A Practical Approach, Second Edition=Ronald D. Ho.pdf

More documents

Recommendations

Info

CLASSES OF TOXICITYOR SIGNALSReproductiveToxicity1. Fertility2. Parturition3. LactationPositivesignalDevelopmentalToxicity1. Mortality2. Dysmorphogenesis3. Alterations to growth4. Functional toxicityFigure 22.3SignalStrengthISignalStrengthIAnimal DataSignalStrengthIISignalStrengthIIPDPDADMETOXProgress to Next StepADMETOXExposureExposureData Integration ProcessClass,AlertsClass,AlertsIntegration tool for reproductive or developmental toxicites with a positive signal.Human DataPredictedto IncreaseHumanRepro. RiskMayIncreaseHumanRepro. RiskDoes NotAppear toIncreaseHumanRepro. RiskHumanDataConcernConcernHumanDataPRINCIPLES OF RISK ASSESSMENT — FDA PERSPECTIVE 901© 2006 by Taylor & Francis Group, LLC
902 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONmore than one species has been studied), multiplicity of effects, and adverse effects seen at morethan one time.a. Cross-Species ConcordanceThe defining characteristic of cross-species concordance is a positive signal in the same class oftoxicity in more than one species. Cross-species concordance is most likely to be identified forstructural abnormalities (dysmorphogenesis) or developmental mortality because these toxicitiesare frequently detected in the organogenesis testing paradigm, in which multiple species aretypically evaluated. In addition, alterations to endocrine function or gonadal histopathology (whichmay alter fertility) may be indirectly detected in subchronic and chronic toxicity studies in rodentsand nonrodents. When cross-species concordance is observed, there is increased concern forreproductive or developmental toxicity in humans. In contrast, there is decreased concern when asignal is detected in only one species (with the proviso that the negative species is an appropriateanimal model and the studies were adequate in design, dosing, and implementation).b. Multiplicity of EffectsMultiplicity of effects refers to observation, in a single species or animal model, of two or more positivesignals within one of the two general categories of toxicity (reproductive or developmental) or withinone of the seven classes of reproductive or developmental toxicities. The observation of increasedembryo-fetal death and structural abnormalities in an animal test species is an example of multiplepositive signals within a general category. The observation of two or more positive signals for structuralabnormalities in tissues of multiple embryonic origin (e.g., defects affecting soft tissue, skeletal tissue,and/or neural tissue) is an example of multiple positive signals in a toxicity class.If all species examined demonstrate multiplicity of effects, there is increased concern forreproductive or developmental toxicity in humans. If there are positive signals in two or morespecies, but multiplicity of effects is observed in only one species, concern is unchanged for thiselement. If no species studied exhibits multiplicity of effects, there is decreased concern.c. Adverse Effects at Different Stages of the Reproductive or Developmental ProcessEvidence of toxicity may arise during any stage of the reproductive or developmental process. Ifa positive signal in animals is observed in multiple stages of development, there is generally greaterconcern for adverse human reproductive outcomes. If a positive signal is observed only during asingle, discrete interval, the level of concern is unchanged. If the positive