Lead Encephalopathy

  • Ivan J. Boyer


Lead is arguably the most studied of the neurotoxicants (Silbergeld, 1992; Dietrich, 1995). Epidemiological and experimental studies of the toxic effects and mechanisms of action of lead have grown exponentially since the 1960s and 1970s. This work has produced an unparalleled body of scientific information on the effects of lead on the central nervous system (CNS). This chapter provides a brief review of the current knowledge and the key hypotheses about the toxicity of lead to the ­central nervous system (CNS).

An enormous amount of lead has been released to the environment through human activities since the 1920s, when tetraethyl lead was first sold as an antiknock agent in gasoline for automobile engines. The use of inorganic lead as an anticorrosive agent in paints and primers represents another important source of lead released to the environment. These practices are largely responsible for widespread and persistent environmental contamination often exceeding concentrations now known to have the potential to cause serious harm to human health.


Vascular Endothelial Growth Factor White Matter Lesion Lead Exposure Blood Lead Concentration Tetraethyl Lead 
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  1. AAP. (2005) Lead exposure in children: Prevention, detection, and management. American Academy of Pediatrics, Committee on environmental health. Pediatrics 116(4): 1036-1046Google Scholar
  2. Adams, R.D. and M. Victor. (1993) Principles of neurology. 5th ed., McGraw-Hill, NewYorkGoogle Scholar
  3. Agre, P., L.S. King, M. Yasui, W.B. Guggino, O.P. Ottersen, Y. Fujiyoshi, A. Engel and S. Nielsen. (2002) Aquaporin water channels: From atomic structure to clinical medicine. J. Physiol. 542: 3–16PubMedCrossRefGoogle Scholar
  4. al Khayat, A., N.S. Menon and M.R. Alidina. (1997) Acute lead encephalopathy in early infancy: clinical presentation and outcome. Ann. Trop. Paediatr. 17: 39–44PubMedGoogle Scholar
  5. Atre, A.L., P.R. Shinde, S.N. Shinde, R.S. Wadia, A.A. Nanivadekar, S.J. Vaid and R.S. Shinde. (2006) Pre- and post-treatment MR imaging findings in lead encephalopathy. AJNR Am. J. Neuroradiol. 27: 902–903PubMedGoogle Scholar
  6. Audesirk, G. and T. Audesirk. (1993) The effects of inorganic lead on voltage sensitive calcium channels differ among cell types and among channel subtypes. Neurotoxicology 14: 259–265PubMedGoogle Scholar
  7. Badaut, J., F. Lasbennes, P.J. Magistretti and L. Regli. (2002) Aquaporins in brain: Distribution, physiology, and pathophysiology. J. Cereb. Blood Flow Metab. 22: 367–378PubMedCrossRefGoogle Scholar
  8. Baghurst, P.A., A.J. McMichael, N.R. Wigg, G.V. Vimpani, E.F. Robertson, R.J. Roberts and S.L. Tong. (1992) Environmental exposure to lead and children’s intelligence at the age of seven years: The Port Pirie cohort study. N. Engl. J. Med. 327: 1279–1284PubMedCrossRefGoogle Scholar
  9. Barone, S.Jr, M.E. Stanton and W.R. Mundy. (1995) Neurotoxic effects of neonatal triethyltin (TET) exposure are exacerbated with aging. Neurobiol. Aging 16: 723–735PubMedCrossRefGoogle Scholar
  10. Basha, M.R., W. Wei, G.R. Reddy, and N.H. Zawia. (2004) Zinc finger transcription factors ­mediate perturbations of brain gene expression elicited by heavy metals. In: Molecular Neurotoxicology, Environmental Agents, and Transcription-Transduction Coupling. N.H. Zawia (editor), CRC Press, Boca Raton, pp 43–64CrossRefGoogle Scholar
  11. Basha, M.R., W. Wei, S.A. Bakheet, N. Benitez, H.K. Siddiqi, Y.W. Ge, D.K. Lahiri and N.H. Zawia. (2005) The fetal basis of amyloidogenesis: Exposure to lead and latent overexpression of amyloid precursor protein and beta-amyloid in the aging brain. J. Neurosci. 25: 823–829PubMedCrossRefGoogle Scholar
  12. Bates, D.O. and F.E. Curry. (1996) Vascular endothelial growth factor increases hydraulic conductivity of isolated perfused microvessels. Am. J. Physiol. 271: H2520–H2528PubMedGoogle Scholar
  13. Bates, D.O. and F.E. Curry. (1997) Vascular endothelial growth factor increases microvascular permeability via a Ca(2+)-dependent pathway. Am. J. Physiol. 273: H687–H694PubMedGoogle Scholar
  14. Bellinger, D.C. (2004) Lead. Pediatrics 113: 1016–1022PubMedGoogle Scholar
  15. Bellinger, D.C. and H.L. Needleman. (2003) Intellectual impairment and blood lead levels. N. Engl. J. Med. 349: 500–502PubMedCrossRefGoogle Scholar
  16. Bellinger, D.C., K.M. Stiles and H.L. Needleman. (1992) Low-level lead exposure, intelligence and academic achievement: A long-term follow-up study. Pediatrics 90: 855–861PubMedGoogle Scholar
