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| Thimerosal Toxicity |
The various mercury guidelines are based on epidemiological and laboratory studies of methyl mercury, whereas thimerosal is a derivative of ethyl mercury. Because they are different chemical entities - ethyl- versus methylmercury - different toxicological profiles are expected. There is, therefore, an uncertainty that arises in applying the methylmercury-based guidelines to thimerosal. Lacking definitive data on the comparative toxicities of ethyl- versus methylmercury, FDA considered ethyl- and methyl-mercury as equivalent in its risk evaluation. There are some data and studies bearing directly on thimerosal toxicity and these are summarized in this Section.
Allergic responses to thimerosal are described in the clinical literature, with these responses manifesting themselves primarily in the form of delayed-type local hypersensitivity reactions, including redness and swelling at the injection site (Cox and Forsyth 1988; Grabenstein 1996). Such reactions are usually mild and last only a few days. Some authors postulate that the thiosalicylate component is the major determinant of allergic reactions (Goncalo et al. 1996). In a clinical setting, however, it is usually not possible to determine whether local reactions are caused by thimerosal or other vaccine components.
The earliest published report of thimerosal use in humans was published in 1931 (Powell and Jamieson 1931). In this report, 22 individuals received 1% solution of thimerosal intravenously for unspecified therapeutic reasons. Subjects received up to 26 milligrams thimerosal/kg (1 milligrams equals 1,000 micrograms) with no reported toxic effects, although 2 subjects demonstrated phlebitis or sloughing of skin after local infiltration. Of note, this study was not specifically designed to examine toxicity; 7 of 22 subjects were observed for only one day, the specific clinical assessments were not described, and no laboratory studies were reported.
Several cases of acute mercury poisoning from thimerosal-containing products were found in the medical literature with total doses of thimerosal ranging from approximately 3 mg/kg to several hundred mg/kg. These reports included the administration of immune globulin (gamma globulin) (Matheson et al. 1980) and hepatitis B immune globulin (Lowell et al. 1996), choramphenicol formulated with 1000 times the proper dose of thimerosal as a preservative (Axton 1972), thimerosal ear irrigation in a child with tympanostomy tubes (Rohyans et al. 1994), thimerosal treatment of omphaloceles in infants (Fagan et al. 1977), and a suicide attempt with thimerosal (Pfab et al. 1996). These studies reported local necrosis, acute hemolysis, disseminated intravascular coagulation, acute renal tubular necrosis, and central nervous system injury including obtundation, coma, and death. (IOM)
Several animal studies have evaluated the toxicity of thimerosal. In 1931 Powell and Jamieson reported acute toxicity studies in several animal species. Maximum tolerated doses not associated with death of the animals were 20 mg thimerosal/kg (rabbits) and 45 mg/kg (rats). Blair evaluated the administration of thimerosal intranasally for 190 days and observed no histopathological changes in the brain or kidney (Blair et al. 1975). Magos et al. directly compared the toxicity of ethyl- versus methylmercury in adult male and female rats administered 5 daily doses of equimolar concentrations of ethyl- or methylmercury by gavage (Magos et al 1985). Magos concluded that ethylmercury, the mercury derivative found in thimerosal, is less neurotoxic than methylmercury, the mercury derivative for which the various guidelines are based.
One final piece of data regarding thimerosal is worth noting. At the initial National Vaccine Advisory Committee-sponsored meeting on thimerosal in 1999, concerns were expressed that infants may lack the ability to eliminate mercury. More recent NIAID-supported studies at the University of Rochester and National Naval Medical Center in Bethesda, MD examined levels of mercury in blood and other samples from infants who had received routine immunizations with thimerosal-containing vaccines. [Pichichero ME, et al. Lancet 360:1737-1741 (2002)] Blood levels of mercury did not exceed safety guidelines for methyl mercury for all infants in these studies. Further, mercury was cleared from the blood in infants exposed to thimerosal faster than would be predicted for methyl mercury; infants excreted significant amounts of mercury in stool after thimerosal exposure, thus removing mercury from their bodies. These results suggest that there are differences in the way that thimerosal and methyl mercury are distributed, metabolized, and excreted. Thimerosal appears to be removed from the blood and body more rapidly than methyl mercury. NIAID is sponsoring a follow-up study with larger numbers of infants in Buenos Aires where thimerosal-containing vaccines are still administered to children. See the NIH/NIAID vaccines/thimerosal web site http://www.niaid.nih.gov/factsheets/thimerosalqa.htm.
