PRINCIPLES OF TOXICOLOGY

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Nephropathy: defined 130 nephrotoxic agents, 141 Nephrotoxicity: agents for, 137-l 39 cadmium, 13 8 lead 139 mercury, 138.-139 bladder structure and function, 134 chemical effects, 137-142 dioxane, 141 evaluation of, 13 5-l 37 glomerular filtration rate (GFR), 1355136 renal plasma flow, 136--l 37 halogenated hydrocarbons, 140 kidney structure and function, 1299134 blood flow, 129-l 30 blood pressure regulation, 134 glomerulus and glomerular filtration, 13 1 loop of Henle, 133 nephron structure, 130-l 3 1 nephron tubules and tubular reabsorption, 131. -133 renal erythropoietic factor, 134 tubular secretion, 133 urine formation, 1333134 vitamin D metabolism, 135 methyl isobutyl ketone, 140 natural venoms and toxins, 413414 nephropathic agents, 141 phenol, 141 solvents, 376-377 therapeutic agents as cause of, 141-142 toxic metals, 139-140 uropathic agents, 141 Nervous system, toxic responses of, 145-146 wNeurotoxin, reptile and amphibian venom toxicology, 424-125 Neuronal transmission: action potential, 146-147 mechanisms of, 146-149 Neurons, toxicant impact on, 149915 1 Neuropathy target esterase (NTE), organophosphate- induced delayed neuropathy (OPIDN), 3499350 Neurotoxicity: anoxia, 150-l 5 1 environmental toxicant exposure, 152 industrial chemical interactions, 15 l-l 52 lead poisoning and 235-236 membrane disruption agents, 149 metals exposure, arsenic, 336 natural venoms and toxins, 411413 nervous system injury evaluation, 152.-153 neuronal transmission mechanisms, 146-149 action potentials, 1466147 nemotransmitter activity, 1477149 organophosphateicarbamate pesticides, delayed effects, 349-350 INDEX 593 peripheral sensorimotor nerves, 149-150 permanent brain lesions, 150 reptile and amphibian venom toxicology, 424-425 research background 145-146 synaptic agents, 15 1 table of chemicals, 1533154 Neurotoxic shellfish poisoning (NSP), toxicology, 417 Neurotransmitters: inhibitors and receptor antagonists, 151 toxic response mechanisms, 147-149 Neutrophils, formation of, 93-94 Nickel: carcinogenicity of, 333-334 dermal exposure to, 330 toxicology of, 342 Nicotine, alkaloidal toxins in, 421 Nicotinic receptors: natural venoms and toxin neurotoxicity, 41 l-41 3 reptile and amphibian venom toxicology, 424425 Nitrates/nitrites, hematotoxicity and 999100 Nitriles, toxicology, 404405 Nitrobenzene, toxicity, 4033404 Niho compounds: carcinogenicity, 275 hemolytic anemia and, 100-101 toxicology of, 4022404 Nitrogen compounds, toxicology, 402 Nitrogen-substituted solvent, toxicology, 398402 aromatic amino acid compounds, 400402 Nitromethane, toxicity, 4033404 Nitrosamines, toxicology, 398402 Nitrous acid, genetic toxicity and 247, 249 Nitrous oxide: health care facilities case study of, 545-546 spontaneous abortion and 227 Nonenzymatic proteins, metals metabolism and storage, 330 Nonmammalian mutagenicity tests, 251-253 bacterial test systems, 252 Drosophila test systems, 253 plant assays, 253 Nonmicrosomal oxidations: biotransformation, 66, 70 enzyme activity, 76-77 Nonthreshold modeling, risk assessment studies, 455459 No-observable-adverse-effect levels (NOAELs): cumulative dose-response curve, 16-17 occupational hazards control, herbicide case study, 542 risk assessment studies, 450454 arsenic risk assessment, 488490 No threshold hypothesis, antimony carcinogenicity risks, 491 Nuclei, hepatocellular degeneration and death, 116-117 Nucleolar organizing region, chromosome structure and function, 244
594 INDEX Nutritional deficiencies, developmental toxicology and, 230 Observational studies, characteristics of, 5 14 Occupational carcinogens: ACGIH table of, 302 environmental factors, 304-J 19 NIOSH table of, 3022304 research background 301l304 Occupational exposure limits (OELs): pentachlorphenol exposure, 31 solvent exposure, 368,371 various chemicals, 8-9 Occupational hazards: case studies: fiberglass layup operation, 5466547 health care facility study, 544-546 herbicide application case, 54 l-544 lead-based paint risk assessment, 549-552 meat-processing industry carbon dioxide exposure, 547-549 control of: administrative issues, 540 hazard assessment, 53 l-536 historical background, 523-524 management commitment to, 530-53 1 program management issues, 530-541 protective equipment and respirators, 540-541 source isolation, 538 substitution and process modification, 5377538 ventilation and exhaust systems, 538-540 worker isolation, 538 exposure limits, 524-529 air-contaminants, 524-528 biological exposure indices, 528-529 integrated exposures, 529 Occupational health studies: definition and scope, 4999501 epidemiologic studies: advantages and disadvantages, 5133514 bias in, 519-520 causation issues, 512 -513 disease and human health effects, 5 15-5 16 exposure issues, 5 14-5 15 frequency measurements, disease or exposure studies, 516-517 historical background, 51 l-5 12 population issues, 5 16 risk assessment measurements, 5 17-5 18 ethical considerations, 507-508 goals of occupational medicine, 502 health provider activities, 503-507 attribution, evaluation of, 5055506 cadmium exposure special requirements, 505 clinical examinations, 503-504 diagnosis and treatment, 503 health surveillance procedures, 5044505 service delivery setting, 5066507 training and education, 506 human resources factor, 503 illness characteristics, 502 incidence rates by industry division and category, 50 1 percent distribution of illnesses, 501 NIOSH list of work-related diseases and injuries, 500 toxic agent distribution, 35-37 Occupational health surveillance, defined, 5044505 Occupational toxicology: diagnosis and treatment, 503 as research discipline, 6 toxicity data in studies of, 12 Ochratoxins, sources of, 419 Ocular toxicology, 165-167 Odds ratio, epidemiologic case control studies, 5 18 Oleander, digitalis compounds in, 419 Olefins (alkenes), toxicity, 378 Oncogenes: carcinogenesis and, 280-281 human tumor activation, 283 occupationally-acquired mutagens and, 257-258 signal transduction pathways, 28 l-283 Oncogenesis. See Carcinogenesis Oocyte toxicity, toxic agents, 219 Open kinetic models, toxic agent distribution, 46647 Oral ingestion. See also Gastrointestinal tract lead toxicology, 340-341 metals, 329 Organic acids and bases, toxic agent absorption, 42 Organic dust toxic syndrome, immunotoxic agents, 203 Organic solvents. See Solvents Organism-related factors, dose-response data, 22-26 age characteristics, 23-24 chemical interaction effects, 24-25 exposure routes, 22-23 gender characteristics, 23 genetics and, 25526 health status, 26 Organochlorine presticides: acute and chronic health effects, 353 biological monitoring, 353 intoxication treatment, 353 mechanisms of action, 352 organophosphate/carbamate use, 352 pharmacokinetics, 352 physical/chemical properties, 352 Organophosphate-induced delayed neuropathy (OPIDN), signs and symptoms, 3499350 Organophosphate pesticides, 346-352 absorption and metabolism, 3477348 acute effects, 348-349 biological monitoring, 350-351 chronic effects, 349 delayed neurotoxicity, 3499350 historical background, 346-347 intoxication treatment, 35 1 mechanism of action, 347
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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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Exposure to aromatic amines can be
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4.10 BONE MARROW SUPPRESSION AND LE
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4.12 TOXICITIES THAT INDIRECTLY INV
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4.15 ANTIDOTES FOR HYDROGEN SULFIDE
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REFERENCES AND SUGGESTED READING 10
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112 HEPATOTOXICITY: TOXIC EFFECTS O
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130 NEPHROTOXICITY: TOXIC RESPONSES
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7 Neurotoxicity: Toxic Responses of
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ions moving out of the cell brings
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an effect seen with some neurotoxic
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7.4 INTERACTIONS OF INDUSTRIAL CHEM
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• A study of the patient’s hist
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• Although much of the damage whi
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158 DERMAL AND OCULAR TOXICOLOGY Fi
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160 DERMAL AND OCULAR TOXICOLOGY P4
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162 DERMAL AND OCULAR TOXICOLOGY ca
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164 DERMAL AND OCULAR TOXICOLOGY ke
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166 DERMAL AND OCULAR TOXICOLOGY Fi
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168 DERMAL AND OCULAR TOXICOLOGY
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170 PULMONOTOXICITY: TOXIC EFFECTS
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10 Immunotoxicity: Toxic Effects on
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10.2 BIOLOGY OF THE IMMUNE RESPONSE
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10.2 BIOLOGY OF THE IMMUNE RESPONSE
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certain situations immunosuppressio
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10.5 TESTS FOR DETECTING IMMUNOTOXI
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10.6 SPECIFIC CHEMICALS THAT ADVERS
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10.6 SPECIFIC CHEMICALS THAT ADVERS
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animal origin have also been shown
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The mainstay of treatment of multip
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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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Page 559 and 560: GLOSSARY Glossary absorption The mo
Page 561 and 562: GLOSSARY 557 antipyretic An agent t
Page 563 and 564: GLOSSARY 559 chloracne An acne-like
Page 565 and 566: GLOSSARY 561 eczema A superficial i
Page 567 and 568: GLOSSARY 563 hemolytic anemia Anemi
Page 569 and 570: GLOSSARY 565 lipoprotein Any of a g
Page 571 and 572: GLOSSARY 567 necrosis Death of one
Page 573 and 574: pernicious anemia The progressive,
Page 575 and 576: GLOSSARY 571 cells have both endoth
Page 577 and 578: GLOSSARY 573 tolerance The ability
Page 579 and 580: 576 INDEX Allergic reaction (contin
Page 581 and 582: 578 INDEX Biotransformation (contin
Page 583 and 584: 580 INDEX Children’s health statu
Page 585 and 586: 582 INDEX Diet and nutrition (conti
Page 587 and 588: 584 INDEX Estrogens: endocrine disr
Page 589 and 590: 586 INDEX Hair, toxic agent excreti
Page 591 and 592: 588 INDEX hnmunoglobulins: autoimmu
Page 593 and 594: 590 INDEX Loop of Henle, structure
Page 595: 592 INDEX Mixed exposure patterns,
Page 599 and 600: 596 INDEX Pesticides (continued) Pe
Page 601 and 602: 598 INDEX Relative potency factor (
Page 603 and 604: 600 INDEX Solvents (continued) phys
Page 605 and 606: 602 INDEX Tumorigenesis (continued)
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