  17. Bernal, J., J.H. Lee, L.L. Cribbs and E. Perez-Reyes. (1997) Full reversal of Pb<Superscript>2+</Superscript> block of L-type Ca<Superscript>2+</Superscript> channels requires treatment with heavy metal antidotes. J. Pharmacol. Exp. Ther. 282: 172–180PubMedGoogle Scholar
  18. Bolin, C.M., R. Basha, D. Cox, N.H. Zawia, B. Maloney, D.K. Lahiri, and F. Cardozo-Pelaez. (2006) Exposure to lead (Pb) and the developmental origin of oxidative DNA damage in the aging brain. FASEB J. 20(6): 788–790PubMedGoogle Scholar
  19. Bouton, C.M., L.P. Frelin, C.E. Forde, H.A. Godwin and J. Pevsner. (2001a) Synaptotagmin I is a molecular target for lead. J. Neurochem. 76: 1724–1735CrossRefGoogle Scholar
  20. Bouton, C.M., M.A. Hossain, L.P. Frelin, J. Laterra, and J. Pevsner. (2001b) Microarray analysis of differential gene expression in lead-exposed astrocytes. Toxicol. Appl. Pharmacol. 176: 34–53CrossRefGoogle Scholar
  21. Bradbury, M.W. and R. Deane. (1993) Permeability of the blood-brain barrier to lead. Neurotoxicology 14: 131–136PubMedGoogle Scholar
  22. Bressler, J.P. and G.W. Goldstein. (1991) Mechanisms of lead neurotoxicity. Biochem. Pharmacol. 41: 479–484PubMedCrossRefGoogle Scholar
  23. Bressler, J., K. Kim, T. Chakraborti and G. Goldstein. (1999) Molecular mechanisms of lead neurotoxicity. Neurochem. Res. 24(4): 595–600PubMedCrossRefGoogle Scholar
  24. Burdo, J.R., J. Martin, S.L. Menzies, K.G. Dolan, M.A. Romano, R.J. Fletcher, M.D. Garrick, L.M. Garrick and J.R. Connor. (1999) Cellular distribution of iron in the brain of the Belgrade rat. Neuroscience 93: 1189–1196PubMedCrossRefGoogle Scholar
  25. Burns, C.B. and B. Currie. (1995) The efficacy of chelation therapy and factors influencing mortality in lead intoxicated petrol sniffers. Aust. N. Z. J. Med. 25: 197–203PubMedCrossRefGoogle Scholar
  26. Bush, A.I. (2003) The metallobiology of Alzheimer’s disease. Trends Neurosci. 26: 207–214PubMedCrossRefGoogle Scholar
  27. Cairney, S., P. Maruff, C. Burns and B. Currie. (2002) The neurobehavioural consequences of petrol (gasoline) sniffing. Neurosci. Biobehav. Rev. 26: 81–89PubMedCrossRefGoogle Scholar
  28. Cairney, S., P. Maruff, C.B. Burns, J. Currie and B.J. Currie. (2004a) Saccade dysfunction associated with chronic petrol sniffing and lead encephalopathy. J Neurol Neurosurg. Psychiatr. 75: 472–476CrossRefGoogle Scholar
  29. Cairney, S., P. Maruff, C.B. Burns, J. Currie and B.J. Currie. (2004b) Neurological and cognitive impairment associated with leaded gasoline encephalopathy. Drug Alcohol Depend. 73: 183–188CrossRefGoogle Scholar
  30. Cairney, S., P. Maruff, C.B. Burns, J. Currie and B.J. Currie. (2005) Neurological and cognitive recovery following abstinence from petrol sniffing. Neuropsychopharmacol. 30: 1019–1027CrossRefGoogle Scholar
  31. Canfield, R.L., C.R. Henderson, D.A. Cory-Slechta, C. Cox, J.A. Jusko and B.P. Lanphear. (2003) Intellectual impairment in children with blood lead concentrations below 10 micrograms per deciliter. N. Engl. J. Med. 348: 1517–1526PubMedCrossRefGoogle Scholar
  32. CDC. (1991) Preventing lead poisoning in young children: A statement by the Centers for Disease Control. Centers for Disease Control and Prevention, Atlanta, GAGoogle Scholar
  33. CDC. (2002) Managing elevated blood lead levels among young children: Recommendations from the Advisory Committee on Childhood Lead Poisoning Prevention. Centers for Disease Control and Prevention, Atlanta, GA.­Manage_main.htm.Google Scholar
  34. Chen, A., K.N. Dietrich, J.H. Ware, J. Radcliffe and W.J. Rogan. (2005) IQ and blood lead from 2 to 7 years of age: are the effects in older children the residual of high blood lead concentrations in 2-year-olds? Environ. Health Perspect. 113(5): 597–601CrossRefGoogle Scholar
  35. Chisolm, J.J.Jr. and H.E. Harrison. (1956) The exposure of children to lead. Pediatrics 18: 943–957PubMedGoogle Scholar
  36. Chisolm, J.J.Jr and E. Kaplan. (1968) Lead poisoning in childhood comprehensive management and prevention. J. Pediatr. 73: 942–950PubMedCrossRefGoogle Scholar
  37. Christian, J.R., B.S. Celewycz and S.H. Andelman. (1964) A three-year study of lead poisoning in Chicago. Am. J. Public Health 54: 1241–1245CrossRefGoogle Scholar
  38. Clark, C.S., R.L. Bornschein, P. Succop, S.S. Que Hee, P.B. Hammond and B. Peace. (1985) Condition and type of housing as an indicator of potential environmental lead exposure and pediatric blood lead levels. Environ. Res. 38: 46–53PubMedCrossRefGoogle Scholar
  39. Cory-Slechta, D.A. (1997) Relationships between Pb-induced changes in neurotransmitter system function and behavioral toxicity. Neurotoxicology 18: 673–688PubMedGoogle Scholar