Recent and Future FDA Action
FDA has been actively addressing the issue of thimerosal as a preservative in vaccines. Under the FDA Modernization Act (FDAMA) of 1997, the FDA conducted a comprehensive review of the use of thimerosal in childhood vaccines. Conducted in 1999, this review found no evidence of harm from the use of thimerosal as a vaccine preservative, other than local hypersensitivity reactions (Ball et al. 2001).
As part of the FDAMA review, the FDA evaluated the amount of mercury an infant might receive in the form of ethylmercury from vaccines under the U.S. recommended childhood immunization schedule and compared these levels with existing guidelines for exposure to methylmercury, as there are no existing guidelines for ethylmercury, the metabolite of thimerosal. At the time of this review in 1999, the maximum cumulative exposure to mercury from vaccines in the recommended childhood immunization schedule was within acceptable limits for the methylmercury exposure guidelines set by FDA, ATSDR, and WHO. However, depending on the vaccine formulations used and the weight of the infant, some infants could have been exposed to cumulative levels of mercury during the first six months of life that exceeded EPA recommended guidelines for safe intake of methylmercury.
As a precautionary measure, the Public Health Service (including the FDA, National Institutes of Health (NIH), Center for Disease Control and Prevention (CDC) and Health Resources and Services Administration (HRSA) and the American Academy of Pediatrics issued two Joint Statements, urging vaccine manufacturers to reduce or eliminate thimerosal in vaccines as soon as possible (CDC 1999) and (CDC 2000). The U.S. Public Health Service agencies have collaborated with various investigators to initiate further studies to better understand any possible health effects from exposure to thimerosal in vaccines.
Available data has been reviewed in several public forums including the Workshop on Thimerosal held in Bethesda in August 1999 and sponsored by the National Vaccine Advisory Committee, two meetings of the Advisory Committee on Immunization Practices of the CDC, held in October 1999 and June 2000, and the Institute of Medicine’s Immunization Safety Review Committee in July 2001 and May 2004. Through its Vaccine Safety Datalink, the CDC has examined the incidence of autism as a function of the amount of thimerosal a child received from vaccines. Preliminary results indicated no change in autism rates relative to the amount of thimerosal a child received during the first six months of life (from 0 micrograms to greater than 160 micrograms). A weak association was found with thimerosal intake and certain neurodevelopmental disorders (such as attention deficit hyperactivity disorder) in one study, but was not found in a subsequent study. Additional studies are planned in these areas.
Much progress has been made to date in removing or reducing thimerosal in vaccines. New pediatric formulations of hepatitis B vaccines have been licensed by the FDA, Recombivax-HB (Merck, thimerosal free) in August 1999 and Engerix-B (Glaxo SmithKline, trace thimerosal) in March 2000. In March 2001 the FDA approved a second DTaP vaccine formulated without thimerosal as a preservative (Aventis Pasteur’s Tripedia, trace thimerosal). Aventis Pasteur, Ltd was also approved to manufacture a thimerosal-free DTaP vaccine, Daptacel, in 2002. In September 2001 Chiron/Evans was approved for manufacturing a preservative-free formulation of their influenza vaccine, Fluvirin, that contained trace thimerosal. In September of 2002, Aventis Pasteur, Inc was approved to manufacture a preservative-free formulation of their influenza vaccine, Fluzone that contained trace thimerosal, and in December 2004, a thimerosal-free formulation of Fluzone was approved. Two Td vaccines are also available in preservative-free formulations, Aventis Pasteur Inc’s Decavac, and Aventis Pasteur, Ltd’s Td vaccine. Also, Aventis Pasteur Inc’s DT vaccine is now available only in a preservative-free formulation. These changes have been accomplished by reformulating products in single dose vials that do not contain a preservative. At present, all routinely recommended vaccines for U.S. infants are available only as thimerosal-free formulations or contain only trace amounts of thimerosal (<1 than micrograms mercury per dose), with the exception of inactivated influenza vaccine. Inactivated influenza vaccine for pediatric use is available in a thimerosal-preservative containing formulation and in formulations that contain either no thimerosal or only a trace of thimerosal, but the latter is in more limited supply; see Table 1. A more extensive tabulation of vaccines and thimerosal content may be found in Table 3.
