Juvenile Animal Research Articles

The anatomy of palate of Chroniosaurus dongusensis (Chroniosuchia, Chroniosuchidae) from the Upper Permian of Russia

Abstract: This article presents a detailed description and reconstruction of the palate of Chroniosaurus dongusensis, a chroniosuchid tetrapod from the Upper Permian of Russia, based on a new, chemically prepared specimen representing a juvenile animal with skull length of about 70 mm. It provides new information on this poorly known portion of the skull. The vomer, palatine and ectopterygoid are elongate bones bearing tusks on their lateral margins: six on the vomer, at least nine on the palatine and at least seven on the ectopterygoid. The anterior portion of the vomer is broad and meets its fellow in the median plane. The pterygoid is the largest and longest element of the palate. The anterior end of the pterygoid is divided into a pair of processes; the medial process meets its fellow in the median plane, and the anterior ends of these fit between the vomers. The medial margin of the palatal ramus bears no denticles and the edge is distinctly bevelled, produced into a dorsally inturned flange. The parasphenoid extends anteriorly into a long and narrow cultriform process located between the medial margins of the palatal rami of the pterygoids. The transverse process of the pterygoid is small, but distinct. The ventral surface of the pterygoid bears rows of small denticles that radiate from a site immediately lateral to the articular portion of the pterygoid. The posterior portion of the parasphenoidal plate extends into a short but distinct laterodorsally oriented processes. Using additional data derived from the current study, we performed a cladistic analysis based on an earlier one by the same authors. This analysis recovered 6 most parsimonious trees. The results differed slightly from the previous analysis in that all placed Chroniosaurus below the Visean and Namurian anthracosaur Eoherpeton at the base of the Embolomeri, a group of Upper Carboniferous stem amniotes, rather than more crownward as in some of the previous trees.

Application of ultrasound dilution technology for cardiac output measurement: Cerebral and systemic hemodynamic consequences in a juvenile animal model

Analysis of cerebral and systemic hemodynamic consequences of ultrasound dilution cardiac output measurements. : Prospective, experimental piglet study. Animal laboratory. Nine piglets. Ultrasound dilution cardiac output measurements were performed in ventilated, anesthetized piglets. Interventions that are required for ultrasound dilution cardiac output measurement were evaluated for its effect on cerebral and systemic circulation and oxygenation. DeltacHbD and DeltactHb, representing changes in cerebral blood flow and cerebral blood volume, respectively, were measured with near infrared spectrophotometry. Pulmonary artery (Q) and left carotid artery (Q) blood flow were assessed with transit time flow probes. Starting and/or stopping blood flowing through the arteriovenous loop did not cause relevant hemodynamic changes. Fast injection of isotonic saline caused a biphasic change in DeltacHbD and DeltactHb. After injection of 0.5 mL/kg, the mean (sd) increase in DeltacHbD and DeltactHb was 0.175 (0.213) micromol/L and 0.122 (0.148) micromol/L, respectively, with a subsequent mean decrease of -0.191 (0.299) micromol/L and -0.312 (0.266) micromol/L. Injection of 1.0 mL/kg caused a mean increase in DeltacHbD and DeltactHb of 0.237 (0.203) micromol/L and 0.179 (0.162) followed by a mean decrease of -0.334 (0.407) micromol/L and -0.523 (0.335) micromol/L, respectively. Q and Q changed shortly with a mean increase of 5.9 (3.0) mL/kg/min and 0.23 (0.10) mL/kg/min after injection of 0.5 mL/kg and with 12.0 (4.2) mL/kg/min and 0.44 (0.18) mL/kg/min after injection of 1.0 mL/kg, respectively. The observed changes were more profound after an injection volume of 1.0 mL/kg compared with 0.5 mL/kg for DeltacHbD (p = .06), DeltactHb (p = .09), Q, and Q (p < .01). No relevant changes in mean arterial blood pressure or heart rate were detected in response to the indicator injection. Cardiac output measurement by ultrasound dilution does not cause clinically relevant changes in cerebral and systemic circulation and oxygenation in a piglet model.

