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Aspects of Postnatal Growth - Ontogeny of Organ Systems
This document discusses organ system maturation in different species. It begins with an overview of concepts like physiologic time and ontogeny recapitulating phylogeny. It then reviews challenges in selecting animal models for preclinical pediatric toxicity testing due to differences in developmental processes across species. The document also compares maturation of organ systems, reproductive development, and other milestones in rats and humans. It notes strengths and weaknesses of current safety assessment approaches and suggests modifications.
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Aspects of Postnatal Growth - Ontogeny of Organ Systems
- 1. Overview Aspects of PostnatalGrowth: Ontogeny of Organ Systems Joseph F. Holson WIL Research Laboratories
- 2. Acknowledgements WIL Research Laboratories SmithKlineBeecham • John M. DeSesso • Catherine F. Jacobson • Amy L. Lavin • Bennett J. Varsho • James L. Schardein • Patrick J. Wier
- 3. Organization • Prenatal Modelsand Ontogeny • Concept of Physiologic Time • Review of Adolph’s Seminal Work • Difficulties in a priori Selection of Models for Nonclinical Pediatric Toxicity • Strengths and Weaknesses of Current Safety Designs
- 4. Why are weinterested in organ system maturation? It is essential for comparing postnatal toxicity among species.
- 5. Prenatal Models andOntogeny
- 6. Attributes of SuccessfulModels for Safety Assessment • • • • Validity Sensitivity Reproducibility Practicability
- 7. Differentiation Increases withAge of Developing Organisms
- 8. Animal: Human ConcordanceStudies for Prenatal Toxicity Authors Attributes Holson et al., 1981 (Tox Forum) Kimmel et al., 1984 (NCTR Report) Interdisciplinary team Criteria for acceptance of data/conclusions Concept of multiple developmental toxicology endpoints No measures of internal dose Nisbet & Karch, 1983 Many chemicals Relied on authors’ conclusions Emphasis on fertility No measures of internal dose
- 9. Animal: Human ConcordanceStudies for Prenatal Toxicity Authors Attributes Hemminki & Vineis, 1985 Interspecies inhalatory doses adjusted Relied on authors’ conclusions 23 occupational chemicals and mixtures No measures of internal dose Newman et al., 1993 Provided detailed information Only 4 drugs Emphasis on morphology Focus on NOAELs No measures of internal dose Schardein, 1995 Many chemicals Relied on authors’ conclusions No measures of internal dose
- 10. Ontogeny Recapitulates Phylogeny (vonBaer, 1828) • General features appear earlier in embryos than do specialized features • Embryos of higher animals pass through stages that are similar to those of embryos of lower species
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- 15. Ontogeny, Inc., basedin Cambridge, MA, applies recent discoveries in developmental biology to the treatment of human diseases. Ontogeny has proprietary rights to a number of molecules known to induce cell differentiation, including several members of the hedgehog gene family that play a role in disorders involving the central nervous system, bone and cartilage, fertility and cancer. Ontogeny has signed a collaborative agreement with Biogen and with Genetics Institute to develop hedgehog proteins for neurological disorders, and Boehringer Mannheim in bone development and repair.
- 16. Concept of PhysiologicTime Comparisons among Species Comparisons among Developmental Stages
- 17. Maturational Data forVarious Species Human Gestation (days) Minimal Breeding Age (weeks) Human to Animal Life Span Syrian Hamster Mouse Rat Rabbit Guinea Pig Rhesus Monkey 267 16 20 22 32 63 167 7 10.5 44 33 728 1.0 5 6.5 66 28 32 12 4 10 17 218 4.4
- 18. Background • Adolph (1949)showed that metabolic rates scale across species according to (body weight)0.73. • Boxenbaum (1982) demonstrated that the disposition kinetics of xenobiotics in species is scaled by the same relationship. • These concepts led to the mathematical relationships that are used to standardize experimental dose regimens and to scale across species in PBPK models.