signal occurs only duringprocesses that are of limited relevance to humans, there would be less concern for adverse humanreproductive outcomes. In addition to its relevance to this evaluation process, it is also importantto define the timing of the period of susceptibility for the observed positive signal to provide acontext for the human risk.9. Factor 2. Signal Strength, Part IIA positive signal should also be analyzed with respect to the coexistence of maternal toxicity,presence of a dose response relationship, and the observation of rare events.a. Maternal ToxicityIn weighing a signal of toxicity, the magnitude of adverse effects in the offspring versus the severityof maternal (and, for fertility studies, paternal) toxicity should be considered when drawing aconclusion about the relevance of the F 0 toxicity to effects observed in the offspring. A positive© 2006 by Taylor & Francis Group, LLC
Page 2 and 3:
Second EditionDEVELOPMENTALandREPRO
Page 4 and 5:
Published in 2006 byCRC PressTaylor
Page 6 and 7:
Chapter 12Chapter 13Chapter 14Chapt
Page 8 and 9:
The EditorRonald D. Hood, Ph.D., is
Page 10 and 11:
Alan M. HobermanArgus ResearchHorsh
Page 12 and 13:
APPENDIX ATerminology of Anatomical
Page 14 and 15:
TERMINOLOGY OF ANATOMICAL DEFECTS 9
Page 16 and 17:
Page 18 and 19:
Page 20 and 21:
Page 22 and 23:
Page 24 and 25:
Organ/StructureCodeNumberObservatio
Page 26 and 27:
Page 28 and 29:
Page 30 and 31:
Organ/Structure10145 Ocular colobom
Page 32 and 33:
Page 34 and 35:
Organ/StructurePulmonaryarteryPulmo
Page 36 and 37:
Page 38 and 39:
Page 40 and 41:
Page 42 and 43:
Terminology of developmental abnorm
Page 44 and 45:
Page 46 and 47:
Page 48 and 49:
Page 50 and 51:
Page 52 and 53:
Page 54 and 55:
Organ/StructureCervicalcentrumCodeN
Page 56 and 57:
Organ/Structure10689 Misshapen thor
Page 58 and 59:
Organ/StructureSacralcentrumSacralv
Page 60 and 61:
Page 62 and 63:
Page 64 and 65:
Page 66 and 67:
Page 68 and 69:
968 DEVELOPMENTAL REPRODUCTIVE TOXI
Page 70 and 71:
Page 72 and 73:
Page 74 and 75:
Page 76 and 77:
Page 78 and 79:
Page 80 and 81:
Page 82 and 83:
Page 84 and 85:
Page 86 and 87:
Page 88 and 89:
Page 90 and 91:
Page 92 and 93:
Page 94 and 95:
Page 96 and 97:
Page 98 and 99:
Page 100 and 101:
1000 DEVELOPMENTAL REPRODUCTIVE TOX
Page 102 and 103:
Page 104 and 105:
Page 106 and 107:
Page 108 and 109:
Page 110 and 111:
Page 112 and 113:
Page 114 and 115:
Page 116 and 117:
Page 118 and 119:
Page 120 and 121:
Page 122 and 123:
Page 124 and 125:
Page 126 and 127:
Page 128 and 129:
Page 130 and 131:
Table 1Human Non-human Primate Rat
Page 132 and 133:
Table 1 (continued)Sertoli CellsHum
Page 134 and 135:
Page 136 and 137:
Page 138 and 139:
Page 140 and 141:
Page 142 and 143:
Page 144 and 145:
Page 146 and 147:
Page 148 and 149:
Page 150 and 151:
Page 152 and 153:
Table 2 (continued) Landmarks in th
Page 154 and 155:
Table 2 (continued) Landmarks in th
Page 156 and 157:
Page 158 and 159:
Page 160 and 161:
Page 162 and 163:
Page 164 and 165:
Page 166 and 167:
Page 168 and 169:
Page 170 and 171:
Page 172 and 173:
Page 174 and 175:
Page 176 and 177:
Page 178 and 179:
Page 180 and 181:
Page 182 and 183:
Page 184 and 185:
Page 186 and 187:
Page 188 and 189:
Page 190 and 191:
Page 192 and 193:
Page 194 and 195:
Page 196 and 197:
Page 198 and 199:
Page 200 and 201:
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 217 and 218:
POSTNATAL DEVELOPMENTAL MILESTONES
Page 219 and 220:
Page 221 and 222:
Page 223 and 224:
Page 225 and 226:
Page 227 and 228:
Page 229 and 230:
Page 231 and 232:
PART IPrinciples and Mechanisms© 2
Page 233 and 234:
4 DEVELOPMENTAL REPRODUCTIVE TOXICO
Page 235 and 236:
Page 237 and 238:
Page 239 and 240:
10 DEVELOPMENTAL REPRODUCTIVE TOXIC
Page 241 and 242:
Page 243 and 244:
Page 245 and 246:
Page 247 and 248:
Page 249 and 250:
Page 251 and 252:
Page 253 and 254:
Table 2.6Receptor(Official Name a )
Page 255 and 256:
Page 257 and 258:
Page 259 and 260:
Page 261 and 262:
Page 263 and 264:
Page 265 and 266:
Page 267 and 268:
Page 269 and 270:
Page 271 and 272:
Clearly, more research needs to be
Page 273 and 274:
Page 275 and 276:
Page 277 and 278:
Page 279 and 280:
Page 281 and 282:
Page 283 and 284:
Page 285 and 286:
Page 287 and 288:
Page 289 and 290:
Page 291 and 292:
Page 293 and 294:
Page 295 and 296:
Page 297 and 298:
Page 299 and 300:
Page 301 and 302:
Page 303 and 304:
Page 305 and 306:
Page 307 and 308:
Page 309 and 310:
Page 311 and 312:
Page 313 and 314:
Page 315 and 316:
Page 317 and 318:
Page 319 and 320:
Page 321 and 322:
Page 323 and 324:
Page 325 and 326:
Page 327 and 328:
Page 329 and 330:
Page 331 and 332:
Page 333 and 334:
Page 335 and 336:
Page 337 and 338:
Page 339 and 340:
Page 341 and 342:
Page 343 and 344:
Page 345 and 346:
Page 347 and 348:
Page 349 and 350:
Page 351 and 352:
Page 353 and 354:
Page 355 and 356:
Page 357 and 358:
Page 359 and 360:
Page 361 and 362:
Page 363 and 364:
Page 365 and 366:
Page 367 and 368:
Page 369 and 370:
Page 371 and 372:
Page 373 and 374:
Page 375 and 376:
CHAPTER 6Comparative Features of Ve
Page 377 and 378:
COMPARATIVE FEATURES OF VERTEBRATE
Page 379 and 380:
Page 381 and 382:
Table 6.2Comparative reproductive a
Page 383 and 384:
Page 385 and 386:
Maturation andRelease ofGametesSper
Page 387 and 388:
Page 389 and 390:
Page 391 and 392:
Amniotic cavity 9.5 1.5 1-4 1-4,6,9
Page 393 and 394:
Posteriorcardinal veinsestablishedT
Page 395 and 396:
PosteriorcardinaldegenerationRight
Page 397 and 398:
StomachappearsThirdpharyngealpouch;
Page 399 and 400:
Table 6.6DescriptionComparative ges
Page 401 and 402:
ParathyroidParathyroids 12.5 6.2 41
Page 403 and 404:
Table 6.8DescriptionComparative ges
Page 405 and 406:
Formation ofchoroid plexusof latera
Page 407 and 408:
Optic nervefibers presentDifferenti
Page 409 and 410:
Table 6.10DescriptionMuscular Syste
Page 411 and 412:
Distalphalanges offingersseparatedF
Page 413 and 414:
Table 6.11DescriptionIntermediateme
Page 415 and 416:
Table 6.12DescriptionComparative ge
Page 417 and 418:
Page 419 and 420:
Page 421 and 422:
Page 423 and 424:
Page 425 and 426:
Page 427 and 428:
CHAPTER 7Developmental Toxicity Tes
Page 429 and 430:
DEVELOPMENTAL TOXICITY TESTING —
Page 431 and 432:
Page 433 and 434:
Page 435 and 436:
Page 437 and 438:
Page 439 and 440:
Page 441 and 442:
Page 443 and 444:
Page 445 and 446:
Page 447 and 448:
Page 449 and 450:
Page 451 and 452:
Page 453 and 454:
Page 455 and 456:
Page 457 and 458:
Female 0.00-0.69 0.004-0.39 0.00-0.
Page 459 and 460:
Page 461 and 462:
Page 463 and 464:
Page 465 and 466:
Page 467 and 468:
Page 469 and 470:
Page 471 and 472:
Page 473 and 474:
Page 475 and 476:
Page 477 and 478:
Page 479 and 480:
Page 481 and 482:
Page 483 and 484:
Page 485 and 486:
Page 487 and 488:
Page 489 and 490:
Page 491 and 492:
Page 493 and 494:
Figure 8.11775Pott DescribesScrotal
Page 495 and 496:
Page 497 and 498:
Page 499 and 500:
Page 501 and 502:
The underlying physiology of juveni
Page 503 and 504:
Page 505 and 506:
Page 507 and 508:
Page 509 and 510:
Page 511 and 512:
Page 513 and 514:
Page 515 and 516:
Page 517 and 518:
Page 519 and 520:
Page 521 and 522:
Page 523 and 524:
Table 8.5Total body composition by
Page 525 and 526:
Page 527 and 528:
Table 8.6Serum chemistry values for
Page 529 and 530:
Table 8.7Parameter bHematology valu
Page 531 and 532:
Page 533 and 534:
Page 535 and 536:
Page 537 and 538:
Page 539 and 540:
Page 541 and 542:
Page 543 and 544:
Page 545 and 546:
Page 547 and 548:
Page 549 and 550:
Page 551 and 552:
Page 553 and 554:
CHAPTER 9Significance, Reliability,
Page 555 and 556:
DEVELOPMENTAL AND REPRODUCTIVE TOXI
Page 557 and 558:
Prior to the early 1980s, numerous
Page 559 and 560:
Page 561 and 562:
Page 563 and 564:
Page 565 and 566:
Page 567 and 568:
Page 569 and 570:
Figure 9.51906Food andDrugs Act2000
Page 571 and 572:
Page 573 and 574:
Page 575 and 576:
Page 577 and 578:
Page 579 and 580:
Page 581 and 582:
Page 583 and 584:
Page 585 and 586:
Page 587 and 588:
Table 9.18Selected comparison point
Page 589 and 590:
Page 591 and 592:
Page 593 and 594:
Page 595 and 596:
Page 597 and 598:
Page 599 and 600:
Page 601 and 602:
Page 603 and 604:
Page 605 and 606:
Page 607 and 608:
Table 9.33Selected comparison point
Page 609 and 610:
Page 611 and 612:
Page 613 and 614:
Page 615 and 616:
Page 617 and 618:
Page 619 and 620:
Page 621 and 622:
Page 623 and 624:
Page 625 and 626:
Page 627 and 628:
Page 629 and 630:
Page 631 and 632:
Page 633 and 634:
Page 635 and 636:
Page 637 and 638:
Page 639 and 640:
Table 9.48What do regulatorswant to
Page 641 and 642:
Page 643 and 644:
Page 645 and 646:
Page 647 and 648:
Page 649 and 650:
CHAPTER 10Testing for Reproductive
Page 651 and 652:
TESTING FOR REPRODUCTIVE TOXICITY 4
Page 653 and 654:
Page 655 and 656:
Page 657 and 658:
Page 659 and 660:
Page 661 and 662:
Page 663 and 664:
Page 665 and 666:
Page 667 and 668:
Page 669 and 670:
Page 671 and 672:
Page 673 and 674:
Page 675 and 676:
Page 677 and 678:
Page 679 and 680:
Page 681 and 682:
Page 683 and 684:
Page 685 and 686:
Page 687 and 688:
Page 689 and 690:
Page 691 and 692:
Page 693 and 694:
Page 695 and 696:
Page 697 and 698:
Page 699 and 700:
Page 701 and 702:
Page 703 and 704:
Page 705 and 706:
Page 707 and 708:
Page 709 and 710:
Page 711 and 712:
Page 713 and 714:
Page 715 and 716:
Page 717 and 718:
Page 719 and 720:
Page 721 and 722:
Page 723 and 724:
Page 725 and 726:
Page 727 and 728:
Page 729 and 730:
Page 731 and 732:
Page 733 and 734:
Page 735 and 736:
Page 737 and 738:
Page 739 and 740:
We would like to acknowledge the ef
Page 741 and 742:
Page 743 and 744:
Page 745 and 746:
Page 747 and 748:
CHAPTER 12Role of Xenobiotic Metabo
Page 749 and 750:
ROLE OF XENOBIOTIC METABOLISM IN DE
Page 751 and 752:
Page 753 and 754:
Page 755 and 756:
Page 757 and 758:
Page 759 and 760:
Page 761 and 762:
Page 763 and 764:
Page 765 and 766:
Page 767 and 768:
y ESR spectrometry. 122 Further ESR
Page 769 and 770:
Page 771 and 772:
Page 773 and 774:
Page 775 and 776:
Page 777 and 778:
Page 779 and 780:
Page 781 and 782:
Page 783 and 784:
Page 785 and 786:
Page 787 and 788:
Page 789 and 790:
Page 791 and 792:
Page 793 and 794:
CHAPTER 13Use of Toxicokinetics in
Page 795 and 796:
USE OF TOXICOKINETICS IN DEVELOPMEN
Page 797 and 798:
Page 799 and 800:
Page 801 and 802:
Page 803 and 804:
Page 805 and 806:
Page 807 and 808:
Page 809 and 810:
Page 811 and 812:
Page 813 and 814:
Page 815 and 816:
Page 817 and 818:
Page 819 and 820:
Page 821 and 822:
Page 823 and 824:
Page 825 and 826:
Page 827 and 828:
