PRINCIPLES OF TOXICOLOGY - Biology East Borneo

More documents

Recommendations

Info

5.1 THE PHYSIOLOGIC AND MORPHOLOGIC BASES <strong>OF</strong> LIVER INJURY 115Figure 5.4 Liver section from mouse given an hepatotoxic dose of acetaminophen. With acetaminophen, livercell swelling and death characteristically occurs in regions around the central vein (Zone 3, arrow); cells near theportal triad (Zone 1, arrow head) are spared.There are several types of liver cells. Hepatocytes, or parenchymal cells, constitute approximately75 percent of the total cells in the human liver. They are relatively large cells and make up the bulk ofthe hepatic lobule. By virtue of their numbers and their extensive xenobiotic metabolizing activity,these cells are the principal targets for hepatotoxic chemicals. The sinusoids are lined with endothelialcells. These cells are small but numerous, making up most of the remaining cells in the liver. Thehepatic microvasculature also contains resident macrophages, called Kupffer cells. Although comparativelyfew in number, these cells play an important role in phagocytizing microorganisms and foreignparticulates in the blood. While these cells are a part of the liver, they are also part of the immune
116 HEPATOTOXICITY: TOXIC EFFECTS ON THE LIVERsystem. They are capable of releasing reactive oxygen species and cytokines, and play an importantrole in inflammatory responses in the liver. The liver also contains Ito cells (also termed fat-storingcells, parasinusoidal cells, or stellate cells) which lie between parenchymal and endothelial cells. Thesecells appear to be important in producing collagen and in vitamin A storage and metabolism.5.2 TYPES <strong>OF</strong> LIVER INJURYAll chemicals do not produce the same type of liver injury. Rather, the type of lesion or effect observedis dependent on the chemical involved, the dose, and the duration of exposure. Some types of injuryare the result of acute toxicity to the liver, while others appear only after chronic exposure or treatment.Basic types of liver injury include the anomalies described in the following paragraphs.Hepatocellular Degeneration and DeathMany hepatotoxicants are capable of injuring liver cells directly, leading to cellular degeneration anddeath. A variety of organelles and structures within the liver cell can be affected by chemicals. Principaltargets include the following:1. Mitochondria. These organelles are important for energy metabolism and synthesis of ATP.They also accumulate and release calcium, and play an important role in calcium homeostasis withinthe cell. When mitochondria become damaged, they often lose the ability to regulate solute and waterbalance, and undergo swelling that can be observed microscopically. Mitochondrial membranes canbecome distorted or rupture, and the density of the mitochondrial matrix is altered. Examples ofchemicals that show damage to hepatic mitochondria include carbon tetrachloride, cocaine, dichloroethylene,ethionine, hydrazine, and phosphorus.2. Plasma Membrane. The plasma membrane surrounds the hepatocyte and is critically importantin maintaining the ion balance between the cytoplasm and the external environment. This ion balancecan be disrupted by damage to plasma membrane ion pumps, or by loss of membrane integrity causingions