- 19. Physiologic Time A methodfor scaling the lifespan of different species so that comparable stages of maturation are congruent, regardless of chronological age An example of the concept of physiologic time that is intrinsic to PBPK models: 0.25 T1/2 = Body Weight rat Body Weight human
- 20. Time to DevelopAdult Characteristics 100 Rat Human % Adult Status 0 0 5 10 Age (years) 15 20
- 21. Relationship Between Extentof Maturation and Birth in Rats and Humans 100% Adult Status = Birth Maturation Human Rat Conception Physiologic Time
- 22. Review of Adolph’sSeminal Work
- 23. Ontogeny of PhysiologicRegulation in Selected Mammals Hamster Rat Rabbit Cat Pig Human Stagemarks Implantation First Heart Beat Exterioception Hemoglobin 8% in Blood Body Weight 1gm Thyroid Iodine Lung Surfactant Liver Glycogen 0.05% Birth Water 85% of Fat-free Na/K one gm/gm Anoxia Tolerance 10 min. Body Fat 5% Arterial Pr. 50 mm/Hg Lethal Temp Shift Resistance to Cooling 4 After Adolph 1970 8 10 20 40 80 100 Days After Conception 200 400
- 24. Perinatal Changes inFetal Water and Fat Content Fat-Free Water Fraction Gestation Duration, Days Hamster Rat Rabbit Cat Guinea Pig Human Age at 90% H2O Days for Transit to 80% H2O 15* 17* 23* 23 19 20 38* 56* 96* 27 72 170 16 21 32 65 67 114 266 * Prenatal Body Fat Fraction Age at 2% Fat Days for Transit to 6% Fat 20 22 32 65 39* 116 210* 17 6 8 10 21 3 27 After Adolph and Heggeness, 1971
- 25. Comparative Perinatal Water Content 95 Pig Rabbit 90 %Water In a Fat-Free Body 85 * GP Rat = Birth Human * * Water fraction decreases with age in all species * Hamster * * 80 * 75 10 30 100 Days After Conception 300 After Adolph and Heggeness, 1971
- 26. Comparative Water Contentat Birth 95 90 % Water In a Fat-Free Body Hamster Rabbit Rat Do g 85 Mouse Pig Human Cat 80 Longer gestation develops drier (“denser”) animals Guinea Pig 75 10 30 100 Days After Conception 300 After Adolph and Heggeness, 1971
- 27. Comparative Ontogeny ofFat Content 30 Hamster Rat Rabbit 25 Guinea Pig Cat % Fat In Body 20 Fetal Guinea Pig and human deposit fat prior to birth Pig Human * 15 * = Birth * 10 5 0 10 * * * 30 * * 100 Days After Conception 300 After Adolph and Heggeness, 1971
- 28. Comparative Perinatal FatContent 15 10 Hamster % Fat In Body Guinea Pig Birth Birth 5 0 10 20 30 40 50 60 Days After Conception After Adolph and Heggeness, 1971 70 80
- 29. Difficulties in apriori Selection of Models for Preclinical Pediatric Toxicity
- 30. Relationship Between Development andPhenotypic Diversity Extent of Differentiation Embryonic Period Fetal Period Postnatal Period Degree of Phenotypic Variability Birth Time in Development (Age)
- 31. Presence of EnzymesDuring Embryonic (E), Fetal (F), and Neonatal (N) Periods CYP1A1 CYP1A2 CYP1B1 CYP2E1 CYP3A4 CYP3A5 CYP3A7 CYP2C8 CYP2C9 CYP2D6 Flavin-containing monooxygenase Prostaglandin synthetase Lipoxygenase Perosidase Epoxide hydrase GSH-S-transferase UDP-glucuronyltranferase Sulfotransferases E + – + – – – Rat F N + + – + + + – – – Mouse E F N + + + – + + + + – – – – – – + + Hamster E F N Rabbit E F N G. Pig E F N + + + – + + – + + Data extracted from Juchau et al., Kulkarni, 1997; Miller et al., 1996; Oesterheld, 1998; Raucy and Carpenter, 1993. CYP=cytochrome P450 + + Human E F N + + – – – + + + + + + – – + + + + + + – + + – – + + + + + + + + + +
- 32. Selected Milestones ofReproductive Development in Rats and Humans Event Rat Human gd 13 gd 35-37 gd 13-14 gd 40-42 gd 17 gd 60-70 gd 15 - pnd 16 fetal - to puberty? Oocytes initiate meiosis gd 17 gd 84 Arrest of meiosis in females pnd 5 by pnd 56 Testes descend into scrotum pnd 21 gd 220-225 Pubertal period: females pnd 30-38 12-13 years Pubertal period: males pnd 35-60 13-15 years Germ cells in genital ridges Gonads begin sexual differentiation Leydig cells differentiate Sertoli cells proliferate
- 33. Comparison of Times inMale Sexual Development Birth Conception Genital Tubercle Genital Development Static Formation Rat Human Adult Status Secondary Sexual Characteristics 3 Days 19 Days 50 Days 14 Days 8 Months 14 Years
- 34. Challenges of “Mining”the Literature • Limited attention given to the issue of postnatal models for safety assessment • There is a paucity of reviews / data compilations • Isolated key information is embedded in papers addressing other concerns • Analysis requires interdisciplinary expertise and commitment of resources • Many and substantial data gaps (species and organ systems) exist
- 35. Strengths and Weaknesses ofCurrent Safety Designs Suggested Modifications Additional Strategies
- 36. Effects on Prenataland Postnatal Development Including Maternal Function ICH 4.1.2 (Segment III) GD 6 Female (Rat) PND 20 Gestation Lactation (Macroscopic Pathology) F1 Denotes Treatment Period Denotes Possible Transfer Via Milk Weaning Growth PN day 21 9 wks PN day 17 Mating 2 wks Gestation 3 wks PN day 80 Behavioral/Anatomic Measures Motor Activity Auditory Startle Water Maze Developmental Landmark Vaginal Patency Preputial Separation F2