  40. Cory-Slechta, D.A. and H.H. Schaumburg. (2000) Lead, inorganic. In: Experimental and Clinical Neurotoxicology (second edition), P.S. Spencer, H.H. Schaumburg, A.C. Ludolph (editors). Oxford University Press, New York, pp. 708–720Google Scholar
  41. Crair, M.C. and R.C. Malenka. (1995) A critical period for long-term potentiation at thalamocortical synapses. Nature 375: 325–328PubMedCrossRefGoogle Scholar
  42. Currie, B., J. Burrow, D. Fisher, D. Howard, M. McEiver and C. Burns. (1994) Petrol sniffer’s encephalopathy. Med. J. Aust. 160: 800PubMedGoogle Scholar
  43. Dietrich, K.N. (1995) A higher level of analysis: Bellinger’s, interpreting the literature on lead and child development. Neurotoxicol. Teratol. 17: 223–225PubMedCrossRefGoogle Scholar
  44. Dietrich, K.N. (1999) Environmental neurotoxicants and psychological development. In: Pediatric Neuropsychology: Research, Theory and Practice. G. Taylor, D. Ris and K.O. Yeates (editors). Guilford Press, New York, pp. 206–34Google Scholar
  45. Dietrich, K.N., O.G. Berger, P.A. Succop, P.B. Hammond and R.L. Bornschein. (1993) The developmental consequences of low to moderate prenatal and postnatal lead exposure: Intellectual attainment in the Cincinnati lead study cohort following school entry. Neurotoxicol. Teratol. 15: 37–44PubMedCrossRefGoogle Scholar
  46. Dietrich, K.N., O.G. Berger, A. Bhattacharya. (2000) Symptomatic lead poisoning in infancy: A prospective case analysis. J. Pediatr. 137: 568–571PubMedCrossRefGoogle Scholar
  47. Dietrich, K.N., M.D. Ris, P.A. Succop, O.G. Berger and R.L. Bornschein. (2001) Early exposure to lead and juvenile delinquency. Neurotoxicol. Teratol. 23: 511–518PubMedCrossRefGoogle Scholar
  48. Dietrich, K.N., J.H. Ware, M. Salganik, J. Radcliffe, W.J. Rogan, G.G. Rhoads, M.E. Fay, C.T. Davoli, M.B. Denckla, R.L. Bornschein, D. Schwarz, D.W. Dockery, S. Adubato and R.L. Jones. (2004) Effect of chelation therapy on the neuropsychological and behavioral development of lead exposed children after school entry. Pediatrics 114: 19–26PubMedCrossRefGoogle Scholar
  49. Ernhart, C.B., M. Morrow-Tlucak, A.W. Wolf, D. Super and D. Drotar. (1989) Low level lead exposure in the prenatal and early preschool periods: Intelligence prior to school entry. Neurotoxicol. Teratol. 11: 161–170PubMedCrossRefGoogle Scholar
  50. Factor-Litvak, P., G. Wasserman, J.K. Kline and J. Graziano. (1999) The Yugoslavia prospective study of environmental lead exposure. Environ. Health Perspect. 107: 9–15PubMedCrossRefGoogle Scholar
  51. Feldman, R.G. and R.F. White. (1992) Lead neurotoxicity and disorders of learning. J. Child Neurol. 7: 354–359PubMedCrossRefGoogle Scholar
  52. Fergusson, D.L., Horwood and M. Lynskey. (1997) Early dentine lead levels and educational outcomes at 18 years. J. Child Psychol. Psychiatr. 38: 471–478CrossRefGoogle Scholar
  53. Finkelstein, Y., M.E. Markowitz and J.F. Rosen. (1998) Low-level lead-induced neurotoxicity in children: An update on central nervous system effects. Brain Res. Rev. 27: 168–176PubMedCrossRefGoogle Scholar
  54. Fischbein, A. (1998) Occupational and environmental exposure to lead. In: Environmental and Occupational Medicine. W. Rom (editor), Lippincott-Raven, Philadelphia, pp. 973–996Google Scholar
  55. Fulton, M., G. Raab, G. Thomson, D. Laxen, R. Hunter, W. Hepburn. (1987) Influence of blood lead on the ability and attainment of children in Edinburgh. Lancet 1: 1221–1226PubMedCrossRefGoogle Scholar
  56. Gabbita, S.P., M.A. Lovell and W.R. Markesbery. (1998) Increased nuclear DNA oxidation in the brain in Alzheimer’s disease. J. Neurochem. 71: 2034–2040PubMedCrossRefGoogle Scholar
  57. Goldstein, G.W. (1990) Lead poisoning and brain cell function. Environ. Health Perspect. 89: 91–94PubMedCrossRefGoogle Scholar
  58. Goldstein, G.W. and D. Ar. (1983) Lead activates calmodulin sensitive processes. Life Sci. 33: 1001–1006PubMedCrossRefGoogle Scholar
  59. Goldstein, G.W., A.K. Asbury and I. Diamond. (1974) Pathogenesis of lead encephalopathy: Uptake of lead and reaction of brain capillaries. Arch. Neurol. 31: 382–389PubMedCrossRefGoogle Scholar
  60. Goodheart, R.S. and J.W. Dunne. (1994) Petrol sniffer’s encephalopathy. Med. J. Aust. 160: 178–181PubMedGoogle Scholar
  61. Gordon, R.A., G. Roberts, Z. Amin, R.H. Williams and F.P. Paloucek. (1998) Aggressive approach in the treatment of acute lead encephalopathy with an extraordinarily high concentration of lead. Arch. Pediatr. Adolesc. Med. 152: 1100–1104PubMedGoogle Scholar
  62. Gunnarson, E., G. Axehult, G. Baturina, S. Zelenin, M. Zelenina and A. Aperia. (2005) Lead induces increased water permeability in astrocytes expressing Aquaporin 4. Neuroscience 136: 105–114PubMedCrossRefGoogle Scholar
