PRINCIPLES OF TOXICOLOGY

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154 NEUROTOXICITY: TOXIC RESPONSES <strong>OF</strong> THE NERVOUS SYSTEM 7.7 SUMMARY Evaluating neurotoxicity can be problematic for several reasons: • The proper functioning of the nervous system depends upon many complicated steps occurring in a precisely controlled fashion, and thus an agent that is disruptive of any of these steps may be potentially neurotoxic. • The operation of the nervous system is intimately involved with that of other systems, such as the respiratory, gastrointestinal, and endocrine systems, so that impairment of respiration or hormone function may occur in conjunction with, or as a result of, neurotoxic symptoms. TABLE 7.1 Some Common Neurotoxic Chemicals Chemical Metals Symptom(s) Site(s) of Action Arsenic Seizures, tremors Peripheral motor neurons Barium Muscle spasms Ion channels Lead Insomnia, tremors Myelin, synapse, axon Manganese Insomnia, confusion Synapse Mercury (organic) Ataxia, tremors, confusion Peripheral motor neurons, axon Thallium Seizures, psychosis Myelin, axon Tin (organic) Organic solvents Headache, psychosis Myelin Acetone CNS depression Neuronal membrane Benzene Giddiness, ataxia Neuronal membrane Carbon tetrachloride CNS depression, giddiness Neuronal membrane Carbon disulfide Dizziness, psychosis Peripheral sensory and motor neurons, synapse n-Hexane Numbness, giddiness Peripheral sensory and motor neurons, axon Methanol Blindness, mild inebriation Neuronal membrane, axon Tetrachloroethylene Dizziness, ataxia Neuronal membrane Toluene Dizziness, euphoria Neuronal membrane Trichloroethylene Organic pesticides Giddiness, tremors Neuronal membrane, axon Chlordane Blurred vision, ataxia Synapse Cyanide Confusion, labored breathing Cytochrome oxidase 2,4-D Muscle spasms, convulsions Neuronal membrane DDT Dizziness, convulsions Ion channels, synapse Endosulfan CNS depression, convulsions Synapse Lindane Headache, convulsions Synapse Malathion Blurred vision, headache Synapse, axon Parathion Ataxia, convulsions Synapse, axon Rotenone Other Tremors, convulsions Electron transport chain Carbon monoxide Headache, dizziness Hemoglobin Ethanol CNS depression, giddiness Ion channels, neuronal membrane Hydrogen sulfide Convulsions, coma Cytochrome oxidase Nicotine Excitability, nausea Synapse Petroleum distillates CNS depression, dizziness Neuronal membrane
• Although much of the damage which may occur in the nervous system is irreversible, some protective adaptations and redundancy of function exist, which sometimes makes predicting the effects of neurotoxicant exposure less than straightforward. The chemicals cited in the sections above serve only as examples and are by no means a comprehensive list of neurotoxic hazards in the workplace. In addition, their symptoms of exposure are often varied and may be attributed to several mechanisms of action, which makes categorizing them by effect somewhat difficult. Recommended exposure limits for chemicals commonly encountered in an occupational setting are published by various agencies in the United States, such as the Occupational Safety 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 groups should be consulted for specific recommended exposure levels of neurotoxic chemicals. Table 7.1 presents a few of the more common industrial neurotoxicants, along with some general symptoms of exposure and their primary sites of action. It should be clear to the reader by now that, as the result of multiple and overlapping effects of many 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 expected as new information is obtained. Nonetheless, considerable progress has been made in recent years toward developing reliable methods of neurotoxicity evaluation and minimizing exposure to potential neurotoxicants. REFERENCES AND SUGGESTED READING REFERENCES AND SUGGESTED READING 155 Annau, 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’s Toxicology: 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, New York, 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 Preventing Work-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 Occupational Health, 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 Science of 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 and Controlling 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, New York, 1994.
