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Study on the Developmental Toxicity of Thimerosal  

곽승준 (국립독성연구원 특수독성부)
이규식 (국립독성연구원 특수독성부)
김순선 (국립독성연구원 특수독성부)
손경희 (국립독성연구원 특수독성부)
김소희 (국립독성연구원 특수독성부)
채수영 (국립독성연구원 특수독성부)
최요우 (국립독성연구원 특수독성부)
원용혁 (국립독성연구원 특수독성부)
박귀례 (국립독성연구원 특수독성부)
Publication Information
Toxicological Research / v.19, no.4, 2003 , pp. 267-275 More about this Journal
Abstract
The purpose of our study was to evaluate the toxicity of the thimerosal in embryos and neonates. Thimerosal (also known as mercurothiolate) is a mercury-containing compound used in trace amounts to prevent bacteria and other organisms from contaminating vaccines, especially in opened multi-dose vials. The toxicity of mercury is well known and those most at risk occurrs in unborn babies and newborn babies. Test methods included in vitro whole embryo culture (WEC) system and in vivo test of neonatal toxicity in Wistar rats. Ethylmercury and methylmercury were used as positive controls for the evaluating of toxic effects of mercury. In WEC assay, treated concentrations of thimerosal, ethylmercury and methylmercury were up to 0.01, 0.025, 0.05, 0.1, 0.25, 0.5, 1, 2.5 and 5 $\mu\textrm{g}$/$\textrm{m}{\ell}$, respectively. All compounds didn't show any morphological abnormalities, but showed retardation of growth and development in dose dependent manner (> 0.5 $\mu\textrm{g}$/$\textrm{m}{\ell}$). These data indicated that thimerosal showed developmental toxicity in vitro. In vivo neonatal toxicity, Wistar rats were administered subcutaneously with thimerosal, ethyl mercury, or methylmercury (5, 25, 50, 250, and 500 $\mu\textrm{g}$/kg) during from postnatal day (PND) 4 to 25. Significant effects of these compounds on relative organ weights and organ morphology were not observed in this experiment. However, accumulation of mercury was detected in the kidney and testis when treated with thimerosal, ethylmercury, or methylmercury. These results suggest that thimerosal may be a harmful compound to embryo and neonate, but used concentration of thimerosal in these experiments is much higher than that of clinical application. Further investigation is needed on the safety of vaccine components, i.e. a thimerosal using in vitro and in vivo tests in the future.
Keywords
Thimerosal; Vaccine; Mercury; Whole embryo culture; Neonatal toxicity;
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1 Bierman-van Eendenburg, M.E., Jurgens-van der Zee, A.D., Olinga, A.A., Huisjes, H.H. and Touwen, B.C. (1981): Predictive value of neonatal neurological examination: a follow-up study at 18 months. Dev. Med. Child. Neurol., 23, 296-305
2 Danscher, G. (1991): Application of autometallography to heavy metal toxicology. Pharmacol. Taxicol., 68, 414-423
3 Kitchin, K.T., Schmid, B.P. and Sanyal, M.K. (1981): Teratogenicity of cyclophosphamide in a coupled microsomal activating/embryo culture system. Biachem. Pharmacol., 30, 59-64
4 Liesegang, R.E. (1911): Die kolloidchemie der histologischen silberfarbungen. In kolloidchemische beihefte (Erganzungshefte zur kolloid-zeifschrift) Ostwald W, ed., Dresden-Leipzig: Verlag von Theodor Steinkopff, 1-44
5 New, D.A. (1978): Whole embryo culture and the study of mammalian embryos during organogenesis. Biol. Rev. Camb. Philos. Soc., 53, 81-122
6 Roberts, W.J. (1935): A new procedure for detection of gold in animal tissue. Proc. R. Acad., 38, 540-544
7 Sadler, T.W. (1980): Effects of maternal diabetes on early embryogenesis: II. Hyperglycemia-induced exencephaly. Teratology, 21, 349-356
8 Vogel, D.G., Margolis, R.L. and Mottet, N.K. (1985): The effects of methylmercury binding to microtubules. Toxicol. Appl. Pharmacol., 80, 473-486
9 Yoshino, Y., Mozai, T. and Nakao, K. (1966): Biochemical changes in the brain in rats poisoned with an alkylmercury compound, with special reference to the inhibition of protein synthesis in brain cortex slices. J. Neurochem., 13, 1223-1230   DOI   PUBMED