Page 829 and 830:
Page 831 and 832:
Page 833 and 834:
Page 835 and 836:
Page 837 and 838:
Page 839 and 840:
Page 841 and 842:
Page 843 and 844:
Page 845 and 846:
Page 847 and 848:
Page 849 and 850:
Page 851 and 852:
Page 853 and 854:
Page 855 and 856:
Page 857 and 858:
Page 859 and 860:
Page 861 and 862:
Page 863 and 864:
Page 865 and 866:
Page 867 and 868:
Page 869 and 870:
Page 871 and 872:
Page 873 and 874:
Page 875 and 876:
Page 877 and 878:
Page 879 and 880:
Page 881 and 882:
Page 883 and 884:
Page 885 and 886:
Page 887 and 888:
Page 889 and 890:
Page 891 and 892:
Page 893 and 894:
Page 895 and 896:
Page 897 and 898:
Page 899 and 900:
Page 901 and 902:
Page 903 and 904:
Page 905 and 906:
Page 907 and 908:
Page 909 and 910:
Page 911 and 912:
Page 913 and 914:
Page 915 and 916:
Page 917 and 918:
CHAPTER 17Statistical Analysis for
Page 919 and 920:
STATISTICAL ANALYSIS FOR DEVELOPMEN
Page 921 and 922:
Page 923 and 924:
Page 925 and 926:
Page 927 and 928:
Page 929 and 930:
Page 931 and 932:
Page 933 and 934:
Page 935 and 936:
Page 937 and 938:
Page 939 and 940:
Page 941 and 942:
Page 943 and 944:
Page 945 and 946:
Page 947 and 948:
Page 949 and 950:
Page 951 and 952:
CHAPTER 19Perspectives on the Devel
Page 953 and 954:
PERSPECTIVES ON THE DEVELOPMENTAL A
Page 955 and 956:
Page 957 and 958:
Page 959 and 960:
Page 961 and 962:
Page 963 and 964:
Page 965 and 966:
Page 967 and 968:
Page 969 and 970:
Guideline OECD 415 (One Generation)
Page 971 and 972:
Page 973 and 974:
Page 975 and 976:
Page 977 and 978:
Page 979 and 980:
Page 981 and 982:
Page 983 and 984:
Page 985 and 986:
Page 987 and 988:
Page 989 and 990:
Page 991 and 992:
Page 993 and 994:
Page 995 and 996:
Page 997 and 998:
The Office of Prevention, Pesticide
Page 999 and 1000:
Page 1001 and 1002:
Page 1003 and 1004:
Page 1005 and 1006:
Page 1007 and 1008:
Page 1009 and 1010:
Page 1011 and 1012:
Page 1013 and 1014:
Page 1015 and 1016:
Page 1017 and 1018:
CHAPTER 20Human Studies — Epidemi
Page 1019 and 1020:
HUMAN STUDIES 801I. INTRODUCTIONEpi
Page 1021 and 1022:
HUMAN STUDIES 803is actively trying
Page 1023 and 1024:
HUMAN STUDIES 805100908070Induced a
Page 1025 and 1026:
HUMAN STUDIES 8071009590>37 w33-36
Page 1027 and 1028:
HUMAN STUDIES 80940003500Mean birth
Page 1029 and 1030:
HUMAN STUDIES 811from monstrous, us
Page 1031 and 1032:
HUMAN STUDIES 813A distinction is s
Page 1033 and 1034:
HUMAN STUDIES 815G. Childhood Cance
Page 1035 and 1036:
HUMAN STUDIES 817( P1- P2) f ( 1 -
Page 1037 and 1038:
HUMAN STUDIES 8195. Misclassificati
Page 1039 and 1040:
HUMAN STUDIES 821Table 20.1Maternal
Page 1041 and 1042:
HUMAN STUDIES 823are used, but the
Page 1043 and 1044:
HUMAN STUDIES 825but also the magni
Page 1045 and 1046:
HUMAN STUDIES 827Table 20.4CaseSmok
Page 1047 and 1048:
HUMAN STUDIES 829B. The Formation o
Page 1049 and 1050:
HUMAN STUDIES 831Table 20.6Smoking
Page 1051 and 1052:
HUMAN STUDIES 833When different dru
Page 1053 and 1054:
HUMAN STUDIES 835of the number of s
Page 1055 and 1056:
HUMAN STUDIES 837with spina bifida
Page 1057 and 1058:
HUMAN STUDIES 83926. Haglund, B. an
Page 1059 and 1060:
CHAPTER 21Developmental and Reprodu
Page 1061 and 1062:
Page 1063 and 1064:
Page 1065 and 1066:
Page 1067 and 1068: DEVELOPMENTAL AND REPRODUCTIVE TOXI
Page 1095 and 1096: 878 DEVELOPMENTAL REPRODUCTIVE TOXI
Page 1117: There are six factors that may affe
show all

A Practical Approach, Second Edition=Ronald D. Ho.pdf

Create successful ePaper yourself

Delete template?

Save as template?