PRINCIPLES OF TOXICOLOGY

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Mechanistic toxicology, as research discipline, 6 Medications, therapeutic vs. virtually safe doseages (VSD) table, 470 Mee’s lines, arsenic exposure markers, 336 Megamouse experiment, cancer risk assessment studies, 455459 Meiosis, genetic toxicology and 244-245 MEK peroxide, occupational hazard control case study of, 5466547 Melanomas, classification, 2677268 Mellitin, hymenoptera toxicology, 427 Membrane barrier transfer, toxic agent absorption and distribution, 3741 active transport, 4041 facilitated diffusion, 40 passive diffusion, 3740 Membrane disruption: solvent exposure, 374-375 toxicants and 149 Menstruation, female reproductive toxicology, 223 Mercury: central nervous system effects, 333 nephrotoxicity, 138-139 neurotoxicants and 150 speciation of: inhalation exposure, 328-329 oral ingestion, 329 toxicology studies, 341-342 Mesenchymal tissue, histogenesis, 267 Mesothelioma, asbestosis and, 182 Messenger RNA (mRNA), genetic toxicology and, transcription and translation mechanisms, 241-244 Metabolism: of metals, 330 organophosphatelcarbamate pesticides, 347-348 urinary excretion, 29 Metal fume fever, metals inhalation exposure and, 329 zinc toxicology, 343 Metallothionein, nephrotoxicity and, 137 Metals: classification, 3255327 common uses and toxic effects, 326 immunotoxicity, 202 nephrotoxicity, 139-140 pharmacokinetics, 328-33 1 absorption and distribution, 328 dermal exposure, 3299330 excretion, 330~-33 1 inhalation, 328-329 metabolism and storage, 330 oral ingestion, 329 sources of exposure, 334-336 anthropogenic sources, 334-335 biomarkers for, 3355336 natural sources, 334 speciation of, 327-328 toxicity, 33 l--334 INDEX 591 acute exposure, 33 1 carcinogenicity, 333-334 chronic exposure, 331,333 target organs, 332 toxicology of: arsenic, 336-337 beryllium, 337-338 cadmium, 338-339 chromium, 3399340 lead, 340-34 1 mercury, 341-342 nickel, 342 zinc, 3422343 Metaplasia, defined, 266 Metastasis, defined, 266 Methanol: eye toxicity, 167 toxicology, 377, 3822383 Methemoglobin: hematoxicity and formation of. 999100 hydrogen sulfide and cyanide poisoning, 107 hemolvtic anemia and 100.-101 I- MethylaGon reactions, biotransformation, 74 Methyl bromide: toxicity, 362 toxicology, 393-397 Methyl chloride exposure: carbon monoxide formation, 99 toxicology, 392-397 Methylcyclopentadienyl manganese tricarbonyl (MMT), health risks of, 335 Methyl ethyl ketone (MEK), toxicology, 389 Methyl isobutyl ketone (MIBK), nephrotoxicity, 140 Methylmercury poisoning, developmental toxicology and, 230-23 1 Methyl -n-butyl ketone, toxicology, 389 Methysergide, ergot as source of, 419 Michaelis-Menten kinetics, toxic agent distribution, 4749 Microlesions, genetic toxicity assessment and, 247, 249 Micronucleus test: chromosomal aberrations, 251 mutagenicity testing, 255 Microsomal enzymes, xenobiotic metabolism, 62 Microsomal oxidation, biotransformation, 65566 Microvesicular steatosis, hepatotoxicity and 120-121 Milk, toxic agent excretion, 53 Minamata disease: anthropogenic study of, 335 methylmercury poisoning, 230-23 1 Minerals, essential metals in, 326 Minimal risk dose (MRL), risk assessment studies, 448449 Mistletoe, peptide and protein toxins in, 422 Mitochondria, hepatocellular degeneration and death, 116 Mitosis, genetic toxicology and, 2444245
