PRINCIPLES OF TOXICOLOGY

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animal studies, 297 cellular and biochemical issues, 298-299 chronic animal bioassay protocol, 289-290 classification of chemicals, 278 dietary and caloric restrictions, 296-297 dose levels, 292-294 dose numbers tested, 295 electrophilic theory, 272 epidemiologic evidence, 268-269 epigenetic mechanisms, 278-279 false-positive/false-negative test results, 290-29 1 genotoxic and epigenetic carcinogens, 273-278 histopathologic issues, 296 initiation and promotion, 2699272 mutagenicity, 273 overview, 265 physiological issues, 298 short-term cancer bioassays, 291-292 somatic mutation theory, 269 species extrapolation reliability, 299-301 test protocols, 292-299 defined, 268 dietary factors, 3 1553 18 genetic risk factors, 307, 3 13 human cancer trends, 3 I9932 1 iatrogenic cancers, 3 18-3 19 molecular aspects, 280-289 cell cycle and apoptosis, 285-289 oncogenes, 280-28 1 signal transduction pathways, 281-283 tumor suppressor genes, 283-285 occupational carcinogens, 301-304 risk assessment, 304-3 19 occupationally-acquired mutagens and, 257-258 smoking as risk factor, 3 1333 15 Carcinogens: cancer risk assessment studies, regulatory issues, 456459 cocarcinogens, defined, 268 defined 268 diet and nutrition and 3 15-3 18 direct-acting or primary carcinogens, defined, 268 herbicides, 356 IARC table of, 308-3 12 metals classified as, 333-334 chromium compounds, 339-340 nickel toxicology, 342 naturally ocurring carcinogens, 3 15-3 17 natural venoms and toxins as, 4 15 procarcinogens. defined, 268 solvents, 3755376 Carcinomas, classification, 2677268 Cardiac glycosides: in amphibian venoms, 425 in flowering plants, 419-421 Cardiotoxins, reptile and amphibian venoms, 4244425 INDEX 579 Cardiovascular toxicity: cardiac glycosides, 419-421 natural venoms and toxins, 4 13 reptile and amphibian venoms, 424425 Case control studies: characteristics of, 5 14 odds ratio in, 5 18 Castor beans, peptide and protein toxins in, 421-422 Catechol: contact dermatitis, poison ivy and 423 toxicology, 385 Catfish venom, toxicology, 425 Causation, epidemiologic studies, 5 12-5 13 CD antigens, immunotoxicity, 190-191 clinical assessment, 196 CD3 cells, T cell markers, 95 CD4 cells, T cell formation, 95 CD8 cells, T cell suppression, 95 CDK inhibitory proteins, cell cycle and 286 Cell cycle, carcinogenesis and, 2855289 Cell-mediated immunity, immunotoxicity, 190, 193 Cell-type specific toxicity, male reproductive toxicology, 213-215 Leydig cells, 2 15 Sertoli cells, 214-215 sperm cell development, 2133214 Cellular immunity, T-cell function and, 190, 194 Central nervous system: metals toxicity, 333 methylene chloride toxicology, 394-397 solvent exposure and depression of, 3744375 Centromere, chromosome structure and function, 244 Charybdotoxin, in scorpion venom, 426 Checkpoints, in cell cycle, 286-287 “Cheese washer’s lung,” 184 Chelation therapy, metals metabolism and storage, 330 Chemical carcinogenesis. See Carcinogenesis Chemical composition: dose-response data, 26 risk evaluation of mixed chemicals, 464468 Chemical interactions: dose-response data, 24426 mathematical representations of, 24 risk evaluation and problems with, 468 Chemical leukemogenesis, mechanisms of, 104 Chemical mutagenesis, historical background on, 239-240 Chemical-specific factors, dose-response data, 26-27 Chemotherapeutic agents: developmental toxicology of, 230 female reproductive toxicology, 223 iatrogenic cancer, 3 18-3 19 male reproductive toxicology: Sertoli cell specificity, 215 spermatogenesis susceptibility, 21 l-213 oocyte toxicity, 2 19 Children’s health status: epidemiologic studies and 5 16
