PRINCIPLES OF TOXICOLOGY

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Isoniazid metabolism, pathways and related toxicities, 80-81 Isopropanol, toxicology, 383-384 Isopropyl ether, toxicology, 391-392 Isotretinoin, developmental toxicology and, 22% 229 “ltai-itai” disease, metals ingestion and, 329 Ito cells, liver morphology, 1 I6 Jaundice, hepatoxicity and 124 Jellyfish: cnidarian venom toxicology, 428429 contact dermatitis, 423 Karyotypes, chromosome structure and function, 244 Keratinocytes allergic contact dermatitis, 16 I- 162 Ketones, toxicology, 386,3888389 Kidney: as biotransformation site, 62 metals toxicology: cadmium exposure, 338-339 lead 341 natural venoms and toxins toxicity, 413414 structure and function, 1299134 blood flow, 1299130 blood pressure regulation, 134 glomerulus and glomerular filtration, 13 1 loop of Henle, 133 nephron structure, 130-131 nephron tubules and tubular reabsorption, 131-133 renal erythropoietic factor, 134 tubular secretion, 133 urine formation, 133-134 vitamin D metabolism, 135 toxic agent excretion in, 5 l-52 xenobiotic metabolism, 62264 Kinetic models, toxic agent distribution, 45-51 classical models, 4649 physiologically-based kinetic (PBK) models, 49-5 1 Knowledge and expertise, ethics concerning, 508 Kupffer cells, liver morphology, 115-l 16 Labeling practices, occupational health hazards control and, 532-533 Lactate production, sperm cell development, cell-type specific toxicity, 2 14 Lactic acid dehydrogenase-X (LDH-X) marker, mutagenicity testing, 254 LacZ assay, mutagenicity assessment, 256 Latency measurements, cancer risk assessment studies, 455459 Latent toxicity, defined, 5 a-Latarotoxin, reptile and amphibian venom toxicology, 427 INDEX 589 Lead poisoning: anthropogenic sources, 335 central nervous system effects, 333 female reproductive toxicology, 221 male reproductive toxicology, 2 12-2 13 nephrotoxicity, 139 neurotoxicity, 235-236 occupational hazard control studies of, 549-552 red blood cell (RBC) toxicity and, 108 risk assessment, child-bearing women, 4811183 threshold level adjustments and, 235-236 toxicology of, 340.-341 Length-of-stain calorimetric cubes, air sampling with, 536 Lethal doses (LD,,): administration route and data accuracy, 23 application of data from, 18-20 comparison of, 708 measurement of, 18820 oral data for chloroform, 2 1 Leukemias: bone marrow suppression, 102-104 chemical leukemogenesis, 104 classification of, 90-91 Leukopenia, defined, 90 Leydig cells, cell-type specific toxicology, 2 15,218 Libido, male reproductive toxicology and, 2 16-217 Life expectancy averages, risks, activities and diseases, 47 1 Lifetime average daily dose (LADD) values; cancer risk assessment studies, 459 risk assessment studies, arsenic risk assessment, 489-490 Lindane isomers, organochlorine insectides, mechanisms of, 352 Linearized multistage (LMS) models, cancer risk assessment studies, 456459 Lipid peroxidation: fatty liver, 121 hepatocellular degeneration and death, 119 sperm cell development, cell-type specific toxicity, 214 Lipid solubility, toxic agent absorption, 4142 Lipoprotein synthesis: fatty liver, 121 metals metabolism and storage, 330 Lithium, developmental toxicology of, 230 Liver. See also Hepatotoxicity biotransformation reactions, sulfation, 72-73 as biotransformation site, 62 circulatory system function and 11 l-l 12 injury mechanisms, 11 l-l 13 morphology, 113-l 16 natural venoms and toxins toxicity, 413-414 toxic agent excretion in, 55-53 xenobiotic metabolism, 62-64 Lobular structure, liver morphology, 113-l 14 Local toxicity, defined, 4 Lead lines, as biomarkers, 334, 336 Logit models, cancer risk assessment studies, 456
590 INDEX Loop of Henle, structure and function, 132-133 Loss of heterozygosity (LOH), tumor suppressor genes, 283-285 Low-dose responses, cancer risk assessment studies, 4555459 Lowest observable adverse effect (LOAEL) levels, risk assessment studies, 451454 Lung cancer: metals exposure: arsenic, 336337 beryllium, 3377338 cadmium, 338-339 chromium compounds, 3399340 nickel toxicology, 342 pulmonotoxic agents and 185 risk studies of, 3 14-3 15 smoking and, 180-181 Lungs: anatomy and physiology, 169-l 8 1 clearance mechanisms, 176 -. 178 deposition mechanisms, 176 gas exchange mechanisms, 172- 174 inhalation VS. ingestion, 174 particle size measurements, 1755176 particulates, 174-l 75 sinus cavities, 170.-171 tracheobronchiolar region, 17 l-1 72 upper airway, 1699170 clearance mechanisms, pulmonotoxicity and, 176.-178 deposition mechanisms, pulmonotoxicity and, 176 excess collagen, pulmonotoxicity and, 182-183 toxic agent absorption, 4345 gases and vapors, 45 solid/liquid particulates, 4445 toxic agent excretion, 53 Lutcinizing hormone (LH): female reproductive toxicology, 221-223 male reproductive toxicology, 2155217 Lymphocytes, immunotoxicity, 190 Lymphoid series: B and T cell formation, 94495 hematopoiesis, S8-90 Lymphomas: bone marrow suppression, 1022104 classification of, 90-9 1 Lysosomes, hepatocellular degeneration and death, 117 Macrolesions, genetic alteration, 249-25 1 Macromolecules, hepatocellular degeneration and death, binding irreversibility, 119-120 Macrophages: formation of, 93-94 pulmonotoxicity and 177-l 78 Macrovesicular steatosis, hepatotoxicity and, 120-121 MADEP risk assessment technique, petroleum hydrocarbons exposure and risk studies, 484486 “Mad hatter’s syndrome,” mercury poisoning, 333 Major histocompatibility complex (MHC), immunotoxicity, 190 Male reproductive system, toxicity effects, 210-2 18 cell-specific toxicity, 2 13-2 15 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, 213-214 suspected toxicant list, 2 18 Malignant tumors: defined, 266 development of, 270-27 1 vs. benign tumors, 267-268 “Malt worker’s lung,” 184 Mammalian development, developmental toxicology and, 2255226 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 Management issues, occupational health hazards control, 530-531 Manganese, central nervous system effects, 333 “Maple bark stripper’s disease,” 184 Margin of exposure: risk assessment studies, 454 risk characterization with, 461462 Margin of safety: dose-response data and, 19-20 herbicide exposure study, 544-545 Marine invertebrates, toxins in, 429430 Massive necrosis, hepatocellular degeneration and death, 117 Mast cell degranulating peptide, bee venom toxicology, 427 Material Safety Data Sheets (MSDS): occupational health hazards control, hazard recognition and, 533 occupational health hazards control and 53 1 Maximally tolerated dose (MTD): carcinogenicity testing protocols, 292-294 chronic animal bioassay, 290 Meat-processing industry, occupational hazard control case study of, 547-549 Mechanism of toxicity, defined, 5 Mechanistic models, cancer risk assessment studies, 456459
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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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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
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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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