  63. Gunshin, H., B. Mackenzie, U.V. Berger, Y. Gunshin, M.F. Romero, W.F. Boron, S. Nussberger, J.L. Gollan and M.A. Hediger. (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388: 482–488PubMedCrossRefGoogle Scholar
  64. Habermann, E., K. Crowell, P. Janicki. (1983) Lead and other metals can substitute for Ca<Superscript>2+</Superscript> in calmodulin. Arch. Toxicol. 54: 61–70PubMedCrossRefGoogle Scholar
  65. Hackley, B. and A. Katz-Jacobson. (2003) Lead poisoning in pregnancy: A case study with implications for midwives. Journal of Midwifery and Women’s Health 48(1): 30–38PubMedCrossRefGoogle Scholar
  66. Holstege, C.P., J.D. Ferguson, C.E. Wolf, A.B. Baer and A. Poklis. (2004) Analysis of moonshine for contaminants. J. Toxicol. 42(5): 597–601Google Scholar
  67. Holtzman, D., C. DeVries, H. Nguyen, J.H. Jameson, J. Olson, M. Carrithers and K. Bensch. (1982) Development of resistance to lead encephalopathy during maturation in the rat pup. J. Neuro. Exp. Neuro. 41: 652–663CrossRefGoogle Scholar
  68. Holtzman, D., C. DeVries, H. Nguyen, J. Olson and K. Bensch. (1984) Maturation of resistance to encephalopathy: Cellular and subcellular mechanism. Neurotoxicology 5: 97–124PubMedGoogle Scholar
  69. Hossain, M.A., J.C. Russell, S. Miknyoczki, B. Ruggeri, B. Lal and J. Laterra. (2004) Vascular endothelial growth factor mediates vasogenic edema in acute lead encephalopathy. Ann. Neurol. 55(5): 660–667PubMedCrossRefGoogle Scholar
  70. Huang, E., W.Y. Ong and J.R. Connor. (2004) Distribution of divalent metal transporter-1 in the monkey basal ganglia. Neuroscience 128: 487–496PubMedCrossRefGoogle Scholar
  71. Huang, E. and W.Y. Ong. (2005) Distribution of ferritin in the rat hippocampus after kainate-induced neuronal injury. Exp. Brain Res. 161: 502–511PubMedCrossRefGoogle Scholar
  72. Ide-Ektessabi, A., Y. Ota, R. Ishihara, Y. Mizuno and T. Takeuchi. (2005) Distribution of lead in the brain tissues from DNTC patients using synchrotron radiation microbeams. Nucl. Instrum. Methods Phys. Res. B 241: 681–684CrossRefGoogle Scholar
  73. Johnston, M.V. (2003) Brain plasticity in paediatric neurology. Eur. J. Paediatr. Neurol. 7: 105–113PubMedCrossRefGoogle Scholar
  74. Johnston, M.V. (2004) Clinical disorders of brain plasticity. Brain and Develop. 26: 73–80CrossRefGoogle Scholar
  75. Johnston, M.V. and G.W. Goldstein. (1998) Selective vulnerability of the developing brain to lead. Curr. Opin. Neurol. 11: 689–693PubMedCrossRefGoogle Scholar
  76. Johnston, M.V., A. Nishimura, K. Harum, J. Pekar and M.E. Blue. (2001) Sculpting the developing brain. Adv. Pediatr. 48: 1–38PubMedGoogle Scholar
  77. Johnston, M.V., L. Alemi and K.H. Harum. (2003) Learning, memory and transcription factors. Pediatr. Res. 53: 369–74PubMedCrossRefGoogle Scholar
  78. Jung, J.S., R.V. Bhat, G.M. Preston, W.B. Guggino, J.M. Baraban and P. Agre. (1994) Molecular characterization of an aquaporin cDNA from brain: Candidate osmoreceptor and regulator of water balance. Proc. Natl. Acad. Sci. USA 91: 13052–13056PubMedCrossRefGoogle Scholar
  79. Kaelan, C., C. Harper and B. Vieira. (1986) Acute encephalopathy and death due to petrol sniffing: Neuropathological findings. Aust. N. Z. J. Med. 16: 804–807PubMedGoogle Scholar
  80. Kerper, L.E. and P.M. Hinkle. (1997a) Lead uptake in brain capillary endothelial cells: activation by calcium store depletion. Toxicol. Appl. Pharmacol. 146: 127–133CrossRefGoogle Scholar
  81. Kerper, L.E. and P.M. Hinkle. (1997b) Cellular uptake of lead is activated by depletion of intracellular calcium stores. J. Biol. Chem. 272: 8346–8352CrossRefGoogle Scholar
  82. Kim, K.A., T. Chakraborti, G.W. Goldstein and J.P. Bressler. (2000) Immediate early gene expression in PC-12 cells exposed to lead: Requirement for protein kinase C. J. Neurochem. 74: 1140–1146PubMedCrossRefGoogle Scholar
  83. Kim, S.A., T. Chakraborti, G. Goldstein, M. Johnston and J. Bressler. (2002) Exposure of lead elevates induction of Zif268 and Arc mRNA in rats after electroconvulsive shock: The involvement of PKC. J. Neurosci. Res. 69: 268–277PubMedCrossRefGoogle Scholar
  84. Kimelberg, H.K. (1995) Current concepts of brain edema: Review of laboratory investigations. J. Neurosurg. 83: 1051–1059PubMedCrossRefGoogle Scholar
  85. Kovalchuk, Y., E. Hanse, K.W. Kafitz and A. Konnerth. (2002) Postsynaptic induction of BDNF-mediated long-term potentiation. Science 295: 1729–1734PubMedCrossRefGoogle Scholar
  86. Landrigan, P.J. and A.C. Todd. (1995) Lead poisoning. West. J. Med. 161: 153–159Google Scholar