Juvenile animal studies for the nonclinical safety evaluation of therapeutic monoclonal antibodies for the paediatric population: Revision of approved medicines in Europe for the last 15 years

In vivo animal studies are required by regulatory agencies to investigate drug safety before clinical trials. In this review, we summarize the process of selecting a relevant non-rodent species for preclinical studies. The dog is the primary, default non-rodent used in toxicology studies with multiple scientific advantages, including adequate background data and availability. Rabbit has many regulatory advantages as the first non-rodent for the evaluation of reproductive and developmental as well as local toxicity. Recently, minipigs have increasingly replaced dogs and rabbits in toxicology studies due to ethical and scientific advantages including similarity to humans and breeding habits. When these species are not relevant, nonhuman primates (NHPs) can be used as the available animal models, especially in toxicology studies investigating biotherapeutics. Particularly, based on the phylogenetic relationships, the use of New-World marmosets can be considered before Old-World monkeys, especially cynomolgus with robust historical data. Importantly, the use of NHPs should be justified in terms of scientific benefits considering target affinity, expression pattern, and pharmacological cross-reactivity. Strict standards are required for the use of animals. Therefore, this review is helpful for the selection of appropriate non-rodent in regulatory toxicology studies by providing sufficient regulatory, ethical, and scientific data for each species.

Understanding Developmental Pharmacodynamics

Developmental pharmacodynamics is the study of age-related maturation of the structure and function of biologic systems and how this affects response to pharmacotherapy. This may manifest as a change in the potency, efficacy, or therapeutic range of a drug. The paucity of studies exploring developmental pharmacodynamics reflects the lack of suitable juvenile animal models and the ethical and practical constraints of conducting studies in children. However, where data from animal models are available, valuable insight has been gained into how response to therapy can change through the course of development. For example, animal neurodevelopmental models have revealed that temporal differences in the maturation of norepinephrine and serotonin neurotransmitter systems may explain the lack of efficacy of some antidepressants in children. GABA(A) receptors that switch from an excitatory to inhibitory mode during early development help to explain paradoxical seizures experienced by infants after exposure to benzodiazepines. The increased sensitivity of neonates to morphine may be due to increased postnatal expression of the mu opioid receptor. An age dependency to the pharmacokinetic-pharmacodynamic relationship has also been found in some clinical studies. For example, immunosuppressive effects of ciclosporin (cyclosporine) revealed markedly enhanced sensitivity in infants compared with older children and adults. A study of sotalol in the treatment of children with supraventricular tachycardia showed that neonates exhibited a higher sensitivity towards QTc interval prolongation compared with older children. However, the data are limited and efforts to increase and establish data on developmental pharmacodynamics are necessary to achieve optimal drug therapy in children and to ensure long-term success of pediatric drug development. This requires a dual 'bottom up' (ontogeny knowledge driven) and 'top down' (pediatric pharmacokinetic-pharmacodynamic studies) approach.

A BURROW CAST WITH LYSTROSAURUS SKELETAL REMAINS FROM THE LOWER TRIASSIC OF SOUTH AFRICA

Abstract We report on a large burrow cast with skeletal contents from Lower Triassic strata of the Palingkloof Member of the Balfour Formation, which forms the lowermost portion of the Lystrosaurus Assemblage Zone (LAZ) of South Africa. The burrow cast is similar to large burrow casts previously described from the LAZ that were identified as large-scale Scoyenia domichnia. It is the first large burrow cast from the LAZ found to contain diagnostic fossil bone. The burrow cast is a relatively straight, subhorizontal (inclined ∼12°), dorsoventrally compressed tube consisting of an entry ramp and living chamber; the entrance to the burrow is not preserved and there is no evidence that the ramp formed a spiral section. The skeletal material comprises a single, partial, disarticulated skeleton of a juvenile animal that can be assigned with confidence to the dicynodont genus Lystrosaurus. Whereas similar large-diameter burrow casts from strata slightly higher in the LAZ have been attributed to Lystrosaurus, we p...

