PRINCIPLES OF TOXICOLOGY

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neurobehavioral sequelae, 350 regulatory information, 351--352 Ovarian tract toxicity, toxic agents, 219-220 Oviduct atrophy, reproductive toxicants and, 221 Oxidation: biotransformation reactions, 65-70 microsomal oxidations, 65-66 nonmicrosomal oxidations, 66, 69 microsomal enzymes, 62 Oxidative metabolism, male reproductive toxicology, 213 Oxygen concentration (P02): hemoglobin structure, 96 hypoxia and, 97 Oxygen transport, impairment: chemicals, 97-99 red blood cell function and 95.-97 Palytoxin, toxicology of, 428-429 p-Aminohippuric acid (PAH), nephrotoxicity measurement, 136 Paraffin. See Alkanes Paralytic shellfish poisoning (PSP), toxicology, 417 Paraquat, structure and characteristics, 356-358 Parenchymal cells, liver morphology, 115 “Particle overload” phenomenon, antimony carcinogenicity risks, 493494 Particle size: lung absorption of particulates, 4445 pulmonotoxicity and, 175-176 Particulate absorption: immunotoxicity, 2022203 in lungs, 44 45 pulmonotoxicity, 1744175 Partition coefficient, passive diffusion, toxic agents, 37-38 Passive diffusion: toxic agent absorption, skin absorption, 43 toxic agent membrane transport, 3740 ionization measurement, 38-40 molecular size, 37.-38 partition coefficient, 37 Pedicellaria, venom toxicology, 429430 Peliosis hepatis, hepatotoxicity and 123 Pentachlorophenol: fmrgicide chemistry, 358-360 Safe Human Dose (SHD) calculations, 30-3 1 P450 enzyme system, solvent exposure, 373 Peptide toxins: in flowering plants, 421422 in scorpion venom, 426 in sea anemones, 428429 Perchloroethene (PERC): carcinogenicity, 376 toxicology, 397 Peripheral nervous system: reptile and amphibian venom toxicology, 423425 sensorimotor nerves, toxic mechanisms on, 149-150 INDEX 595 solvent exposure and depression of. 374 Periportal veins, liver morphology. 1 lb I, Perivenular cells, liver morphology, 114 Permeability coefficient, passive diffusion, toxic agents, partition coefficient ratio, 3940 Permissible exposure limits (PELs): occupational health hazards analysis, air sampling, 536 vsolvent exposure, 368,372 Pesticides: biological insecticides, 353-355 Bucillus thuringiensis, 355 pyrethrum and pyrethrins, 354 rotenone, 355 synthetic pyrethroids, 354-355 diet and carcinogenicity, 3 15-3 17 endocrine disruption research on, 234-235 fumigants, 361-362 ethylene oxide, 362 methyl bromide, 362 sulthydryl fluoride, 362 fungicides, 358-360 chlorothalonil, 359 copper compounds, 360 dithiocarbamates/thiocarbamates, 359 health effects of, 345-346 herbicides: acute toxicity, 356 biphenyl compounds, 356-358 carcinogenicity, 356 chlorophenoxy herbicides, 355-356 triazines, 358 household exposure, cancer risk table, 470 immunotoxicity, 203 male reproductive toxicology and, 217 metals ingestion from, 329 organochlorine insecticides: acute and chronic health effects, 353 biological monitoring, 353 historical background, 352 intoxication treatment, 353 mechanisms of action, 352 pharmacokinetics, 352 physical/chemical properties. 352 organophosphate and carbamate insecticides, 346-352 absorption and metabolism, 347-348 acute effects, 348-349 biological monitoring, 350-351 chronic effects, 349 delayed neurotoxicity, 3499350 historical background, 3466347 intoxication treatment, 351 mechanism of action, 347 neurobehavioral sequelae, 350 regulatory information, 351-352 rodenticides, 360-361 sodium fluoroacetate, 361 thallium sulfate, 360~-36 1
