This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Dorman, D. C. Search for Related Content PubMed PubMed Citation Articles by Dorman, D. C. Pubmed/NCBI databases Medline Plus Health Information Neurologic Diseases Social Bookmarking                         What's this?

An Integrative Approach to Neurotoxicology

Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709

Exposure of human populations to a wide variety of chemicals has generated concern about the potential neurotoxicity of new and existing chemicals. Experimental studies conducted in laboratory animals remain critical to the study of neurotoxicity. An integrative approach using pharmacokinetic, neuropathological, neurochemical, electrophysiological, and behavioral methods is needed to determine whether a chemical is neurotoxic. There are a number of factors that can affect the outcome of a neurotoxicity study, including the choice of animal species, dose and dosage regimen, route of administration, and the intrinsic sensitivity of the nervous system to the test chemical. The neurotoxicity of a chemical can vary at different stages of brain development and maturity. Evidence of neurotoxicity may be highly subjective and species specific and can be complicated by the presence of systemic disease. The aim of this paper is to give an overview of these and other factors involved in the assessment of the neurotoxic potential for chemicals. This article discusses the neurotoxicity of several neurotoxicants (eg, acrylamide, trimethyltin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, manganese, and ivermectin), thereby highlighting a multidisciplinary approach to the assessment of chemically induced neurotoxicity in animals. These model chemicals produce a broad range of effects that includes peripheral axonopathy, selective neuronal damage within the nervous system, and impaired neuronal-glial metabolism.

Key Words: Neurotoxicology • risk assessment • trimethyltin • acrylamide • 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) • manganese