Juvenile animal testing in drug development – Is it useful?

In pharmaceutical drug development, there has been increased interest in the need to perform juvenile animal studies to support the safety of use of new medicines in the pediatric population. Although such studies are not new, the increased interest has been “formalized” in recent regulatory guidelines. As a result, companies are now performing many more studies in juvenile animals, even when there is a lack of robust knowledge of cross-species functional and kinetic differences among juveniles that means extrapolation of any toxicology study finding to an immature human may not be easy or even relevant, especially if performed in the wrong species at the wrong time. It will be shown by presentation of some basic considerations needed in order to perform such testing, that juvenile animal studies are indeed feasible. However, it will also be highlighted that (based on available knowledge) there are currently not enough clear-cut examples to answer the question of whether juvenile animal toxicology studies to support pediatric development (by affecting the performance or design of a pediatric clinical trial or identifying a potential different-from-adult safety risk in clinical use) are truly useful or necessary.

Cardiac output measurement using an ultrasound dilution method: A validation study in ventilated piglets

To assess agreement between a new method of cardiac output monitoring, using ultrasound dilution technology and ultrasound transit time-based measurement of pulmonary blood flow in a piglet model. Prospective, experimental juvenile animal study. Animal laboratory of a university hospital. Nine random-bred piglets. After the animals received general anesthesia, we placed intravascular arterial and central venous catheters with the tip positioned in the abdominal aorta and the right atrium, respectively. The catheters were connected to the ultrasound dilution cardiac output monitor. An ultrasound transit time perivascular flow probe was positioned around the common pulmonary artery and served as the standard reference measurement. Cardiac output was manipulated during the experiment by creating hemorrhagic hypotension. Ultrasound dilution cardiac output was measured intermittently with injection volumes of 0.5 mL/kg and 1.0 mL/kg of isotonic saline at body temperature. Ultrasound dilution cardiac output (Q) measurement was compared with pulmonary blood flow (Q). Bias, defined as Q minus Q, was calculated for each measurement. Mean bias with standard deviation was calculated for measurements with volumes of injected saline, 0.5 mL/kg and 1.0 mL/kg, and compared using the Mann-Whitney U test. Mean bias (sd) between Q and Q was 0.040 (0.132) and 0.058 (0.136) L/min for measurement with 0.5 mL/kg and 1.0 mL/kg of isotonic saline, respectively (no statistically significant difference). Ultrasound dilution cardiac output measurement is reliable in piglets with the use of a small volume of a nontoxic indicator (isotonic saline).

Juvenile animal toxicity study designs to support pediatric drug development

The objective of juvenile animal toxicity studies of pharmaceuticals is to obtain safety data, including information on the potential for adverse effects on postnatal growth and development. Studies in juvenile animals may assist in identifying postnatal developmental toxicities or other adverse effects that are not adequately assessed in the routine toxicity evaluations and that cannot be safely or adequately measured in pediatric clinical trials. Unlike the traditional reproductive and developmental toxicology studies that have been discussed in the accompanying reports, the design requirements for toxicity studies in juvenile animals are not explicitly defined in regulatory guidance. However, studies in juvenile animals can be useful in providing safety information necessary to enable pediatric clinical trials in pediatric patients or when there are special concerns for toxicities that cannot be safely or adequately measured in clinical trials. These juvenile animal toxicity studies are designed on a case-by-case basis. General design considerations and examples of study designs for assessment of juvenile animal toxicity are discussed.