596 INDEX Pesticides (continued) Petroleum hydrocarbons, exposure and risk assessment studies, 483-486 p53 gene: apoptosis, 2866289 cell life and death and, 284 short-term cancer bioassays, 291.-292 Phagocytosis, membrane transport of toxic agents, 41 Pharmacokinetics: metals, 328-33 1 absorption and distribution, 328 dermal exposure, 329-330 excretion, 330-33 1 inhalation, 328-329 metabolism and storage, 330 oral ingestion, 329 natural toxins and venoms, 43 1 organochlorine insectides, 352 Phenols: nephrotoxicity, 141 toxicology, 384-385 Phenylacetic acid conjugation, in primates, physiologically-based kinetic (PBK) models, 50 -51 Phenytoin, fetal hydantoin syndrome and 229 pH levels: nephrotoxicity measurement, 137 toxic agent absorption, gastrointestinal tract, 4243 Phosgene, pulmonary edema and, 183-l 84 Phospholipasc A, hymenoptera toxicology, 427 Phosphoslipidosis, fatty liver, 121 3’-Phosphoadenosine-5’-phosphosulfate (PAPS) cofactor, biotransformation reactions, 72 Photosensitivity, dermal toxicity 1644165 Phthalates: ester compounds, toxicology, 390 male reproductive toxicology, 2 13 Sertoli cell specificity, 2 15 spontaneous abortion and, 227 Physiologically-based kinetic (PBK) models: risk assessment studies: dose metrics, 460 dose-response relationships, 454 exposure pathways and dosages, 449 toxic agent distribution, 49-5 1 Phytoestrogens, endocrine disruption research, 232 -235 Pigment disturbances, dermal toxicity, 164 Pigment-induced nephropathy, nephrotoxic agents, 141 Pinocytosis, membrane transport of toxic agents, 41 Piperidine alkaloids, fire ant venom, 427 Pit vipers, venom toxicology, 423424 Placental cord blood sampling, mutagenicity testing, 254 Plant assays, mutagenicity testing with, 253 Plaque-forming cell (PFC) assay, animal models of immunotoxicity, 1988199 Plasma membrane, hepatocellular degeneration and death, 116 Platelets: aggregation mechanisms, 93 formation of, 92-93 Pneumoconiosis, industrial-related exposure, 18 1 Pneumonitis, beryllium exposure, 337-338 Point mutations: chromosomes, 250.-251 genetic alteration and 246-247 mechanisms of, 25 1 Poison ivy, contact dermatitis, 422--423 Poisons, defined, 409 Polychlorinated biphenyls (PCBs): endocrine disruption research, 2333235 male reproductive toxicology and 217 toxic equivalency factors (TEF) relative to dioxin, 466 Polychlorinated dibenzofmans (PCDFs), endocrine disruption research, 233-235 Polychlorinated dibenzo(p)dioxins, immunotoxicity, 202 Polycyclic aromatic hydrocarbons (PAH): carcinogenicity, 274 diet sources, 3 17 developmental toxicology and, 230 genetic alteration and 247 skin cancer, 164 toxic agents, 2 19 toxicology, 381-382 xenobiotic metabolism, enzyme activity, 75-76 Polycythemia, erythropoietin inhibition, 88-90 Polymorphism: carcinogenic agents, 3 13 xenobiotic metabolism, human variations in, 80-8 1 Population identification: epidemiologic studies, size as factor in, 520 in epidemiologic studies, selection bias, 519-520 epidemiologic studies and, 5 16 risk assessment procedures, 440441 Pores of Kohn, pulmonotoxicity, 173 Porphyrins, toxicology of, 354 Portals of entry, biotransformation sites, 62 Portal triad, liver morphology, 1133114 Portuguese man-o’-war, venom toxicology, 428429 Positive cooperativity hemoglobin structure, 96 Potassium ions, action potential mechanisms, 1466147 Potentiation, dose-response data and 24-26 Pralidoxime, organophosphate/carbamate pesticides exposure treatment, 351 Pregnancy: female reproductive toxicology, 223 lead exposure during, risk assessment of, 481.-483 Prevalence data, epidemiologic studies, 5 16-5 17 Primary carcinogens, defined, 268 Primary irritants, contact dermatitis, 161 Probabilistic risk assessment, vs. deterministic risk assessment, 462464
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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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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: 594 INDEX Nutritional deficiencies,
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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