PRINCIPLES OF TOXICOLOGY

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Carcinogenicity and Mutagenicity The relationship between mutagenicity and carcinogenicity as it related to the effects of ionizing radiation has been known since the early part of the twentieth century. Sufficient doses of ionizing radiation produce large structural alterations in the genetic material. The first chemical mutagens to be identified were the nitrogen and sulfur mustards (mustard gas). These chemicals were studied because their biological effects were similar to those of ionizing radiation. The nitrogen mustards and other radiomimetic compounds have the ability to form crosslinks between strands of DNA or between DNA and proteins. When such lesions are not repaired, large-scale alterations in the DNA can occur. These types of effects are referred to as clastogenic, and chemicals that cause them are known as clastogens. The identification of DNA as the genetic material along with the proposition that many chemical carcinogens are, or become, metabolically activated to reactive electrophiles paved the way for the identification of a strong link between chemical mutagenicity and carcinogenicity. As described in Chapter 12, there are now many short-term tests for the identification of chemical mutagens. The most widely used is the Salmonella mutation assay (Ames assay). It is important to note that the combination of this assay with mammalian metabolic activation systems was a critical step in the identification of a large number of chemical carcinogens as mutagens. Analyses conducted by Tennant and Ashby (1991) indicate that there is an approximately 60 percent concordance between carcinogenicity in rodent bioassays and mutagenicity in the Salmonella assay. In other words, the Salmonella assay predicts whether a chemical will be a carcinogen in rodents approximately 60 percent of the time. These investigators also identified a number of structural “alerts” that are indicative of potential mutagenicity and carcinogenicity. Initially, it had been hoped that such short-term tests would be highly predictive of carcinogenicity in rodents, and by extension, humans. However, much experimental evidence now suggests that there are a large number of chemicals that do not act via a genotoxic mechanism and thus will not be detected by such short-term tests. Genotoxic and Epigenetic Carcinogens With the realization that carcinogens elicited their effects via diverse mechanisms, a number of classification schemes based on carcinogenic mechanism were developed. One popular scheme was offered by Williams (Table 13.3). This scheme divides chemical carcinogens into two broad categories based on whether they act in a genotoxic fashion. Accordingly, the two main groups of carcinogenic chemicals are • Genotoxic carcinogens • Epigenetic (or nongenotoxic) carcinogens 1 13.3 CARCINOGENESIS BY CHEMICALS 273 Genotoxic carcinogens are those chemicals that are capable of modifying the primary sequence of DNA (i.e., initiators). This group includes chemicals that induce mutational and clastogenic changes or changes in the fidelity of DNA replication. Epigenetic carcinogens do not alter the primary sequence of DNA; instead they can affect cell proliferation and differentiation by a number of mechanisms including cytotoxicity and compensatory cell proliferation, receptor mediated events, and by altering the expression or repression of certain genes and cellular events related to cell proliferation and differentiation. It is estimated that at least 40 percent of carcinogens identified by rodent bioassays elicit their affects via an epigenetic mechanism. Many epigenetic agents favor the proliferation of cells with altered genotypes due to an interaction with an initiating carcinogen. While epigenetic carcinogens and tumor promoters share many of the same characteristics, there is some debate regarding whether classic tumor promoters should be considered carcinogens at all. However, since tumor promoters can 1 The term epigenetic carcinogen may seem confusing since many of these chemicals have the ability to alter the regulation of critical genes. This is why some prefer the term non-genotoxic carcinogen because it implies that the chemical does not alter the primary sequence of DNA by direct interaction. The two terms are often used synonymously and for our purposes we will use the term epigenetic carcinogen.
274 CHEMICAL CARCINOGENESIS Figure 13.3 Chemical structures of some representative chemical carcinogens. [Adapted from Cancer Biology, Third Edition by Raymond W. Ruddon. copyright © 1981, 1987, 1995 by Oxford University Press, Inc. Used by permission of Oxford University Press, Inc.]
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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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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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