Blood and Brain Mercury Content in Infant Monkeys after Exposure to Methylmercury or Thimerosal
Thomas M. Burbacher, Ph.D.
University of Washington
R01ES003745 and P30ES007033
Background: There has been great interest and debate over the past decade regarding the use of the mercury-containing preservative thimerosal and autism. According to some published reports, autism rates around the world are rising and the rise coincides with the availability of more vaccines containing thimerosal and a lowering of the age at which vaccines are given to babies. Thimerosal, which is about 50% ethylmercury, has been used since the 1930’s in vaccines to prevent bacterial and fungal contamination, particularly in multidose containers. Mercury has long been known to be a neurotoxicant, but much of the scientific literature has focused on methylmercury. In 1999, an FDA review noted that with the increased number of vaccines then recommended for infants, the total amount of mercury in vaccines containing thimerosal might exceed recommended levels. To be cautious, the U.S. Public Health Service and the American Academy of Pediatrics asked doctors to minimize exposure to thimerosalcontaining vaccines and manufacturers to remove thimerosal from vaccines as soon as possible.
Advance: To further understand the differences in absorption and metabolism of both forms of mercury, a team of NIEHS-supported investigators exposed 41 neonatal Macaca fasicularis, or "crab-eating" monkeys to either thimerosal or methylmercury. These monkeys are considered a very good model for human infants. Monkeys in the thimerosal group received a series of injections typical of what a human infant would receive over the first few weeks of life. Those animals in the methylmercury group were given equivalent doses of mercury through a feeding tube. Initially, absorption and distribution of total mercury appeared to be similar between the two groups. However, ethylmercury from thimerosal was cleared much faster than methylmercury. Peak blood concentrations of mercury were three times higher in the methylmercury group. Brain concentrations of total mercury were significantly lower for the thimerosal group; however, a higher percentage of the total brain mercury was in the form of inorganic mercury for the thimerosal group (37% vs. 7%).
Implications:The authors conclude that knowledge of the fate and transport of methylmercury is not a suitable surrogate for risk assessments for exposure to thimerosal. Therefore, additional research is necessary to fully characterize the biotransformation of thimerosal so that a meaningful interpretation of any developmental effects from immunization with thimerosal-containing vaccines can be determined.
EMERGENCY OVERVIEW
Appearance: silver liquid.
Danger! Corrosive. Harmful if inhaled. May be absorbed through intact skin. Causes eye and skin irritation and possible burns. May cause severe respiratory tract irritation with possible burns. May cause severe digestive tract irritation with possible burns. May cause liver and kidney damage. May cause central nervous system effects. This substance has caused adverse reproductive and fetal effects in animals. Inhalation of fumes may cause metal-fume fever. Possible sensitizer.
Target Organs: Blood, kidneys, central nervous system, liver, brain.
Potential Health Effects
Eye: Exposure to mercury or mercury compounds can cause discoloration on the front surface of the lens, which does not interfere with vision. Causes eye irritation and possible burns. Contact with mercury or mercury compounds can cause ulceration of the conjunctiva and cornea.
Skin: May be absorbed through the skin in harmful amounts. May cause skin sensitization, an allergic reaction, which becomes evident upon re-exposure to this material. Causes skin irritation and possible burns. May cause skin rash (in milder cases), and cold and clammy skin with cyanosis or pale color.
Ingestion: May cause severe and permanent damage to the digestive tract. May cause perforation of the digestive tract. May cause effects similar to those for inhalation exposure. May cause systemic effects.
Inhalation: Causes chemical burns to the respiratory tract. Inhalation of fumes may cause metal fume fever, which is characterized by flu-like symptoms with metallic taste, fever, chills, cough, weakness, chest pain, muscle pain and increased white blood cell count. May cause central nervous system effects including vertigo, anxiety, depression, muscle incoordination, and emotional instability. Aspiration may lead to pulmonary edema. May cause systemic effects. May cause respiratory sensitization.
Chronic: May cause liver and kidney damage. May cause reproductive and fetal effects. Effects may be delayed. Chronic exposure to mercury may cause permanent central nervous system damage, fatigue, weight loss, tremors, personality changes. Chronic ingestion may cause accumulation of mercury in body tissues. Prolonged or repeated exposure may cause inflammation of the mouth and gums, excessive salivation, and loosening of the teeth.
The source document upon which this CICAD is based is the Toxicological profile for mercury (update), published by the Agency for Toxic Substances and Disease Registry of the US Department of Health and Human Services (ATSDR, 1999). Data identified as of January 1999 were considered in the source document. Data identified as of November 1999 were considered in the preparation of this CICAD. Information on the availability and the peer review of the source document is presented in Appendix 1. Information on the peer review of this CICAD is presented in Appendix 2. This CICAD was considered at a meeting of the Final Review Board, held in Helsinki, Finland, on 26–29 June 2000 and approved as an international assessment by mail ballot of the Final Review Board members on 27 September 2002. Participants at the Final Review Board meeting are presented in Appendix 3. The International Chemical Safety Cards for elemental mercury and six inorganic mercury compounds, produced by the International Programme on Chemical Safety, have also been reproduced in this document.