580 INDEX Children’s health status (continued) lead-based paint case study, 549-552 Chironexfleckeri, venom toxicology, 428429 Chloestyramine, organochlorine insectide exposure treatment, 353 Chloracne, dermal toxicity, 164 Chlorate salts, hematotoxicity and, 999100 Chlordecone, male reproductive toxicology and 217 Chloride ions, action potential mechanisms, 146-147 Chlorine: pulmonary edema and, 183-l 84 pulmonotoxicity and dose-response relationships, 181 Chloroform: inhalation, toxicity studies, 10 nephrotoxicity, 140 toxicology, 395-397 Chloromethane, toxicology, 393-397 Chlorophenoxy herbicides, structure and properties, 355-357 Chloroprene, spontaneous abortion and 227 Chlorothalonil, structure and toxicity, 359 Chlorpromazine, sperm cell development, cell-type specific toxicity, 214 Cholangiocarcinomas, hepatoxicity and, 123 Cholangiofibromas, hepatoxicity and, 123 Cholera toxin, toxicology, 416 Cholestasis, hepatotoxicity and, 122 Cholinesterase levels, biological monitoring, organophosphate/carbamate pesticides, 350-351 Chromatid exchange hypothesis, chromosomal aberrations, 25 1 Chromium: carcinogenicity of, 333-334 dermal exposure to, 330 toxicology of, 3399340 Chromosomes: aberrations in, 250-25 1 germ cell assays of, 254 mutagenicity testing of, Drosophila assays, 253 structure and function, genetic toxicology and, 244 Chronic active hepatitis, cirrhosis and, 123 Chronic animal bioassay, chemical carcinogens, 2899290 Chronic beryllium disease, mechanisms of, 337-338 Chronic exposure: defined, 4 metals toxicity, 331, 333 organochlorine insectides, 353 organophosphate/carbamate pesticides, 349 Chronic toxicity, defined, 4 Ciguatoxin, in fish venom, 426 Cirrhosis, hepatotoxicity and 123 Clastogenic chemicals, defined, 273 Clear cell adenocarcinomas, diethylstilbestrol (DES) toxicity and 2299230 Clinical signs: neurotoxicity, 152-l 53 occupational health practice and examination of, 5033504 Clinical toxicology: as research discipline, 6 toxicity data in studies of, 12 Clomiphene citrate, female reproductive toxicology, 2222223 Clotting factors: anticoagulant action and, 108 hepatoxicity and 125 Cluster determinants, T cell formation, 95 Cnidarian venoms, toxicology 428429 Cobalt, dermal exposure to, 330 Cocarcinogens, defined, 268 Coelenterate venoms, toxicology, 428429 Coenzyme A, biotransformation, amino acid conjugation and methylation, 74 Cognitive function, lead poisoning research and, 235-236 Cohort studies, epidemiologic studies as, 517 Colony forming unit-erythrocyte (CFU-E), red blood cell development, 91-92 Commercial secrets, ethics concerning, 508 Comparative risk analysis, procedures for, 468472 Competitive inhibition, xenobiotic metabolism, 77-79 Complement, immunotoxicity and, 1922193 Component toxicity, risk evaluation using, 465468 Concentration data, risk assessment studies, exposure pathways and dosages, 446449 Confidentiality issues, for occupational health practices, 507 Confounding bias, in epidemiologic studies, 5 19 Congenital defects: developmental toxicology and, 224-232 embryonic and fetal toxic responses and, 228-23 1 suspected toxicants and teratogens, 23 l-232 Coniine, toxicology of, 421 Conjugation products, biotransformation, 83-85 Conjunctivitis, toxicity mechanisms, 193 Conservatism in risk assessment: occupational health hazards control, 534-536 regulatory issues, 439440 Contact dermatitis. See Dermatitis Control technologies: carbon dioxide exposure studies, 547-549 occupational health hazards, 536-541 administrative controls, 540 exhaust and ventilation systems, 538-540 protective equipment and respirators, 540-541 source isolation, 538 substitution and process modification, 537-538 worker isolation, 538 Conus venom, toxicology of, 427428 Convallaria, digitalis compounds in, 3 9 Cooking techniques, diet and carcinogenicity, 316-317 Copper compounds: in fungicides, 360
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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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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
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Page 585 and 586: 582 INDEX Diet and nutrition (conti
Page 587 and 588: 584 INDEX Estrogens: endocrine disr
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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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