PRINCIPLES OF TOXICOLOGY

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Probability density functions (PDF), probabilistic risk assessment, 463464 Probit models, cancer risk assessment studies, 456 Procarcinogens: defined, 268 electrophilic theory, 272 examples of, 276 Process modification, control technologies for hazardous materials, 537-538 Professional independence, in occupational health, 508 Proflavin, genetic alteration and 247 Progression, cancer initiation and promotion, 270 Promotion, of carcinogenesis, 269-272 n-Propanol, toxicology, 383.-384 Proportional mortality ratio (PMR), epidemiologic studies, 5 18 Prostaglandin H synthase (PHS), bladder structure and function, 134 Protective equipment, control technologies for hazardous materials, 540-541 Protein toxins: in flowering plants, 421-422 in marine invertebrates, 429-430 in sea anemones, 428-429 Prothrombin time, hepatoxicity and, 125 Protooncogenes: defined, 280-281 encoded protein functions, 282 Protoporphyrin, lead poisoning and 108 Proximal tubule, structure and function, 132 Proximate carcinogens: electrophilic theory, 272 examples of, 276 Pruritis, hepatoxicity and 124 PutTerfish, venom toxicology in, 4255426 Pulmonary defense, smoking and interference with, 180 Pulmonary edema: industrial-related disease mechanisms, 1833184 pulmonotoxicity, gas exchange mechanisms, 173 Pulmonotoxicity: air-pollutant gases, 180 gas/vapor exposure, 1788179 industrial-related disease mechanisms, 18 l-1 85 airway irritation, 18 1 allergic responses, 184 asbestosis, 182 emphysema, 183 excess lung collagen, 182 -183 fibrosis and pneumoconiosis, 18 1 lung cancer, 185 occupational asthma, 185 occupational inhaled allergic disorders, 184 pulmonary edema, 1833184 silicosis, 182 lung anatomy and physiology, 169-l 8 1 clearance mechanisms, 176-178 deposition mechanisms, 176 INDEX 597 gas exchange mechanisms, 172-- 174 inhalation vs. ingestion, 174 particle size measurements, 1755176 particulates, 174-175 sinus cavities, 170-171 tracheobronchiolar region, 171-172 upper airway, 169-l 70 smoking, 180-l 8 1 Putative carcinogenic mechanisms, antimony carcinogenicity risks, 493494 Pyrethrins: chemical structure, 354 history of use, 346 Pyrethroids. See Synthetic pyrethroids Pyrethrum, chemical structure, 354 Pyridine compounds, toxicology, 405 Radical compounds, sperm cell development, cell- type specific toxicity, 214 Radioactive materials, lung cancer and, 185 Radiomimetic compounds, carcinogenicity, 273 Rate difference, epidemiologic studies, 5 17 Ratio ratio, epidemiologic studies, 5 17 Reactive intermediates: enzymatic generation, 84-85 toxicant classification, 83-85 Real-time analysis, occupational health hazards control, 536 Reasonable maximal exposure (RME) levels: arsenic risk assessment studies, 487488 deterministic risk assessment, 462 Receptor antagonists: natural venoms and toxin neurotoxicity, 413 neurotransmitter inhibitors, 15 1 Receptors, natural venoms and toxin neurotoxicity, 411413 Recognition of hazardous effects, occupational health hazards control and, 532-533 Red blood cells (RBCs): aromatic amine exposure and 100-I 0 1 autoimmune hemolytic anemia, 101 growth and development, 91-92 oxygen transport impairment, 95-97 hemoglobin structure, 95-96 hypoxia, 96-97 toxic agents, 1055106 cyanide poisoning, 105 hydrogen sulfide, 1055106 Reductive metabolism, biotransformation, 71-72 Reference dose (RtD): risk assessment studies, 4488449 arsenic risk assessment, 487490 petroleum hydrocarbons exposure and risk, 484486 Safe Human Dose (SHD) calculations, 29 Regulatory issues: organophosphateicarbamate pesticides, 351-352 risk assessment, conservatism issue, 439440