10 Grandjean, P., Budtz-Jorgensen, E., White, R.F., Jorgensen, P.J., Weihe, P., Debes, F. and Keiding, N. (1999): Methylmercury exposure biomarkers as indicators of neurotoxicity in children aged 7 years. Am. J. Epidemiol., 150, 301-305
11 Zeiger, K. (1938): Physikochemische grundlagen der histologischen methodik. Wiss. Forschungsber, 48, 55-105
12 Faustman, E.M. (1988): Short-term tests for teratogens. Mutation Res., 205, 355-384
13 Maele-Fabry, G.V., Delhaise, F. and Picard, J.J. (1990): Morphogenesis and quantification of the development of postimplantation mouse embryos. Taxical. In vitro, 4, 149-156
14 Hunter, D, and Russel, D.S. (1954): Focal cerebral and cerebellar atrophy in a human 녀bject due to organic mercury compounds. J. Neurol. Neurasurg. Psychiatry, 17, 235-241
15 Orisakwe, O.E, Afonne, O.J., Nwobodo, E, Asomugha, L. and Dioka, C.E (2001): Low-dose mercury induces testicular damage protected by zinc in mice. Eur. J. Obstet. Gynecol. Reprod. BioI., 95, 92-96   DOI   ScienceOn
16 Ross, J.F., Switzer, R.C., Poston, M.R. and Lawhorn, G.T. (1996): Distribution of bismuth in the brain after intraperitoneal dosing of bismuth subnitrate in mice; implications for routes of entry of xenobiotic metals into the brain. Brain Res., 725, 137-154
17 Liesegang, R.E. and Rieder, W. (1921): Versuche miteiner ‘Keimmethode’ zum nachweis von silber in gewebsschnitten. Z. Wiss. Mikrosk., 38, 334-338
18 Stoltenberg, M. and Danscher, G. (2000): Histochemical differentiation of autometallographically traceable metals (Au, Ag, Hg, Bi, Zn): Protocols for chemical removal of separate autometallographic metal clusters in Epon sections. Histochemical J., 32, 645-652
19 Steuerwald, U., Weihe, P., Jorgensen, P.J., Bjerve, K., Brock, J., Heinzow, B., Budtz-Jorgensen, E. and Grandjean, P. (2000): Maternal seafood diet, methylmercury exposure, and neonatal neurologic function. J. Pediatr., 136, 599-605
20 Danscher, G. (1984): Autometallography: A new technique for light and electron microscopic visualization of metals in biological tissues (gold, silver, metal sulphides and metal selenides). Histachem., 81, 331-335
21 Davidson, P.W., Myers, G.J., Cox, C., Axtell, C., Shamlaye, C., Sloane-Reeves, J., Cernichiari, E., Needham, L., Choi, A., Wang, Y., Berlin, M. and Clarkson, T.W. (1998): 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, 280, 701-707   DOI   ScienceOn
22 Abe, T., Haga, T. and Kurokawa, M. (1975): Blockage of axoplasmic transport and depolymerisation of reassembled microtubules by methylmercury. Brain Res., 86, 504-508
23 Cho, HW., Kim, M.H., Hwang, K.Y. and Yee, S.T. (1997): Detection of mercury in kidney, liver, spleen and cerebellum of the mouse by autometallography. Korean J. Taxicol., 13, 401-408
24 Kinoshita, Y., Ohnishi, A., Kohshi, K. and Yokota, A. (1999): Apparent diffusion coefficient on rat brain and nerves intoxicated with methylmercury. Environm. Res., 80, 348-354
25 Pamphlett, R., Ewan, K.B., McQuilty, R. and Waley, P. (1997): Gender differences in the uptake of inorganic mercury by motor neurons. Neurotoxicol. Teratol., 19, 287-293
26 Yimm, F. (1962): Histochemische lokalisation und nachweis der schwermwtalle. Acta Histochem. (suppl.) , 3, 142-158
27 Miura, K., Inokawa, M. and Imura, N. (1984): Effects of methylmercury and some metal ions on microtubule networks in mouse glioma cells and in vitro tubulin polymerization. Taxicol. Appl. Pharmacol., 73, 218-231
28 Elferink, J.G. (1999): Thimerosal: A versatile sulfhydryl reagent, calcium mobilizer, and cell tunction-modulating agent. General Pharmacol., 33, 1-6
29 Stajich, G.V., Lopez, G.P., Harry, S.W. and Sexson, W.R. (2000): Iatrogenic exposure to mercury after hepatitis B vaccination in preterm infants. J. Pediatr., 136, 679-681   DOI   ScienceOn