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Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal: a descriptive study


After reading this study please see
 Safe Minds Assessment of the Pichichero Thimerosal Study 

Michael E Pichichero, Elsa Cernichiari, Joseph Lopreiato, John Treanor

The Lancet Volume 360, Number 9347     30 November 2002

http://www.thelancet.com/journal/vol360/iss9347/full/llan.360.9347.original_research.23350.1

http://pdf.thelancet.com/pdfdownload?uid=llan.360.9347.original_research.23350.1&x=x.pdf

Departments of Microbiology/Immunology (Prof M E Pichichero MD), Environmental Medicine (E Cernichiari), and Medicine (J Treanor MD), University of Rochester, Rochester, New York, NY, USA; and National Naval Medical Center, Bethesda, MD (J Lopreiato MD)

Correspondence to: Dr Michael E Pichichero, Department of Microbiology/Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, NY 14642, USA (e-mail:michael_pichichero@urmc.rochester.edu)

Summary

Background
Thiomersal is a preservative containing small amounts of ethylmercury that is used in routine vaccines for infants and children. The effect of vaccines containing thiomersal on concentrations of mercury in infants' blood has not been extensively assessed, and the metabolism of ethylmercury in infants is unknown. We aimed to measure concentrations of mercury in blood, urine, and stools of infants who received such vaccines.

Methods
40 full-term infants aged 6 months and younger were given vaccines that contained thiomersal (diptheria-tetanus-acellular pertussis vaccine, hepatitis B vaccine, and in some children Haemophilus influenzae type b vaccine). 21 control infants received thiomersal-free vaccines. We obtained samples of blood, urine, and stools 3-28 days after vaccination. Total mercury (organic and inorganic) in the samples was measured by cold vapour atomic absorption.

Findings
Mean mercury doses in infants exposed to thiomersal were 45·6 µg (range 37·5-62·5) for 2-month-olds and 111·3 µg (range 87·5-175·0) for 6-month-olds. Blood mercury in thiomersal-exposed 2-month-olds ranged from less than 3·75 to 20·55 nmol/L (parts per billion); in 6-month-olds all values were lower than 7·50 nmol/L. Only one of 15 blood samples from controls contained quantifiable mercury. Concentrations of mercury were low in urine after vaccination but were high in stools of thiomersal-exposed 2-month-olds (mean 82 ng/g dry weight) and in 6-month-olds (mean 58 ng/g dry weight). Estimated blood half-life of ethylmercury was 7 days (95% CI 4-10 days).

Interpretation
Administration of vaccines containing thiomersal does not seem to raise blood concentrations of mercury above safe values in infants. Ethylmercury seems to be eliminated from blood rapidly via the stools after parenteral administration of thiomersal in vaccines.

Lancet 2002; 360: 1737-41


Introduction

Thiomersal is a preservative used in vaccines routinely administered to infants and children. Its antimicrobial activity is due to small amounts of ethylmercury; the usual dose of paediatric vaccine contains 12·5-25 µg of mercury.1-3 When vaccines containing thiomersal are administered in the recommended doses, allergic reactions have been rarely noted, but no other harmful effects have been reported.4 Massive overdoses from inappropriate use of products containing thiomersal have resulted in toxic effects.5-9

Mercury occurs in three forms: the metallic element, inorganic salts, and organic compounds (eg, methylmercury, ethylmercury, and phenylmercury). The toxicity of mercury is complex and dependent on the form of mercury, route of entry, dosage, and age at exposure. Mercury is present in the environment in inorganic and organic forms, and everyone is exposed to small amounts.10,11 The main route of environmental exposure to organic mercury is consumption of predatory fish, especially shark and swordfish. A 6-ounce can of tuna contains 2-127 µg (average 17 µg) of mercury.12 Freshwater fish (eg, walleye, pike, muskie, and bass) can also contain high concentrations of mercury.

Most of the toxic effects of organic mercury compounds take place in the central nervous system, although the kidneys and immune system can also be affected.10,11,13 Organic mercury readily crosses the blood-brain barrier, and fetuses are more sensitive to mercury exposure than are children or adults. Data about potential differences in toxicity between ethylmercury and methylmercury are few. Both are associated with neurotoxicity in high doses; in-utero poisoning with methylmercury causes problems that are similar to cerebral palsy. Findings about the effect of low-dose methylmercury exposure on neurodevelopment in infants are contradictory.14,15 In-utero exposure could be related to subtle neurodevelopmental effects (eg, on attention, language, and memory) that can be detected by sophisticated neuropsychometric tests-- although the conclusion is confounded by concomitant ingestion of polychlorinated biphenyls in the patients investigated.14,15

No toxic effects of low-dose exposure to thiomersal in children have been reported.3 The effect of the small amounts of mercury contained in vaccines on concentrations of mercury in infants' blood has not been extensively assessed, and the metabolism of ethylmercury in infants is unknown. We aimed to assess concentrations of mercury in full-term infants after administration of routine vaccinations according to the schedule used in the USA, and to obtain additional information about the presence of mercury at other body sites including urine and stool. Samples of hair and breast milk were also obtained from some mothers of infants participating in the study

Methods

Study populations

We studied two groups of full-term infants who differed in their history of exposure to vaccines containing thiomersal. Infants in the exposure group were recruited at the Elmwood Pediatric Group, a large paediatric practice in Rochester, NY, USA, where vaccinations with thiomersal preservative were routinely given. 20 infants aged 2 months and 20 aged 6 months were studied at this practice to obtain information about the range of total thiomersal exposures likely to take place during infancy. The control group consisted of 21 infants who did not receive vaccines containing thiomersal and were recruited from the National Naval Medical Center, Bethesda, MD. All the infants were recruited during routine well-child examination and vaccination visits by the investigators (between November, 1999 and October, 2000). Written informed consent was obtained from parents for all procedures.

Vaccines

Vaccines containing thiomersal that were given to infants in the exposure group included Tripedia (diphtheria-tetanus-acellular pertussis vaccine; Aventis Pasteur, Swiftwater, PA; 0·01% thiomersal, 25 µg mercury per dose) Engerix (hepatitis B vaccine; GlaxoSmithKline, Rixensart, Belgium; 0·005% thiomersal, 12·5 µg mercury per dose), and in some children HibTITER (Haemophilus influenzae type b conjugate vaccine, Wyeth-Lederle, Pearl River, NY, USA; 0·01% thiomersal, 25 µg mercury per dose). Vaccines administered to the control group included Infanix (diptheria-tetanus-acellular pertussis vaccine; GlaxoSmithKline, Rixensart, Belgium), Recombivax HB (hepatitis B vaccine; Merck, West Point, PA, USA), and ActHIB (Haemophilus influenzae b conjugate vaccine, Aventis Pasteur, Swiftwater, PA, USA).