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PRINCIPLES OF TOXICOLOGY
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This book is printed on acid-free p
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vi CONTRI BUTORS PAUL J. MIDDENDORF
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viii CONTENTS 4 Hematotoxicity: Che
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x CONTENTS 12 Mutagenesis and Genet
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xii CONTENTS III APPLICATIONS 435 1
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PREFACE Purpose of This Book Princi
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ACKNOWLEDGMENTS A text of this unde
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PART I Conceptual Aspects Principle
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4 GENERAL PRINCIPLES OF TOXICOLOGY
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36 ABSORPTION, DISTRIBUTION, AND EL
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3 Biotransformation: A Balance betw
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BIOTRANSFORMATION: A BALANCE BETWEE
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BIOTRANSFORMATION: A BALANCE BETWEE
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Figure 3.5 Diagrammatic rendition o
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3.2 BIOTRANSFORMATION REACTIONS The
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TABLE 3.4 Important Cytochrome P450
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Figure 3.8 Cytochrome P450-catalyze
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oth of which are suitable for conju
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TABLE 3.6 Changes in Rat Hepatic Dr
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3.2 BIOTRANSFORMATION REACTIONS 75
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TABLE 3.7 Induction of Xenobiotic-M
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3.2 BIOTRANSFORMATION REACTIONS 79
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pyridoxal phosphate depletion by th
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Biotransformation: A Balance betwee
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een shown to be responsible for the
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4 Hematotoxicity: Chemically Induce
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Figure 4.1 Formation of blood. Matu
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TABLE 4.2 Leukemias and Lymphomas 4
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4.3 THE MYELOID SERIES 93 to contra
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function and response to stimuli, (
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Hypoxia can result from a variety o
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4.7 INORGANIC NITRATES/NITRITES AND
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Page 181 and 182: 170 PULMONOTOXICITY: TOXIC EFFECTS
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PART II Specific Areas of Concern P
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210 REPRODUCTIVE TOXICOLOGY continu
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212 REPRODUCTIVE TOXICOLOGY Underst
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214 REPRODUCTIVE TOXICOLOGY spermat
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216 REPRODUCTIVE TOXICOLOGY gonadot
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218 REPRODUCTIVE TOXICOLOGY TABLE 1
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Figure 11.3 Cycle of follicular dev
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222 REPRODUCTIVE TOXICOLOGY Figure
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224 REPRODUCTIVE TOXICOLOGY TABLE 1
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226 Figure 11.5 Developmental tree
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228 REPRODUCTIVE TOXICOLOGY is clea
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230 REPRODUCTIVE TOXICOLOGY genital
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232 REPRODUCTIVE TOXICOLOGY to occu
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234 REPRODUCTIVE TOXICOLOGY these r
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236 REPRODUCTIVE TOXICOLOGY Two imp
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238 REPRODUCTIVE TOXICOLOGY Sundara
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240 MUTAGENESIS AND GENETIC TOXICOL
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248 Figure 12.5 Example of DNA addu
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TABLE 12-3 NTP and Gene-Tox Evaluat
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266 CHEMICAL CARCINOGENESIS 13.1 TH
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268 CHEMICAL CARCINOGENESIS TABLE 1
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270 CHEMICAL CARCINOGENESIS researc
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272 CHEMICAL CARCINOGENESIS Figure
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276
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280 CHEMICAL CARCINOGENESIS 13.4 MO
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286 CHEMICAL CARCINOGENESIS make a
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288 Figure 13.8 A genetic model of
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290 CHEMICAL CARCINOGENESIS Increas
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292 CHEMICAL CARCINOGENESIS may be
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294 CHEMICAL CARCINOGENESIS • The
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296 CHEMICAL CARCINOGENESIS evaluat
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298 CHEMICAL CARCINOGENESIS In rats
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302 CHEMICAL CARCINOGENESIS with ex
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316 CHEMICAL CARCINOGENESIS similar
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324 CHEMICAL CARCINOGENESIS Knudson
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326 PROPERTIES AND EFFECTS OF METAL
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332 TABLE 14.2 Target Organ Toxicit
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346 PROPERTIES AND EFFECTS OF PESTI
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368 PROPERTIES AND EFFECTS OF ORGAN
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370 TABLE 16.1 (Continued) Water So
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410 PROPERTIES AND EFFECTS OF NATUR
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PART III Applications Principles of