A Pumpless Lung Assist Device Reduces Mechanical Ventilation-Induced Lung Injury in Juvenile Piglets

Respiratory failure is a major contributor to mortality and morbidity in newborn infants. The lung assist device (LAD) is a novel gas exchange device that supplements mechanical ventilation. The objective is to test the effect of the LAD on pulmonary histopathology in juvenile piglets with acute lung injury caused by saline lung lavage (SLL) followed by intermittent mandatory ventilation (IMV). Three- to 4-wk-old piglets were randomized to no intervention (control group), SLL alone (SLL group), SLL + IMV (IMV group), or SLL + IMV + LAD (LAD group) (n = 6 per group). The carotid artery and jugular vein were cannulated and an arteriovenous circuit completed, and the LAD was inserted into this circuit. Gas exchange via the LAD was initiated by passage of 100% oxygen over the blood-carrying hollow fibers of the LAD. Hemodynamic variables were recorded. Mechanical ventilation was systematically weaned. Lung histology was scored by two observers masked to treatment group. There were no differences in hemodynamic variables between the study groups. There was a significant increase in the total lung injury score in the IMV group compared with the LAD group. The novel pumpless low-resistance LAD has shown feasibility and potential to decrease ventilator-induced lung injury in a juvenile animal model.

Evaluation of a Pumpless Lung Assist Device in Hypoxia-Induced Pulmonary Hypertension in Juvenile Piglets

Persistent pulmonary hypertension is an important cause of mortality and morbidity in term infants. The lung assist device (LAD) is a novel, pumpless, low-resistance extracorporeal oxygenator to supplement mechanical ventilation. The LAD may be associated with fewer complications compared with conventional extracorporeal membrane oxygenation. The objective was to test the feasibility and efficacy of the LAD in juvenile piglets with hypoxia-induced pulmonary hypertension. Pulmonary hypertension was acutely induced by hypoxia in six 3- to 4-wk-old acutely instrumented and intubated piglets. The LAD was attached between a carotid artery and jugular vein. Gas exchange and hemodynamic variables, including pulmonary arterial pressure (PAP) and cardiac output (CO), were measured. Successful LAD cannulation was achieved without complications in all animals. Extracorporeal shunt flow through the device averaged 18% of CO. The LAD achieved oxygen delivery of 20% of total oxygen consumption. PAP was reduced by 35% from 28 +/- 5 to 18 +/- 4 mm Hg (p < 0.05) and systemic Pao2 increased by 33% from 27 +/- 2 to 36 +/- 4 mm Hg (p < 0.05). Other hemodynamic variables remained stable. The novel LAD shows feasibility and efficacy in improving gas exchange and reducing PAPs in a juvenile animal model of hypoxia-induced pulmonary hypertension.

FACE BITING ON A JUVENILE TYRANNOSAURID AND BEHAVIORAL IMPLICATIONS

The juvenile tyrannosaurid specimen BMR P2002.4.1 possesses a series of four partially healed, oblong lesions along the left maxilla and nasal bones. The morphology of the lesions and their positioning and orientation are compatible with the jaws of the specimen, suggesting that the lesions may have been the result of a bite from an attacker of similar size and species as the bite victim. Bone remodeling of the lesions indicates partial healing and demonstrates that the injury was not fatal. The injury appears to have affected the growth of the skull, causing a slight warping of the left maxilla and a slight leftward curvature of the nasal. Previous examples of intraspecific behavior in theropods have noted various injuries on skulls; the majority of documented injuries are in adults. The presence and nature of these wounds suggests that juvenile tyrannosaurid behavior included intraspecific aggression among similar-sized individuals, as has been observed in modern crocodilians. Although it is not possible to unequivocally infer behavior from a fossil specimen, as a juvenile animal it is unlikely that the behavior directly reflects sexual competition or conflict, although it may represent learning behavior for later conflict as competing adults or territoriality over food or spatial resources.