Procedures

We obtained vaccination histories--including type of vaccine, manufacturer, lot number, and dates of administration--from the medical records. In the exposure group, we obtained samples of heparinised whole blood, stool, and urine, during a visit 3-28 days after vaccination. Blood and urine were kept at 4°C, and stools were frozen until assessment. Urine was sampled by use of a urine bag at the clinic, and stool was taken from a diaper (nappy) provided by the parent. Whole blood and urine were obtained from the control children. At both sites, we obtained at least 50 hairs from the mother by cutting at the base near the scalp in the occipital area, to assess potential transplacental exposure of infants to mercury. Additionally, several samples of breastmilk or formula were obtained from mothers of infants at Elmwood Pediatric Group, as well as stool samples from a few infants who were not exposed to thiomersal.

We measured total mercury in all samples (and inorganic mercury in stool samples) by cold vapour atomic absorption as previously described.16,17 The limit of reliable quantitation in this assay ranged between 7·50 nmol/L and 2·50 nmol/L, dependant on sample volume.

Population pharmacokinetic calculations

To estimate the half-life of thiomersal mercury in the blood, we developed a prediction model for the expected concentrations of mercury in blood for half-lives of mercury ranging from 1 day to 45 days, on the basis of bodyweight of the infant, the doses of thiomersal administered, and the times between the individual doses of thiomersal and when the blood was obtained. To do these calculations, we assumed that 5% of the mercury dose was distributed to blood,7 that blood volume represented about 8% of the infant's bodyweight, and that elimination of mercury from blood followed a single-compartment model with first-order kinetics. For each possible half-life between 1 and 45 days, we then calculated the difference between the predicted and actual recorded concentrations in blood for each infant. Only measurements within the range of reliable quantitation were used in these calculations.

The best estimate of the blood half-life of mercury was judged to be the hypothetical half-life, which resulted in the smallest difference between predicted and observed values. We constructed a 95% CI based on a likelihood ratio for this estimate with the assumption that errors from the decay model were independent, additive, and normally distributed. The 95% confidence limits were the points where the curve crossed the minimum sum of squares multiplied by 1+chi2(1)/(n-1) where n is the number of data points and chi2(1) is the upper 5% point of the chi2 distribution on one degree of freedom.

Statistical analysis

Because this was a descriptive study we did no formal calculations for sample size. Student's t test and Fisher's exact test were used to compare results for the exposure and control group, with ple0·05 judged to be significant.

Role of the funding source

The sponsors of the study approved the study design but had no other involvement in the in study design, data collection, data analysis, data interpretation, or writing of the report.

Results

61 infants were enrolled in this study (table). Among infants aged 2 months in the exposure group, samples were taken from eight within 7 days of vaccination, from five between 8 and 14 days after vaccination, and from seven between 15 and 21 days after vaccination. Among 6-month-old infants in the exposure group, samples were taken from seven between 4 and 7 days after vaccination, from eight between 8 and 14 days after vaccination, and from five between 15 and 27 days after vaccination. Samples were obtained from infants in the control group at regularly scheduled visits at 2 or 6 months of age. All children remained healthy throughout the study and during 24-36 months of follow-up.

 


Infants aged 2 months Infants aged 6 months
Thiomersal-exposed (n=20) Controls (n=11) Thiomersal-exposed (n=20) Controls (n=10)
Bodyweight (kg)
Mean (range) 5·3 (4·0-6·4) NR 8·1 (6·7-10·6) NR
Total mercury exposure (µg)*
Mean (range) 45·6 (37·5-62·5) 0 111·3 (87·5-175·0) 0
Blood mercury (nmol/L)
Number of samples tested 17 8 16 7
Number with mercury in range 12 1 9 0
Mean (SD)† 8·20 (4·85) 4·90 5·15 (1·20) ..
Median (IQR)† 6·15 (4·60-10·85) 4·90 5·30 (4·55-6·10) ..
Range† 4·50-20·55 .. 2·85-6·90 ..
Urinary mercury (nmol/L)
Number of samples tested 12 6 15 8
Number with mercury in range 1 0 3 0
Mean (SD)† 3·8‡ .. 5·75 (1·05) ..
Median (range)† 3·8‡ .. 6·2 (4·55-6·45) ..
Stool mercury (ng/g dry weight)
Number of samples tested 12 NT 10 NT
Number with mercury in range 12 .. 10 ..
Mean (SD)† 81·8 (40·3) .. 58·3 (21·2) ..
Median (IQR)† 83·5 (47·0-121·3) .. 58·0 (42·0-68·5) ..
Range† 23·0-141·0 .. 29·0-102·0 ..
NR=Not recorded. NT=not tested. *Via vaccination. †All calculations done only with samples within range of accurate quantitation. ‡Only one value so SD and range are not applicable.
Concentrations of mercury in blood, urine, and stool of infants who received vaccines containing thiomersal and those who did not

 

Sufficient volumes of blood (ge1 mL) for the measurement of mercury by the atomic absorption technique were obtained from 17 infants aged 2 months and 16 aged 6 months in the exposure group. Mercury concentrations were below the range of reliable quantitation in five of 17 blood samples from 2-month-olds, and seven of 16 blood samples from 6-month olds (p=0·48). The mean concentration of blood mercury in samples with quantifiable mercury was higher in 2-month-olds than in 6-month olds (difference 3·05 nmol/L, 95% CI 0·03-1·24, p=0·06), but was low in both these groups (table). Sufficient blood volumes for measurement of mercury were obtained from 15 infants in the control group, including eight aged 2 months and seven aged 6 months. Blood mercury was below the level of reliable quantitation in seven of the eight samples from the 2-month-olds and in all seven samples from 6-month-olds. The only detectable value from the control group was 4·65 nmol/L.