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438 RISK ASSESSMENT 18.1 RISK ASSES
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440 RISK ASSESSMENT control populat
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442 RISK ASSESSMENT there are some
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444 RISK ASSESSMENT • It identifi
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446 RISK ASSESSMENT chemical poses
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448 RISK ASSESSMENT • Estimating
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450 RISK ASSESSMENT Figure 18.3 Est
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452 RISK ASSESSMENT • As discusse
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454 RISK ASSESSMENT divided by a de
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456 RISK ASSESSMENT Because low-dos
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458 RISK ASSESSMENT TABLE 18.1 Expe
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460 RISK ASSESSMENT leading to impo
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462 RISK ASSESSMENT characterizatio
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464 RISK ASSESSMENT Figure 18.7 Sim
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466 RISK ASSESSMENT The RPF values
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468 RISK ASSESSMENT producing the e
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470 RISK ASSESSMENT TABLE 18.4b Can
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472 RISK ASSESSMENT TABLE 18.7 Acti
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474 RISK ASSESSMENT A second reason
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476 RISK ASSESSMENT Barnard, R. C.,
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19 Example of Risk Assessment Appli
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19.3 LEAD EXPOSURE AND WOMEN OF CHI
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19.4 PETROLEUM HYDROCARBONS: ASSESS
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19.4 PETROLEUM HYDROCARBONS: ASSESS
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19.5 RISK ASSESSMENT FOR ARSENIC 48
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19.5 RISK ASSESSMENT FOR ARSENIC 48
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19.6 REEVALUATION OF THE CARCINOGEN
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REFERENCES AND SUGGESTED READING RE
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20 Occupational and Environmental H
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20.1 DEFINITION AND SCOPE OF THE PR
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20.4 HUMAN RESOURCES IMPORTANT TO O
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treatment, or medical removal from
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Academic practices welcome complica
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Occupational and environmental medi
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512 EPIDEMIOLOGIC ISSUES IN OCCUPAT
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22 Controlling Occupational and Env
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22.2 EXPOSURE LIMITS 525 The TLVs
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modified “reference doses” to r
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observation process, followed by re
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• Hazard-specific training to ens
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22.3 PROGRAM MANAGEMENT 533 Conside
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Figure 22.1 22.3 PROGRAM MANAGEMENT
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fundamental viability of the work p
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Figure 22.2. 22.3 PROGRAM MANAGEMEN
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• Physical assessment and fit tes
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The study was designed to minimize
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TABLE 22.3 Margins of Safety at For
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top, and numerous slots with smalle
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TABLE 22.5 Comparison of Time-Weigh
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• Housing or building code violat
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• Environmental exposure limits,
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GLOSSARY Glossary absorption The mo
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GLOSSARY 557 antipyretic An agent t
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GLOSSARY 559 chloracne An acne-like
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GLOSSARY 561 eczema A superficial i
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GLOSSARY 563 hemolytic anemia Anemi
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GLOSSARY 565 lipoprotein Any of a g
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GLOSSARY 567 necrosis Death of one
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pernicious anemia The progressive,
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GLOSSARY 571 cells have both endoth
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GLOSSARY 573 tolerance The ability
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576 INDEX Allergic reaction (contin
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578 INDEX Biotransformation (contin
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580 INDEX Children’s health statu
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582 INDEX Diet and nutrition (conti
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584 INDEX Estrogens: endocrine disr
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586 INDEX Hair, toxic agent excreti
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588 INDEX hnmunoglobulins: autoimmu
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590 INDEX Loop of Henle, structure
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592 INDEX Mixed exposure patterns,
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594 INDEX Nutritional deficiencies,
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596 INDEX Pesticides (continued) Pe
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598 INDEX Relative potency factor (
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600 INDEX Solvents (continued) phys
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602 INDEX Tumorigenesis (continued)
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