PRINCIPLES OF TOXICOLOGY

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REFERENCES AND SUGGESTED READING 55 Sha’afi, R. I., C. M. Gary-Bobo, and A. K. Solomon, “Permeability of red cell membranes to small hydrophilic and lipophilic solutes,” J. Gen. Physiol. 58: 238–258 (1971). U.S. Environmental Protection Agency, Update to the Health Risk Assessment Document and Addendum for Dichloromethane: Pharmacokinetics, Mechanism of Action and Epidemiology, EPA 600/8-87/030A (1987). Wagner, J. G., “Properties of the Michaelis-Menten equation and its integrated form which are useful in pharmacokinetics,” J. Pharmacokinet. Biopharmaceut. 1: 103–121 (1973). Williams, R. T., “Interspecies scaling,” in T. Teorell, R. L. Dedrick, and P. G. Condliffe, eds., Pharmacology and Pharmacokinetics, Plenum, New York, 1974, Table IV, p. 108.
3 Biotransformation: A Balance between Bioactivation and Detoxification BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATION MICHAEL R. FRANKLIN and GAROLD S. YOST This chapter identifies the fundamental principles of foreign compound (xenobiotic) modification by the body and discusses • How xenobiotics enter, circulate, and leave the body • The sites of metabolism of the xenobiotic within the body • The chemistry and enzymology of xenobiotic metabolism • The bioactivation as well as inactivation of xenobiotics during metabolism • The variations in xenobiotic metabolism resulting from prior or concomitant exposure to xenobiotics and from physiological factors The body is continuously exposed to chemicals, both naturally occurring and synthetic, which have little or no value in sustaining normal biochemistry and cell function. These chemical substances (xenobiotics) can be absorbed from the environment following inhalation, ingestion in food or water, or simple exposure to the skin (Figure 3.1). Biotransformation or metabolism of the chemicals allows the elimination of the absorbed chemicals to occur. Without this process, chemicals that were readily absorbed through lipid membranes because of a high octanol/water partition coefficients would fail to leave the body. They would be passively reabsorbed through the lipid membrane of the kidney tubule instead of remaining in, and passing out with, the urine (Figure 3.2). In addition, they would not be subject to active transport mechanisms capable of actively secreting many xenobiotic metabolites. Thus, an important objective of biotransformation is to promote the excretion of chemicals by the formation of water-soluble metabolites or products. Biotransformation can also alter the biological activity of chemicals, including endogenous chemicals released in the body, such as steroids and catecholamines, both by structural alteration and by enhancing their partition away from cellular compartments, membranes, and receptors. Thus biotransformation helps to both terminate the biological activity of chemicals and increase their ease of elimination. Biotransformation is defined as the chemical alteration of substances by reactions in the living organism. For convenience, the conversion of xenobiotics is divided into two phases: metabolic transformations (phase I reactions) and conjugation with natural body constituents (phase II reactions) (Figure 3.3). The reactions of both of these phases are predominantly enzyme-catalyzed. A xenobiotic does not necessarily undergo metabolism by a sequential combination of phase I followed by phase II reactions for successful elimination. It may undergo phase I metabolism alone, phase II alone, and occasionally, phase I reactions subsequent to phase II conjugations are encountered. An important objective of biotransformation is to promote the excretion of absorbed chemicals by the formation of water-soluble drug metabolites or products (p in Figure 3.1). Increased water solubility is derived primarily from the phase II reactions since most conjugates exist in the ionized state at physiological pH levels. This promotes excretion (e in Figure 3.1) by decreasing xenobiotic reabsorp- Principles of Toxicology: Environmental and Industrial Applications, Second Edition, Edited by Phillip L. Williams, Robert C. James, and Stephen M. Roberts. ISBN 0-471-29321-0 © 2000 John Wiley & Sons, Inc. 57
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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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4.15 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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222 REPRODUCTIVE TOXICOLOGY Figure
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224 REPRODUCTIVE TOXICOLOGY TABLE 1
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226 Figure 11.5 Developmental tree
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228 REPRODUCTIVE TOXICOLOGY is clea
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230 REPRODUCTIVE TOXICOLOGY genital
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232 REPRODUCTIVE TOXICOLOGY to occu
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234 REPRODUCTIVE TOXICOLOGY these r
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236 REPRODUCTIVE TOXICOLOGY Two imp
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238 REPRODUCTIVE TOXICOLOGY Sundara
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240 MUTAGENESIS AND GENETIC TOXICOL
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248 Figure 12.5 Example of DNA addu
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TABLE 12-3 NTP and Gene-Tox Evaluat
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266 CHEMICAL CARCINOGENESIS 13.1 TH
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268 CHEMICAL CARCINOGENESIS TABLE 1
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270 CHEMICAL CARCINOGENESIS researc
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272 CHEMICAL CARCINOGENESIS Figure
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276
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280 CHEMICAL CARCINOGENESIS 13.4 MO
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286 CHEMICAL CARCINOGENESIS make a
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288 Figure 13.8 A genetic model of
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290 CHEMICAL CARCINOGENESIS Increas
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292 CHEMICAL CARCINOGENESIS may be
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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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302 CHEMICAL CARCINOGENESIS with ex
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316 CHEMICAL CARCINOGENESIS similar
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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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