Overall, mercury concentrations were below the range of quantitation in 12 of 33 samples from thiomersal-exposed infants and in 14 of 15 unexposed infants (p=0·04). The highest level of blood mercury detected in any infant in this study was 20·55 nmol/L, which was measured 5 days after vaccination in a 2-month-old infant weighing 5·3 kg, who had received vaccines (Tripedia and Engerix B) containing a total dose of 37·5 µg mercury. The relation between time between vaccination and sampling and the concentration of mercury in the blood in the exposed group is shown in figure 1. Although mercury concentrations were uniformly low, the highest levels were recorded soon after vaccination.

http://image.thelancet.com/lancet/issues/vol360no9347/article1737/tn02art4136_1.gif

Figure 1: Blood mercury concentrations in infants aged 2 months (diamonds) and 6 months (squares) by time of sampling

Filled symbols represent measured values and open symbols represent samples at the limit of quantitation, either 7·50 nmol/L, 3·75 nmol/L, or 2·5 nmol/L, dependent on sample volume.

Mercury was undetectable in most of the urine samples from the infants in this study. Only one of 12 urine samples from 2-month-olds, and three of 15 from 6-month-olds in the exposure group, and none of the 14 samples from the controls, contained detectable mercury. The highest concentration of urinary mercury detected was 6·45 nmol/L, in a 6-month old infant in the exposure group (table).

Stool samples were collected from infants in the exposure group. All of the stool samples from infants who received thiomersal-containing vaccines had detectable mercury, with concentrations in stools from 2-month-old infants slightly higher than those in 6-month-olds (p=0·098, table). As expected, most of the mercury in stools was inorganic. Stool samples were not obtained from control infants; therefore, to determine whether dietary intake could contribute to the mercury content of stools, we also obtained samples from nine infants at Elmwood Pediatric Group who were age-matched with the infants in the exposure group and were not exposed to vaccines containing thiomersal. The mean mercury concentration in the stools of these infants was 22 ng/g dry weight (SD 16), which was significantly lower (p=0·002) than the mean of the samples collected from thiomersal-exposed infants.

Amounts of mercury measured in maternal hair are shown in figure 2. The mean concentration of hair mercury in mothers of the exposure group was 0·45 µg/g hair, whereas the mean amount in mothers of the control infants was 0·32 µg/g (p=0·22). Eight mothers of infants in the 6-month-old cohort provided breast milk samples. Concentrations of mercury in these samples were low (mean=0·30 µg/g, range 0·24-0·42 µg/g).

http://image.thelancet.com/lancet/issues/vol360no9347/article1737/tn02art4136_2.gif

Figure 2: Mercury concentrations in hair from mothers of infants 

Bar represents mean concentration of mercury in maternal hair.

We estimated the half-life of mercury in blood after vaccination to be 7 days, since this result gave the smallest difference between the expected and recorded (measured) concentration (figure 3). The 95% CI around this estimate was 4-10 days. The half-life estimate was very similar when only measurements in 2-month-olds (7 days, 95% CI 4-11) or 6-month-olds (5 days, 3-9) were included, suggesting that the rate of elimination of thiomersal mercury from blood was similar in both age-groups.

http://image.thelancet.com/lancet/issues/vol360no9347/article1737/tn02art4136_3.gif

Figure 3: Estimated blood half-life of mercury in infants who were exposed to thiomersal 

Lines represent sum of square of differences between observed concentrations of blood mercury (nmol/L) and those predicted for every individual infant on the basis of bodyweight and time of sampling, with a series of hypothetical half-lives shown on x axis. Arrow shows point with lowest value for squared difference, indicating best estimate for serum half-life.

Discussion

We have shown that very low concentrations of blood mercury can be detected in infants aged 2-6 months who have been given vaccines containing thiomersal. However, no children had a concentration of blood mercury exceeding 29 nmol/L (parts per billion), which is the concentration thought to be safe in cord blood;18 this value was set at ten times below the lower 95% CI limit of the minimal cord blood concentration associated with an increase in the prevalence of abnormal scores on cognitive function tests in children. Blood mercury concentrations indicate concentrations in organs well.18

Although our study was not designed as a formal assessment of the pharmacokinetics of mercury, we did obtain samples of blood at various time points after exposure. Assessment of these samples suggested that the blood half-life of ethylmercury in infants might differ from the 40-50 day half-life of methylmercury (range 20-70 days) in adults and breastfeeding infants.10,19 The concentrations of blood mercury 2-3 weeks after vaccination noted in our study were not consistent with such a long half-life, but suggested a half-life of less than 10 days. However, this conclusion is based on several assumptions and a very simple model, and does not take into account the fact that at least some of the mercury detected in the blood of the infants in this study is likely to have been derived from exposures other than vaccination. Because of the short period between vaccination and sampling, the findings of Strajich and colleagues20 could be consistent with either a 6-day or 40-day half-life, but are otherwise consistent with the assumptions made in our model. Because we expected a 45-day half-life on the basis of methylmercury pharmacokinetics, the first blood samples were obtained 3 days after vaccination. Blood samples taken in the first 72 hours after vaccination, stool samples obtained every 24 h, and samples from premature newborn babies (weighingge2000 g) given a birth dose of hepatitis B vaccine would have helped us to reach stronger conclusions. Thus, additional studies of the pharmacology of thiomersal in infants are underway.

At the times tested after vaccination, mercury excretion in urine in our study population was low. By contrast, concentrations of mercury in stool were high, and combined with the finding that stool mercury concentrations in infants who were not exposed to thiomersal were significantly lower is consistent with the hypothesis that the gastrointestinal tract represents a possible mode of elimination of thiomersal mercury in infants.

Overall, the results of this study show that amounts of mercury in the blood of infants receiving vaccines formulated with thiomersal are well below concentrations potentially associated with toxic effects. Coupled with 60 years of experience with administration of thiomersal-containing vaccines, we conclude that the thiomersal in routine vaccines poses very little risk to full-term infants, but that thiomersal-containing vaccines should not be administered at birth to very low birthweight premature infants. Decisions about the elimination of thiomersal from these vaccines must balance the potential benefit of reduced exposure to mercury against the risks of decreased vaccine coverage because of higher costs, the risk of sepsis in recipients because of bacterial contamination of preservative-free formulations, and the risks of exposure to alternative preservatives that might replace thiomersal.

Conflict of interest statement

None declared.

M Pichichero and J Treanor contributed to the study conception and design; obtained, assessed, and interpreted data; drafted and revised the manuscript; and provided statistical expertise and supervision. E Cernichiari contributed to analysis and interpretation of data, revision of the manuscript, and technical support. J Lopreiato contributed to revision of the manuscript, and obtained data.

