PRINCIPLES OF TOXICOLOGY - Biology East Borneo

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Figure 13.1 Schematic diagram of the development of a malignant tumor from a normal cell.271
272 CHEMICAL CARCINOGENESISFigure 13.2 Generalized scheme of initiation-promotion experiments. Initiation is caused by a single dose of aninitiating agent such as a carcinogenic polycyclic aromatic hydrocarbon; promotion is carried out by repeatedapplication or chronic dosing with a tumor promotor such as TPA. (I, initiator; P, promoter; solid line indicatescontinual application of agent; dotted lines indicate the duration of time without exposure to an agent.)• Initiation must occur prior to promotion.• Repeated exposure to a promoter alone will result in few, if any tumors.Experiments with initiation–promotion models have demonstrated that there are chemicals thatpossess both initiator and promoter activity. These chemicals are known as complete carcinogens. Bythe same token, chemicals that cannot by themselves induce cancer in experimental animal models arecalled incomplete carcinogens. In reality, dosage is a critical factor in determining whether a chemicalis a complete carcinogen. At sufficiently low doses, most initiators require subsequent promotion forthe development of a tumor, while at very high doses, most carcinogens possess initiating andpromoting ability. As you will learn later, this has important implications for the identification and theassessment of risk associated with potential carcinogens.Electrophilic TheoryThe nature of the initiation step in chemical carcinogenesis was the subject of much scientific inquiryand debate for decades. Until 1940, the only known chemical carcinogens were aromatic hydrocarbonsand amines. Soon afterward, other aliphatic chemicals were also shown to be carcinogenic and by the1960s the various chemical carcinogens belonged to over a dozen chemical classes (Figure 13.3).Attempting to explain this structural diversity, in 1969 James and Elizabeth Miller hypothesized that“most, if not all, chemical carcinogens either are, or are converted to, reactive electrophilic derivativeswhich combine with nucleophilic growth crucial tissue components, such as nucleic acids or proteins.”In what became known as the electrophilic theory of chemical carcinogenesis, the Millers describedthe metabolic activation of inactive procarcinogens to intermediates they called proximate carcinogensand on to ultimate carcinogens that covalently bind DNA and cause mutations. Examples of chemicalcarcinogens that require metabolic activation include benzo[a]pyrene and other polycyclic aromatichydrocarbons, 1,3-butadiene, and 2-acetylaminofluorene. The bioactivation of several chemical carcinogensis illustrated in Figure 13.4.
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CONTRIBUTORSLOUIS ADAMS, PH.D. Prof
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CONTENTSPREFACExvACKNOWLEDGMENTSxvi
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CONTENTSix7.3 Agents that Act on th
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CONTENTSxi15.4 Herbicides 35615.5 F
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CONTENTSxiii21.6 Population Issues
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xviPREFACE• The approach is scien
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PRINCIPLES OF TOXICOLOGY
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1 General Principles of ToxicologyG
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1.2 WHAT TOXICOLOGISTS STUDY 5Delay
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1.3 THE IMPORTANCE OF DOSE AND THE
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1.4 HOW DOSE-RESPONSE DATA CAN BE U
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1.5 AVOIDING INCORRECT CONCLUSIONS
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1.6 FACTORS INFLUENCING DOSE-RESPON
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1.6 FACTORS INFLUENCING DOSE-RESPON
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26 GENERAL PRINCIPLES OF TOXICOLOGY
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36 ABSORPTION, DISTRIBUTION, AND EL
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2.4 DISPOSITION: DISTRIBUTION AND E
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2.5 SUMMARY 53the transfer from liv
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REFERENCES AND SUGGESTED READING 55
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58 BIOTRANSFORMATION: A BALANCE BET
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60Figure 3.3 Xenobiotic metabolism
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TABLE 3.4 Important Cytochrome P450
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88 HEMATOTOXICITY: CHEMICALLY INDUC
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100 HEMATOTOXICITY: CHEMICALLY INDU
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5 Hepatotoxicity: Toxic Effects on
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5.1 THE PHYSIOLOGIC AND MORPHOLOGIC
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5.1 THE PHYSIOLOGIC AND MORPHOLOGIC
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5.2 TYPES OF LIVER INJURY 117cause
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5.2 TYPES OF LIVER INJURY 119Exampl
