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

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234 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONTable 7.8Summary of morphological abnormalities in control CD ® rat fetuses:listing by defect type a (continued)Gestational Days of DosingParameter 6–15 6–19Enlarged nasal sinus 1 (1) 2 (2)Agenesis of the innominate artery 1 (1) 5 (5)Pulmonary artery and aorta arise side by side from heart 1 (1)Extra piece of liver tissue on median liver lobe 1 (1)Very soft tissue: liver 1 (1)Blood under kidney capsule: Right 1 (1)Small papilla: Right 1 (1)Distended ureter:Bilateral 37 (21) 27 (18)Left 20 (17) 15 (12)Right 12 (9) 11 (10)Skeletal VariationsMisaligned sternebrae 2 (2)Unossified sternebra (I, II, III, and/or IV only) 5 (4)Rib on lumbar I:Bilateral full 3 (2)Left full 4 (4)Right full 1 (1) 1 (1)Bilateral rudimentary 31 (20) 6 (4)Left rudimentary 40 (29) 7 (6)Right rudimentary 15 (12) 3 (3)Short rib: XIII 5 (3) 2 (2)Wavy rib 1 (1)Incomplete ossification, cartilage present: thoracic centrum 1 (1)Dumbbell cartilage, normal ossification center: thoracic centrum 1 (1)Dumbbell cartilage, dumbbell ossification center: thoracic centrum 33 (19) 3 (3)Dumbbell cartilage, bipartite ossification center: thoracic centrum 10 (10) 40 (23)Normal cartilage, bipartite ossification center: thoracic centrum 36 (22) 70 (32)Normal cartilage, no ossification center: thoracic centrum 1 (1)Normal cartilage, unossified ossification center: thoracic centrum (VI-XIII only) 1 (1)aA single fetus may be represented more than once in listing individual defects. Data are presented as numberof fetuses (number of litters). See Table 7.7 for summary and statistical analysis of fetal malformation/variationincidence.bOnly live fetuses were examined.cIncludes only litters with live fetuses.dFor many studies, a single fetus was examined externally, viscerally, and skeletally.eOne fetus was lost during processing prior to skeletal examination.Source: Marr, M.C., Myers, C.B., Price, C.J., Tyl, R.W., and Jahnke, G.D., Teratology, 59, 413, 1999 (tablesprovided by the authors).E. Necropsy and Postmortem Examination1. MaternalMated females that die during the course of the study should be necropsied in an attempt todetermine the cause of death, with target tissues saved for possible histopathology. Females thatappear moribund should be humanely euthanized (by CO 2 asphyxiation for rodents and i.v. euthanasiasolution for rabbits) and necropsied to attempt to determine the cause of the morbidity, withtarget tissues saved for optional histopathology. Females showing signs of abortion or prematuredelivery should also be sacrificed, as described above, as soon as the event is detected. They shouldbe subjected to a gross necropsy, and any products of conception should be saved in neutral buffered© 2006 by Taylor & Francis Group, LLC
DEVELOPMENTAL TOXICITY TESTING — METHODOLOGY 235Table 7.9Some typical maternal clinical observationsAlteration of:Body positionActivityCoordinationGaitUnusual behavior, such as:Head flickingCompulsive biting or lickingCirclingRooting in bedding aPresence of:HemorrhagesPetechiaeConvulsions or tremorsIncreased salivationaIncreased lacrimation or other ocular dischargeRed-colored tears (chromodacryorrhea)Nasal dischargeIncreased or decreased urination or defecation (including diarrhea)PiloerectionMydriasis or miosis (enlarged or constricted pupils)Unusual respiration (fast, slow, gasping, or retching)VocalizationaSalivation pre- or postdosing and/or rooting in bedding postdosing mayindicate taste aversion (from gavage dosing). Palatability problemsfrom dosed feed or water are most likely to be detectable from reducedfeed or water intake initially, with “recovery” back to normal intakevalues over time.10% formalin. Approximately 1.0 to 1.5 d before expected parturition (GD 17 or 18 for mice, 20or 21 for rats, and 29 or 30 for rabbits), all surviving dams/does should be killed by CO 2 asphyxiation(rodents) or i.v. injection into the marginal ear vein (rabbits). They should be laparotomized, theirthoracic and abdominal cavities and organs examined, and their pregnancy status confirmed byuterine examination. Uteruses that present no visible implantation sites or that contain one-hornpregnancies should be stained with ammonium sulfide (10%) to visualize any implantation sitesthat may have undergone very early resorption. 62 Immersion of the uterus in ammonium (or sodium)sulfide renders it useless for fixation and histopathologic examination. When it is to be subsequentlyfixed and examined, the authors stain the fixed uterus with potassium ferricyanide by a methodthey developed to detect resorption sites. The stain is then washed out of the uterus, and the uterusis replaced in fixative for subsequent histopathologic examination (the staining does not interferewith subsequent evaluations).At sacrifice, the body, liver, any identified target organs, and the uterus of each mated femaleshould be removed and weighed. Any maternal lesions should be retained in appropriate fixativefor possible subsequent histologic examination. The ovarian corpora lutea should be counted todetermine the number of eggs ovulated (to allow calculation of preimplantation loss and to put thenumber of implants in perspective). For rabbits, each corpus luteum is a round, convex body witha central nipplelike projection; for rats, each corpus luteum is a round, slightly pink, discreteswelling (counted with the naked eye or under a dissecting microscope). For mice, the ovariancapsule must be removed (peeled off) and the corpora lutea counted under a dissecting microscope;each appears as a rounded, slightly pink, discrete swelling. For partially resorbed litters, the numberof corpora lutea may be less than the number of total implantation sites since corpora lutea involute(to become small corpora albicantia) when they no longer sustain live implants (note that theconcordance between number of resorbed implants and the loss of corpora lutea is not exact).Corpora lutea can be discounted for summarization when the count is less than the number of© 2006 by Taylor & Francis Group, LLC
