PRINCIPLES OF TOXICOLOGY

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(in humans) of chromatids are thus separated, forming pairs of daughter chromosomes that are pulled toward one mitotic spindle or the other. In telophase, the mitotic spindle grows longer, completing the separation of daughter chromosomes. A new nuclear membrane is formed, and shortly thereafter the cell constricts at the midpoint between the two nuclei, forming two new cells. Meiosis is the term for the process by which immature germ cells produce gametes (sperm or ova) that are haploid. During meiosis, DNA is replicated, producing 46 chromosomes with sister chromatids. The 46 chromosomes arrange into 23 pairs at the center of the nucleus, and in the first division the pairs separate. In a second division, the sister chromatids separate, with one chromosome of each pair being incorporated into four gametes. At the time of fertilization, or zygote formation, the fusion of gametes once again forms a cell with a full complement of 46 chromosomes. Genetic Alteration 12.2 GENETIC FUNDAMENTALS AND EVALUATION <strong>OF</strong> GENETIC CHANGE 245 Tests for genotoxicity in higher organisms may be placed into one of three basic categories: gene mutation tests, chromosomal aberration tests, and DNA damage tests. These tests are conducted individually or in combination to identify various types of mutagenic events (Figure 12.3) or other genotoxic effects. For the purpose of this discussion, the principles of each test category will be reviewed and specific tests will be discussed by broad phylogenetic classifications. Over 200 individual test methods have been developed to assess the extent and magnitude of genetic alteration; however, less than 20 have been validated or are in common use. Numerous mutagenic agents have the demonstrated capacity to cause genetic change in one or more of these test systems, but no well-documented cases of human mutation are available. This latter conclusion may change as a result of improvements in the ability to detect human genetic change. Nevertheless, as discussed in this section, use of a reasonable battery of tests is capable of identifying almost all of the known human carcinogens, consistent with the hypothesis that somatic cell mutations are, at least in part, responsible for a large proportion of human cancers. A transmissible change in the linear sequence of DNA can result from any one of three basic events: • Infidelity in DNA replication • Point mutation • Chromosomal aberration Figure 12.3 Types of mutagenic changes (Adapted from Brusick, 1980).
246 MUTAGENESIS AND GENETIC <strong>TOXICOLOGY</strong> One possibility, infidelity or inexact copying of a DNA strand during normal cellular replication, may result from inaccurate initiation of replication, failure of the transcription enzymes to accurately “read” the DNA, or interruption of the transcription process by agents that interpose (intercalate) themselves within the DNA molecule or between the DNA and an enzyme. Point mutations, as the second possibility, may be subdivided into basepair changes and frameshift mutations (Figure 12.4). The former result from transition or transversion of DNA base pairs so that Figure 12.4 Schematic representation of point mutations (frameshift and basepair changes).
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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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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
Page 221 and 222: 212 REPRODUCTIVE TOXICOLOGY Underst
Page 223 and 224: 214 REPRODUCTIVE TOXICOLOGY spermat
Page 225 and 226: 216 REPRODUCTIVE TOXICOLOGY gonadot
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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 245 and 246: 236 REPRODUCTIVE TOXICOLOGY Two imp
Page 247 and 248: 238 REPRODUCTIVE TOXICOLOGY Sundara
Page 249 and 250: 240 MUTAGENESIS AND GENETIC TOXICOL
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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 301 and 302: 292 CHEMICAL CARCINOGENESIS may be
Page 303 and 304: 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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PRINCIPLES OF TOXICOLOGY

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