PRINCIPLES OF TOXICOLOGY - Biology East Borneo

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154 NEUROTOXICITY: TOXIC RESPONSES <strong>OF</strong> THE NERVOUS SYSTEM7.7 SUMMARYEvaluating neurotoxicity can be problematic for several reasons:• The proper functioning of the nervous system depends upon many complicated stepsoccurring in a precisely controlled fashion, and thus an agent that is disruptive of any ofthese steps may be potentially neurotoxic.• The operation of the nervous system is intimately involved with that of other systems, suchas the respiratory, gastrointestinal, and endocrine systems, so that impairment of respirationor hormone function may occur in conjunction with, or as a result of, neurotoxic symptoms.TABLE 7.1 Some Common Neurotoxic ChemicalsChemical Symptom(s) Site(s) of ActionMetalsArsenic Seizures, tremors Peripheral motor neuronsBarium Muscle spasms Ion channelsLead Insomnia, tremors Myelin, synapse, axonManganese Insomnia, confusion SynapseMercury (organic) Ataxia, tremors, confusion Peripheral motor neurons, axonThallium Seizures, psychosis Myelin, axonTin (organic) Headache, psychosis MyelinOrganic solventsAcetone CNS depression Neuronal membraneBenzene Giddiness, ataxia Neuronal membraneCarbon tetrachloride CNS depression, giddiness Neuronal membraneCarbon disulfide Dizziness, psychosis Peripheral sensory and motorneurons, synapsen-Hexane Numbness, giddiness Peripheral sensory and motorneurons, axonMethanol Blindness, mild inebriation Neuronal membrane, axonTetrachloroethylene Dizziness, ataxia Neuronal membraneToluene Dizziness, euphoria Neuronal membraneTrichloroethylene Giddiness, tremors Neuronal membrane, axonOrganic pesticidesChlordane Blurred vision, ataxia SynapseCyanide Confusion, labored breathing Cytochrome oxidase2,4-D Muscle spasms, convulsions Neuronal membraneDDT Dizziness, convulsions Ion channels, synapseEndosulfan CNS depression, convulsions SynapseLindane Headache, convulsions SynapseMalathion Blurred vision, headache Synapse, axonParathion Ataxia, convulsions Synapse, axonRotenone Tremors, convulsions Electron transport chainOtherCarbon monoxide Headache, dizziness HemoglobinEthanol CNS depression, giddiness Ion channels, neuronal membraneHydrogen sulfide Convulsions, coma Cytochrome oxidaseNicotine Excitability, nausea SynapsePetroleum distillates CNS depression, dizziness Neuronal membrane
REFERENCES AND SUGGESTED READING 155• Although much of the damage which may occur in the nervous system is irreversible, someprotective adaptations and redundancy of function exist, which sometimes makes predictingthe effects of neurotoxicant exposure less than straightforward.The chemicals cited in the sections above serve only as examples and are by no means a comprehensivelist of neurotoxic hazards in the workplace. In addition, their symptoms of exposure are often variedand may be attributed to several mechanisms of action, which makes categorizing them by effectsomewhat difficult. Recommended exposure limits for chemicals commonly encountered in anoccupational setting are published by various agencies in the United States, such as the OccupationalSafety and Health Administration (OSHA), the National Institute for Occupational Safety and Health(NIOSH), and the American Conference of Governmental Industrial Hygienists (ACGIH). In addition,several other countries have organizations with similar purposes. The publications of these groupsshould be consulted for specific recommended exposure levels of neurotoxic chemicals. Table 7.1presents a few of the more common industrial neurotoxicants, along with some general symptoms ofexposure and their primary sites of action.It should be clear to the reader by now that, as the result of multiple and overlapping effects ofmany neurotoxic chemicals, any listing of effects must necessarily be a simplified representation. Also,the science of neurotoxicity is continually evolving, so that revisions of such lists are to be expectedas new information is obtained. Nonetheless, considerable progress has been made in recent yearstoward developing reliable methods of neurotoxicity evaluation and minimizing exposure to potentialneurotoxicants.REFERENCES AND SUGGESTED READINGAnnau, Z., ed., Neurobehavioral Toxicology, Johns Hopkins Univ. Press, Baltimore, 1986.Anthony, D. C., T. J. Montine, and D. G. Graham. “Toxic responses of the nervous system,” in Casarett and Doull’sToxicology: The Basic Science of Poisons, 5th ed., C. D. Klaassen, ed., McGraw-Hill, New York, 1966, pp.463–486.Anthony, D. C., and D. G. Graham. “Toxic responses of the nervous system,” in Casarett and Doull’s Toxicology:The Basic Science of Poisons, 4th ed., M. O. Amdur, J. Doull, and C. D. Klaassen, eds., McGraw-Hill, NewYork, 1991.Araki, S., ed., Neurobehavioral Methods and Effects in Occupational and Environmental Health, Academic Press,London, 1995.Baker, E. L. Jr., “ Neurologic and behavioral disorders,” in Occupational Health: Recognizing and PreventingWork-Related