  87. Lanphear, B.P., K. Dietrich, P. Auinger and C. Cox. (2000) Cognitive deficits associated with blood lead levels < 10 μg/dl in US children and adolescents. Public Health Rep. 115: 521–529PubMedCrossRefGoogle Scholar
  88. Lanphear, B.P., R. Hornung, M. Ho, C.R. Howard, S. Eberly and K. Knauf. (2002) Environmental lead exposure during early childhood. J. Pediatr. 140: 40–47PubMedCrossRefGoogle Scholar
  89. Lasley, S.M. and M.E. Gilbert. (2002) Rat hippocampal glutamate and GABA release exhibit biphasic effects as a function of chronic lead exposure level. Toxicol. Sci. 66: 139–47PubMedCrossRefGoogle Scholar
  90. Laterra, J., J.P. Bressler, R.R. Indurti, L. Belloni-Olivi and G.W. Goldstein. (1992) Inhibition of astroglial-induced endothelial differentiation by inorganic lead: A role for protein kinase C. Proc. Natl. Acad. Sci. USA 89: 10748–10752PubMedCrossRefGoogle Scholar
  91. Lee, W.T., H. Yoon, D.J. Lee, C.H. Koo and K.A. Park. (2002) Effects of postnatally administered inorganic lead on the tyrosine hydroxylase immunoreactive norepinephrinergic neurons of the locus ceruleus of the rat. Arch. Histol. Cytol. 65: 45–53PubMedCrossRefGoogle Scholar
  92. Leggett, R.W. (1993) An age-specific kinetic model of lead metabolism in humans. Environ. Health Perspect. 101: 598–616PubMedCrossRefGoogle Scholar
  93. Leung, D.W., G. Cachianes, W.J. Kuang, and N. Ferrara. (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246: 1306–1309PubMedCrossRefGoogle Scholar
  94. Lidsky, T.I. and J.S. Schneider. (2003) Lead neurotoxicity in children: Basic mechanisms and clinical correlates. Brain. 126: 5–19PubMedCrossRefGoogle Scholar
  95. Lindahl, L.S., L. Bird, M.E. Legare, G. Mikeska, G.R. Bratton and E. Tiffany-Castiglioni. (1999) Differential ability of astroglia and neuronal cells to accumulate lead: Dependence on cell type and on degree of differentiation. Toxicol. Sci. 50: 236–243PubMedCrossRefGoogle Scholar
  96. Links, J.M., B.S. Schwartz, D. Simon, K. Bandeen-Roche and W.F. Stewart. (2001) The influence of toxicant “residence time” and bioavailability from body stores in estimation of cumulative target organ dose: Application to lead-associated neurocognitive decline. Environ. Health Perspect. 109: 361–368PubMedCrossRefGoogle Scholar
  97. Liu, X., K.N. Dietrich, J. Radcliffe, N.B. Ragan, G.G. Rhoads and W.J. Rogan. (2002) Do children with falling blood lead levels have improved cognition. Pediatrics 110: 787–791PubMedCrossRefGoogle Scholar
  98. Lovell, M.A., S.P. Gabbita and W.R. Markesbery. (1999) Increased DNA oxidation and decreased levels of repair products in Alzheimer’s disease ventricular CSF. J. Neurochem. 72: 771–776PubMedCrossRefGoogle Scholar
  99. Lu, T., Y. Pan, S.Y. Kao, C. Li, I. Kohane, J. Chan and B. Yankner. (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429: 883–891PubMedCrossRefGoogle Scholar
  100. Malinow, R. and R.C. Malenka. (2002) AMPA receptor trafficking and synaptic plasticity. Annu. Rev. Neurosci. 25: 103–26PubMedCrossRefGoogle Scholar
  101. Mani, J., N. Chaudhary, M. Kanjalkar and P.U. Shah. (1998) Cerebellar ataxia due to lead encephalopathy in an adult. J. Neurol. Neurosurg. Psychiatr. 65: 797–798PubMedCrossRefGoogle Scholar
  102. Markovac, J. and G.W. Goldstein. (1988a) Lead activates protein kinase C in immature rat brain microvessels. Toxicol. Appl. Pharmacol. 96: 14–23CrossRefGoogle Scholar
  103. Markovac, J. and G.W. Goldstein. (1988b) Picomolar concentrations of lead stimulate brain protein kinase C. Nature 334: 71–73CrossRefGoogle Scholar
  104. Markowitz, M. (2000) Lead Poisoning. Pediatr. Rev. 21: 327–35PubMedCrossRefGoogle Scholar
  105. McCall, R.B. (1983) A conceptual approach to early mental development. In: Origins of Intelligence. M. Lewis (editor). Plenum Press, New York, pp. 107–133Google Scholar
  106. McDonald, J.W. and M.V. Johnston. (1990) Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res. Rev. 15: 41–70PubMedCrossRefGoogle Scholar
  107. Mendola, P., S.G. Selevan, S. Gutter and D. Rice. (2002) Environmental factors associated with a spectrum of neurodevelopmental deficits. Ment. Retard. Dev. Disabil. 8: 188–197CrossRefGoogle Scholar
  108. Minnema, D.J., R.D. Greenland and I.A. Michaelson. (1986) Effect of in vitro inorganic lead on dopamine release from superfused rat striatal synaptosomes. Toxicol. Appl. Pharmacol. 84: 400–411PubMedCrossRefGoogle Scholar
  109. Needleman, H.L. and C.A. Gatsonis. (1990) Low-level lead exposure and the IQ of children: A meta-analysis of modern studies. JAMA 263: 673–678PubMedCrossRefGoogle Scholar
