PRINCIPLES OF TOXICOLOGY

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speciation of, 327-328 Corpus luteum, reproductive tract toxicity, 219-221 Creatinine clearance, herbicide exposure study, 543 Cresols, toxicology, 385 Crotoxin: antivenin therapy, 43043 1 reptile and amphibian venoms, 423-425 Cryptorchism, reproductive tract toxicity, 2 10-2 12 Cumulative-response graphs, I 1, 15-16 Cutaneous anergy, immunotoxicity assessment, 196 Cutaneous sensitization, dermal contact sensitivity, 163 Cyanide (CN) poisoning: antidotes, 107 red blood cells (RBCs) toxicity and, 105 Cyclic compounds, diet and carcinogenicity, 3 16-3 1 Cyclic peptide toxins, natural venoms and toxins toxicity, 414 Cyclin-activating kinases (CAKs), cell cycle and, 286 Cyclin-dependent kinases (CDKs), cell cycle and 286 Cyclins, cell cycle and, 286 Cyclobutane, toxicity, 378-379 Cyclopropane, toxicity, 378-379 Cystitis, bladder irritation and, 134 Cytochrome p450 enzymes: animal species/strain variations, 79-8 1 benzene exposure, 103-104 biotransformation: oxidation cycle, 66,70 oxidation reactions, 65-66 catalyzed oxidations, 69 important strains, 67-68 reactive intermediates, 83-85 xenobiotic metabolism, 62 human variations in, 80-8 1 inhibition mechanisms, 77-79 Cytokines, immunotoxicity, 191-192 Cytolysins, natural venoms and toxins, 414 Cytosis, defined, 90 Cytosolic GSB transferases, nonmicrosomal oxidations, 76 Cytotoxic lymphocyte (CTL) assay, immunotoxicity assessment, 197 Cytotoxic proteins, bacterial toxins, 416 Cytotoxic response, classification of, 194 Cytotoxic T cells, immunotoxicity, 193 Cytoxicity, natural venoms and toxins, 414 Dapsone N-hydroxylamine, red blood cell changes and, 100-101 Dehydrogenases, nonmicrosomal oxidation, 66,70 Deimercaptosuccinic acid (DMSA), metals metabolism and storage, 330 Delayed toxicity, defined, 5 Delivered dose, defined, 4 De manifestis levels, risk characterization with, 461-462 INDEX 581 De minimus risk levels, risk characterization with, 461462 Dermal contact sensitivity: herbicides, 356 immunotoxic agents, 200 metals exposure, 329-330 arsenic, 336 nickel toxicology, 342 solvent toxicology, benzene toxicity, 379-380 Dermal toxicology: contact dermatitis, 160-l 65 acneiform dermatoses, 163-164 allergic reactions, 161-163 irritants, 160-161 photosensitivity, 164-l 65 pigment disturbances, 164 toxic epidermal necrolysis (TEN), 163 urticaria, 163 skin cancer, 165 skin function, 158-160 skin histology, 157-l 58 Dermatitis: dermal toxicology, 160-165 acneiform dermatoses, 163-164 allergic reactions, 161-162 irritants, 160-16 1 photosensitivity, 164-l 65 pigment disturbances, 164 toxic epidermal necrolysis (TEN), 163 urticaria, 163 marine invertebrate venoms, 430 metals exposure, 330 plant toxins and, 422-423 ulcers, 162-163 Descriptive toxicology: dose-response data in, 27-28 as research discipline, 5-6 Deterministic risk assessment, vs. probabilistic risk assessment, 462464 Detoxification: bioactivation and, 83-85 role of liver in, 113 Developmental toxicology, 224-232 diethylstilbestrol (DES) cancer endpoints, 229-230 drug abuse and maternal nutrition, 230 embryonic/fetal toxic response, 228-23 1 fetal hydantoin syndrome, 229 human teratogens, 230 methylmercury poisoning, 230-23 1 spontaneous abortion and embryonic loss, 225, 227.-228 suspected toxicants and teratogens, 23 l-232 tissue organization disruption, 228-229 Dibromochloropropane (DBCP): mutagenicity of, 26 1 sperm cell development, cell-type specific toxicity, 213-214 Diet and nutrition: cancer risk an4 3 15-3 18