References

• Abbott NJ, Revest PA, Romero IA (1992). Astrocyte-endothelial interaction: Physiology and pathology. Neuropathol Appl Neurobiol 18: 424-433.[Web of Science][Medline] [Order article via Infotrieve]
• Albee RR, Mattson JL, Yano BL, Chang LW (1987). Neurobehavioral effects of dietary restriction in rats. Neurotoxicol Teratol 9: 203-211.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Alessandri B., Fitzgerald RE, Schaeppi U., Krinke GJ, Classen W. (1994). The use of an unbaited tunnel maze in neurotoxicology: I. Trimethyltin-induced brain lesions. Neurotoxicology 15: 349-357.[Web of Science][Medline] [Order article via Infotrieve]
• Aschner M. (1999). Manganese homeostasis in the CNS. Environ Res 80: 105-109.[Medline] [Order article via Infotrieve]
• Barbeau A. (1984). Manganese and extrapyramidal disorders. A critical review and tribute to Dr. George C. Cotzia. Neurotoxicology 5: 1336.
• Besser R., Kramer G., Thumler R., Bohl J., Gutmann L., Hopf HC ( 1987). Acute trimethyltin limbic-cerebellar syndrome. Neurology 37: 94550.
• Boyes WK, Miller DB (1988). A review of rodent models of manganese neurotoxicity. Neurotoxicology 19: 468 (abstract).
• Brenneman KA, Cattley RC, Ali SF, Dorman DC (1999). Manganese-induced developmental neurotoxicity in the CD rat: Is oxidative damage a mechanism of action? Neurotoxicology 20: 477-488.[Web of Science][Medline] [Order article via Infotrieve]
• Broxup B., Robinson K., Losos G., Beyrouty P. (1989). Correlation between behavioral and pathological changes in the evaluation of neurotoxicity. Toxicol Appl Pharmacol 101: 510-520.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Bushnell PJ, Angell KE (1992). Effects of trimethyltin on repeated acquisition (learning) in the radial-arm maze. Neurotoxicology 13: 429-441.[Medline] [Order article via Infotrieve]
• Butterworth RF (1993). Portal-systemic encephalopathy: A disorder of neuron-astrocytic metabolic trafficking. Dev Neurosci 15: 313-319.[Web of Science][Medline] [Order article via Infotrieve]
• Calleman CJ, Wu Y., He F., Tian G., Bergmark E., Zhang S., Deng H., Wang Y., Crofton KM, Fennell T., Costa LG (1994). Relationships between biomarkers of exposure and neurological effects in a group of workers exposed to acrylamide. Toxicol Appl Pharmacol 126: 361-371.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Calne DB, Chu NS, Huang CC, Lu SS, Olanow W. (1994). Manganism and idiopathic Parkinsonism: Similarities and differences. Neurology 44: 1583-1586.[Free Full Text]
• Chang LW (1990). The neurotoxicology and pathology of organo-mercury, organolead, and organotin. J Toxicol Sci 15(suppl 4): 125-151.[Medline] [Order article via Infotrieve]
• Cohn J., MacPhail RC (1996). Acute trimethyltin exposure produces nonspecific effects on learning in rats working under a multiple repeated acquisition and performance schedule. Neurotoxicol Teratol 18: 99-111.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Di Monte DA, Royland JE, Irwin I., Langston J. (1996). Astrocytes as the site for bioactivation of neurotoxins. Neurotoxicology 17: 697-703.[Web of Science][Medline] [Order article via Infotrieve]
• Dobbing J., Sands J. (1971). Vulnerability of developing brain. IX. The effect of nutritional growth retardation on the timing of the brain growth-spurt. Biol Neonate 19: 363-378.[Web of Science][Medline] [Order article via Infotrieve]
• Dyer RS, Walsh TJ, Wonderlin WF, Bercegeay M. (1982). The trimethyltin syndrome in rats. Neurobehav Toxicol Teratol 4: 127-133.[Web of Science][Medline] [Order article via Infotrieve]
• Earley B., Burke M., Leonard BE (1982). Behavioural, biochemical and histological effects of trimethyltin (TMT) induced brain damage in the rat. Neurochem Int 21: 351-366.
• Eriksson H., Gillberg PG, Aquilonius SM, Hedstrom KG, Heilbronn E. (1992). Receptor alterations in manganese intoxicated monkeys. Arch Toxicol 66: 359-364.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Eriksson H., Tedroff J., Thuomas KA, Aquilonius SM, Hartvig P., Fasth KJ, Bjurling P., Langstrom B., Hedstrom KG, Heilbronn E. (1992). Manganese induced brain lesions in Macaca fascicularis as revealed by positron emission tomography and magnetic resonance imaging. Arch Toxicol 66: 403-407.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Evans PH (1993). Free radicals in brain metabolism and pathology. Br Med Bull 49: 577-587.[Abstract/Free Full Text]
• Felipo V., Hermenegildo C., Montoliu C., Llansola M., Minana MD (1998). Neurotoxicity of ammonia and glutamate: Molecular mechanisms and prevention. Neurotoxicology 19: 675-681.[Web of Science][Medline] [Order article via Infotrieve]