Disease, 2nd ed., B. S. Levy and D. H. Wegman, eds., Little, Brown, Boston, 1988.Chang, L. W., and W. Slikker, Jr., eds., Neurotoxicology: Approaches and Methods, Academic Press, London, 1995.Feldman, R. G., Occupational and Environmental Neurotoxicology, Lippincott, Williams and Wilkins Publishers,Philadelphia, 1998.Johnson, B. L., ed., Advances in Neurobehavioral Toxicology: Applications in Environmental and OccupationalHealth, Lewis Publishers, Chelsea, MI, 1990.Kilburn, K. H., Chemical Brain Injury, Van Nostrand-Reinhold, New York, 1998.Norton, S., “Toxic responses of the central nervous system,” in Casarett and Doull’s Toxicology: The Basic Scienceof Poisons, 3rd ed., C. D. Klassen, M. O. Amdur, and J. Doull, eds., Macmillan, New York, 1986.Office of Technology Assessment, Congressional Board of the 101st Congress, Neurotoxicity: Identifying andControlling Poisons of the Nervous System, Van Nostrand-, New York, 1990.Tilson, H. A., and G. J. Harry, eds., Neurotoxicology (Target Organ Toxicology Series), Taylor and Francis, London,1999.Tilson, H. A., and C. L. Mitchell, Neurotoxicology, Raven Press, New York, 1992.Weiss, B., and J. L. O’Donoghue, eds., Neurobehavioral Toxicity: Analysis and Interpretation, Raven Press, NewYork, 1994.
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CONTRIBUTORSLOUIS ADAMS, PH.D. Prof
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CONTENTSPREFACExvACKNOWLEDGMENTSxvi
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CONTENTSix7.3 Agents that Act on th
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CONTENTSxi15.4 Herbicides 35615.5 F
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CONTENTSxiii21.6 Population Issues
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xviPREFACE• The approach is scien
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PRINCIPLES OF TOXICOLOGY
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1 General Principles of ToxicologyG
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1.2 WHAT TOXICOLOGISTS STUDY 5Delay
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1.3 THE IMPORTANCE OF DOSE AND THE
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1.4 HOW DOSE-RESPONSE DATA CAN BE U
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1.5 AVOIDING INCORRECT CONCLUSIONS
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1.6 FACTORS INFLUENCING DOSE-RESPON
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1.6 FACTORS INFLUENCING DOSE-RESPON
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26 GENERAL PRINCIPLES OF TOXICOLOGY
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36 ABSORPTION, DISTRIBUTION, AND EL
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2.4 DISPOSITION: DISTRIBUTION AND E
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2.5 SUMMARY 53the transfer from liv
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REFERENCES AND SUGGESTED READING 55
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58 BIOTRANSFORMATION: A BALANCE BET
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60Figure 3.3 Xenobiotic metabolism
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TABLE 3.4 Important Cytochrome P450
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88 HEMATOTOXICITY: CHEMICALLY INDUC
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100 HEMATOTOXICITY: CHEMICALLY INDU
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Page 130 and 131: 5.2 TYPES OF LIVER INJURY 117cause
Page 132 and 133: 5.2 TYPES OF LIVER INJURY 119Exampl
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Page 138 and 139: 5.3 EVALUATION OF LIVER INJURY 125f
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Page 142 and 143: 6 Nephrotoxicity: Toxic Responses o
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Page 168 and 169: 8 Dermal and Ocular Toxicology: Tox
Page 170 and 171: 8.2 FUNCTIONS 159corneum is the pri
Page 172 and 173: 8.3 CONTACT DERMATITIS 161TABLE 8.2
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Page 178 and 179: 8.4 SUMMARY 167The structure of the
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Page 196 and 197: 9.3 SUMMARY 185Industrially Related
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206 IMMUNOTOXICITY: TOXIC EFFECTS O
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11 Reproductive ToxicologyREPRODUCT
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11.1 MALE REPRODUCTIVE TOXICOLOGY 2
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11.2 FEMALE REPRODUCTIVE TOXICOLOGY
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11.3 DEVELOPMENTAL TOXICOLOGY 225de
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11.3 DEVELOPMENTAL TOXICOLOGY 227af
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11.3 DEVELOPMENTAL TOXICOLOGY 229ri
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11.3 DEVELOPMENTAL TOXICOLOGY 231to
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11.4 CURRENT RESEARCH CONCERNS 233T