Clinical Trial Simulations in Pediatric Patients Using Realistic Covariates: Application to Teduglutide, a Glucagon-Like Peptide-2 Analog in Neonates and Infants With Short-Bowel Syndrome

Teduglutide, a synthetic glucagon-like peptide-2 (GLP-2) analog with activity relating to the regeneration, maintenance, and repair of the intestinal epithelium, is currently being evaluated for the treatment of short-bowel syndrome (SBS), Crohn's disease, and other gastrointestinal disorders. On the basis of promising results from teduglutide studies in adults with SBS and from studies in neonatal and juvenile animal models, a pediatric multiple-dose phase I clinical study was designed to determine the safety, efficacy, and pharmacokinetics of teduglutide in pediatric patients with SBS who have undergone resection for necrotizing enterocolitis, malrotation, or intestinal atresia. This report details the application of clinical trial simulations coupled with a novel approach using generalized additive modeling for location, scale, and shape (GAMLSS) that facilitates the simulation of demographic covariates specific to the targeted patient populations. The goal was to optimize phase I dosing strategies and the likelihood of achieving target exposure and therapeutic effect.

Sexually Dimorphic Effects of Alcohol Exposure during Development on the Processing of Social Cues

The study used an animal model of fetal alcohol spectrum disorders (FASD) to investigate the impact of alcohol exposure during a period equivalent to all three trimesters in humans on social recognition memory. It was hypothesized that the effects on specific aspects of social recognition memory would be sexually dimorphic. This study exposed rats to ethanol during both the prenatal and early postnatal periods. Two control groups included a group exposed to the administration procedures but not ethanol and a non-treated group. At approximately 90 days, all rats were tested repeatedly in a test of social recognition memory with a juvenile animal of the same sex. Experimental rats of both sexes were allowed to investigate an unknown juvenile for either 2, 3 or 5 min and then, after a delay of 30, 60, 120 and 180 min, were allowed to investigate the same juvenile for 5 min. Male rats investigated the juvenile for much longer than female rats. Ethanol-exposed male rats showed a deficit in recognition memory that was evident with longer delays when the initial investigation time was either 2- or 3-min long. In contrast, ethanol-exposed female rats showed a deficit in recognition memory only when the initial investigation period was of 2 min. Measurement of oxytocin receptor binding in the amygdala region indicated that ethanol exposure lowered oxytocin receptor binding in females but not males. The results suggest that ethanol exposure during development caused a deficit in memory duration but not encoding in males and a deficit in encoding but not memory duration in females. The deficit in ethanol-exposed females may be related to changes in oxytocin receptors in the amygdala.

On the need for juvenile animal studies in paediatric drug development: Experience from paediatric investigation plans

On the need for juvenile animal studies in paediatric drug development: Experience from paediatric investigation plans

Isoflurane enhances spontaneous Ca2+ oscillations in developing rat hippocampal neurons in vitro

During the nervous system development, spontaneous synchronized Ca(2+) oscillations are thought to possess integrative properties because their amplitude and frequency can influence the patterning of neuronal connection, neuronal differentiation, axon outgrowth, and long-distance wiring. Accumulating studies have confirmed that some drugs such as volatile anesthetic isoflurane produced histopathologic changes in the central nervous system in juvenile animal models. Because the hippocampus plays an important role in learning and memory, the present work was designed to characterize the Ca(2+) oscillations regulated by volatile anesthetic isoflurane in primary cultures of developing hippocampal neurons (5-day-cultured). Primary cultures of rat hippocampal neurons (5-day-cultured) were loaded with the Ca(2+) indicator Fluo-4AM (4 microM) and were studied with a confocal laser microscope. Approximately 22% of 5-day-cultured hippocampal neurons exhibited typical Ca(2+) oscillations. These oscillations were dose-dependently enhanced by isoflurane (EC50 0.5 MAC, minimum alveolar concentration) and this effect could be reverted by bicuculline (50 microM), a specific gamma-aminobutyric acid (GABA(A)) receptor antagonist. Unlike its depressant effect on the Ca(2+) oscillations in adult neurons in previous researches, isoflurane dose-dependently enhanced calcium oscillations in developing hippocampal neurons by activating GABA(A) receptors, a major excitatory receptor in synergy with N-methyl-d-aspartate receptors at the early stages of development. It may be involved in the mechanism of an isoflurane-induced neurotoxic effect in the developing rodent brain.