582 INDEX Diet and nutrition (continued) carcinogenicity studies, 2966297 developmental toxicology, 230 metals ingestion, 329 Di(2-ethylhexyl)phthalate (DEHP), toxicology, 390 Diethylstilbestrol (DES): endocrine disruption research, 233-235 teratogenic effects, 2299230 Diffusion mean equivalent diameter (DMED), lung absorption of particulates, 44-15 Digitoxin, in flowering plants, 419 Digoxin, in flowering plants, 419 Dihydroxy aromatics, toxicology, 384-385 Dilution ventilation systems, control technologies for hazardous materials, 540 Dimethylaniline, toxicology, 401402 Dimethylformamide, spontaneous abortion and 227 Dimethyl sulfoxide (DMSO), toxicology, 405407 Dinitrobenzene (DNB), male reproductive toxicology, Sertoli cell specificity, 2 15 Dinitrophenol (DNP), toxicity, 404 Dinoflagellate toxins, toxicology, 417 Dioxane, nephrotoxicity, 141 Dioxins: female reproductive toxicology, 223 male reproductive toxicology and 217 toxic equivalency factors (TEF) relative to PCB congeners, 466 Diquat, structure and characteristics, 3566358 Direct acting toxicants, male reproductive toxicology, 212-213 Direct carcinogens, defined, 268 Disease clusters, epidemiologic studies, 520 Disease mechanisms, epidemiologic studies and 5155516 Disease rates, epidemiologic studies and 5 16-5 17 Disposition mechanisms, toxic agents, 45553 biotransformation, 5 1 excretion, 5 1-53 kinetic models, 4555 1 Disseminated intravascular coagulation (DIC), autoimmune hemolytic anemia, 10 1 Distal tubule, structure and function, 132 Distribution mechanisms: in human body, 3 5-3 6 metals pharmacokinetics, 328 solvent exposure, 372-373 Dithiocarbamates, structure and toxicity, 359 DNA damage: antimony carcinogenicity risks, 493 apoptosis, 2866289 bacterial testing and assessment of, 252 biomarkers for, 260 epigenetic carcinogens, 273,278-279 genetic alteration mechanisms, 2455251 genetic toxicology and transcription and translation mechanisms, 241-244 hepatocellular degeneration and death, 116-l 17 male reproductive toxicology, spermatogenesis susceptibility, 211-212 methylation patterns: animal studies, 298-299 epigenetic carcinogens, 279 mutagenesis research and 240 p53 gene, 284 primary damage testing, 256 somatic mutation theory of cancer, 269 Dominant lethal assays, mutagenicity testing, 255 Dose: carcinogenicity testing protocols: maximally tolerated dose (MTD), 2922294 number of tested doses, 295 defined 4,9 risk assessment studies: animal vs. human dosages, 444 exposure pathways and dosages, 446449 role of, in toxocology research, 778 Dose addition technique, risk evaluation using, 4655468 Dose metrics, risk assessment studies, 4599460 Dose-response relationship: applications of data from, 18-20 chemical composition and, 26 chemical leukemogenesis, 104 chemical-specific factors in, 26-27 cumulative dose-response curve, 16-18 descriptive toxicology testing, 27-28 endocrine disruption research and, 234-235 exposure conditions and 26-27 hydrogen sulfide poisoning, 106 lead poisoning research and, 235-236 limits on interpretation of, 20-22 organism-related factors in, 22-26 age characteristics, 23-24 chemical interaction effects, 24-25 exposure routes, 22-23 gender characteristics, 23 genetics and 25-26 health status, 26 risk assessment procedures, 438,449460 cancer risk assessment studies, 4555459 dose metrics, 459460 nonthreshold models, 4555459 threshold models, 4499454 role of, in toxocology research, 7-18 toxicity test components and 9-l 1 Drinking water, metals ingestion, 329 nickel toxicology, 342 zinc toxicology, 342-343 Drosophila species, mutagenicity testing with, 253 Drug clearance tests, hepatoxicity and, 126 Drug development, natural toxins as sources of, 43 1432 Drug lupus, immunotoxicity, 195 Drug metabolism: biotransformation factors, 74-77 initiation and promotion, 270-272 iatrogenic cancer, 3 18-3 19
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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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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: 580 INDEX Children’s health statu
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 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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