PRINCIPLES OF TOXICOLOGY - Biology East Borneo

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TABLE 12-1. Correspondence of the Genetic Code with the Appropriate Amino Acids (Note Unambiguity and Degeneracy)Second position in tripletFirst position in tripletU C A GThird position in tripletA Isoleucine Threonine Asparagine Serine UIsoleucine Threonine Asparagine Serine CIsoleucine Threonine Lysine Arginine A*Methionine Threonine Lysine Arginine GC Leucine Proline Histidine Arginine ULeucine Proline Histidine Arginine CLeucine Proline Glutamate Arginine ALeucine Proline Glutamate Arginine GG Valine Alanine Aspartate Glycine UValine Alanine Aspartate Glycine CValine Alanine Glutamate Glycine AValine Alanine Glutamate Glycine GU Phenylalanine Serine Tyrosine Cysteine UPhenylalanine Serine Tyrosine Cysteine CLeucine Serine STOP STOP ALeucine Serine STOP Tryptophan G*The sequence AUG, in addition to coding for methionine, is part of the initiator sequence that starts the translation process by which mRNA is formed from the DNA template.243
244 MUTAGENESIS AND GENETIC <strong>TOXICOLOGY</strong>which results in a gene product that is partially or completely unable to perform its normal function.Such changes may be correlated with carcinogenesis, fetal death, fetal malformation, or biochemicaldysfunction, depending on the cell type that has been affected. However, cause and effect relationshipsfor such correlations typically are lacking.Initiation and termination of DNA transcription are controlled by a separate set of regulatory genes.Most regulatory genes respond to chemical cues, so that only those genes that are needed at a giventime are expressed or available. The remaining genes are in an inactive state. The processes of geneactivation and inactivation are believed to be critical to cellular differentiation, and interruption of theseprocesses may result in the expression of abnormal conditions such as tumors. This represents anexample of a case in which a non-genetic event may result in tumorigenesis. Oncogenes represent anexample of a situation where activation of a genetic phenomenon may act to initiate carcinogenicity.In contrast, loss of “tumor suppressor” genes may, by omission, result in initiation of the carcinogenicprocess.Chromosome Structure and FunctionThe DNA of mammalian species, including humans, is packaged in combination with specializedproteins (predominantly histones) into units termed chromosomes, which are found in the nucleus ofthe cell. The proteins are thought to “cover” certain segments of the DNA and may act as inhibitorsof expression for some regions. Each normal human cell (except germ cells) contains 46 chromosomes(23 pairs). Chromosomes may be present singly (haploid), as in germ cells (sperm or ovum), or inpairs (diploid), as in somatic cells or in fertilized ova. In haploid cells, all functional genes present inthe cell can be expressed. In diploid cells, one allele may be dominant over the other, and in this case,only the dominant gene of each functional pair is expressed. The unexpressed allele is termed recessive,and recessive genes are expressed only when both copies of the recessive type are present. Some celltypes in mammals are found in forms other than diploid. Functionally normal liver cells, for example,are occasionally found to be tetraploid (two chromosome pairs instead of one pair).Some features and terminology that are important to cytogenetics, or the study of chromosomes,include:• Karyotype—the array of chromosomes, typically taken at the point in the cell cycle knownas metaphase, which is unique to a species and forms the basis for cellular taxonomy; maybe used to detect physical or chemical damage• Centromere—the primary constriction, which represents the site of attachment of the spindlefiber during cell division; useful in identifying specific chromosomes, as its location isrelatively consistent• Nucleolar organizing region—the secondary constriction, which represents the site ofsynthesis of RNA, subsequently used in ribosomes for protein synthesis• Satellite—the segment terminal to the nucleolar organizing region; useful in specificchromosome identification• Heterochromatin—tight-coiling region; relatively inactive• Euchromatin—loose-coiling region; primary transcription siteMitosis, Meiosis, and FertilizationThe process by which a somatic cell divides into two diploid daughter cells is called mitosis. The firststage of mitosis is called prophase, during which the spindle is formed and the chromatin material(DNA and protein) of the nucleus becomes shortened into well-defined chromosomes. Duringmetaphase, the centriole pairs are pulled tightly by the attached microtubules to the very center of thecell, lining up in the equatorial plane of the mitotic spindle. With still further growth of the spindle,the chromatids in each pair of chromosomes are broken apart, a stage called anaphase. All 46 pairs
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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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Page 218 and 219: 11 Reproductive ToxicologyREPRODUCT
Page 220 and 221: 11.1 MALE REPRODUCTIVE TOXICOLOGY 2
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Page 236 and 237: 11.3 DEVELOPMENTAL TOXICOLOGY 227af
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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
Page 278 and 279: 13.3 CARCINOGENESIS BY CHEMICALS 26
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13.6 INTERPRETATION ISSUES RAISED B
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13.7 EMPIRICAL MEASURES OF RELIABIL
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13.8 OCCUPATIONAL CARCINOGENS 301TA
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13.8 OCCUPATIONAL CARCINOGENS 303TA
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13.9 CANCER AND OUR ENVIRONMENT 305
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13.10 CANCER TRENDS AND THEIR IMPAC
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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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