Mercury is a metallic element that occurs naturally in the environment. There are three primary categories of mercury and its compounds: elemental mercury, which may occur in both liquid and gaseous states; inorganic mercury compounds, including mercurous chloride, mercuric chloride, mercuric acetate, and mercuric sulfide; and organic mercury compounds. Organic mercury compounds are outside the scope of this document.
Elemental mercury is the main form of mercury released into the air as a vapour by natural processes.
Exposure to elemental mercury by the general population and in occupational settings is primarily through inhaling mercury vapours/fumes. The average level of atmospheric mercury is now approximately 3–6 times higher than the level estimated for preindustrial ambient air.
Dental amalgam constitutes a potentially significant source of exposure to elemental mercury, with estimates of daily intake from amalgam restorations ranging from 1 to 27 µg/day, the majority of dental amalgam holders being exposed to less than 5 µg mercury/day. Mercuric chloride, mercuric oxide, mercurous acetate, and mercurous chloride are, or have been, used for their antiseptic, bactericidal, fungicidal, diuretic, and/or cathartic properties. A less well documented use of elemental mercury among the general population is its use in ethnic or folk medical practices. These uses include the sprinkling of elemental mercury around the home and automobile. No reliable data are currently available to determine the extent of such exposure.
Analytical methods exist for the specific assessment of organic and inorganic mercury compounds; however, most available information on mercury concentrations in environmental samples and biological specimens refers to total mercury.
Intestinal absorption varies greatly among the various forms of mercury, with elemental mercury being the least absorbed form (<0.01%) and only about 10% of inorganic mercury compounds being absorbed. For elemental mercury, the main route of exposure is by inhalation, and 80% of inhaled mercury is retained. Inorganic mercury compounds may be absorbed through the skin in toxicologically relevant quantities.
Elemental mercury is lipid soluble and easily penetrates biological membranes, including the blood–brain barrier. Metabolism of mercury compounds to other forms of mercury can occur within the tissues of the body. Elemental mercury can be oxidized by the hydrogen peroxide–catalase pathway in the body to its inorganic divalent form. After exposure to elemental mercury or inorganic mercury compounds, the main route of excretion is via the urine. Determination of concentrations in urine and blood has been extensively used in the biological monitoring of exposure to inorganic forms of mercury; hair mercury levels do not reliably reflect exposure to elemental mercury or inorganic mercury compounds.
Neurological and behavioural disorders in humans have been observed following inhalation of elemental mercury vapour, ingestion or dermal application of inorganic mercury-containing medicinal products, such as teething powders, ointments, and laxatives, and ingestion of contaminated food. A broad range of symptoms has been reported, and these symptoms are qualitatively similar, irrespective of the mercury compound to which one is exposed. Specific neurotoxic symptoms include tremors, emotional lability, insomnia, memory loss, neuromuscular changes, headaches, polyneuropathy, and performance deficits in tests of cognitive and motor function. Although improvement in most neurological dysfunctions has been observed upon removal of persons from the source of exposure, some changes may be irreversible. Acrodynia and photophobia have been reported in children exposed to excessive levels of metallic mercury vapours and/or inorganic mercury compounds. As with many effects, there is great variability in the susceptibility of humans to the neurotoxic effects of mercury.
The primary effect of long-term oral exposure to low amounts of inorganic mercury compounds is renal damage. Inorganic forms of mercury have also been associated with immunological effects in both humans and susceptible strains of laboratory rodents, and an antibody-mediated nephrotic syndrome has been demonstrated through a variety of exposure scenarios. However, conflicting data from occupational studies preclude a definitive interpretation of the immunotoxic potential of inorganic forms of mercury.
Mercuric chloride has been shown to demonstrate some carcinogenic activity in male rats, but the data for female rats and for mice have been equivocal or negative. There is no credible evidence that exposure of humans to either elemental mercury or inorganic mercury compounds results in cancer.
There is convincing evidence that inorganic mercury compounds can interact with and damage DNA in vitro. Data from in vitro studies indicate that inorganic mercury compounds may induce clastogenic effects in somatic cells, and some positive results have also been reported in in vivo studies. The combined results from these studies do not suggest that metallic mercury is a mutagen.
Parenteral administration of inorganic mercury compounds is embryotoxic and teratogenic in rodents at sufficiently high doses. Animal data from studies in which the exposure pattern was similar to human exposure patterns and limited human data do not indicate that elemental mercury or inorganic mercury compounds are developmental toxicants at dose levels that are not maternally toxic.
Several studies are in agreement that mild subclinical signs of central nervous system toxicity can be observed among people who have been exposed occupationally to elemental mercury at a concentration of 20 µg/m3 or above for several years. Extrapolating this to continuous exposure and applying an overall uncertainty factor of 30 (10 for interindividual variation and 3 for extrapolation from a lowest-observed-adverse-effect level, or LOAEL, with slight effects to a no-observed-adverse-effect level, or NOAEL), a tolerable concentration of 0.2 µg/m3 was derived. In a 26-week study, a NOAEL for the critical effect, nephrotoxicity, of 0.23 mg/kg body weight was identified for oral exposure to mercuric chloride. Adjusting to continuous dosage and applying an uncertainty factor of 100 (10 for interspecific extrapolation and 10 for interindividual variation), a tolerable intake of 2 µg/kg body weight per day was derived. Use of a LOAEL of 1.9 mg/kg body weight in a 2-year study as a starting point yields a similar tolerable intake.
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