  110. Needleman, H.L., C. Gunnoe, A. Leviton, R. Reed, H. Peresie, C. Maher and P. Barrett. (1979) Deficits in psychologic and classroom performance of children with elevated dentine lead ­levels. N. Engl. J. Med. 300: 689–695PubMedCrossRefGoogle Scholar
  111. Needleman, H.L., A. Schell, D. Bellinger, A. Leviton and E.N. Allred. (1990) The long-term effects of exposure to low doses of lead in childhood: An 11-year follow-up report. N. Engl. J. Med. 322: 83–88PubMedCrossRefGoogle Scholar
  112. Needleman, H.L. J.A. Riess, M.J. Tobin, G.E. Biesecker and J.B. Greenhouse. (1996) Bone lead levels and delinquent behavior. JAMA 275: 363–369PubMedCrossRefGoogle Scholar
  113. Needleman, H.L., C. McFarland, R.B. Ness, S.E. Fienberg and M.J. Tobin. (2002) Bone lead levels in adjudicated delinquents. A case control study. Neurotoxicol. Teratol. 24: 711–717CrossRefGoogle Scholar
  114. Nicchia, G.P., A. Frigeri, G.M. Liuzzi, M.P. Santacroce, B. Nico, G. Procino, F. Quondamatteo, R. Herken, L. Roncali and M. Svelto. (2000) Aquaporin-4-containing astrocytes sustain a temperature- and mercury-insensitive swelling in vitro. Glia 31: 29–38PubMedCrossRefGoogle Scholar
  115. Nielsen, S., E.A. Nagelhus, M. Amiry-Moghaddam, C. Bourque, P. Agre and O.P. Ottersen. (1997) Specialized membrane domains for water transport in glial cells: High-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J. Neurosci. 17: 171–180PubMedGoogle Scholar
  116. Niemietz, C.M. and S.D. Tyerman. (2002) New potent inhibitors of aquaporins: Silver and gold compounds inhibit aquaporins of plant and human origin. FEBS Lett. 531: 443–447PubMedCrossRefGoogle Scholar
  117. Ong, W.Y. and A.A. Farooqui. (2005) Iron, neuroinflammation, and Alzheimer’s disease. J. Alzheimer’s Dis. 8: 183–200Google Scholar
  118. Ong, W.Y., M.Q. Ren, J. Makjanic, T.M. Lim and F. Watt. (1999) A nuclear microscopic study of elemental changes in the rat hippocampus after kainate-induced neuronal injury. J. Neurochem. 72: 1574–1579PubMedCrossRefGoogle Scholar
  119. Ong, W.Y., X. He, L.H. Chua and C.N. Ong. (2006) Increased uptake of divalent metals lead and cadmium into the brain after kainite-induced neuronal injury. Exp. Brain Res. 173: 468–474PubMedCrossRefGoogle Scholar
  120. Papanikolaou, N.C., E.G. Hatzidaki, S. Belivanis, G.N. Tzanakakis, A.M. Tsatsakis. (2005) Lead toxicity update: A brief review. Med. Sci. Monit. 11(10): RA329–RA336PubMedGoogle Scholar
  121. Peng, S., R.K. Hajela and W.D. Atchison. (2002) Characteristics of block by Pb<Superscript>2+</Superscript> of function of human neuronal L-, N-, and R-type Ca<Superscript>2+</Superscript> channels transiently expressed in human embryonic kidney cells. Mol. Pharmacol. 62: 1418–1430PubMedCrossRefGoogle Scholar
  122. Penn, A.A. and C.J. Shatz. (1999) Brain waves and brain wiring: The role of endogenous and sensory driven neural activity in development. Pediatr. Res. 45: 447–458PubMedCrossRefGoogle Scholar
  123. Pentschew, A. and F. Garro. (1966) Lead encephalomyelopathy of the suckling rat and its implications on the porphyrinopathic nervous diseases: With special reference to the permeability disorders of the nervous system capillaries. Acta Neuropathol. 6: 266–278PubMedCrossRefGoogle Scholar
  124. Perelman, S., L. Hertz-Pannier, M. Hassan, and A. Bourrillon. (1993) Lead encephalopathy mimicking a cerebellar tumor. Acta Paediatr. 82: 423–425PubMedCrossRefGoogle Scholar
  125. Perlstein, M.A. and R. Attala. (1966) Neurologic sequelae of plumbism in children. Clin. Pediatr. 5: 292–298CrossRefGoogle Scholar
  126. Philip, A.T. and B. Gerson. (1994) Lead poisoning — Part I. Clin. Lab. Med. 14: 423–44PubMedGoogle Scholar
  127. Pocock, S.J., M. Smith and P. Baghurst. (1994) Environmental lead and children’s intelligence: A systematic review of the epidemiological evidence. Br. Med. J. 309: 1189–1197CrossRefGoogle Scholar
  128. Press, M.F. (1977) Lead encephalopathy in neonatal long-evans rats: Morphologic studies. J. Neuropathol. Exp. Neurol. 36: 169–193PubMedCrossRefGoogle Scholar
  129. Preston, G.M., T.P. Carroll, W.P. Guggino and P. Agre. (1992) Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science 256: 385–387PubMedCrossRefGoogle Scholar
  130. Raff, M.C., B.A. Barres, J.F. Burne, H.S. Coles, Y. Ishizaki, and M.D. Jacobson. (1993) Programmed cell death and the control of cell survival: Lessons from the nervous system. Science 262: 695–700PubMedCrossRefGoogle Scholar
  131. Regan, C.M. (1989) Lead-impaired neurodevelopment: Mechanisms and threshold values in the rodent. Neurotoxicol. Teratol. 11: 533–537PubMedCrossRefGoogle Scholar
  132. Regan, C.M. (1991) Neural cell adhesion molecules: Neuronal development, and lead toxicity. In: Proceedings, Ninth International Neurotoxicology Conference, J. Cranmer (editor), Little RockGoogle Scholar