• Fortemps E., Amand G., Bomboir A., Lauwerys R., Laterre EC (1978). Trimethyltin poisoning. Report of two cases. Int Arch Occup Environ Health 41: 1-6.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Gerber GJ, O'Shaughnessy D. (1986). Comparison of the behavioral effects of neurotoxic and systemically toxic agents: How discriminatory are behavioral tests of neurotoxicity? Neurobehav Toxicol Teratol 8: 703-710.[Web of Science][Medline] [Order article via Infotrieve]
• Gerlach M., Riederer P., Przuntek H., Youdim MB (1991). MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease. Eur J Pharmacol 208: 273-286.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• He FS, Zhang SL, Wang HL, Li G., Zhang ZM, Li FL, Dong XM, Hu FR (1989). Neurological and electroneuromyographic assessment of the adverse effects of acrylamide on occupationally exposed workers. Scand J Work Environ Health 15: 125-129.[Web of Science][Medline] [Order article via Infotrieve]
• Heiss WD (1981). Cerebral blood flow: Physiology, pathophysiology and pharmacological effects. Adv Otorhinolaryngol 27: 26-39.[Medline] [Order article via Infotrieve]
• Hill JM, Switzer RC III (1985). The regional distribution and cellular localization of iron in the rat brain. Neuroscience 11: 595-603.[CrossRef][Web of Science]
• Janzer RC (1993). The blood-brain barrier: Cellular basis. J Inherited Metab Dis 16: 639-647.[CrossRef][Medline] [Order article via Infotrieve]
• Johannessen JN (1991). A model of chronic neurotoxicity: Long-term retention of the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) within catecholaminergic neurons. Neurotoxicology 12: 285-302.[Web of Science][Medline] [Order article via Infotrieve]
• Johansson BB (1990). The physiology of the blood-brain barrier. Adv Exp Med Biol 274: 25-39.[Medline] [Order article via Infotrieve]
• Juurlink BH, Paterson PG (1998). Review of oxidative stress in brain and spinal cord injury: Suggestions for pharmacological and nutritional management strategies. J Spinal Cord Med 21: 309-334.[Medline] [Order article via Infotrieve]
• Kastin AJ, Kuzemchak B., Tompkins RG, Schally AV, Miller MC III (1976). Melanin in the rat brain. Brain Res Bull 1: 567-572.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Langston JW, Ballard P., Tetrud JW, Irwin I. (1983). Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219: 979-980.[Abstract/Free Full Text]
• Lankas GR, Cartwright ME, Umbenhauer D. (1997). P-glycoprotein deficiency in a subpopulation of CF-1 mice enhances avermectininduced neurotoxicity. Toxicol Appl Pharmacol 143: 357-365.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Lankas GR, Wise LD, Cartwright ME, Pippert T., Umbenhauer DR (1998). Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod Toxicol 12: 457-463.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• LoPachin RM, Aschner M. (1999). Neuronal-glial interactions as potential targets of neurotoxicant effect. In: Neurotoxicology, Tilson HA and Harry GJ (eds). Taylor and Francis, Philadelphia, Pennsylvania, pp 53-80.
• Lyden A., Larsson BS, Lindquist NG (1984). Melanin affinity of manganese. Acta Pharmacol Toxicol 55: 133-138.[Medline] [Order article via Infotrieve]
• Lynch JJ III, Silveira LC, Perry VH, Merigan WH (1992). Visual effects of damage to P ganglion cells in macaques. Vis Neurosci 8: 575-583.[Web of Science][Medline] [Order article via Infotrieve]
• Marsden CD (1969). Brain melanin. In: Pigments in Pathology, Wolman M (ed). Academic Press, New York, pp 395-420.
• Maurissen JP, Weiss B., Davis HT (1983). Somatosensory thresholds in monkeys exposed to acrylamide. Toxicol Appl Pharmacol 71: 266-279.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Merigan WH, Barkdoll E., Maurissen JP (1982). Acrylamide-induced visual impairment in primates. Toxicol Appl Pharmacol 62: 342-345.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Moorcraft WH (1981). Heightened arousal in the 2-week-old rat: The importance of starvation. Dev Psychobiol 14: 187-199.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Nagatomo S., Umehara F., Hanada K., Nobuhara Y., Takenaga S., Arimura K., Osame M. (1999). Manganese intoxication during total parenteral nutrition: Report of two cases and review of the literature. J Neurol Sci 162: 102-105.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Nicklas WJ, Saporito M., Basma A., Geller HM, Heikkila RE (1992). Mitochondrial mechanisms of neurotoxicity. Ann NY Acad Sci 648: 28-36.[Web of Science][Medline] [Order article via Infotrieve]
