PRINCIPLES OF TOXICOLOGY

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A Multidisciplinary Approach 12.5 OCCUPATIONAL SIGNIFICANCE <strong>OF</strong> MUTAGENS 259 Figure 12.8 Proposed relationships between mutagenicity and carcinogenicity. (Adapted from Fishbein, 1979). Although each of the mutagenicity tests described in this chapter has individual strengths, likewise each is weak in some facets of detection capacity. Clearly, therefore, the accurate and efficient testing of chemicals and the protection from potential occupational mutagens require a multidisciplinary approach that integrates toxicology, clinical chemistry, microbiology, pathology, epidemiology, industrial hygiene, and occupational medicine. Testing intact animals has the advantage of increasing the reliability of any extrapolations that must be made from the data; however, cost considerations often limit the application of in vivo mammalian assays except when it is expected that they will verify lower tier assays. There are three areas where the results of mutagenicity testing of a given substance may be applied:
260 MUTAGENESIS AND GENETIC <strong>TOXICOLOGY</strong> • Extrapolation of test results in order to make a quantitative evaluation of the hazard of exposures for humans • Prioritization of human hazards caused by specific compounds • Institution of remedial procedures that should be undertaken to minimize the human hazard One of the most difficult areas of analysis is the correct application of mutagenicity tests to arrive at a quantifiable human hazard from exposure to a given substance. There is frequently good correlation between the mutagenicity and carcinogenicity of a substance in animal tests (Table 12.4). However, this may be misleading because models for carcinogenicity determination are often characterized by chronic procedures utilizing very high doses in nonprimate species. These may bear little resemblance to aspects of exposure in the human model, such as magnitude and route of exposure, metabolic patterns, and environment (which are qualitative factors), and exposure dose (which is quantitative). As noted previously, the time and expense that are involved with lifetime carcinogenicity assays have strongly influenced the use of test batteries as predictive measures of carcinogenic potential. Among many others, Ashby and Tennant (1994), Anderson et al. (1994), Benigni and Giuliani (1987), and Blake et al. (1990), have addressed the question of applicability of multiple test systems to the classification of a substance as genotoxic or not, and carcinogenic or not. It is important in these efforts to distinguish among “sensitivity” (ability to identify a known carcinogen), “specificity” (ability to identify a noncarcinogen), and “accuracy” (correct results of either type). Parodi et al. (1990) reported on qualitative correlations associated with studies of up to 300 substances conducted during the period 1976 through 1988. Initial measures of sensitivity, specificity, and accuracy were approximately 90 percent, if the decision is based solely on Salmonella assays. As more substances have been tested, this estimate has ranged from 45 to 91 percent. Best results typically are reported for sensitivity, where accuracy generally is on the order of 65 to 75 percent. Consideration of the quantitative correlation between short-term genotoxicity tests and carcinogenic potency has yielded extremely variable estimates, ranging from approximately 30 to over 90 percent. The overwhelming conclusion was that a battery of test systems that addresses differing endpoints is required if the goal is to develop a confident conclusion regarding predictivity. As is the case with many areas of toxicology, one may choose between in vivo and in vitro test systems, each with their attendant advantages and disadvantages. The testing of chemicals in experimental animals has all the advantages of any intact in vivo system; that is, it has all of the biochemical and physiological requirements to make anthropomorphization more reliable. However, in vivo mutagenicity testing may require an investment of many thousands of dollars and a long period of time. These disadvantages often force the tester to use a less expensive, well-established short-term TABLE 12.4 Comparative Mutagenicity of Various Compounds Compound Established human carcinogen Bacteria Yeast Drosophila Mammalian cells Epichlorohydrin N N O Y Y Y Ethyleneimine N O Y Y Y Y Trimethyl phosphate O Y O Y Y Y Tris N Y O Y Y Y Ethylene dibromide N Y Y Y Y N Vinyl chloride Y Y Y Y Y Y Chloroprene Y Y O O O Y Urethane N Y Y Y Y O N = no; Y = yes; O = not tested. Human cells
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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
Page 217 and 218: PART II Specific Areas of Concern P
Page 219 and 220: 210 REPRODUCTIVE TOXICOLOGY continu
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Page 227 and 228: 218 REPRODUCTIVE TOXICOLOGY TABLE 1
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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
Page 257 and 258: 248 Figure 12.5 Example of DNA addu
Page 267: TABLE 12-3 NTP and Gene-Tox Evaluat
Page 275 and 276: 266 CHEMICAL CARCINOGENESIS 13.1 TH
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Page 297 and 298: 288 Figure 13.8 A genetic model of
Page 299 and 300: 290 CHEMICAL CARCINOGENESIS Increas
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Page 303 and 304: 294 CHEMICAL CARCINOGENESIS • The
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Page 307 and 308: 298 CHEMICAL CARCINOGENESIS In rats
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310 CHEMICAL CARCINOGENESIS TABLE 1
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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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