to leak in or out of the cell following their concentration gradients. Loss of ionic control can causea net movement of water into the cell, resulting in cell swelling. Blisters or “blebs” in the plasmamembrane may also occur in response to chemical toxicants. Examples of chemicals that show damageto plasma membrane include acetaminophen, ethanol, mercurials, and phalloidin.3. Endoplasmic Reticulum. The endoplasmic reticulum is responsible for synthesis of proteinsand phospholipids in the hepatocyte. It is the principal site of biotransformation of foreign chemicalsand, along with the mitochondria, sequesters and releases calcium ions to promote calcium homeostasis.As discussed in Chapter 3, hepatic biotransformation enzyme activity is substantially increased inresponse to treatment or exposure to a variety of chemicals. Many of these enzymes, includingcytochrome P450, are located in the endoplasmic reticulum, which undergoes proliferation as part ofthe enzyme induction process. Because the endoplasmic reticulum is the site within the cell of mostoxidative metabolism of foreign (xenobiotic) chemicals, it is also the site where reactive metabolitesfrom these chemicals are formed. This makes it a logical target for toxicity for chemicals that produceinjury through this mechanism. Morphologically, damage to the endoplasmic reticulum often appearsin the form of dilation. Examples of chemicals that show damage to endoplasmic reticulum includeacetaminophen, bromobenzene, carbon tetrachloride, and cocaine.4. Nucleus. There are several ways in which the nuclei can be damaged by chemical toxicants.Some chemicals or their metabolites can bind to DNA, producing mutations (see Chapter 12). Thesemutations can alter critical functions of the cell leading to cell death, or can contribute to malignanttransformation of the cell to produce cancer. Some chemicals appear to cause activation of endonucleases,enzymes located in the nucleus that digest chromatin material. This leads to uncontrolleddigestion of the cell’s DNA—obviously not conducive to normal cell functioning. Some chemicals
Page 4 and 5:
CONTRIBUTORSLOUIS ADAMS, PH.D. Prof
Page 6 and 7:
CONTENTSPREFACExvACKNOWLEDGMENTSxvi
Page 8 and 9:
CONTENTSix7.3 Agents that Act on th
Page 10 and 11:
CONTENTSxi15.4 Herbicides 35615.5 F
Page 12 and 13:
CONTENTSxiii21.6 Population Issues
Page 14 and 15:
xviPREFACE• The approach is scien
Page 16 and 17:
PRINCIPLES OF TOXICOLOGY
Page 18 and 19:
1 General Principles of ToxicologyG
Page 20 and 21:
1.2 WHAT TOXICOLOGISTS STUDY 5Delay
Page 22 and 23:
1.3 THE IMPORTANCE OF DOSE AND THE
Page 24 and 25:
Page 26 and 27:
Page 28 and 29:
Page 30 and 31:
Page 32 and 33:
1.4 HOW DOSE-RESPONSE DATA CAN BE U
Page 34 and 35:
1.5 AVOIDING INCORRECT CONCLUSIONS
Page 36 and 37:
1.6 FACTORS INFLUENCING DOSE-RESPON
Page 38:
1.6 FACTORS INFLUENCING DOSE-RESPON
Page 41 and 42:
26 GENERAL PRINCIPLES OF TOXICOLOGY
Page 43 and 44:
Page 45 and 46:
Page 47 and 48:
Page 49 and 50:
Page 51 and 52:
36 ABSORPTION, DISTRIBUTION, AND EL
Page 53 and 54:
Page 55 and 56:
Page 57 and 58:
Page 59 and 60:
Page 62 and 63:
2.4 DISPOSITION: DISTRIBUTION AND E
Page 64 and 65:
Page 66 and 67:
Page 68 and 69:
2.5 SUMMARY 53the transfer from liv
Page 70 and 71:
REFERENCES AND SUGGESTED READING 55
Page 72 and 73:
58 BIOTRANSFORMATION: A BALANCE BET
Page 74 and 75:
60Figure 3.3 Xenobiotic metabolism
Page 76 and 77:
62 BIOTRANSFORMATION: A BALANCE BET
Page 78 and 79: 64 BIOTRANSFORMATION: A BALANCE BET
Page 82 and 83: TABLE 3.4 Important Cytochrome P450
Page 102 and 103: 88 HEMATOTOXICITY: CHEMICALLY INDUC
Page 114 and 115: 100 HEMATOTOXICITY: CHEMICALLY INDU
Page 124 and 125: 5 Hepatotoxicity: Toxic Effects on
Page 126 and 127: 5.1 THE PHYSIOLOGIC AND MORPHOLOGIC
Page 130 and 131: 5.2 TYPES OF LIVER INJURY 117cause
Page 132 and 133: 5.2 TYPES OF LIVER INJURY 119Exampl
Page 134 and 135: 5.2 TYPES OF LIVER INJURY 121TABLE
Page 136 and 137: 5.2 TYPES OF LIVER INJURY 123to pro
Page 138 and 139: 5.3 EVALUATION OF LIVER INJURY 125f
Page 140 and 141: REFERENCES AND SUGGESTED READING 12
Page 142 and 143: 6 Nephrotoxicity: Toxic Responses o
Page 144 and 145: 6.1 BASIC KIDNEY STRUCTURES AND FUN
Page 146 and 147: 6.1 BASIC KIDNEY STRUCTURES AND FUN
Page 148 and 149: 6.2 FUNCTIONAL MEASUREMENTS TO EVAL
Page 150 and 151: 6.3 ADVERSE EFFECTS OF CHEMICALS ON
Page 156 and 157: REFERENCES AND SUGGESTED READING 14
Page 158 and 159: 146 NEUROTOXICITY: TOXIC RESPONSES
Page 168 and 169: 8 Dermal and Ocular Toxicology: Tox
Page 170 and 171: 8.2 FUNCTIONS 159corneum is the pri
Page 172 and 173: 8.3 CONTACT DERMATITIS 161TABLE 8.2
Page 174 and 175: 8.3 CONTACT DERMATITIS 163mucous me
Page 176 and 177: 8.3 CONTACT DERMATITIS 165light to
Page 178 and 179:
8.4 SUMMARY 167The structure of the
Page 180 and 181:
9 Pulmonotoxicity: Toxic Effects in
Page 182 and 183:
9.1 LUNG ANATOMY AND PHYSIOLOGY 171
Page 184 and 185:
Page 186 and 187:
Page 188 and 189:
Page 190 and 191:
Page 192 and 193:
9.2 MECHANISMS OF INDUSTRIALLY RELA
Page 194 and 195:
9.2 MECHANISMS OF INDUSTRIALLY RELA
Page 196 and 197:
9.3 SUMMARY 185Industrially Related
Page 198 and 199:
Page 200 and 201:
190 IMMUNOTOXICITY: TOXIC EFFECTS O
Page 202 and 203:
Page 204 and 205:
Page 206 and 207:
Page 208 and 209:
Page 210 and 211:
Page 212 and 213:
Page 214 and 215:
Page 216 and 217:
Page 218 and 219:
11 Reproductive ToxicologyREPRODUCT
Page 220 and 221:
11.1 MALE REPRODUCTIVE TOXICOLOGY 2
Page 222 and 223:
Page 224 and 225:
Page 226 and 227:
Page 228 and 229:
11.2 FEMALE REPRODUCTIVE TOXICOLOGY
Page 230 and 231:
Page 232 and 233:
Page 234 and 235:
11.3 DEVELOPMENTAL TOXICOLOGY 225de
Page 236 and 237:
11.3 DEVELOPMENTAL TOXICOLOGY 227af
Page 238 and 239:
11.3 DEVELOPMENTAL TOXICOLOGY 229ri
Page 240 and 241:
11.3 DEVELOPMENTAL TOXICOLOGY 231to
Page 242 and 243:
11.4 CURRENT RESEARCH CONCERNS 233T
Page 244 and 245:
11.4 CURRENT RESEARCH CONCERNS 235
Page 246 and 247:
Page 248 and 249:
12 Mutagenesis and Genetic Toxicolo
Page 250 and 251:
12.2 GENETIC FUNDAMENTALS AND EVALU
Page 252 and 253:
TABLE 12-1. Correspondence of the G
Page 254 and 255:
Page 256 and 257:
Page 258 and 259:
Page 260 and 261:
12.3 NONMAMMALIAN MUTAGENICITY TEST
Page 262 and 263:
12.4 MAMMALIAN MUTAGENICITY TESTS 2
Page 264 and 265:
12.4 MAMMALIAN MUTAGENICITY TESTS 2
Page 266 and 267:
12.5 OCCUPATIONAL SIGNIFICANCE OF M
Page 268 and 269:
Page 270 and 271:
Page 272 and 273:
REFERENCES CITED AND SUGGESTED READ
Page 274 and 275:
13 Chemical CarcinogenesisCHEMICAL
Page 276 and 277:
13.1 THE TERMINOLOGY OF CANCER 267H
Page 278 and 279:
13.3 CARCINOGENESIS BY CHEMICALS 26
Page 280 and 281:
Figure 13.1 Schematic diagram of th
Page 282 and 283:
Page 284 and 285:
Page 286 and 287:
Figure 13.4 Metabolic activation of
Page 288 and 289:
Page 290 and 291:
13.4 MOLECULAR ASPECTS OF CARCINOGE
Page 292 and 293:
Page 294 and 295:
Page 296 and 297:
Figure 13.7 DNA damage leads to p53
Page 298 and 299:
13.5 TESTING CHEMICALS FOR CARCINOG
Page 300 and 301:
13.5 TESTING CHEMICALS FOR CARCINOG
Page 302 and 303:
13.6 INTERPRETATION ISSUES RAISED B
Page 304 and 305:
Page 306 and 307:
Page 308 and 309:
13.7 EMPIRICAL MEASURES OF RELIABIL
Page 310 and 311:
13.8 OCCUPATIONAL CARCINOGENS 301TA
Page 312 and 313:
13.8 OCCUPATIONAL CARCINOGENS 303TA
Page 314 and 315:
13.9 CANCER AND OUR ENVIRONMENT 305
Page 316 and 317:
Page 318 and 319:
Page 320 and 321:
Page 322 and 323:
Page 324 and 325:
Page 326 and 327:
Page 328 and 329:
13.10 CANCER TRENDS AND THEIR IMPAC
Page 330 and 331:
13.11 SUMMARY 321from non-Hodgkin
Page 332 and 333:
Page 334 and 335:
14 Properties and Effects of Metals
Page 336 and 337:
14.2 SPECIATION OF METALS 327Most o
Page 338 and 339:
14.3 PHARMACOKINETICS OF METALS 329
Page 340 and 341:
14.4 TOXICITY OF METALS 331reflex i
Page 342 and 343:
14.4 TOXICITY OF METALS 333Several
Page 344 and 345:
14.5 SOURCES OF METAL EXPOSURE 335H
Page 346 and 347:
14.6 TOXICOLOGY OF SELECTED METALS
Page 348 and 349:
Page 350 and 351:
Page 352 and 353:
14.7 SUMMARY 343Zinc is required fo
Page 354 and 355:
15 Properties and Effects of Pestic
Page 356 and 357:
15.1 ORGANOPHOSPHATE AND CARBAMATE
Page 358 and 359:
Page 360 and 361:
Page 362 and 363:
15.3 INSECTICIDES OF BIOLOGICAL ORI
Page 364 and 365:
15.3 INSECTICIDES OF BIOLOGICAL ORI
Page 366 and 367:
15.4 HERBICIDES 357ClClO CH 2 C OOH
Page 368 and 369:
15.5 FUNGICIDES 359temperatures as
Page 370 and 371:
15.7 FUMIGANTS 361thallium sulfate-
Page 372 and 373:
Page 374 and 375:
Page 376 and 377:
16 Properties and Effects of Organi
Page 378 and 379:
TABLE 16.1 Physicochemical Properti
Page 380 and 381:
16.2 BASIC PRINCIPLES 371TABLE 16.2
Page 382 and 383:
16.2 BASIC PRINCIPLES 373Once absor
Page 384 and 385:
16.2 BASIC PRINCIPLES 375the additi
Page 386 and 387:
16.3 TOXIC PROPERTIES OF REPRESENTA
Page 388 and 389:
Page 390 and 391:
Page 392 and 393:
Page 394 and 395:
Page 396 and 397:
Page 398 and 399:
16.10 TOXIC PROPERTIES OF REPRESENT
Page 400 and 401:
Page 402 and 403:
Page 404 and 405:
Page 406 and 407:
Page 408 and 409:
Page 410 and 411:
Page 412 and 413:
16.15 TOXIC PROPERTIES 403observed
Page 414 and 415:
16.18 SULFUR-SUBSTITUTED SOLVENTS 4
Page 416 and 417:
Page 418 and 419:
17 Properties and Effects of Natura
Page 420 and 421:
17.3 NATURAL ROLES OF TOXINS AND VE
Page 422 and 423:
17.4 MAJOR SITES AND MECHANISMS OF
Page 424 and 425:
17.5 TOXINS IN UNICELLULAR ORGANISM
Page 426 and 427:
17.6 TOXINS OF HIGHER PLANTS 417phy
Page 428 and 429:
17.6 TOXINS OF HIGHER PLANTS 419whi
Page 430 and 431:
17.6 TOXINS OF HIGHER PLANTS 421TAB
Page 432 and 433:
17.7 ANIMAL VENOMS AND TOXINS 423of
Page 434 and 435:
17.7 ANIMAL VENOMS AND TOXINS 425ac
Page 436 and 437:
17.7 ANIMAL VENOMS AND TOXINS 427co
Page 438 and 439:
17.7 ANIMAL VENOMS AND TOXINS 429Fi
Page 440 and 441:
17.8 TOXIN AND VENOM THERAPY 431One
Page 442 and 443:
Page 444 and 445:
18 Risk AssessmentRISK ASSESSMENTRO
Page 446 and 447:
18.1 RISK ASSESSMENT BASICS 439Step