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Second EditionDEVELOPMENTALandREPRO
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Published in 2006 byCRC PressTaylor
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Chapter 12Chapter 13Chapter 14Chapt
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The EditorRonald D. Hood, Ph.D., is
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Alan M. HobermanArgus ResearchHorsh
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APPENDIX ATerminology of Anatomical
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TERMINOLOGY OF ANATOMICAL DEFECTS 9
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Organ/StructureCodeNumberObservatio
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Organ/Structure10145 Ocular colobom
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Organ/StructurePulmonaryarteryPulmo
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Terminology of developmental abnorm
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Organ/StructureCervicalcentrumCodeN
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Organ/Structure10689 Misshapen thor
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Organ/StructureSacralcentrumSacralv
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968 DEVELOPMENTAL REPRODUCTIVE TOXI
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1000 DEVELOPMENTAL REPRODUCTIVE TOX
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Table 1Human Non-human Primate Rat
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Table 1 (continued)Sertoli CellsHum
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Table 2 (continued) Landmarks in th
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Table 2 (continued) Landmarks in th
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POSTNATAL DEVELOPMENTAL MILESTONES
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PART IPrinciples and Mechanisms© 2
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4 DEVELOPMENTAL REPRODUCTIVE TOXICO
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10 DEVELOPMENTAL REPRODUCTIVE TOXIC
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Table 2.6Receptor(Official Name a )
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Clearly, more research needs to be
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CHAPTER 6Comparative Features of Ve
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COMPARATIVE FEATURES OF VERTEBRATE
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Table 6.2Comparative reproductive a
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Maturation andRelease ofGametesSper
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Amniotic cavity 9.5 1.5 1-4 1-4,6,9
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Posteriorcardinal veinsestablishedT
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PosteriorcardinaldegenerationRight
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StomachappearsThirdpharyngealpouch;
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Table 6.6DescriptionComparative ges
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ParathyroidParathyroids 12.5 6.2 41
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Table 6.8DescriptionComparative ges
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Formation ofchoroid plexusof latera
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Optic nervefibers presentDifferenti
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Table 8.5Total body composition by
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Table 8.6Serum chemistry values for
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Table 8.7Parameter bHematology valu
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CHAPTER 9Significance, Reliability,
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DEVELOPMENTAL AND REPRODUCTIVE TOXI
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Prior to the early 1980s, numerous
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Figure 9.51906Food andDrugs Act2000
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Table 9.18Selected comparison point
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Table 9.33Selected comparison point
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Table 9.48What do regulatorswant to
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CHAPTER 10Testing for Reproductive
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TESTING FOR REPRODUCTIVE TOXICITY 4
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We would like to acknowledge the ef
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CHAPTER 12Role of Xenobiotic Metabo
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ROLE OF XENOBIOTIC METABOLISM IN DE
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y ESR spectrometry. 122 Further ESR
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CHAPTER 13Use of Toxicokinetics in
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USE OF TOXICOKINETICS IN DEVELOPMEN
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CHAPTER 17Statistical Analysis for
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STATISTICAL ANALYSIS FOR DEVELOPMEN
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CHAPTER 19Perspectives on the Devel
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PERSPECTIVES ON THE DEVELOPMENTAL A
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Guideline OECD 415 (One Generation)
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The Office of Prevention, Pesticide
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CHAPTER 20Human Studies — Epidemi
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HUMAN STUDIES 801I. INTRODUCTIONEpi
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HUMAN STUDIES 803is actively trying
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CHAPTER 21Developmental and Reprodu
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There are six factors that may affe
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