PRINCIPLES OF TOXICOLOGY

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62 BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATION 3.1 SITES <strong>OF</strong> BIOTRANSFORMATION Xenobiotic metabolism occurs in all organs and tissues in the body. Because many of the chemicals metabolized can have deleterious effects on the body, xenobiotic metabolism can be considered a defense mechanism that hastens the elimination of a toxic chemical and thus terminates the exposure. When viewed as a defense mechanism, it is not surprising that the exposure is best terminated at the point of exposure. These are the so-called portals of entry (shown as sites of absorption [a] for xenobiotics [X] in Figure 3.1), and constitute mainly the skin, lung, and intestinal mucosa. While drug metabolizing enzymes are present in all these tissues (Table 3.2), and at relatively high activity in some, particularly intestine and lung, the liver is by far the most important tissue for xenobiotic metabolism (site [m] in Figure 3.1). Although it is not the first tissue of the body to be exposed to chemicals, the liver receives the entire chemical load absorbed from the gastrointestinal tract, which is the predominant portal of entry for most xenobiotics (Figure 3.1). The xenobiotic metabolizing enzymes are present in high concentrations and the organ itself has large bulk, approximately 5 percent of the total body weight. Xenobiotics absorbed from the lungs and skin can also quickly move to the liver for metabolism. Once in the liver, the highly vascular nature of the tissue and the intimate contact between blood and hepatocytes, which contain the xenobiotic metabolizing enzymes, allows for the rapid diffusion of chemicals in and metabolites out (Figure 3.5). Although not a portal of entry, the kidney is an organ where xenobiotics are likely to be concentrated during the excretion process, and this may be the reason for the relatively high level of xenobiotic metabolizing enzymes in this tissue. Although the data presented in Table 3.2 are from laboratory animals, there is little evidence to contraindicate the existence of a similar distribution pattern in humans. Within the liver, hepatocytes or parenchymal cells are the major site of drug biotransformation, and within these cells it is the endoplasmic reticulum, which occupies about 15 percent of the hepatocyte volume and contains 20 percent of the hepatocyte protein, which houses the bulk of the critical drug metabolizing enzyme activity. (The nonparenchymal cells, including endothelial and Kupffer cells, constitute 35 percent of liver cell number but only contribute 5–10 percent of liver mass. Their drug metabolizing enzyme activities are typically less than 20 percent of that in hepatocytes). When liver is carefully homogenized, fragments of the endoplasmic reticulum are converted to microsomes (an artifact of cell disruption). The drug-metabolizing enzymes located in the endoplasmic reticulum are often referred to as microsomal enzymes, and it is often stated that chemicals are metabolized by liver microsomes. Enriched microsomal fractions are usually obtained by differential sedimentation, either as a suspension with cytoplasm (10,000g supernatant) or as a sediment free of cytosol (105,000g precipitate) (Table 3.3). Many important xenobiotic metabolizing enzymes reside in the cytoplasm and microsomal fractions (Figures 3.3 and 3.6). Oxidations and glucuronidations are the most common reactions occurring in microsomes. The terminal oxidase responsible for many of the oxidations, cytochrome P450, represents about 5 percent of the microsomal protein under normal conditions; more if induction has occurred (see text below). Other flavoproteins necessary for cytochrome P450 function and epoxide hydrolase, an enzyme important in the further metabolism of epoxides formed by cytochrome P450–dependent oxidation, are also conveniently located in the endoplasmic reticulum (Figure 3.6). Microsomal metabolism in tissues other than liver is seldom quantitatively important in overall drug elimination, but local generation of active metabolites may be important in drug-induced tissue damage, carcinogenesis, and other effects. Enzymes located in the cytoplasm of the hepatocyte catalyze a wide variety of both phase I and phase II reactions. Dehydrogenases and esterases are examples of phase I enzymes found predominantly in the cytosol. The sulfotransferase and glutathione transferase enzymes also depicted in Figure 3.6 serve as examples of phase II enzymes that are similarly located.
Figure 3.5 Diagrammatic rendition of hepatic lobule blood flow. TABLE 3.2 Drug-Metabolizing Enzyme Activities a in Various Organs Lung 3.1 SITES <strong>OF</strong> BIOTRANSFORMATION 63 Intestine Mucosa Liver Kidney Cortex Brain Rabbit Cytochrome P450 0.4 0.34 1.45 0.33 0.02 UDP-glucuronosyltransferase (p-nitrophenol) b 0.4 — 6.6 2.9 Glutathione S-transferase (DCNB) b Rat 5.3 — 21.9 7.4 Cytochrome P450 0.09 0.05 0.84 0.12 0.01 Ethoxyresorufin demethylase (P4501A) 0.003 0.001 0.034 0.001 Erythromycin demethylase (P4503A) — 0.12 0.47 0.06 UDP-glucuronosyltransferase (p-nitrophenol) b 0.8 — 4.4 3.3 Glutathione S-transferase (DCNB) b 2.1 — 76.4 3.8 a All activities are expressed on a per milligram of protein basis (DCNB = 1,2-dichloro 4-nitrobenzene). b Litterst CL, Mimnaugh EG, Reagan RL, Gram TE, Drug Metab. Disp. 3: 259 (1975).
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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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114 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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