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

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Table 19.6Comparison of current guidelines for the assessment of embryo and fetal developmentGuideline ICH 4.1.3 2 EPA OPPTS 870.3700 22 FDA Red Book 21 OECD 27Species (No.)MatingRoute of testcompoundadministrationExposure to testcompoundProcedures on testanimalsOne rodent, preferably rats; onenonrodent, preferably rabbitsPlug, sperm, or insemination is day0Similar to the route used byhumansFrom implantation to the closure ofthe hard palateDam: clinical signs, body weight,feed; necropsy, preserve organswith macroscopic findings; countcorpora lutea; implantations (liveand dead conceptuses)Fetal: gender, body weight, fetalabnormalities (gross, soft tissue,and skeletal; rodents: half skeletaland half soft tissue; rabbits: allfetuses, gross evaluation ofplacentasRodent, e.g., rat, and nonrodent,e.g., rabbit (approximately 20animals with implantation sites atnecropsy)Mate females with males of thesame strain and species; plug orsperm is day 0Orally by intubation or potentialhuman exposure (needjustification)From at least the day ofimplantation to day beforeparturition, or from fertilization today before terminationDam: clinical signs, body weight,feed; terminal weight, grossnecropsy; examine uterinecontents (live and deadconceptuses), examine nongraviduteruses, weigh gravid uterus(with cervix), count corpora luteaFetal: gender, body weight, fetalabnormalities (external, skeletal,and soft tissue anomalies;rodents: half skeletal and half softtissue; rabbits: all fetuses)Rats, rabbits, hamsters, or mice(minimum 20 pregnant)In-house recommended; one maleto one or two females; plug orsperm is day 0Intended human exposure (diet ordrinking water)From implantation to day beforeparturition, or from fertilization toterminationDam: clinical signs, body weight,feed; terminal weight, grossnecropsy; gravid uterine weight,examine uterine contents (live anddead conceptuses), countcorpora luteaFetal: gender, body weight, fetalabnormalities (external, skeletal,and soft tissue anomalies;rodents: half for skeletal and halffor soft tissue; rabbits: all fetuses)Rats, rabbits, mice, or hamsters(20 pregnant)Mate females with males of thesame strain and species; plug orsperm is day 0Orally by intubation; alternate routewith justificationFrom preimplantation throughentire gestation period to the daybefore caesarean-sectioningDam: clinical signs, body weight,feed, terminal weight, grossnecropsy; examine nongraviduteri, gravid uterine weight (withcervix), examine uterine contents(live or dead conceptuses), countcorpora luteaFetal: gender, body weight, fetalabnormalities (external, skeletal,and soft tissue anomalies;rodents: half for skeletal and halffor soft tissue; rabbits: all fetuses)748 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITION© 2006 by Taylor & Francis Group, LLC
PERSPECTIVES ON THE DEVELOPMENTAL AND REPRODUCTIVE TOXICITY GUIDELINES 749Table 19.7Comparison of current guidelines for the postnatal and behavioral assessmentsGuideline ICH 4.1.2 a EPA OPPTS 870.6300 b Book cFDA RedSpecies (No.)MatingRoute of testcompoundadministrationExposure to testcompoundProcedures on testanimalsAt least one species,preferably ratsPlug, sperm, orinsemination is day 0Similar to the route usedby humansFrom implantation to theend of lactationFemales deliver and rearoffspring to weaning;select oneweanling/sex/litter toassess reproductivecompetenceMaternal observations:clinical signs, bodyweight, and feedconsumptionNecropsy: all adults,preserve organs withmacroscopic findingsfor possible histologicalevaluation;implantations,abnormalities inoffspring, live or deadoffspring at birth, bodyweight at birth, pre- andpostweaning survivaland growth and bodyweight, maturation andfertility, physicaldevelopment, sensoryfunctions, reflexes, andbehaviorOECD dApproximately 20 pregnant rats incontrol group; similar numbers formating pairs in treatment groups— —Mate females with males of the— —same strain and species (plug orsperm is day 0)Oral (diet, drinking water, or gavage) — —From implantation through day 10postnatallyDams: detailed clinical observations,including assessment of signs ofautonomic function; description ofabnormal movements, posture,gait, and behavior, etc.; bodyweights (at least weekly, day ofdelivery, and PDs 11 and 21)Observation of offspring: dailycageside observations (PDs 4, 11,21, 35, 45, and 60) for gross signsof mortality or morbidityDevelopmental landmarks: countand weigh live pups (PDs 0, 4, 7,14, and 21, then every 2 weeks)and assess sexual maturation; cullon PD 4Behavior: learning and memory(weaning and adulthood), motoractivity (PDs 13, 17, 21, and60 ± 2), auditory startle (PDs 22and approximately PD 60)Neuropathology: on PND 11 and attermination, remove and weighbrains of 1 pup/sex/litter (total10/sex/dosage group), then select6 pups/sex/dose forneuropathological evaluation— —— —aFDA, Fed. Regist., 59(183), 1994.bPostnatal assessments are covered in the EPA OPPTS 870.6300 Development Neurotoxicity study and EPAOPPTS 870.3800 multigeneration guideline.cPostnatal assessments are covered in the FDA “Redbook” two generation guideline.dPostnatal assessments are covered in the OECD 415 and 416 multigeneration guidelines PND(s) = day(s)postnatal.toxicity studies. As noted for male animals, reduced fertility may have many causes, and theproduction of a litter is not sufficient to assume the absence of an effect on reproductive performance.Rats and mice generally have multiple intromissions in one copulatory interval, and such activitygenerally is associated with improved fertility in the females. Should it appear that aberrant copulatorybehavior is present, videotaping the animals and grading the numbers of copulations (matings) andintromissions, duration of intromission, and expected female receptivity (lordosis) is recommended.The ICH guidelines do not identify specific methods for performing the sperm evaluations,while EPA protocols require evaluation of specific parameters by recommended methodologies,generally including automated sperm evaluations. There are two generally used automated techniques,the Cellsoft System and the Hamilton Thorne System. While the Cellsoft system had themost advanced technical capacity, and hand methods are sufficient to meet the guideline requirements,86,87 the Hamilton Thorne System has become that most widely used.© 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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CHAPTER 7Developmental Toxicity Tes
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DEVELOPMENTAL TOXICITY TESTING —
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Female 0.00-0.69 0.004-0.39 0.00-0.
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Figure 8.11775Pott DescribesScrotal
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The underlying physiology of juveni
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Table 8.5Total body composition by
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Table 8.6Serum chemistry values for
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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 9.48What 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 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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