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11.4 CURRENT RESEARCH CONCERNS 235
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12 Mutagenesis and Genetic Toxicolo
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12.2 GENETIC FUNDAMENTALS AND EVALU
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TABLE 12-1. Correspondence of the G
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12.3 NONMAMMALIAN MUTAGENICITY TEST
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12.4 MAMMALIAN MUTAGENICITY TESTS 2
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12.4 MAMMALIAN MUTAGENICITY TESTS 2
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12.5 OCCUPATIONAL SIGNIFICANCE OF M
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REFERENCES CITED AND SUGGESTED READ
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13 Chemical CarcinogenesisCHEMICAL
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13.1 THE TERMINOLOGY OF CANCER 267H
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13.3 CARCINOGENESIS BY CHEMICALS 26
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Figure 13.1 Schematic diagram of th
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Figure 13.4 Metabolic activation of
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13.4 MOLECULAR ASPECTS OF CARCINOGE
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Figure 13.7 DNA damage leads to p53
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13.5 TESTING CHEMICALS FOR CARCINOG
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13.5 TESTING CHEMICALS FOR CARCINOG
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13.6 INTERPRETATION ISSUES RAISED B
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13.7 EMPIRICAL MEASURES OF RELIABIL
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13.8 OCCUPATIONAL CARCINOGENS 301TA
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13.8 OCCUPATIONAL CARCINOGENS 303TA
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13.9 CANCER AND OUR ENVIRONMENT 305
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13.10 CANCER TRENDS AND THEIR IMPAC
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13.11 SUMMARY 321from non-Hodgkin
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14 Properties and Effects of Metals
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14.2 SPECIATION OF METALS 327Most o
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14.3 PHARMACOKINETICS OF METALS 329
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14.4 TOXICITY OF METALS 331reflex i
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14.4 TOXICITY OF METALS 333Several
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14.5 SOURCES OF METAL EXPOSURE 335H
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14.6 TOXICOLOGY OF SELECTED METALS
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14.7 SUMMARY 343Zinc is required fo
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15 Properties and Effects of Pestic
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15.1 ORGANOPHOSPHATE AND CARBAMATE
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15.3 INSECTICIDES OF BIOLOGICAL ORI
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15.3 INSECTICIDES OF BIOLOGICAL ORI
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15.4 HERBICIDES 357ClClO CH 2 C OOH
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15.5 FUNGICIDES 359temperatures as
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15.7 FUMIGANTS 361thallium sulfate-
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16 Properties and Effects of Organi
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TABLE 16.1 Physicochemical Properti
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16.2 BASIC PRINCIPLES 371TABLE 16.2
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16.2 BASIC PRINCIPLES 373Once absor
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16.2 BASIC PRINCIPLES 375the additi
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16.3 TOXIC PROPERTIES OF REPRESENTA
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16.10 TOXIC PROPERTIES OF REPRESENT
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16.15 TOXIC PROPERTIES 403observed
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16.18 SULFUR-SUBSTITUTED SOLVENTS 4
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17 Properties and Effects of Natura
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17.3 NATURAL ROLES OF TOXINS AND VE
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17.4 MAJOR SITES AND MECHANISMS OF
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17.5 TOXINS IN UNICELLULAR ORGANISM
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17.6 TOXINS OF HIGHER PLANTS 417phy
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17.6 TOXINS OF HIGHER PLANTS 419whi
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17.6 TOXINS OF HIGHER PLANTS 421TAB
