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

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242 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITION432Brain olfactory labesVitreous chamberwith lensCuts and faces ofsections shown below1ComeaPalate3Nasal sinusRetina1CerebralhemispheresLateralventriclesNasal sinusesThirdventricleNasal seplum42PalateFigure 7.7Diagram of five sections typically observed during examination of a normal term (GD 20) fetalrodent head.The fourth cut is made through the largest vertical diameter of the cranium, well in front ofthe ear flaps. The thalamus, surrounding the slitlike third ventricle, will occupy a large central area,and the left and right cerebral hemispheres should surround it dorsolaterally. The lateral ventriclesand cerebellum can be visualized, as can the pons and medulla oblongata (brainstem). After thiscut, the final posterior section of the brain should be lifted from the cranial vault for a superficialobservation of the cerebellum and surrounding structures.After examination, the fetal head sections (rodents) may be stored in labeled cassettes (e.g.,Tissue-Tek Uni-Cassette, Miles, Inc., Diagnostics Division, Elkhart, IN) and sealed in plastic bags(one per litter), with 70% ethanol as a preservative. Rabbit head sections from each fetus may besealed in an individual, plastic, heat-sealable bag with 70% ethanol. All the bags from a litter canbe stored in a single larger bag.© 2006 by Taylor & Francis Group, LLC
DEVELOPMENTAL TOXICITY TESTING — METHODOLOGY 243g. Skeletal ExaminationCurrently, the remaining 50% of the litter for rodents (intact, not decapitated) and 100% of thelitter for rabbits are processed and examined for skeletal alterations. Fetal carcasses are evisceratedand prepared for staining with alizarin red S (for ossified bone) 83 or “double stained” with alizarinred S and alcian blue (for ossified and cartilaginous bone plus other permanent cartilaginousstructures, such as the tip of the nose, external pinnae, etc.). 84,85 New guidelines require evaluationof both cartilaginous and ossified skeletal components but do not specify how (double staining isthe preferred method and strongly recommended).1) Single Staining for Ossified Bone — Two and one-half days is the minimum time requiredto hand stain rodent fetuses for skeletal evaluation. <strong>Ho</strong>wever, commercially available automaticstainers (e.g., the Sakura Teratology Processor from Sakura Finetek, USA, Inc., Torrance, CA)allow very rapid single or double staining of fetuses, with appropriate documentation for GLPcompliance.Once fetuses are eviscerated, they are immersed in 70% ethanol at least overnight in preparationfor staining. 86,87 The ethanol is drained off the next morning and replaced with 1% potassiumhydroxide (KOH) solution containing alizarin red S (25 mg/liter of solution) for 24 h. After 24 h,this is poured off and replaced with a fresh 1% KOH solution (without alizarin). 88 Six hours later,the 1% KOH is replaced with 2:2:1 solution (2 parts 70% ethanol to 2 parts glycerin to 1 partbenzyl alcohol). The next morning the 2:2:1 solution is decanted and replaced with a 1:1 solution(1 part 70% ethanol to 1 part glycerin). The skeletons can remain in this solution indefinitely forevaluation and storage.Seven to eight days is the minimum time required to process a rabbit fetus for skeletalexamination. Once the fetus has been eviscerated, it is skinned, placed in a partitioned plastic box,and either air dried overnight or placed in 70% ethanol. The following morning, the ethanol isdrained off and replaced with KOH solution containing alizarin red S as described above. Fortyeighthours later, this staining solution is decanted and replaced with a fresh 1% KOH solution.After up to 4 d, depending on the size of the fetus, the 1% KOH is replaced with the abovementioned2:2:1 solution. The next morning the 2:2:1 solution is decanted and replaced with 1:170% ethanol to glycerin for evaluation and storage.2) Double Staining for Ossified Bone and Cartilaginous Tissue — Rodents — Fetusesshould be skinned (or the skin should be separated from the underlying tissue at least) afterevisceration to allow the alcian blue to penetrate. The fetus is immersed in a 70°C water bath forapproximately 7 s (the fetus will appear to “unfold”). The epidermis is then peeled off the body,paws, and tail. This is best done by a gentle rubbing between the thumb and fingers, as the skeletonat this point is extremely fragile. The skeleton is placed in 95% ethanol overnight. The followingmorning, the ethanol is drained and replaced with alcian blue stain (15 mg alcian blue to 80 ml95% ethanol to 20 ml glacial acetic acid). This is decanted after 24 h and replaced with 95% ethanolfor 24 h. The following morning, the 95% ethanol is decanted, and the skeletons are placed inalizarin red S staining solution (25 mg/l of 1% KOH) for 24 to 48 h. The stain is drained andreplaced with 0.5% KOH for 24 h; this step may not be necessary for small specimens. After the0.5% KOH solution is decanted, it is replaced with 2:2:1 solution (70% ethanol to glycerin tobenzyl alcohol). The following morning the fetal skeletons are placed in 1:1 70% ethanol to glycerinfor evaluation and storage. 89,90Rabbits — The process is the same as for staining with alizarin red S, with the following alterations.After skinning, the fetal skeletons are placed in 95% ethanol. The following morning the ethanolis decanted and replaced with the alcian blue stain (see rodent staining for formulation). Thespecimens remain in the alcian blue for approximately 24 h and are then placed in 95% ethanol© 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 6.10DescriptionMuscular Syste
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Distalphalanges offingersseparatedF
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Table 6.11DescriptionIntermediateme
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Table 6.12DescriptionComparative ge
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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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HUMAN STUDIES 805100908070Induced a
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HUMAN STUDIES 80940003500Mean birth
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HUMAN STUDIES 813A distinction is s
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HUMAN STUDIES 829B. The Formation o
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HUMAN STUDIES 837with spina bifida
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HUMAN STUDIES 83926. Haglund, B. an
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CHAPTER 21Developmental and Reprodu
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There are six factors that may affe
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