PRINCIPLES OF TOXICOLOGY

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TABLE 12-1. Correspondence of the Genetic Code with the Appropriate Amino Acids (Note Unambiguity and Degeneracy) Second position in triplet Third position in triplet U C A G First position in triplet A Isoleucine Threonine Asparagine Serine U Isoleucine Threonine Asparagine Serine C Isoleucine Threonine Lysine Arginine A *Methionine Threonine Lysine Arginine G C Leucine Proline Histidine Arginine U Leucine Proline Histidine Arginine C Leucine Proline Glutamate Arginine A Leucine Proline Glutamate Arginine G G Valine Alanine Aspartate Glycine U Valine Alanine Aspartate Glycine C Valine Alanine Glutamate Glycine A Valine Alanine Glutamate Glycine G U Phenylalanine Serine Tyrosine Cysteine U Phenylalanine Serine Tyrosine Cysteine C Leucine Serine STOP STOP A Leucine 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 biochemical dysfunction, depending on the cell type that has been affected. However, cause and effect relationships for 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 given time are expressed or available. The remaining genes are in an inactive state. The processes of gene activation and inactivation are believed to be critical to cellular differentiation, and interruption of these processes may result in the expression of abnormal conditions such as tumors. This represents an example of a case in which a non-genetic event may result in tumorigenesis. Oncogenes represent an example 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 carcinogenic process. Chromosome Structure and Function The DNA of mammalian species, including humans, is packaged in combination with specialized proteins (predominantly histones) into units termed chromosomes, which are found in the nucleus of the cell. The proteins are thought to “cover” certain segments of the DNA and may act as inhibitors of 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 in pairs (diploid), as in somatic cells or in fertilized ova. In haploid cells, all functional genes present in the 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 cell types 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 known as metaphase, which is unique to a species and forms the basis for cellular taxonomy; may be used to detect physical or chemical damage • Centromere—the primary constriction, which represents the site of attachment of the spindle fiber during cell division; useful in identifying specific chromosomes, as its location is relatively consistent • Nucleolar organizing region—the secondary constriction, which represents the site of synthesis of RNA, subsequently used in ribosomes for protein synthesis • Satellite—the segment terminal to the nucleolar organizing region; useful in specific chromosome identification • Heterochromatin—tight-coiling region; relatively inactive • Euchromatin—loose-coiling region; primary transcription site Mitosis, Meiosis, and Fertilization The process by which a somatic cell divides into two diploid daughter cells is called mitosis. The first stage 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. During metaphase, the centriole pairs are pulled tightly by the attached microtubules to the very center of the cell, 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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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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Page 205 and 206: certain situations immunosuppressio
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Page 213 and 214: animal origin have also been shown
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Page 217 and 218: PART II Specific Areas of Concern P
Page 219 and 220: 210 REPRODUCTIVE TOXICOLOGY continu
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Page 223 and 224: 214 REPRODUCTIVE TOXICOLOGY spermat
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Page 229 and 230: Figure 11.3 Cycle of follicular dev
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Page 235 and 236: 226 Figure 11.5 Developmental tree
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Page 247 and 248: 238 REPRODUCTIVE TOXICOLOGY Sundara
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Page 257 and 258: 248 Figure 12.5 Example of DNA addu
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Page 275 and 276: 266 CHEMICAL CARCINOGENESIS 13.1 TH
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Page 289 and 290: 280 CHEMICAL CARCINOGENESIS 13.4 MO
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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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300 CHEMICAL CARCINOGENESIS TABLE 1
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302 CHEMICAL CARCINOGENESIS with ex
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314 CHEMICAL CARCINOGENESIS Figure
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316 CHEMICAL CARCINOGENESIS similar
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322 CHEMICAL CARCINOGENESIS Figure
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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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The study was designed to minimize
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TABLE 22.3 Margins of Safety at For
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top, and numerous slots with smalle
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TABLE 22.5 Comparison of Time-Weigh
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• Housing or building code violat
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• Environmental exposure limits,
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GLOSSARY Glossary absorption The mo
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GLOSSARY 557 antipyretic An agent t
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GLOSSARY 559 chloracne An acne-like
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GLOSSARY 561 eczema A superficial i
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GLOSSARY 563 hemolytic anemia Anemi
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GLOSSARY 565 lipoprotein Any of a g
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GLOSSARY 567 necrosis Death of one
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pernicious anemia The progressive,
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GLOSSARY 571 cells have both endoth
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GLOSSARY 573 tolerance The ability
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576 INDEX Allergic reaction (contin
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578 INDEX Biotransformation (contin
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580 INDEX Children’s health statu
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582 INDEX Diet and nutrition (conti
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584 INDEX Estrogens: endocrine disr
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586 INDEX Hair, toxic agent excreti
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588 INDEX hnmunoglobulins: autoimmu
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590 INDEX Loop of Henle, structure
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592 INDEX Mixed exposure patterns,
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594 INDEX Nutritional deficiencies,
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596 INDEX Pesticides (continued) Pe
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598 INDEX Relative potency factor (
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600 INDEX Solvents (continued) phys
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602 INDEX Tumorigenesis (continued)
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