Contributors

Acknowledgments

We thank Tom Clarkson for advice about the interpretation of mercury assays, David Oakes for statistical advice, Doreen Francis for recruiting participants and obtaining samples, and Margaret Langdon and Nicole Zur for technical assistance. The investigation was funded by the US National Institutes of Health (NIH), Bethesda, MD, under contract 1 AF-45248.

References

1 Clements CJ, Ball LK, Ball R, Pratt D. Thiomersal in vaccines.  Lancet  2000; 355: 1279-79. [Text]

2 American Academy of Pediatrics, Committee on Infectious Diseases, and Committee on Environmental Health. Thimerosal in vaccines--An interim report to clinicians.  Pediatrics  1999; 104: 570-74. [PubMed]

3 Ball LK, Ball R, Pratt, RD. An assessment of thimerosal use in childhood vaccines.  Pediatrics  2001; 107: 1147-54. [PubMed]

4 Cox NH, Forsyth A. Thimerosal allergy and vaccination reactions.  Contact Dermatitis  1988; 18: 229-33. [PubMed]

5 Axton JH. Six cases of poisoning after a parenteral organic mercurial compound (merthiolate).  Postgrad Med J  1972; 561: 417-21. [PubMed]

6 Fagan DG, Pritchard JS, Clarkson TW, Greenwood MR. Organ mercury levels in infants with omphaloceles treated with organic mercurial antiseptic.  Arch Dis Child  1977; 52: 962-64. [PubMed]

7 Matheson DS, Clarkson TW, Gelfand EW. Mercury toxicity (acrodynia) induced by long-term injection of gammaglobulin.  J Pediatr  1980; 97: 153-55. [PubMed]

8 Lowell JA, Burgess S, Shenoy S, Curci JA, Peters M, Howard TK. Mercury poisoning associated with high-dose hepatitis-B immune globulin administration after liver transplantation for chronic hepatitis B.  Liver Transpl Surg  1996; 2: 475-78. [PubMed]

9 Pfab R, Muckter H, Roider G, Zilker T. Clinical course of severe poisoning with thimerosal. J Toxicol Clin Toxicol 1996; 34: 453-60.

10 Clarkson TW. Mercury: major issues in environmental health.  Environ Health Perspect 1992; 100: 31-38. [PubMed]

11 Clarkson TW. The toxicology of mercury.  Crit Rev Clin Lab Sci  1977; 34: 369-403. [PubMed]

12 Yess NJ. US food and Drug Administration survey of methylmercury in canned tuna.  J AOAC Int  1993; 76: 36-38. [PubMed]

13 Shenker BJ, Guo TL, Shapiro IM. Low-level methylmercury exposure causes human T-cells to undergo apoptosis: evidence of mitochondrial dysfunction.  Environ Res  1998; 77: 149-59. [PubMed]

14 Grandjean P, Weihe P, White RF, et al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury.  Neurotoxicol Teratol  1997; 6: 417-28. [PubMed]

15 Davidson PW, Myers GJ, Cox C, 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: 701-07. [PubMed]

16 Cernichiari E, Toribara TY, Liang L, et al. The biological monitoring of mercury in the Seychelles study.  Neurotoxicology  1995; 16: 613-28. [PubMed]

17 Cernichiari E, Brewer R, Myers GJ, et al. Monitoring methylmercury during pregnancy: maternal hair predicts fetal brain exposure.  Neurotoxicology  1995; 16: 705-10. [PubMed]

18 Nielsen JB, Andersen O, Grandjean P. Evaluation of mercury in hair, blood and muscle as biomarkers for methylmercury exposure in male and female mice.  Arch Toxicol  1994; 68: 317-21. [PubMed]

19 National Academy of Sciences. Toxicologic effects of methylmercury. Washington DC: National Research Council, 2000.

20 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. [PubMed]

After reading this study please see
 Safe Minds Assessment of the Pichichero Thimerosal Study 


Commentary

Mercury in vaccines--reassuring news

The Lancet Volume 360, Number 9347     30 November 2002

http://www.thelancet.com/journal/vol360/iss9347/full/llan.360.9347.editorial_and_review.23382.1

The mass media and alternative-medicine publications increasingly report that exposure to and the build-up of mercury within the body is associated with chronic ill-health, particularly conditions such as myalgic encephalitis. Mercury is widespread in the environment; it is found naturally in rocks, soils, and plants and as a contaminant in air, water, and food. The element is used a lot in the electrical industry, and in many domestic products, including paints, pesticides, fabric softeners, waxes, and polishes. Mercury is often used as a preservative in vaccines, skin creams, cosmetics, and other medications. Mercury is the major component of dental amalgams and there is a growing lobby against its use.1 Everyone is exposed to small amounts of mercury as elemental metallic vapour from dental amalgams or organic mercury from fish, sea foods, and vaccines, or to inorganic salts from other food stuffs, water, and air. Faecal excretion is the major route of elimination of inorganic or organic mercury.

Elemental mercury from amalgams is lipid-soluble and freely passes through cell membranes.2 By contrast, organic and inorganic mercury from the diet and other sources are charged and must be complexed with other counter-ions or low-molecular-weight sulphur compounds to pass through cell membranes. The major targets in proteins susceptible to binding of metals, including mercury, are the sulphydryl group of cysteine and the iminonitrogen of histidine. The aromatic ring nitrogens of the nucleotide bases form mercury complexes, with thymine and uracil being more reactive than cytosine, guanine, and adenine.3,4 The most abundant single nucleophile reactant is the antioxidant glutathione, typically present at concentrations of 5 mmol/L in cells, serum, and bile.5 Glutathione mops up ionised mercury derived from oxidation of elemental mercury and from organic and inorganic mercury. There may be an inverse relation between the concentration of intracellular glutathione and mercury toxicity.6 Once bound to glutathione, mercury can leave the cell and circulate freely in serum and lymph from where it can be deposited in other organs and tissues. Glutathione-complexed mercury is eventually eliminated via the kidney or downloaded via bile into the intestinal lumen from where it is excreted in faeces. After mercury is released from tissues, faecal excretion is the predominant route for elimination.

In this issue of The Lancet, Michael Pichichero and colleagues investigate mercury levels and excretion in infants receiving vaccines containing thiomersal (ethyl mercury). Little is known about the harmful effects of mercury in infants and children and at what level these effects occur. At between 12·5 and 25 mg mercury per vaccine dose, the infants may be receiving over 100 mg ethyl mercury in the first 6 months of life. Pichichero and colleagues show that the levels in blood are much lower than the prescribed limits and that much of the ethyl mercury appears to be eliminated rapidly in faeces. This study gives comforting reassurance about the safety of ethyl mercury as a preservative in childhood vaccines.