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5.2 TYPES OF LIVER INJURY 121TABLE
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5.2 TYPES OF LIVER INJURY 123to pro
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5.3 EVALUATION OF LIVER INJURY 125f
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6 Nephrotoxicity: Toxic Responses o
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6.1 BASIC KIDNEY STRUCTURES AND FUN
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6.1 BASIC KIDNEY STRUCTURES AND FUN
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6.2 FUNCTIONAL MEASUREMENTS TO EVAL
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6.3 ADVERSE EFFECTS OF CHEMICALS ON
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146 NEUROTOXICITY: TOXIC RESPONSES
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8 Dermal and Ocular Toxicology: Tox
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8.2 FUNCTIONS 159corneum is the pri
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8.3 CONTACT DERMATITIS 161TABLE 8.2
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8.3 CONTACT DERMATITIS 163mucous me
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8.3 CONTACT DERMATITIS 165light to
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8.4 SUMMARY 167The structure of the
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9 Pulmonotoxicity: Toxic Effects in
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9.1 LUNG ANATOMY AND PHYSIOLOGY 171
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9.2 MECHANISMS OF INDUSTRIALLY RELA
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9.2 MECHANISMS OF INDUSTRIALLY RELA
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9.3 SUMMARY 185Industrially Related
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190 IMMUNOTOXICITY: TOXIC EFFECTS O
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11 Reproductive ToxicologyREPRODUCT
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11.1 MALE REPRODUCTIVE TOXICOLOGY 2
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11.2 FEMALE REPRODUCTIVE TOXICOLOGY
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Page 240 and 241: 11.3 DEVELOPMENTAL TOXICOLOGY 231to
Page 242 and 243: 11.4 CURRENT RESEARCH CONCERNS 233T
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Page 246 and 247: REFERENCES AND SUGGESTED READING 23
Page 248 and 249: 12 Mutagenesis and Genetic Toxicolo
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Page 274 and 275: 13 Chemical CarcinogenesisCHEMICAL
Page 276 and 277: 13.1 THE TERMINOLOGY OF CANCER 267H
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Page 286 and 287: Figure 13.4 Metabolic activation of
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13.11 SUMMARY 321from non-Hodgkin
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14 Properties and Effects of Metals
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14.2 SPECIATION OF METALS 327Most o
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14.3 PHARMACOKINETICS OF METALS 329
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14.4 TOXICITY OF METALS 331reflex i
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14.4 TOXICITY OF METALS 333Several
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14.5 SOURCES OF METAL EXPOSURE 335H
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14.6 TOXICOLOGY OF SELECTED METALS
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14.7 SUMMARY 343Zinc is required fo
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15 Properties and Effects of Pestic
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15.1 ORGANOPHOSPHATE AND CARBAMATE
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15.3 INSECTICIDES OF BIOLOGICAL ORI
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15.3 INSECTICIDES OF BIOLOGICAL ORI
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15.4 HERBICIDES 357ClClO CH 2 C OOH
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15.5 FUNGICIDES 359temperatures as
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15.7 FUMIGANTS 361thallium sulfate-
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16 Properties and Effects of Organi
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TABLE 16.1 Physicochemical Properti
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16.2 BASIC PRINCIPLES 371TABLE 16.2
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16.2 BASIC PRINCIPLES 373Once absor
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16.2 BASIC PRINCIPLES 375the additi
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16.3 TOXIC PROPERTIES OF REPRESENTA
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16.10 TOXIC PROPERTIES OF REPRESENT
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16.15 TOXIC PROPERTIES 403observed
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16.18 SULFUR-SUBSTITUTED SOLVENTS 4
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17 Properties and Effects of Natura
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17.3 NATURAL ROLES OF TOXINS AND VE
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17.4 MAJOR SITES AND MECHANISMS OF
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17.5 TOXINS IN UNICELLULAR ORGANISM
