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

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402 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONwere the topics of interest because of recent experience with the pharmaceutical class effects ofinhibitors of the cyclooxygenase enzymes (COX inhibitors). Although there have been manyprevious examples of rare-effect issues, most have gone unnoticed or unpublicized, and not untilthis major class effect was identified was the topic given any focused regulatory attention. Becausethis issue is so important and intrinsic to developmental and reproductive toxicity bioassays, thissection of the chapter was modified from the Toxicology Forum presentation in which both thetopics of developmental and reproductive effects, and cancer were addressed. It is important tounderstand that in developmental and reproductive toxicity studies, most responses are likely tomanifest at substatistical rates. For a review of the COX-2 rare events evaluation, see Cook et al. 128In this section, examples from the authors’ historical control database illustrate the importanceof accruing and managing consistent control data (over time and based on good animal husbandryand techniques) to assist in the interpretation of results. The advantages of having a highly skilledand stable work force are also discussed. A few case studies are included to demonstrate how datawere interpreted in selected controversial study outcomes. Finally, a stepwise approach to evaluatingrare findings and low incidence occurrences is presented.B. Scope of the ProblemThe goal for regulators is to gain knowledge of whether a condition, procedure, or chemical ordrug exerts adverse effects on reproduction or development. Their mandate is to evaluate risk tohumans with a sufficient degree of confidence to enable sound decision-making. This is accomplishedby critically reviewing results of animal safety studies and then extrapolating those resultsto humans. A high degree of concordance has been shown between human adverse effect scenariosand what can be demonstrated in rodents (as well as in the rabbit). 11,129–132 <strong>Ho</strong>wever, when theincidence of a finding is too low for statistical identification or confirmation, it becomes moredifficult to separate an adverse effect from normal biological variability. For example, what doesa ventricular septal defect in one high-dose group fetus (out of 150 to 325 fetuses evaluated) signifyin terms of potential human effects? Likewise, what is the human hazard of two to three rodentswith total litter loss during the lactation period?The FDA has defined rare incidence as “…an endpoint that occurs in less than 1% of the controlanimals in a study and in historical control animals.” 5 This definition, from a statistical point ofview, has an inherent problem. Animal safety studies are not (per guideline) designed with such adegree of statistical power (number of animals) that the statistical significance of 1 in 100 occurrencescan be detected. Furthermore, upon evaluation of historical control data, responses for almostall of the critical developmental defects are seen to occur at a frequency of less than 1 in 100.Table 9.37 provides a comparison of overall spontaneous malformation prevalence in differentspecies. 133 The data demonstrate the challenge of detecting rare events in safety testing. In additionto the rare event–related statistical issues, incidences of malformations are much lower in laboratoryanimals than in humans, further complicating extrapolation. The background incidence of spontaneousmalformations is particularly low in the rat. Because of this, the rat is a sensitive model fordetecting rare events.Concern for two to three malformations per group in animal studies is appropriate, even thoughthere may not be statistically significant differences from the concurrent control group for theincidences of individual or total malformations. The challenge is how to differentiate the effect ofa test agent from mere biological variation.An example of the challenge inherent in evaluating low incidence findings occurred in a recentstudy in the authors’ laboratory in which athyrosis was noted upon macroscopic examination in ahigh-dose group Crl:CD ® (SD)IGS BR rat fetus (this malformation had not been seen previouslyin approximately 80,000 control and test fetuses of this rat strain). Several other fetuses distributedin multiple litters in the high-dose group had enlarged or rudimentary thyroids, and cleft palatewas observed at 4.5% per litter in that same dosage group. Although athyrosis occurred in only© 2006 by Taylor & Francis Group, LLC
DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 403Table 9.37Spontaneous malformation rates invarious species aSpecies Mean (%) Range (%) Fetuses (N)Rat 0.33 0–1.6 9643Mouse 1.2 0–3 5207Rabbit 3.2 0–10 4708Dog 5.5 5.3–5.7 167Human 4 3–9 Multiple surveysSource: Data for rat, mouse, rabbit, and dog malformationrates originate from the historical control databaseat WIL Research Laboratories, Inc. Human data wereobtained from the March of Dimes (2003) and personalcommunication from Ken Jones (2003).Table 9.38Selected malformation rates in control fetuses(means of study means)Rat Incidence Rabbit IncidenceMalformation (% per Litter) a (% per Litter) bVentricular septal defect 0.00 0.02Cleft lip or palate 0.02 0.04Abdominal wall defect (including gastroschisis) 0.04 0.06Hydrocephaly 0.03 0.20Spina bifida 0.00 0.17Renal agenesis 0.01 0.02Diaphragmatic hernia 0.00 0.04Retroesophageal aortic arch 0.01 0.01a61 Crl:CD ® (SD)IGS BR rat developmental toxicity studies conducted at WIL (1998 to 2003)b81 Hra:(NZW)SPF rabbit developmental toxicity studies conducted at WIL (1992 to 2003)one fetus, this finding was considered an adverse effect in view of the following: (1) the rare natureof the finding, (2) other clear signals of structural malformation (cleft palate) at the high dose level,and (3) other alterations in fetal thyroid structure, revealing a pattern of insult. The relationship totreatment of a single case of athyrosis occurring independently would have been much less clear.To further illustrate the challenge of discerning the significance of rare event findings, a fewexamples of malformations that have occurred as rare events or low incidence findings in numerousscenarios are listed in Table 9.38. Among the 21,000+ control Crl:CD ® (SD)IGS BR rat fetuses inthe authors’ historical control database, ventricular septal defects, spina bifida, and diaphragmatichernia have never been detected. <strong>Ho</strong>wever, spina bifida and diaphragmatic hernia have beenobserved in treated fetuses. Because any occurrence of a malformation is such a rare event, therelationship between the agent tested and the occurrence of a malformation is difficult to discern.On the other hand, the low background incidence of malformations makes it easier to distinguishsubtle teratogenic events in those cases where the agent causes only a few malformations, givenappropriately rigid and consistent historical control values. In the absence of such standards, thehistorical control database will be of limited use for identification of teratogens, and interpretationof the findings becomes even more confounded and without a reliable basis for comparison.Further complicating matters is the interdependence of endpoints. The developing embryo orfetus, for example, is entirely reliant upon the maternal milieu for proper growth and development.Maternal stress has been shown to cause cleft palate in mice. 70 Antibiotics may produce embryoor fetal lethality and/or cause abortion in rabbits by adversely affecting the maternal gut flora, 75,134and the rat embryo and fetus has been shown to depend upon maternal zinc for proper development.135 Therefore, determining whether a fetal malformation is caused by the maternal condition© 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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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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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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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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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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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 837with spina bifida
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CHAPTER 21Developmental and Reprodu
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There are six factors that may affe
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