D C Henderson

 


Department of Immunology, Faculty of Medicine, Imperial College of Science Technology and Medicine, Chelsea & Westminster Hospital, London SW10 9NH, UK (e-mail:d.henderson@ic.ac.uk)

 

1 Henderson DC, Clifford R, Young DM. Mercury-reactive lymphocytes in peripheral blood are not a marker for dental amalgam associated disease.  J Dentistry 2001; 29: 469-74. [PubMed]

2 Lorscheider FL, Vimy MJ, Summers AO. Mercury exposure from "silver" tooth fillings: emerging evidence questions a dental paradigm.  FASEB J 1995; 9: 504-08. [PubMed]

3 Magos L, Halbach S, Clarkson TW. Role of catalase in the oxidation of mercury vapour.  Biochem Pharmacol 1978; 27: 1373-77. [PubMed]

4 O'Halloran TV. Transition metals in control of gene expression.  Science 1993; 261: 715-25. [PubMed]

5 Meister A, Anderson ME. Glutathione.  Annu Rev Biochem 1983; 52: 711-60. [PubMed]

6 Naganuma A, Anderson ME, Meister A. Cellular glutathione as a determinant of sensitivity to mercuric chloride toxicity.  Biochem Pharmacol 1990; 40: 693-97. [PubMed]

 


http://www.urmc.rochester.edu/gebs/faculty/Michael_Pichichero.htm

 

Michael Pichichero
 Professor of Microbiology & Immunology
M.D. (1976) Rochester

Primary Appointment:  Microbiology & Immunology

GEBS Cluster Affiliations:  Immunology, Microbiology, and Vaccine Biology - IMV

Contact Information:

University of Rochester
School of Medicine and Dentistry
601 Elmwood Ave, Box 672
Rochester, New York 14642

Medical Center 2-5431
Phone: (585) 275-1534
E-Mail: mepo@uhura.cc.rochester.edu
Research:
Vaccine Development and Evaluation

Research Overview

Dr. Pichichero and his colleagues' vaccine studies helped define the key variables that determine immunogenicity of the Haemophilus influenzae b (Hib) conjugate vaccines in the young infant. Encouraging findings have been made with Streptococcus pneumoniae capsular polysaccharide vaccines of several serotypes employing the conjugate vaccine technology. Continuation of these studies should further define structural factors governing immunogenicity of conjugate vaccines, analyze the role of epitopes of the carrier component, and pursue structure-immunogenicity relationships in conjugates of specific pneumococcal serotypes.

Combination vaccines are a necessity for the future of human vaccine development. The immunogenicity of acellular pertussis (DTaP) vaccines combined with various Hib conjugate vaccines, Hepatitis B vaccine, and inactivated poliovirus vaccine results in reduced immunogenicity for some of the included antigens. The mechanism(s) and biological relevance of this immunologic interference phenomena is an area of active research in Dr. Pichichero's lab.

Bacteria resistant to standard antibiotic therapy are causing acute otitis media with increasing frequency. New antibiotics are needed to cure these infections and to prevent long-term middle ear disease and associated hearing loss. Dr. Pichichero's group studies the epidemiology, etiology, and optimal treatment of otitis media. Sore throat caused by Group A beta hemolytic streptococci occur with concomitant colonization by organisms that may protect the streptococci through beta lactamase inactivation of penicillin at the site of infection. Dr. Pichichero's group evaluates alternative treatments to decrease the relapse rate of streptococcal infections.

Recent Publications

 

  • Publication list, as provided by PubMed.
    PubMed is maintained by the National Library of Medicine and provides complete abstracts of all publications, as well as links to the full text of many articles (at journal homepages).

  • Rennels MB, Deloria MA, Pichichero ME, Englund JA, Anderson EL, Steinhoff MC, Decker MD, Edwards KM. Lack of consistent relationship between quantity of aluminum in diphtheria-tetanus-acellular pertussis vaccines and rates of extensive swelling reactions. Vaccine. 20 Suppl 3:S44-7, 2002. http://www.ncbi.nlm.nih.gov/entrez/query.Retrieve&db=PubMed&list_uids=12184364&dopt=Abstract
  • Pichichero ME, Casey JR. Otitis media. Expert Opin Pharmacother. 3:1073-90, 2002.
  • Pichichero ME. Dynamics of antibiotic prescribing for children. JAMA. 287:3133-5, 2002.
  • Shelly MA, Pichichero ME, Treanor JJ. Low baseline antibody level to diphtheria is associated with poor response to conjugated pneumococcal vaccine in adults. Scand J Infect Dis. 33:542-4, 2001.
  • Pichichero ME, Anderson EL, Rennels MB, Edwards KM, England JA. Fifth vaccination with dipthteria, tetanus and acellular pertussis is beneficial in four- to six-year-olds.Pediatr Infect Dis J 20:427-33, 2001.
  • Pichichero ME, Marsocci SM, Murphy ML, Hoeger W, Francis AB, Green JL. A prospective observational study of 5-, 7-, and 10-day antibiotic treatment for acute otitis media. Otolaryngol Head Neck Surg 124:381-7, 2001.
  • Pichichero ME, Gooch WM 3rd. Comparison of cefdinir and penicillin V in the treatment of pediatric streptococcal tonsillopharyngitis. Pediatr Infect Dis 19:S171-3, 2000.
  • Hoe NP, Kordari P, Cole R, Liu M, Palzkill T, Huang W, McLellan D, Adams GJ, Hu M, Vuopio-Varkila J, Cate TR, Pichichero ME, Edwards KM, Eskola J, Low DE, Musser JM. Human immune response to streptococcal inhibitor of complement, a serotype M1 group A streptococcus extracellular protein involved in epidemics. J Infect Dis. 182:1425-36, 2000.
  • Anderson P, Ingram DL, Pichichero ME, Peter G. A high degree of natural immunologic priming to the capsular polysaccharide may not prevent Haemophilus influenzae type b meningitis. Pediatr Infect Dis J. 19:589-91, 2000.
  • Novotny LA, Jurcisek JA, Pichichero ME, Bakaletz LO. Epitope mapping of the outer membrane protein P5-homologous fimbrin adhesin of nontypeable Haemophilus influenzae. Infect Immun. 68:2119-28, 2000.
  • Pichichero ME, Edwards KM, Anderson EL, Rennels MB, Englund JA, Yerg DE, Blackwelder WC, Jansen DL, Meade BD. Safety and immunogenicity of six acellular pertussis vaccines and one whole-cell pertussis vaccine given as a fifth dose in four- to six-year-old children. Pediatrics. 105:e11, 2000.