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17.6 TOXINS OF HIGHER PLANTS 417phy
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17.6 TOXINS OF HIGHER PLANTS 419whi
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17.6 TOXINS OF HIGHER PLANTS 421TAB
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17.7 ANIMAL VENOMS AND TOXINS 423of
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17.7 ANIMAL VENOMS AND TOXINS 425ac
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17.7 ANIMAL VENOMS AND TOXINS 427co
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17.7 ANIMAL VENOMS AND TOXINS 429Fi
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17.8 TOXIN AND VENOM THERAPY 431One
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18 Risk AssessmentRISK ASSESSMENTRO
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18.1 RISK ASSESSMENT BASICS 439Step
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18.1 RISK ASSESSMENT BASICS 441For
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18.2 HAZARD IDENTIFICATION 443chemi
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18.3 EXPOSURE ASSESSMENT: EXPOSURE
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18.3 EXPOSURE ASSESSMENT: EXPOSURE
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18.4 DOSE-RESPONSE ASSESSMENT 449Af
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18.4 DOSE-RESPONSE ASSESSMENT 451me
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18.4 DOSE-RESPONSE ASSESSMENT 453Fi
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18.4 DOSE-RESPONSE ASSESSMENT 455No
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18.4 DOSE-RESPONSE ASSESSMENT 457Fi
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18.4 DOSE-RESPONSE ASSESSMENT 459Ge
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18.5 RISK CHARACTERIZATION 461likel
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18.6 PROBABILISTIC VERSUS DETERMINI
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18.7 EVALUATING RISK FROM CHEMICAL
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18.7 EVALUATING RISK FROM CHEMICAL
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18.8 COMPARATIVE RISK ANALYSIS 469r
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18.8 COMPARATIVE RISK ANALYSIS 471T
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18.9 RISK COMMUNICATION 473TABLE 18
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480 EXAMPLE OF RISK ASSESSMENT APPL
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500 OCCUPATIONAL AND ENVIRONMENTAL
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21 Epidemiologic Issues inOccupatio
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21.3 TYPES OF EPIDEMIOLOGIC STUDIES
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21.5 DISEASE AND HUMAN HEALTH EFFEC
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21.8 MEASUREMENT OF ASSOCIATION OR
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21.9 BIAS 519increased or decreased
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524 CONTROLLING OCCUPATIONAL AND EN
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556 GLOSSARYaliphatic Organic compo
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558 GLOSSARYbenign tumor A new tiss
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560 GLOSSARYcytokinesis The divisio
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562 GLOSSARYerythropoietic stimulat
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564 GLOSSARYinhalation route The mo
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566 GLOSSARYmitochondria Small sphe
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568 GLOSSARYoral route The entry of
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570 GLOSSARYporphyrin Any of a grou
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572 GLOSSARYspirometry The measurem
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INDEXAbsorbed dose, defined, 4Absor
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INDEX 577Area under the tissue conc
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INDEX 579animal studies, 297cellula
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INDEX 581speciation of, 327-328Corp
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INDEX 583organ-specific activities,
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INDEX 585Follicle-stimulating hormo
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INDEX 587fatty liver, 120-122hepato
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INDEX 589Isoniazid metabolism, path
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INDEX 591Mechanistic toxicology, as
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INDEX 593Nephropathy:defined 130nep
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INDEX 595neurobehavioral sequelae,
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INDEX 597Probability density functi
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INDEX 599Rodenticides, 360.-361sodi
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INDEX 601Safe Human Dose (SHD) appr
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INDEX 603drug metabolism factors, 7
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