598 INDEX Relative potency factor (RPF), risk evaluation using, 465468 Renal clearance: schematic of, 130 toxic agent excretion, 5 1-52 Renal erythropoietic factor, nephrotoxicity and 134 Renal plasma flow, nephrotoxicity measurement, 136 -137 Reproductive toxicology: chromium compounds, 339.-340 developmental toxicology, 224-232 diethylstilbestrol (DES) cancer endpoints, 229.-230 drug abuse and maternal nutrition, 230 embryonic/fetal toxic response, 22X--231 fetal hydantoin syndrome, 229 human teratogens, 230 methylmercury poisoning, 230-23 1 spontaneous abortion and embryonic loss, 225, 227-228 tissue organization disruption, 228-229 diethylstilbestrol (DES) toxicity and 2299230 endocrine disruption, 232-235 female reproductive toxicology, 222-223 female reproductive system, 218-224 hormonal regulation, 221-223 oocyte toxicity, 219 somatic ovarian and reproductive tract toxicity, 219-221 lead poisoning, 2355236 toxicity mechanisms, 340~-341 male reproductive system, 2 1 O-2 18 cell-specific toxicity, 2133215 direct/indirect toxicity modes, 212-213 endocrine feedback and dysregulation, 217 hormonal regulation, hypothalamic-pituitary- gonadal axis, 2 15-2 17 Leydig cell toxicity, 215 Sertoli cell toxicity, 214-215 spermatogenesis susceptibility, 210-212 sperm cell development, 2 13-2 14 suspected toxicant list, 2 18 Reptile venoms, toxicology, 423425 Resorcinol, toxicology, 385 Respirators, control technologies for hazardous materials, 540-541 Response, defined, 9 Response addition, risk evaluation using, 466468 Restriction point, cell cycle, 285.-286 Retinoblastoma (Rb) gene, discovery of, 284-285 Retroviruses, oncogenes, 280-281 Reversible toxicity, defined 4 Right-to-know issues, occupational health hazards control and, 53 1 Risk: defined 5 epidemiologic studies, measurement of association or risk, 516-517 Risk assessment: applications of: antimony trioxide carcinogenicity, 490496 arsenic exposure, 486490 lead exposure in child-bearing women, 481483 petroleum hydrocarbons, exposure and risk assessment, 483486 tiered approach, 479480 applied toxicology research in, 6 basic paradigms of, 438439 carcinogenicity studies, 292-299 administration routes and vehicle issues, 295-296 animal models, 2977299 dietary and caloric restrictions, 296-297 histopathological examination, 296 maximally tolerated dose (MTD) levels, 292-294 number of doses tested 295 chemical mixture risk assessment, 464-468 comparative risk analysis, 468472 defined 5,437 dose-response assessment, 438,4499460 dose metrics, 459460 nonthreshold models, 455459 threshold models, 4499454 elements of, 438 examples of, 480481 exposure pathways and dosages, 439,445449 hazard identification, 438, 442445 animal studies, 443445 epidemiologic studies and case reports, 443 human health vs. ecological risk assessment, 441442 occupational carcinogens, 304-3 19 alcohol, 3 15 diet, 3 15-3 18 iatrogenic cancer, 3 18-3 19 lead-based paint case study, 549-552 NTP table of suspected carcinogens, 3055307 smoking, 3 13--3 15 probabilistic vs. deterministic techniques, 462-464 problem definition, 440441 regulatory context of, 439440 risk characterization techniques, 439,460462 risk communication procedures, 4722474 toxicology research, 6 Risk characterization: defined, 438439 procedures for, 460462 Risk communication: occupational health hazards control and 530-53 1 techniques and procedures, 472474 Risk models, chemical leukemogenesis, 104 RNA: genetic toxicology and transcription and translation mechanisms, 241-244 oncogenes, 280-281 point mutations and 249-250 toxin/venom diversity and, 4 104 11
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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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• Physical assessment and fit tes
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The study was designed to minimize
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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 and 596: 592 INDEX Mixed exposure patterns,
Page 597 and 598: 594 INDEX Nutritional deficiencies,
Page 599: 596 INDEX Pesticides (continued) Pe
Page 603 and 604: 600 INDEX Solvents (continued) phys
Page 605 and 606: 602 INDEX Tumorigenesis (continued)
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PRINCIPLES OF TOXICOLOGY

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