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17.7 ANIMAL VENOMS AND TOXINS 423of
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17.7 ANIMAL VENOMS AND TOXINS 425ac
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17.7 ANIMAL VENOMS AND TOXINS 427co
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17.7 ANIMAL VENOMS AND TOXINS 429Fi
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17.8 TOXIN AND VENOM THERAPY 431One
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18 Risk AssessmentRISK ASSESSMENTRO
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18.1 RISK ASSESSMENT BASICS 439Step
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18.1 RISK ASSESSMENT BASICS 441For
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18.2 HAZARD IDENTIFICATION 443chemi
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18.3 EXPOSURE ASSESSMENT: EXPOSURE
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18.3 EXPOSURE ASSESSMENT: EXPOSURE
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18.4 DOSE-RESPONSE ASSESSMENT 449Af
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18.4 DOSE-RESPONSE ASSESSMENT 451me
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18.4 DOSE-RESPONSE ASSESSMENT 453Fi
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18.4 DOSE-RESPONSE ASSESSMENT 455No
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18.4 DOSE-RESPONSE ASSESSMENT 457Fi
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18.4 DOSE-RESPONSE ASSESSMENT 459Ge
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18.5 RISK CHARACTERIZATION 461likel
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18.6 PROBABILISTIC VERSUS DETERMINI
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18.7 EVALUATING RISK FROM CHEMICAL
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18.7 EVALUATING RISK FROM CHEMICAL
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18.8 COMPARATIVE RISK ANALYSIS 469r
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18.8 COMPARATIVE RISK ANALYSIS 471T
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18.9 RISK COMMUNICATION 473TABLE 18
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480 EXAMPLE OF RISK ASSESSMENT APPL
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500 OCCUPATIONAL AND ENVIRONMENTAL
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21 Epidemiologic Issues inOccupatio
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21.3 TYPES OF EPIDEMIOLOGIC STUDIES
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21.5 DISEASE AND HUMAN HEALTH EFFEC
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21.8 MEASUREMENT OF ASSOCIATION OR
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21.9 BIAS 519increased or decreased
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524 CONTROLLING OCCUPATIONAL AND EN
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556 GLOSSARYaliphatic Organic compo
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558 GLOSSARYbenign tumor A new tiss
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560 GLOSSARYcytokinesis The divisio
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562 GLOSSARYerythropoietic stimulat
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564 GLOSSARYinhalation route The mo
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566 GLOSSARYmitochondria Small sphe
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568 GLOSSARYoral route The entry of
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570 GLOSSARYporphyrin Any of a grou
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572 GLOSSARYspirometry The measurem
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INDEXAbsorbed dose, defined, 4Absor
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INDEX 577Area under the tissue conc
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INDEX 579animal studies, 297cellula
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INDEX 581speciation of, 327-328Corp
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INDEX 583organ-specific activities,
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INDEX 585Follicle-stimulating hormo
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INDEX 587fatty liver, 120-122hepato
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INDEX 589Isoniazid metabolism, path
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INDEX 591Mechanistic toxicology, as
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INDEX 593Nephropathy:defined 130nep
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INDEX 595neurobehavioral sequelae,
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INDEX 597Probability density functi
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INDEX 599Rodenticides, 360.-361sodi
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INDEX 601Safe Human Dose (SHD) appr
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INDEX 603drug metabolism factors, 7
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