  133. Regan, C.M. (1993) Neural cell adhesion molecules, neuronal development and lead toxicity. Neurotoxicology 14: 69–76PubMedGoogle Scholar
  134. Reyes, P.F., C.F. Gonzalez, M.K. Zalewska and A. Besarab. (1986) Intracranial calcification in adults with chronic lead exposure. AJR Am. J. Roentgenol. 146: 267–270PubMedGoogle Scholar
  135. Rice, D. (1989) Delayed neurotoxicity in monkeys exposed developmentally to methyl mercury. Neurotoxicology. 10: 645–650PubMedGoogle Scholar
  136. Rice, D.C. (1993) Lead-induced changes in learning: Evidence for behavioral mechanisms from experimental animal studies. Neurotoxicology 14: 167–178PubMedGoogle Scholar
  137. Rogan, W.J., K.N. Dietrich, J.H. Ware, D.W. Dockery, M. Salganik, J. Radcliffe, R.L. Jones, N.B. Ragan, J.J. Chisolm and G.G. Rhoads. (2001) The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead. N. Engl. J. Med. 344: 1421–1426PubMedCrossRefGoogle Scholar
  138. Roger, S.D., D. Crimmins, C. Yiannikas and D.C. Harris. (1990) Lead intoxication in an anuric patient: Management by intraperitoneal EDTA. Aust. N. Z. J. Med. 20: 814–817PubMedCrossRefGoogle Scholar
  139. Rowland, A.S. and R.C. McKinstry. (2006) Lead toxicity, white matter lesions, and aging. Neurology 66: 1464–1465CrossRefGoogle Scholar
  140. Ruff, H.A., P.E. Bijur, M. Markowitz, Y.C. Ma and J.F. Rosen. (1993) Declining blood lead levels and cognitive changes in moderately lead-poisoned children. JAMA 269: 1641–1646PubMedCrossRefGoogle Scholar
  141. Ruff, H.A., M.E. Markowitz, P.E. Bijur and J. Rosen. (1996) Relationships among blood lead ­levels, iron deficiency and cognitive development in two-year-old children. Environ. Health Perspect. 104(2): 180–185PubMedGoogle Scholar
  142. Sanchez-Ramos, J., E. Overvik and B. Ames. (1994) A marker of oxyradical-mediated DNA damage (8-hydroxy-2′-deoxyguanosine) is increased in nigrostriatum of Parkinson′s disease brain. Neurodegen. 3: 197–204Google Scholar
  143. Saper, R.B., S.N. Kales, J. Paquin, M.J. Burns, D.M. Eisenberg, R.B. Davis and R.S. Phillips. (2004) Heavy metal content of ayurvedic herbal medicine products. JAMA 292: 2868–2873PubMedCrossRefGoogle Scholar
  144. Saryan, L.A. and C. Zenz. (1994) Lead and its compounds. In: Occupational Medicine (third edition). L.A. Saryan and C. Zenz (editors), Mosby, St. Louis, pp. 506–541Google Scholar
  145. Schwartz, J. (1994) Low-level lead exposure and children’s IQ: A meta-analysis and search for a threshold. Environ. Res. 65: 42–55PubMedCrossRefGoogle Scholar
  146. Schwartz, B.S., W.F. Stewart, K.I. Bolla, D. Simon, K. Bandeen-Roche, B. Gordon, J.M. Links, A.C. Todd, W. Shi, S. Bassett and P. Youssem. (2000) Past adult lead exposure is associated with longitudinal decline in cognitive function. Neurology. 55: 1144–1150PubMedCrossRefGoogle Scholar
  147. Sciarillo, W.G., G. Alexander and K.P. Farrell. (1992) Lead exposure and child behavior. Am. J. Public Health. 82: 1356–1360PubMedCrossRefGoogle Scholar
  148. Sheng, M. and M.J. Kim. (2002) Postsynaptic signaling and plasticity mechanisms. Science. 298: 776–80PubMedCrossRefGoogle Scholar
  149. Silbergeld, E.K. (1992) Mechanisms of lead neurotoxicity, or looking beyond the lamppost. FASEB J. 6: 3201–3206PubMedGoogle Scholar
  150. Stewart, W.F., B.S. Schwartz, D. Simon, K.I. Bolla, A.C. Todd and J. Links. (1999) The relation between neurobehavioral function and tibial and chelatable lead levels in former organolead manufacturing workers. Neurology. 52: 1610–1617PubMedCrossRefGoogle Scholar
  151. Stewart, W.F., B.S. Schwartz, C. Davatzikos, D. Shen, D. Liu, X. Wu, A.C. Todd, W. Shi, S. Bassett and D. Youssem. (2006) Past adult lead exposure is linked to neurodegeneration measured by brain MRI. Neurology. 66: 1476–1484PubMedCrossRefGoogle Scholar
  152. Sweatt, J.D. (2001) The neuronal MAP kinase cascade: A biochemical signal integration system subserving synaptic plasticity and memory. J. Neurochem. 76: 1–10PubMedCrossRefGoogle Scholar
  153. Teo, J.G.C., K.Y.C. Goh, A. Ahuja, H.K. Ng and W.S. Poon. (1997) Intracranial vascular calcifications, glioblastoma multiforme, and lead poisoning. AJNR Am. J. Neuroradiol. 18: 576–579PubMedGoogle Scholar
  154. Tiffany-Castiglioni, E., E.M. Sierra, J.-N. Wu and T.K. Rowles. (1989) Lead toxicity in neuroglia. Neurotoxicology 10: 417–443PubMedGoogle Scholar
  155. Toews, A.D., A. Kolber, J. Hayward, M.R. Krigman and P. Morell. (1978) Experimental lead encephalopathy in the suckling rat: Concentration of lead in cellular fractions enriched in brain capillaries. Brain Res. 147: 131–138PubMedCrossRefGoogle Scholar