Medscape Medscape Medical News

Mercury in Vaccines: A Newsmaker Interview With Michael E. Pichichero, MD

Laurie Barclay, MD

Medscape Medical News 2002.

http://www.medscape.com/viewarticle/445538_print

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


Safe Minds Assessment of the Pichichero Thimerosal Study

December 3, 2002

Contact: Sallie Bernard, Executive Director, Safe Minds

sbernard@arcresearch.com; 908 295-6648; www.safeminds.org

http://www.medscape.com/viewarticle/447240

INTRODUCTION

This analysis describes the concerns which Safe Minds has over a recently published study in The Lancet by Michael Pichichero et al.(1) in which blood measurements were taken of infants after administration of vaccines containing thimerosal. The article and accompanying commentary contain several sweeping statements about thimerosal safety:

  • "Overall, the results of this study show that amounts of mercury in the blood of infants receiving vaccines formulated with thiomersal are well below concentrations potentially associated with toxic effects."
  • "Administration of vaccines containing thimerosal does not seem to raise blood concentrations of mercury above safe values in infants."
  • "This study gives comforting reassurance about the safety of ethyl mercury as a preservative in childhood vaccines."

The design and results of the study do not support these statements. In fact, the results suggest that thimerosal exposure from vaccines may have caused neurological damage in some children.  Safe Minds questions the objectivity of the study authors, due to their ties to vaccine research and vaccine manufacturers, which may have resulted in a biased study design and biased interpretation of the results.

OBJECTIVITY OF THE AUTHORS

  • Pichichero has an acknowledged financial tie to Eli Lilly, the developer of thimerosal and the main target of thimerosal litigation.  He has also claimed financial ties to a number of vaccine manufacturers, including manufacturers of thimerosal-containing vaccines.(2) For example, in an article in the American Academy of Family Physicians newsletter of April 2000, Dr. Pichichero makes this disclosure statement (3):

"The author has received research grants and/or honoraria from the following pharmaceutical companies: Abbott Laboratories, Inc.; Bristol-Myers Squibb Company; Eli Lilly & Company; Merck & Co.; Pasteur Merieux Connaught; Pfizer Labs; Roche Laboratories; Roussel-Uclaf; Schering Corporation; Smith Kline Beecham Pharmaceuticals; Upjohn Company; and Wyeth-Lederle."

  • Pichichero's work has been cited in 21 vaccine patent applications He was involved in the recommendation for the Wyeth rotavirus vaccine and failed to anticipate its risks. (4) This vaccine was withdrawn soon after licensure due to adverse reactions.  

 

  • A substantial proportion of Dr. Pichichero's work involves vaccines. Safe Minds conducted a simple Medline search of publications listing M Pichichero as an author.(5) A breakdown of these publications by subject area shows that many focus on vaccines, especially those which contained thimerosal.

    • 161 publications
    • 23 DPT
    • 7 Hib
    • 1 HepB
    • 1 Polio
    • 3 Pneumococcal Conjugate
    • 3 Rotavirus
    • 4 New combination vaccines or general vaccine discussions
    • The remainder deal with otitis media and use of antibiotics
    • Note some articles were counted more than once because they addressed more than one vaccine
  • Similarly, the University of Rochester web site provides biographical information on Dr. Pichichero, which describes his focus on vaccine research. (6) It describes him as an immunologist, not a toxicologist. None of his work involves safety assessment of a heavy metal or other toxicant. One paragraph cites his work on the Haemophilus influenzae type B vaccine, one of the thimerosal-containing vaccines that was added to the CDC/AAP-recommended infant schedule in 1991, nearly doubling the thimerosal load.

 

  • John Treanor, another author, has also conducted substantial research into thimerosal-containing vaccines, and the University of Rochester is one of a few sites designated by NIH for evaluating new vaccines. Investigators at the University of Rochester helped develop the Haemophilus influenzae B vaccine. Per its web site, "Rochester has become a national model...in ensuring that as many people as possible are immunized." (7)

STUDY DESIGN ISSUES

Sample

· The sample size was small. Although the overall sample size was stated as 61 infants, there were only 33 exposed children who were used for the blood mercury assessment upon which the safety conclusions were made.  One major shortcoming of a small sample size is the low chance of including infants who are especially sensitive to mercury's effects, or who may have detoxification difficulties. We know from the mercury literature that there is wide variability in the population in regard to mercury sensitivity and clearance. Since vaccines are given to virtually all infants, even if 1% retained mercury to a much greater degree than the "norm", this would represent a large number of injured children.

· The small sample size means that the study lacks sufficient power to establish safety claims

· The sample was not randomly drawn, but was a convenience sample, and therefore not representative of all infants in terms of health status, socio-economic status, ethnicity, and other potentially important factors.

Dose

· Given that the half life of ethylmercury appears to be 6-7 days, virtually all, if not all, blood draws missed the peak blood concentrations of mercury. It is evident that earlier peaks existed because the feces contained high mercury values, and feces reflect earlier blood levels.  It is impossible to state what the peak values are if they were not measured. It is also impossible to calculate average blood concentrations unless peak concentrations are measured. Standard methylmercury pharmacokinetic (PK) studies consider peak and average blood concentrations, along with tissue distribution, as necessary components of toxicity assessment. It is disingenuous to compare the blood levels in this study with past methylmercury ones without any type of adjustment factor, because the methylmercury studies incorporated peak levels into their values, whereas this study only included the smaller values.

· The dose of ethylmercury given to subjects varied greatly and was less than what a typical child in the 1990s could receive. In a rationally designed PK study, the dose is kept constant. In the Pichichero study, the 2 month old subjects were injected with between 37.5 mcg and 62.5 mcg of ethylmercury reflecting a 67% difference between the lowest and highest dose. The mean was 45.6 mcg. The typical child in the 1990s could receive 62.5 mcg of mercury at age 2 months and an additional 12.5 mcg at birth (from the Hepatitis B vaccine), or 37% and 64% more Hg, respectively, than the children in this study. The 6 month old subjects were injected with between 87.5 mcg and 175 mcg of ethylmercury reflecting a 100% difference between the lowest and highest dose. The mean was 111.3 mcg. By 6 months of age, the typical child in the 1990s would have received 187.5 mcg Hg, or 68% more than the Pichichero study group average.

