus—considered the “organism” most sensitive to the effects of mercury.

Nonetheless, with the widely acknowledged value of reducing exposure to mercury, vaccine manufacturers are working to reduce or eliminate the use of thimerosal as a preservative. The Advisory Committee on Immunization Practices has recommended that hepatitis B vaccination for infants at birth be with a vaccine that does not contain thimerosal,⁹ although The Committee has acknowledged that the risk, if any, to infants from exposure to thimerosal is slight. Because the risks associated with not vaccinating children far outweigh the theoretical risk of exposure to thimerosal in vaccines, if the mother’s hepatitis B surface antigen status is positive or unknown, thimerosal-containing vaccine should be used even if an alternative is unavailable.

Are there any new implications of the studies in this issue regarding exposure to mercury? Steuerwald et al¹ found a weak, but statistically significant, association between a lower score on a standardized neonatal neurodevelopment scale and only one (cord blood) of several measures of mercury exposure that were examined in their cohort of infants from the Faeroe Islands. However, there are several problems in interpreting this finding. First, cord blood is more representative of exposure near term than of long-term maternal exposure during pregnancy (better represented by maternal hair concentration). In this study no significant relationship with maternal hair levels was found. Longer-term follow-up studies from this population, in which exposure to polychlorinated biphenyls and other organochlorines was also reported, has uncovered subtle impairment on domain-specific neuropsychologic tests among children evaluated at 7 years, associated with maternal exposure to mercury during pregnancy.⁶ These effects are not universal. In a cohort also being studied on the Seychelles Islands,⁴ no impairment was detected in children followed up at 5.5 years of age who were exposed in utero by mothers who consumed fish daily. However, the primarily global neuropsychologic scale used (rather than domain-specific testing done in the Faeroe study) was believed to be less sensitive to subtle neurologic impairment. A panel of experts, assembled in 1998 for an interagency workshop on issues relevant to the assessment of health effects from exposure to methylmercury, recommended that further domain-specific testing be conducted for the Seychellois cohort.¹⁰ Such testing was completed last year for the children in the 96-month Seychelles cohort, and the data are being evaluated; the results should be published soon.

Second, neonatal assessment tools have not always been shown to be predictive of later dysfunction. A study by Bierman-van Eendenburg et al¹¹ in 1981 demonstrated a high rate of false-positive results with the examination. Further, it is unclear whether a 2-point difference in this neurologic score, which is all that was found, suggests a true difference in morbidity, and further, whether it has any predictive validity of later developmental outcomes.

Stajich et al,² on the other hand, simply assessed blood mercury levels before and after hepatitis B vaccination in a small group of term and premature babies. This work is laudable: until this study, no investigator had empirically examined the direct effect of a dose of mercury-containing vaccine on blood levels. However, it is not yet possible to translate the findings into clinical significance. Measurements among the premature infants were highly variable, and their baseline mercury levels were, for unknown reasons, elevated compared with those of term infants. The clinical effect of the peak blood levels measured in these infants was not determined, nor could the level be compared with any existing standard. It is unfortunate that maternal hair mercury levels were not measured and that no attempts were made to investigate potential sources of exposure during gestation. With the recommendation to use thimerosal-free hepatitis B vaccine at birth, repeating this study to pursue this issue may no longer be possible in the United States. However, a small acute rise in blood mercury levels resulting from an injection of vaccine has never been shown to cause harm, but infants born to mothers with positive hepatitis B surface antigen status and infants whose status is unknown are at very real risk from hepatitis B.¹²

Although the knowledge of the nature of mercury exposure and toxicity continues to increase, much research still needs to be done to bridge data gaps, particularly in the areas of route- and duration-specific exposures for the individual organic compounds. The 2 articles in this issue of The Journal provide contributions to the existing database on organic mercury exposure; but 2 pieces do not solve a puzzle. Any re-examination of the validity of exposure guidelines for mercury must await other work.

Discussion will likely continue over the use of thimerosal-containing childhood vaccines in countries around the world, as more products that do not contain thimerosal as a preservative are developed. Indeed, assuring the safety of vaccine recipients anywhere in the world demands that inquiry and innovation proceed apace. Preservative-free vaccines are not always an option: a preservative must always be used in multi-dose vials to prevent bacterial and fungal contamination, and multi-dose vials are as yet the only option in many parts of the developing world. So as efforts to uncover the true effects of mercury continue, these efforts will both allow exposure guidelines to be refined based on better information and address some of the questions that remain regarding mercury and vaccination. The public health experts, pediatricians, and parents of infants receiving vaccines, who must base decisions on the implications of any finding, positive or negative, deserve these efforts.

1. Steuerwald U, Weihe P, Jørgensen PJ, Bjerve K, Brock J, Heinzow B, et al. Maternal seafood diet, methylmercury exposure, and neonatal neurologic function. J Pediatr 2000;136:599-605. 

2. Stajich GV, Lopez GP, Harry SW, Sexson WR. Iatrogenic exposure to mercury after hepatitis B vaccination in preterm infants. J Pediatr 2000;136:679-81. 

3. Mahaffey KR. Methyl mercury: a new look at the risks. Public Health Rep 1999;114:396-13. 

4. Davidson PW, Myers GJ, Cox C, Axtell C, Shamlaye C, Sloane-Reeves J, et al. Effects of prenatal and postnatal methylmercury exposure from fish consumption on neurodevelopment: outcomes at 66 months of age in the Seychelles Child Development Study. JAMA 1998;280:701-7. 

5. Grandjean P, Weihe P, White RF, Debes F. Cognitive performance of children prenatally exposed to “safe” levels of methylmercury. Environ Res 1998;77:165-72. 

6. Grandjean P, Budtz-Jorgensen E, White RF, Jorgensen PJ, Weihe P, Debes F, et al. Methylmercury exposure biomarkers as indicators of neurotoxicity in children aged 7 years. Am J Epidemiol 1999;150:301-5. 

7. Agency for Toxic Substances and Disease Registry. Toxicological profile for mercury. U.S. Department of Health and Human Services. March 1999.

8. Bender MT, Williams JM. A real plan of action on mercury. Public Health Rep 1999;114:416-20. 

9. Centers for Disease Control and Prevention (CDC). Thimerosal in vaccines: a joint statement of the American Academy of Pediatrics and the Public Health Service. MMWR Morb Mortal Wkly Rep 1999;48:563-5. 

10. National Institute of Environmental Health Sciences. Committee on Environment and Natural Resources and the Office of Science and Technology Policy. Workshop on scientific issues relevant to assessment of health effects from exposure to methyl mercury; November 1998; Raleigh, NC.

11. Bierman-van Eendenburg ME, Jurgens-van der Zee AD, Olinga AA, Huisjes HH, Touwen BC. Predictive value of neonatal neurological examination: a follow-up study at 18 months. Dev Med Child Neurol 1981;23:296-305. 

12. Margolis HS, Alter MJ, Hadler SC. Hepatitis B: evolving epidemiology and implications for control. Semin Liver Dis 1991;11:84-92. 

·         Medical Epidemiologist, Vaccine Safety and Development Branch, Epidemiology and Surveillance Division, National Immunization Program, Centers for Disease Control and Prevention
Chemical Manager for Mercury, Division of Toxicology, Agency for Toxic Substances and Disease Registry, Atlanta, GA 30333

·         J Pediatr 2000;136:571-3.

·         9/18/106797

·         doi:10.1067/mpd.2000.106797