- 37. Comparison of Prenatal andPostnatal Toxicity Profiles Maternal Toxicity Developmental Log of Dose Prenatal – valid and insightful – Embryonic exposure – Mode of action Postnatal – valid only – when xenobiotic level is measured in both mother and offspring
- 38. Comparison of Prenataland Postnatal Modes of Exposure Prenatal Embryo/Fetus Placenta Treatment Mother Prenatal Postnatal Mammae Neonate Postnatal Drug Transfer to Offspring Nearly all transferred Apparent selectivity (“barrier”) Drug Levels in Offspring Cmax and AUC measured Not routinely measured Maternal Blood vs. Offspring Levels Maternal often a surrogate Maternal levels probably NOT a good predictor Exposure Route to Offspring Modulated IV exposure, via placenta Oral, via immature GI tract Commentary Timing of exposure is critical Extent of transfer to milk and neonatal bioavailability is key to differentiating indirect (maternal) effects from neonatal sensitivity
- 39. Critical Periods forStructural and Functional Effects Structural Development Sensitivity Functional Development Organogenesis Time
- 40. ACE Inhibition-Induced Fetopathy (Human) ACEinh Fetal Hypotension Renal Compromise (Anuria) Calvarial Hypoplasia Oligohydramnios NeonatalAnuria IUGR Death • Organogenesis (classically defined) is unaffected • Effects are severe • Risk is low • Caused by ACEinh that cross placenta
- 41. ACE Inhibition inDeveloping Rats • RAS (renin-angiotensin system) matures around GD17 • No ‘apparent’ effect in initial reproductive studies • Subsequent postnatal studies with direct administration to pups – Growth retardation – Renal alterations (anatomic and functional) – Death
- 42. Examples of Perinatal/Juvenile Toxicants •The following examples are not the result of an exhaustive literature search. • In most instances, the cause of postnatal morbidity/ mortality has not been investigated or is not known. • The absence of standard blood biochemistry/hematology assays and target organ pathology hinders the identification of sites and modes of action.
- 43. Examples of Perinatal/Juvenile(?) Developmental Toxicants Toxicant Exposure Period Species Endpoint Estrogen PND1-5 mouse cervical/vaginal cancer adult Dunn & Green, 1963; Takasagi & Bern, 1964 DES prenatal human vaginal cancer/ reprod. tract effects pubescence Herbst & Skully, 1970 DES Sex hormone PND1-5 PND1-5 mouse mouse vaginal adenosis vaginal adenosis/ cancer adult adult Forsberg, 1976 GD15, 16, 17 mouse vaginal adenosis, transverse ridges adult Walker, 1980 (DES) DES Time of Manifestation (14 mo.) Reference Bern et al., 1976
- 44. Selective Juvenile Toxicityof Quinilones Drug Ofloxacin (and other quinilones) Species & Treatment Effects Remarks Multiple Species, postnatal exposure. 20mg/kg (dog, 3 mo.) 600mg/kg (rat, 5 wk) Chondrotoxic effects. Cartilage erosion in weightbearing joints. Human relevance unknown; drugs contraindicated in juvenile patients. Gait alterations in juvenile dogs only. Mechanism: Probable deficiency of bioavailable Mg2+ in cartilage (quinilones chelate divalent cations). No effect in routine segment III studies. Modified from Stahlmann et al., 1997.
- 45. Reasons for IncreasedAttention to Juvenile Toxicity • New Trends in Drug Discovery – Chiral molecules – Rational, structure-based molecular design – Targeted pharmacology • Attention to Sensitive Subpopulations in Human Risk Assessment – Food Quality Protection Act – FDA Modernization Act
- 46. Challenges • Identifying andmanaging risks – Modulation of growth – Alteration of functional maturation • Examples: – EGF, TGF, Leptin, KGF, CRF
- 47. Pediatric Classifications • Neonates Birthto 1 month • Infants 1 month to 2 years • Children 2 to 12 years • Adolescents 12 to <16 Years • Comparable categories for animal species dependent on individual organ or system
- 48. Non-Human Developmental Classifications Category Neonate Dog Rat(days) (wks) Primate (mos) Mini-Pig (wks) <10 <3 <0.5 <2 Infant 10-21 3-6 0.5-6 2-4 Child 21-35 6-20 6-36 4-14 Adolescent 35-60 20-28 36-48 14-26
- 49. Primary Reasons thatExperimental Models Appear to be Invalid • Findings at, or extrapolated to, exaggerated doses • Exposure to and internal dose of noxious agent not measured • Timing of exposure does not coincide with the appearance of the developmental target • Duration of exposure not scaled to physiologic time • Incorrect / unvalidated endpoints assessed • Too little knowledge / data concerning mode of action
- 50. Conclusions • Parallelism existsamong species regardless of lifespan. • Additional measurements and changes to current guidelines could increase our ability to predict postnatal toxicity. • Molecular biology and genomics have influenced pharmaceutical development toward agents with increasing specificity. • For novel, selective pharmaceutical agents, nonclinical testing must be preceded by literature mining and analysis.