· The total recorded dose of ethylmercury was not administered during the study data collection period. According to the national immunization schedule that existed during the data collection period (November 1999 to October 2000), it is not possible for a six month old infant to receive 175 mcg of ethyl mercury at only the six month visit.  Rather, at 6 months of age, an infant would receive a maximum of 62.5 mcg Hg, from a DTaP, a HiB, and a Hep B vaccine. Thus, the Pichichero study, in calculating dose, included exposures which occurred months prior to the last injection. Thus, when the study characterizes blood draws as being "X" days after the mercury exposure, this is misleading, because it refers only to the last injection. Thus, the reader really doesn't know how much dose any infant received at that last exposure from the data presented in the table in the study.

· In a properly designed PK study, multiple blood draws should be taken from each subject, and blood collection times should be consistent for all subjects. In this study, there was a single draw per child, and the collection times varied from 3 to 21 days for two month old infants, a 700% difference, and from 4 to 27 days for six month old infants, a 675% difference.

Modeling

· The single compartment model and safety assumptions looked at blood levels as the determinant of safety. However, a more important measure is mercury distribution into tissue, particularly the brain. Estimation of brain accumulation would require a two compartment model and measurement of peak blood levels, neither of which were components of this study. Yet it is apparent that the mercury is moving through the body and is redistributing because it is in the feces at substantial levels.

STUDY INTERPRETATION

· Improper use of methylmercury safety levels as a marker for ethylmercury risk: the Pichichero study compares ethylmercury blood levels with levels from methylmercury risk assessments, but obviously, ethylmercury is a different molecule than methylmercury, and therefore it needs its own safety assessment. A slight change in molecular structure can have very different effects in the body. There has never been a full safety assessment of thimerosal, as the FDA has admitted. The only way to do this is to conduct a series of cellular or molecular level studies as well as population studies consisting of either (a) animal studies which measure behavioral, neuropsychological, or physiological outcomes (that is, does "x" dose result in "y" aberrant behavior or "z" reduction on memory tests, etc.), or (b) human studies on exposed populations, again looking at behavioral, neuropsychological, or physiological outcomes. These types of studies have been done extensively for methylmercury, and this is why methylmercury blood levels can be correlated with certain outcomes or risk, but it has never been done thoroughly for thimerosal. The Pichichero study does not address adverse outcomes at all, and therefore does not constitute a true safety assessment.

· Improper interpretation of 1994 Grandjean study to assess safety:  the Lancet study authors cite a 1994 article by Philippe Grandjean as saying that a 29 nMol/L blood concentration is the level for methylmercury which is thought to be safe, since it is ten times lower than the levels at which adverse effects have been found in methylmercury research. (Ten times 29 nMol/L equates to 290 nMol/L, or 59 part per billion.) Actually, as the EPA explains (8), the EPA incorporated a ten-fold factor into their safety assessments due to "uncertainty factors" because the methylmercury studies are small, have a high margin of error, and there is immense variability in human response to mercury. Thus, to be truly protective of the population, blood levels should not exceed 29 nMol/L (which equates to 5.8 parts per billion, or the 6 mcg/L the EPA refers to in their document). The EPA was concerned when a national study (NHANES) showed that 10% of the US women of child bearing age had blood mercury over 6 ppb. Thus, a level of 6 ppb or over, equivalent to 29+ nMol/L, is considered by EPA to be cause for alarm.

  • In the Pichichero study, there is one infant blood level out of the 17 2-month old blood samples (12%) which was 20.55 nMol/L, or 4.1 ppb. This infant had its blood drawn at day 5, received 37.5 mcg/Hg, and weighed 5.3 kg.
  • a) Day 5 is past the peak value in blood, meaning that at days 1-3, levels would be much             higher.
  • b) A 37.5 mcg dose is (conservatively) 60% of what a typical 1990s infant may have received (37.5/62.5=60%).
  • c) A 5.3 kg infant is at the 95th percentile of weight for a 2 month old, that is, a large, heavy baby. Since blood Hg concentrations are in part dependent on weight, a child with a lower weight than this infant (that is, 95% of the 2 month old population) would have had a higher blood level than this infant.
  • The implications of points a, b, and c are that (1) if the study infant's blood were taken at 1-3 days, it is more than likely that the Hg levels would have exceeded 6 ppb; (2) it is likely that the peak levels of more than 12% of 2 month old children children given the full 62.5 mcg of mercury would exceed 6 ppb; and (3) a larger percentage of smaller infants - but still those of "normal" weight - would be likely to have blood levels exceeding 6 ppb.
  • In addition, there were two other 2 year olds with mercury levels at between 10 and 15 nMol/L. These values are with 1/2-1/3 of the EPA margin of safety, with blood draws on days 6-7.
  • For these reasons alone, the results of the Pichichero study are anything but "reassuring" to parents whose children were exposed to thimerosal as infants.

LEARNING FROM THE STUDY

  • Despite its many limitations, the Pichichero study does provide new or confirming information about the pharmacokinetics of ethylmercury injected into infants.

· The half life of ethymercury in infants appears to be shorter than methytlmercury, approximately 6-7 days. Pharmacologically, this period would be considered a very long half life and a long time for a toxic substance to be circulating in the body. In fact, the single blood draw after 20 days for which mercury quantitation could be made showed mercury being circulated at about 5 nMol/L. In a developing brain a few days are significant time periods for an agent that interferes with cell division and organization.

· The control group had no detectable mercury, indicating that the mercury in the exposed group was due to the thimerosal in the vaccines

SUMMARY

  • The Pichichero is a small-scale descriptive study with many design limitations, which has moderate value in advancing understanding of ethylmercury pharmacokinetics. It has little if no value as a safety assessment of thimerosal from vaccines, and its conclusions are overreaching, perhaps reflecting a bias on the part of its lead author towards absolving lisenced vaccines of any adverse effects.

References


A few comments may be added to this excellent review:

By Per Dalen MD

The Lancet article starts, somewhat disingenuously, with the following sentence:

"Thiomersal is a preservative containing small amounts of ethylmercury that is used in routine vaccines for infants and children."

Thiomersal contains 50% Hg by weight!

According to a University of Rochester Medical Center press release http://www.newswise.com/articles/2002/11/VACCINES.URM.html?sc=wire) the study was initiated as follows:

"In response to the debate, the National Institute of Allergy and Infectious Diseases (NIAID) asked vaccine researchers at the University of Rochester Medical Center to investigate. With funding from NIAID, the Rochester team measured mercury concentrations in urine, blood, and stools of 61 infants ..."

