PRINCIPLES OF TOXICOLOGY

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5.2 TYPES <strong>OF</strong> LIVER INJURY 117 cause disarrangement of chromatin material within the nucleus. Morphologically, damage to the nucleus appears as alterations in the nuclear envelope, in chromatin structure, and in arrangement of nucleoli. Examples of chemicals that produce nuclear alterations include aflatoxin B, beryllium, ethionine, galactosamine, and nitrosamines. 5. Lysosomes. These subcellular structures contain digestive enzymes (e.g., proteases) and are important in degrading damaged or aging cellular constituents. In hepatocytes injured by chemical toxicants, their numbers and size are often increased. Typically, this is not because they are a direct target for chemical attack, but rather reflects the response of the cell to the need to remove increased levels of damaged cellular materials caused by the chemical. Not all hepatocellular toxicity leads to cell death. Cells may display a variety of morphologic abnormalities in response to chemical insult and still recover. These include cell swelling, dilated endoplasmic reticulum, condensed mitochondria and chromatin material in the nucleus, and blebs on the plasma membrane. More severe morphological changes are indicative that the cell will not recover, and will proceed to cell death, that is, undergo necrosis. Examples of morphological signs of necrosis are massive swelling of the cell, marked clumping of nuclear chromatin, extreme swelling of mitochondria, breaks in the plasma membrane, and the formation of cell fragments. Necrosis from hepatotoxic chemicals can occur within distinct zones in the liver, be distributed diffusely, or occur massively. Many chemicals produce a zonal necrosis; that is, necrosis is confined to a specific zone of the hepatic acinus. Table 5.1 provides examples of drugs and chemicals that produce hepatic necrosis and the characteristic zone in which the lesion occurs. Figure 5.4 shows an example of zone 3 hepatic necrosis from acetaminophen. Confinement of the lesion to a specific zone is thought to be a consequence of the mechanism of toxicity of these agents and the balance of activating and inactivating enzymes or cofactors. Interestingly, there are a few chemicals for which the zone of necrosis can be altered by treatment with other chemicals. These include cocaine, which normally produces hepatic necrosis in zone 2 or 3 in mice, but in phenobarbital-pretreated animals causes necrosis in zone 1. Limited observations of liver sections from humans experiencing cocaine hepatotoxicity are consistent with this shift produced by barbiturates. The reason for the change in site of necrosis with these chemicals is unknown. Necrotic cells produced by some chemicals are distributed diffusely throughout the liver, rather than being localized in acinar zones. Galactosamine and the drug methylphenidate are examples of chemicals that produce a diffuse necrosis. Diffuse necrosis is also seen in viral hepatitis and some forms of idiosyncratic liver injury. The extent of necrosis can vary considerably. When most of the cells of the liver are involved, this is termed massive necrosis. As the name implies, this involves destruction of most or all of the hepatic acinus. Not all the acini in the liver are necessarily affected to the same extent, but at least some acini will have necrosis that extends across the lobule from the portal triad to the hepatic vein, called bridging necrosis. Massive necrosis is not so much a characteristic of specific hepatotoxic chemicals as of their dose. Because of the remarkable ability of the liver to regenerate itself, it is able to withstand moderate zonal or diffuse necrosis. Over a period of several days, necrotic cells are removed and replaced with new cells, restoring normal hepatic architecture and function. If the number of damaged cells is too great, however, the liver’s capacity to restore itself becomes overwhelmed, leading to hepatic failure and death. Another form of cell death is apoptosis, or programmed cell death. Apoptosis is a normal physiological process used by the body to remove cells when they are no longer needed or have become functionally abnormal. In apoptosis, the cell “commits suicide” through activation of its endonucleases, destroying its DNA. Apoptotic cells are morphologically distinct from cells undergoing necrosis as described above. Unlike cells undergoing necrosis, which swell and release their cellular contents, apoptotic cells generally retain plasma membrane integrity and shrink, resulting in condensed cytoplasm and dense chromatin in the nucleus. There are normally few apoptotic cells in liver, but the number may be increased in response to some hepatotoxic chemicals, notably thioacetamine and ethanol. Also, some chemicals produce hypertrophy, or growth of the liver beyond its normal size.
118 HEPATOTOXICITY: TOXIC EFFECTS ON THE LIVER TABLE 5.1 Drugs and Chemicals that Produce Zonal Hepatic Necrosis Site of Necrosis Chemical Zone1 Zone 2 Zone 3 Acetaminophen X Aflatoxin X X Allyl alcohol X Alloxan X α-Amanitin X Arsenic, inorganic X Beryllium X Botulinum toxin X Bromobenzene X Bromotrichoromethane X Carbon tetrachloride X Chlorobenzenes X Chloroform X Chloroprene X Cocaine a X X Dichlorpropane X Dioxane X DDT X Dimethylnitrosamine X Dinitrobenzene X Dinitrotoluene X Divinyl ether X Ethylene dibromide X Ethylene dichloride X Ferrous sulfate X Fluoroacetate X Iodobenzene X Iodoform X Manganese compounds X Methylchloroform X Naphthalene X Ngaione X Paraquat X X Phalloidin X Pyridine X Pyrrolidizine alkaloids X Rubratoxin X Tannic acid X Thioacetamide X Urethane X Xylidine X Source: Adapted from Cullen and Reubner, 1991. a Necrosis is shifted to zone 1 in phenobarbital-pretreated animals.
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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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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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