• Niittykoski M., Lappalainen R., Jolkkonen J., Haapalinna A., Riekkinen P., Sirvio J. (1998). Systemic administration of atipamezole, a selective antagonist of alpha-2 adrenoceptors, facilitates behavioural activity but does not influence short-term or long-term memory in trimethyltin-intoxicated and control rats. Neurosci Biobehav Rev 22: 735-750.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Olanow CW, Good PF, Shinotoh H., Hewitt KA, Vingerhoets F., Snow BJ, Beal MF, Calne DB, Perl DP ( 1996). Manganese intoxication in the rhesus monkey: A clinical, imaging, pathologic, and biochemical study. Neurology 46: 492-498.[Abstract/Free Full Text]
• O'Shaughnessy DJ, Losos GJ (1986). Comparison of central and peripheral nervous system lesions caused by high-dose short-term and low-dose subchronic acrylamide treatment in rats. Toxicol Pathol 14: 389-394.[Medline] [Order article via Infotrieve]
• Pardridge WM (1998). CNS drug design based on principles of blood-brain barrier transport. J Neurochem 70: 1781-1792.[Web of Science][Medline] [Order article via Infotrieve]
• Riachi NJ, Behmand RA, Harik SI (1991). Correlation of MPTP neurotoxicity in vivo with oxidation of MPTP by the brain and blood-brain barrier in vitro in five rat strains. Brain Res 555: 19-24.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Saita K., Ohi T., Hanaoka Y., Furukawa S., Furukawa Y., Hayashi K., Matsukura S. (1995). Effects of 4-methylcatechol, a stimulator of endogenous nerve growth factor synthesis, on experimental acrylamide-induced neuropathy in rats. Neurotoxicology 16: 403-412.[Web of Science][Medline] [Order article via Infotrieve]
• Saunders NR, Habgood MD, Dziegielewska KM (1999). Barrier mechanisms in the brain. II. Immature brain. Clin Exp Pharmacol Physiol 26: 85-91.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Sette WF, MacPhail RC (1992). Qualitative and quantitative issues in assessment of neurotoxic effects. In: Neurotoxicology, Tilson HA and Mitchell C (eds). Raven Press Ltd, New York, pp 345-361.
• Shinotoh H., Snow BJ, Hewitt KA, Pate BD, Doudet D., Nugent R., Perl DP, Olanow W., Calne DB (1995). MRI and PET studies of manganese-intoxicated monkeys. Neurology 45: 1199-1204.[Abstract/Free Full Text]
• Spencer PS, Schaumburg HH (1975). Nervous system degeneration produced by acrylamide monomer. Environ Health Perspect 11: 129-133.[Medline] [Order article via Infotrieve]
• Sundstrom E., Samuelsson EB (1997). Comparison of key steps in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in rodents. Pharmacol Toxicol 81: 226-231.[Web of Science][Medline] [Order article via Infotrieve]
• Trevor AJ, Singer TP, Ramsay RR, Castagnoli N.Jr (1987). Processing of MPTP by monoamine oxidases: Implications for molecular toxicology. J Neural Transm 23(suppl): 73-89.
• van Asperen J., Mayer U., van Tellingen O., Beijnen JH (1997). The functional role of P-glycoprotein in the blood-brain barrier. J Pharm Sci 86: 881-884.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Wild HM, Kulikowski JJ (1984). Neurotoxic effects of acrylamide on rat retinogeniculate fibres. Behav Brain Res 13: 201-207.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Zola-Morgan S., Squire LR, Ramus SJ (1994). Severity of memory impairment in monkeys as a function of locus and extent of damage within the medial temporal lobe memory system. Hippocampus 4: 483-495.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Zuddas A., Fascetti F., Corsini GU, Piccardi MP (1994). In brown Norway rats, MPP+ is accumulated in the nigrostriatal dopaminergic terminals but it is not neurotoxic: A model of natural resistance to MPTP toxicity. Exp Neurol 127: 54-61.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

Toxicologic Pathology, Vol. 28, No. 1, 37-42 (2000)
DOI: 10.1177/019262330002800106


CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				B. Bolon, D. C. Anthony, M. Butt, D. Dorman, M. V. Green, P. B. Little, W. M. Valentine, D. Weinstock, J. Yan, and R. C. Sills "Current Pathology Techniques" Symposium Review: Advances and Issues in Neuropathology Toxicol Pathol, October 1, 2008; 36(6): 871 - 889. [Abstract] [Full Text] [PDF]

				B. Bolon Comparative and Correlative Neuroanatomy for the Toxicologic Pathologist Toxicol Pathol, January 1, 2000; 28(1): 6 - 27. [Abstract] [PDF]

This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Dorman, D. C. Search for Related Content PubMed PubMed Citation Articles by Dorman, D. C. Pubmed/NCBI databases Medline Plus Health Information Neurologic Diseases Social Bookmarking                         What's this?