<snip>

"The research was done at the Vaccine Treatment and Evaluation Unit that the NIAID funds at the University of Rochester Medical Center."

The Lancet article contains the following, under the subheading "Role of the funding source":

"The sponsors of the study approved the study design but had no other involvement in the in study design, data collection, data analysis, data interpretation, or writing of the report."

Control of the design goes a long way in controlling the results in a study like this.

Per

Per Dalen MD E-mail: pdalen@algonet.se


 

Mercury in Vaccines Is at Safe Levels

University of Rochester Medical Center
29-Nov-02

http://www.newswise.com/articles/2002/11/VACCINES.URM.html

Library: MED
Keywords: VACCINES MERCURY THIMEROSAL

Description: The first detailed analysis of blood mercury levels in infants who received vaccines containing the preservative thimerosal indicates that blood levels of mercury in children are comfortably below current safety limits. (Lancet, 30-Nov-2002)

For more information, contact:
Tom Rickey
(585) 275-7954
trickey@admin.rochester.edu

Embargoed for release at 6:30 p.m. Eastern Time Thursday, Nov. 28, per Lancet embargo

Mercury in Vaccines Is at Safe Levels, Study Suggests

The first detailed analysis of blood mercury levels in infants who received vaccines containing the preservative thimerosal indicates that blood levels of mercury in children are comfortably below current safety limits. The study of 61 children by physicians and scientists at the University of Rochester Medical Center, published in the Nov. 30 issue of The Lancet, also found that the form of mercury in vaccines is eliminated from the blood much more quickly than scientists had predicted.

"The results are very reassuring," says pediatrician Michael E. Pichichero, M.D., the lead investigator of the study and professor of microbiology and immunology, pediatrics, and medicine. "The amount of mercury is well below all established safety levels."

The issue is at the core of a national debate over the safety of vaccines. While some parents and politicians have asserted that the minuscule amounts of mercury used in vaccines could be responsible for a range of disorders including autism in some children, no scientific study has found a link. The current study adds evidence to the argument by most pediatricians and public health officials that vaccines are safe.

"Every day we see families who are reluctant to have their children vaccinated because of this issue," says Pichichero. "We work with them, and many decide to go ahead with vaccinations, but some do not, and so they put their children at increased risk for developing serious diseases. It's no longer a routine office visit."

During the 1990s the number of vaccines given to infants increased markedly, with the addition of immunizations against diseases like hepatitis B and meningitis. Though each vaccine contained only a small amount of thimerosal and a minute amount of mercury, some became concerned that perhaps the cumulative amounts might harm children.

In 1999, the American Academy of Pediatrics and public health officials urged vaccine manufacturers to remove thimerosal from vaccines administered in the United States. The compound has since been removed from nearly all vaccines given to U.S. children, though there is no scientific evidence that the compound has harmed children. The preservative is still used widely in other countries to make vaccines available to millions of children at a lower cost.

In response to the debate, the National Institute of Allergy and Infectious Diseases (NIAID) asked vaccine researchers at the University of Rochester Medical Center to investigate. With funding from NIAID, the Rochester team measured mercury concentrations in urine, blood, and stools of 61 infants -- 40 received vaccines containing thimerosal, and 21 received thimerosal-free vaccines. All the children in the study had received diphtheria-tetanus-acellular pertussis vaccine and hepatitis B vaccine, and some also received Haemophilus influenzae type B vaccine. The immunizations are typically given to children at the ages of two months, four months, and six months.

Most of the children in the study had blood mercury levels of 1 or 2 nanograms per milliliter; the highest level, found in one child, was 4.11 ng/ml. By comparison, the most stringent public safety limit, established by the Environmental Protection Agency, is above 5.8 nanograms per milliliter. That number itself is a small fraction of the amount that scientists believe is the level of mercury that would actually harm a child.

The team also found that children eliminate thimerosal mercury from the blood six times faster than predicted from data on methyl mercury, mostly through the stools. The compound's "half life" in the blood is 6 or 7 days, compared to the 45 days that scientists had assumed. Thus, by the time a child receives another round of vaccines containing mercury, virtually all of the compound from the previous doses has been eliminated.

Removing thimerosal from U.S. vaccines has had several effects, Pichichero says. Since vaccines don't last as long without a preservative, the elimination of thimerosal caused some vaccine makers to produce single-dose vials, which are more expensive to produce, store, and ship. For some vaccines, manufacturers use thimerosal throughout the manufacturing process, then remove the compound, which also adds to the cost of the vaccine. Such actions raised the cost of vaccines, making it less likely that they'll be used as widely as possible.

Thimerosal is still part of vaccines widely used in other nations. In October the World Health Organization announced guidelines suggesting that thimerosal-containing vaccines are safe and should continue to be used, a conclusion based partly on Pichichero's findings.

"In countries that are still confronting diseases like whooping cough and tetanus and measles, where millions of children die of the disease, there is no argument. Where people are dying of these diseases, switching to a thimerosal-free vaccine would raise the prices such that millions of children would go unvaccinated.

"Although America can afford to pay a higher price for newly formulated vaccines, much of the rest of the world cannot afford the increased cost of thimerosal-free vaccines. For them, it's a critical issue of life and death."

While mercury is known to be toxic in high amounts, scientists continue to debate the health effects of exposure to very low levels. Everyone on Earth has some mercury in the blood stream -- the chemical is present naturally, from the belching of volcanoes, and is also present in power-plant emissions. Everyone who smokes cigarettes contributes a bit of mercury to the air we breathe. Mercury is found especially in seafood like swordfish and tuna; a tuna sandwich contains much more mercury than a typical vaccine dose.

The University of Rochester team has just begun a similar but larger study -- of about 200 children -- with funding from NIAID, to elaborate on the results of the study published in the Lancet. The work is being conducted with colleagues in Buenos Aires, Argentina, since most vaccines now given to children in the United States no longer contain thimerosal.

The research was done at the Vaccine Treatment and Evaluation Unit that the NIAID funds at the University of Rochester Medical Center. Also taking part in the study were John Treanor, M.D., associate professor of medicine and director of the Rochester VTEU; Elsa Cernichiari, assistant professor in the Department of Environmental Medicine; and Joseph Lopreiato, M.D., of the National Naval Medical Center in Bethesda, Md.

 

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