Page 448 and 449:
18.1 RISK ASSESSMENT BASICS 441For
Page 450 and 451:
18.2 HAZARD IDENTIFICATION 443chemi
Page 452 and 453:
18.3 EXPOSURE ASSESSMENT: EXPOSURE
Page 454 and 455:
18.3 EXPOSURE ASSESSMENT: EXPOSURE
Page 456 and 457:
18.4 DOSE-RESPONSE ASSESSMENT 449Af
Page 458 and 459:
18.4 DOSE-RESPONSE ASSESSMENT 451me
Page 460 and 461:
18.4 DOSE-RESPONSE ASSESSMENT 453Fi
Page 462 and 463:
18.4 DOSE-RESPONSE ASSESSMENT 455No
Page 464 and 465:
18.4 DOSE-RESPONSE ASSESSMENT 457Fi
Page 466 and 467:
18.4 DOSE-RESPONSE ASSESSMENT 459Ge
Page 468 and 469:
18.5 RISK CHARACTERIZATION 461likel
Page 470 and 471:
18.6 PROBABILISTIC VERSUS DETERMINI
Page 472 and 473:
18.7 EVALUATING RISK FROM CHEMICAL
Page 474 and 475:
18.7 EVALUATING RISK FROM CHEMICAL
Page 476 and 477:
18.8 COMPARATIVE RISK ANALYSIS 469r
Page 478 and 479:
18.8 COMPARATIVE RISK ANALYSIS 471T
Page 480 and 481:
18.9 RISK COMMUNICATION 473TABLE 18
Page 482 and 483:
Page 484 and 485:
Page 486 and 487:
480 EXAMPLE OF RISK ASSESSMENT APPL
Page 488 and 489:
Page 490 and 491:
Page 492 and 493:
Page 494 and 495:
Page 496 and 497:
Page 498 and 499:
Page 500 and 501:
Page 502 and 503:
Page 504 and 505:
Page 506 and 507:
500 OCCUPATIONAL AND ENVIRONMENTAL
Page 508 and 509:
Page 510 and 511:
Page 512 and 513:
Page 514 and 515:
Page 516 and 517:
21 Epidemiologic Issues inOccupatio
Page 518 and 519:
21.3 TYPES OF EPIDEMIOLOGIC STUDIES
Page 520 and 521:
21.5 DISEASE AND HUMAN HEALTH EFFEC
Page 522 and 523:
21.8 MEASUREMENT OF ASSOCIATION OR
Page 524 and 525:
21.9 BIAS 519increased or decreased
Page 526 and 527:
Page 528 and 529:
524 CONTROLLING OCCUPATIONAL AND EN
Page 530 and 531:
Page 532 and 533:
Page 534 and 535:
Page 536 and 537:
Page 538 and 539:
Page 540 and 541:
Page 542 and 543:
Page 544 and 545:
Page 546 and 547:
Page 548 and 549:
Page 550 and 551:
Page 552 and 553:
Page 554 and 555:
Page 556 and 557:
Page 558 and 559:
Page 560 and 561:
556 GLOSSARYaliphatic Organic compo
Page 562 and 563:
558 GLOSSARYbenign tumor A new tiss
Page 564 and 565:
560 GLOSSARYcytokinesis The divisio
Page 566 and 567:
562 GLOSSARYerythropoietic stimulat
Page 568 and 569:
564 GLOSSARYinhalation route The mo
Page 570 and 571:
566 GLOSSARYmitochondria Small sphe
Page 572 and 573:
568 GLOSSARYoral route The entry of
Page 574 and 575:
570 GLOSSARYporphyrin Any of a grou
Page 576 and 577:
572 GLOSSARYspirometry The measurem
Page 578 and 579:
INDEXAbsorbed dose, defined, 4Absor
Page 580 and 581:
INDEX 577Area under the tissue conc
Page 582 and 583:
INDEX 579animal studies, 297cellula
Page 584 and 585:
INDEX 581speciation of, 327-328Corp
Page 586 and 587:
INDEX 583organ-specific activities,
Page 588 and 589:
INDEX 585Follicle-stimulating hormo
Page 590 and 591:
INDEX 587fatty liver, 120-122hepato
Page 592 and 593:
INDEX 589Isoniazid metabolism, path
Page 594 and 595:
INDEX 591Mechanistic toxicology, as
Page 596 and 597:
INDEX 593Nephropathy:defined 130nep
Page 598 and 599:
INDEX 595neurobehavioral sequelae,
Page 600 and 601:
INDEX 597Probability density functi
Page 602 and 603:
INDEX 599Rodenticides, 360.-361sodi
Page 604 and 605:
INDEX 601Safe Human Dose (SHD) appr
Page 606:
INDEX 603drug metabolism factors, 7
show all

PRINCIPLES OF TOXICOLOGY - Biology East Borneo

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?