  156. Tong, S., P. Baghurst, A. McMichael, M. Sawyer and J. Mudge. (1996) Lifetime exposure to environmental lead and children’s intelligence at 11-13 years: The Port Pirie cohort study. Br. Med. J. 312: 1569–1575CrossRefGoogle Scholar
  157. Tong, S., P.A. Baghurst, M.G. Sawyer, J. Burns and A.J. McMichael. (1998) Declining blood lead levels and changes in cognitive function during childhood: The Port Pirie cohort study. JAMA 280: 1915–1919PubMedCrossRefGoogle Scholar
  158. Toscano, C.D., H. Hashemazadeh-Gargari, J.L. McGlothan and T.R. Guilarte. (2002) Developmental Pb(<Superscript>2+</Superscript>) exposure alters NMDA subtypes and reduces CREB phosphorylation in the rat brain. Dev. Brain Res. 139: 217–226CrossRefGoogle Scholar
  159. Tsai, Y.-T., C.-C. Huang, H.-C. Kuo, H.-M. Wang, W.-S. Shen, T.-S. Shih and N.-S. Chu. (2006) Central nervous system effects in acute thallium poisoning. Neurotoxicol. 27: 291–295CrossRefGoogle Scholar
  160. Valpey, R., M. Sumi, M. Copass and G. Goble. (1978) Acute and chronic progressive encephalopathy due to gasoline sniffing. Neurology 28: 507–510PubMedCrossRefGoogle Scholar
  161. Wang, W., M.J. Merrill and R.T. Borchardt. (1996) Vascular endothelial growth factor affects permeability of brain microvessel endothelial cells in vitro. Am. J. Physiol. 271: C1973–C1980PubMedGoogle Scholar
  162. Wang, X.S., W.Y. Ong and J.R. Connor. (2001) A light and electron microscopic study of the iron transporter protein DMT-1 in the monkey cerebral neocortex and hippocampus. J. Neurocytol. 30: 353–360PubMedCrossRefGoogle Scholar
  163. Wang, X.S., W.Y. Ong and J.R. Connor. (2002a) A light and electron microscopic study of divalent metal transporter-1 distribution in the rat hippocampus, after kainate-induced neuronal injury. Exp. Neurol. 177: 193–201CrossRefGoogle Scholar
  164. Wang, X.S., W.Y. Ong and J.R. Connor. (2002b) Increase in ferric and ferrous iron in the rat hippocampus with time after kainate-induced excitotoxic injury. Exp. Brain Res. 143: 137–148CrossRefGoogle Scholar
  165. Wasserman, G.A., X. Liu, N.J. Lolacono, P. Factor-Litvak, J.K. Kline, D. Popovac, N. Morina, A. Musabegovic, N. Vrenezi, S. Capuni-Paracka, V. Lekic, E. Preteni-Redjepi, S. Hadzialjevic, V. Slavkovich and J.H. Graziano. (1997) Lead exposure and intelligence in 7-year-old children: The Yugoslavia prospective study. Environ. Health Perspect. 105: 956–962PubMedCrossRefGoogle Scholar
  166. Wasserman, G.A., X. Liu, D. Popovac, P. Factor-Litvak, J. Kline, C. Waternaux, N. Lolacono and J.H. Graziano. (2000) The Yugoslavia prospective lead study: Contributions of prenatal and postnatal lead exposure to early intelligence. Neurotoxicol. Teratol. 22: 811–818PubMedCrossRefGoogle Scholar
  167. Weiss, B. (1991) Cancer and the dynamics of neurodegenerative processes. Neurotoxicol. 12: 379–386Google Scholar
  168. Wilson, M.A., M.V. Johnston, G.W. Goldstein and M.E. Blue. (2000) Neonatal lead exposure impairs development of rodent barrel field cortex. Proc. Natl. Acad. Sci. USA. 97: 5540–5545PubMedCrossRefGoogle Scholar
  169. WHO. (1995) Environmental health criteria 165, inorganic lead. World Health Organization International Programme for Chemical Safety, Geneva, SwitzerlandGoogle Scholar
  170. Yasui, M., T.H. Kwon, M.A. Knepper, S. Nielsen and P. Agre. (1999) Aquaporin-6: An intracellular vesicle water channel protein in renal epithelia. Proc. Natl. Acad. Sci. USA 96: 5808–5813PubMedCrossRefGoogle Scholar
  171. Yule, W., R. Lansdown, I.B. Millar and M.A. Urbanowicz. (1981) The relationship between blood lead concentrations, intelligence and attainment in a school population: A pilot study. Dev. Med. Child Neurol. 23: 567–576PubMedCrossRefGoogle Scholar
  172. Zawia, N.H. (2003) Transcriptional involvement in neurotoxicity. Toxicol. Appl. Pharmacol. 190: 177–188PubMedCrossRefGoogle Scholar
  173. Zelenina, M., A.A. Bondar, S. Zelenin and A. Aperia. (2003) Nickel and extracellular acidification inhibit the water permeability of human Aquaporin-3 in lung epithelial cells. J. Biol. Chem. 278: 30037–30043PubMedCrossRefGoogle Scholar
  174. Zelenina, M., S. Tritto, A.A. Bondar, S. Zelenin and A. Aperia. (2004) Copper inhibits the water and glycerol permeability of Aquaporin-3. J. Biol. Chem. 279: 51939–51943PubMedCrossRefGoogle Scholar
  175. Ziegler, E.E., B.B. Edwards, R.I. Jensen, K.R. Mahaffey and S.J. Fomon. (1978) Absorption and retention of lead by infants. Pediatr. Res. 12: 29–34PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Ivan J. Boyer
    • 1
  1. 1.DABT, Noblis (Mitretek)Falls ChurchVirginiaUSA

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