592 INDEX Mixed exposure patterns, epidemiologic studies of, 515 Mixed-function oxidases. See Cytochrome P450 enzymes; Monooxygenases Mixed-lymphocyte reaction (MLR) test, immunotoxicity assessment, 197 Molecular dosimerry, risk assessment studies, exposure pathways and dosages, 449 Molecular size, passive diffusion, toxic agents, 37-38 Mollusc venoms and toxins, toxicology, 427428 Monoamine oxidases, oxidation reactions, 70 Monoclonal antibodies, antivenin therapy and 43 1 Monocytes, formation of, 93-94 Monooxygenases: biotransformation, oxidation reactions, 65-66 flavoprotein metabolism, 66, 70 Morbidity/mortality studies: cancer inU.S., 319-321 increased risk activities table, 472 Mouse skin model, cancer initiation and promotion, 2699270 Mouse-specific locus assay, mutagenicity testing, 254 Mucosal lining, pulmonotoxicity, 170.-171 Multihit models, cancer risk assessment studies, 456459 Multiple-chemical sensitivity, immunotoxicity and, 2033205 Muscarinic symptoms, organophosphateicarbamate pesticide exposure, 348-349 Mushroom toxins, toxicology, 417419 Mustard gases: carcinogenicity, 273 genetic toxicity and 247, 249 Mutagenesis: carcinogenicity and, 273 classification of genetic change, 2455246 comparative mutagenicity of compounds, 259 genetic toxicology and 239 mammalian mutagenicity tests, 253-257 dominant lethal assays, 255 germ cell assays, 254 heritable translocation assay, 255 micronucleus testing, 255 primary DNA damage testing, 256 spermhead morphology assay, 255 transgenic mouse assays, 256 in vitro testing, 256-257 multidisciplinary testing of, 258-259 nonmammalian mutagenicity tests, 251-253 bacterial test systems, 252 Drosophila test systems, 253 plant assays, 253 occupational significance of mutagens, 257-261 future research issues, 260-261 gene pool and oncogenesis, 257 monitoring techniques, genetic biomarkers, 260 mutidisciplinary approach, 257.-259 Mutagens: naturally occurring mutagens, 240-241 occupational mutagens, 240-241 Mutation, defined 239 Myeloid series: hematopoiesis, 88.-90 red blood cells (RBCs): erythrocytes, 91-92 NADPH, cytochrome ~450 reductase, biotransformation, 66 Nails, toxic agent excretion, 53 Naphthalene, toxicology, 381-382 National Health and Nutrition Examination Surveys (NHANES), cancer risk and 316 Natural immunity, immunotoxicity and 1899190 Natural killer (NK) cells, immunotoxicity, 193 Natural sources, metals exposure from, 334 Natural toxins: animal venoms and toxins: arthropod toxins and venoms, 426427 coelentrate (cnidarian) venoms, 428429 fish venoms and toxins, 425426 molhtsc venoms and toxins, 427428 reptiles and amphibians, 423425 toxic marine invertebrates, 429430 carcinogenicity, 275 cardiovascular toxins, 413 cytotoxins, 414 as drug therapy, 43 1432 functional value of, 411 inflammatory and carcinogenic toxins, 415 liver and kidney toxins, 413414 molecular and functional diversity, 4 104 11 neurotoxic actions, 411413 plant toxins, 4 17423 contact dermatitis, 422423 flowering plants, 419422 mushrooms and fungi, 417419 poisons, toxins, and venoms, 409 second messenger toxins, 414415 therapy: counter-ingestion techniques, 430 immunotherapy, 43043 1 organism identification, 430 pharmacotherapy, 43 1 unicellular organisms, 415417 amebic dysentery, 4 16-4 17 bacterial toxins, 4 154 16 dinoflagellate toxins, 417 Necrosis, hepatocellular degeneration and death, 117-118 Nematocysts, venom toxicology, 428429 Neoplasia, defined, 266 Neoplasms: behavior of, 267 benign vs. malignant, 267-268 classification, 267-268 Nephrons: structure and function, 130-132 classification of, 2399240 tubules and tubular reabsorption, 13 1-133
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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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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: 590 INDEX Loop of Henle, structure
Page 597 and 598: 594 INDEX Nutritional deficiencies,
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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