The Safety Review of Thimerosal-containing Vaccines and Neurodevelopmental Disorders Conducted by the Institute of Medicine
In 2001, the Institute of Medicine convened a committee (the Immunization Safety Review Committee) to review selected issues related to immunization safety. [For more information regarding this committee, their charge, and their reports, see the IOM web site.] The IOM has, to date, completed reviews in two areas. The first review by this committee focused on a potential link between autism and the combined mumps, measles, and rubella vaccine. The second review focused on a potential relationship between thimerosal use in vaccines and neurodevelopmental disorders (IOM 2001). This latter issue was brought to the fore primarily as the result of the hypothesis, formulated by S. Bernard and others from Cure Autism Now, that autism is a novel form of mercury poisoning (Bernard et al. 2001); this hypothesis, linking autism to mercury, was based on a comprehensive review of the scientific literature on mercury toxicity.
In its report of October 1, 2001, the IOM’s Immunization Safety Review Committee concluded that the evidence was inadequate to either accept or reject a causal relationship between thimerosal exposure from childhood vaccines and the neurodevelopmental disorders of autism, attention deficit hyperactivity disorder (ADHD), and speech or language delay. Additional studies were needed to establish or reject a causal relationship. The Committee did conclude that the hypothesis that exposure to thimerosal-containing vaccines could be associated with neurodevelopmental disorders was biologically plausible.
The Committee believed that the effort to remove thimerosal from vaccines was "a prudent measure in support of the public health goal to reduce mercury exposure of infants and children as much as possible." Furthermore, in this regard, the Committee urged that "full consideration be given to removing thimerosal from any biological product to which infants, children, and pregnant women are exposed."
In 2004, the IOM's Immunization Safety Review Committee issued its final report, examining the hypothesis that vaccines, specifically the MMR vaccines and thimerosal containing vaccines, are causally associated with autism. In this report, the committee incorporated new epidemiological evidence from the U.S., Denmark, Sweden, and the United Kingdom, and studies of biologic mechanisms related to vaccines and autism since its report in 2001. The committee concluded that this body of evidence favors rejection of a causal relationship between thimerosal-containing vaccines and autism, and that hypotheses generated to date concerning a biological mechanism for such causality are theoretical only. Further, the committee stated that the benefits of vaccination are proven and the hypothesis of susceptible populations is presently speculative, and that widespread rejection of vaccines would lead to increases in incidences of serious infectious diseases like measles, whooping cough and Hib bacterial meningitis.
The FDA is continuing its efforts to reduce the exposure of infants, children, and pregnant women to mercury from various sources. Discussions with the manufacturers of influenza virus vaccines (which are now routinely recommended for pregnant women and children 6-23 months of age) regarding their capacity to potentially increase the supply of thimerosal-reduced and thimerosal-free presentations are ongoing. Discussions are also underway with regard to other vaccines. Of note, all hepatitis B vaccines for the U.S., including for adults, are now available only as thimerosal-free or trace-thimerosal-containing formulatons. In addition, all immune globulin preparations including hepatitis B immune globulin, and Rho(D) immune globulin preparations are manufactured without thimerosal. For additional information on the issue of thimerosal in vaccines, see Frequently Asked Questions (FAQs)).
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