Low rates of transmission of SRV‐2 and STLV‐I to juveniles in a population of Macaca fascicularis facilitate establishment of specific retrovirus‐free colonies

Prevalence of simian retrovirus-2 (SRV-2) and simian T lymphotropic virus type I (STLV-I), was unknown in 337 captive cynomolgus macaques. Molecular assays identified 29% of animals as SRV-2 mono-infected, 4% of animals as STLV-I mono-infected and 9% of animals as dual-infected. Of 108 juvenile animals, 83% were SRV-2-negative and no juvenile animal was STLV-I-positive. A subsequent study of juvenile macaques over a period of 2.5 years detected no STLV-I and 10 SRV-2 infections, six of which occurred between testing and day of colony formation. The study also highlighted that an anti-SRV-2 serological response does not presuppose infection. Tissue reservoirs of latent SRV-2 were not identified in suspected SRV-2 infections. Low transmissibility of the viruses present in the parental cohort and improved knowledge of the host response to SRV-2 has facilitated the creation of specific-retrovirus-free colonies of cynomolgus macaques.

Current developments in reproductive toxicity testing of pesticides

A protocol to evaluate the potential developmental and reproductive effects of test chemicals has been developed by the Life Stages Task Force of the International Life Sciences Institute (ILSI)/Health and Environmental Sciences Institute (HESI) Agricultural Chemical Safety Assessment (ACSA) Technical Committee. Since the original publication, several international groups have provided public comment on conducting the test. The extended one-generation reproductive toxicity test is now under consideration as a potential test guideline. The protocol uses a flexible approach that is markedly different from the current multigenerational guidelines. It encourages the use of toxicokinetics when setting the doses, evaluates more than one rat per sex per litter in the F1 offspring and does not necessarily require mating of the F1 to produce an F2 (F1 mating may be triggered by the presence of effects in the P0 and developing F1 rats). A number of additional reproductive endpoints, and the neurotoxicity and immunotoxicity cohorts are included. The ACSA protocol was developed with the goal of assuring that the methods are scientifically appropriate and the toxicological endpoints and exposure durations are relevant for risk assessment. Compared to existing testing strategies, the proposed approach uses substantially fewer animals, provides additional information on the neonate, juvenile and pubertal animal, and includes an estimation of human exposure potential for making decisions about the extent of testing required. In this paper, the evolution of the protocol since the 2006 publication is discussed. These changes reflect the collective input of a U.S. expert panel of government and industrial scientist convened in 2007 and discussions of an OECD expert group held in Paris, France (October, 2008).

Treatment with escitalopram but not desipramine decreases escape latency times in a learned helplessness model using juvenile rats

The pharmacological treatment of depression in children and adolescents is different from that of adults due to the lack of efficacy of certain antidepressants in the pediatric age group. Our current understanding of why these differences occur is very limited. To develop more effective treatments, a juvenile animal model of depression was tested to validate it as a possible model to specifically study pediatric depression. Procedures for use with juvenile rats at postnatal day (PND) 21 and 28 were adapted from the adult learned helplessness model in which, 24 h after exposure to inescapable stress, animals are unable to remove themselves from an easily escapable stressor. Rats were treated for 7 days with either the selective serotonin reuptake inhibitor escitalopram at 10 mg/kg or the tricyclic antidepressant desipramine at 3, 10, or 15 mg/kg to determine if treatment could decrease escape latency times. Escitalopram treatment was effective at decreasing escape latency times in all ages tested. Desipramine treatment did not decrease escape latency times for PND 21 rats, but did decrease times for PND 28 and adult animals. The learned helplessness model with PND 21 rats predicts the efficacy of escitalopram and the lack of efficacy of desipramine seen in the treatment of pediatric depression. These findings suggest that the use of PND 21 rats in a modified learned helplessness procedure may be a valuable model of human pediatric depression that can predict pediatric antidepressant efficacy and be used to study antidepressant mechanisms involved in pediatric depression.

Estradiol prevents ozone-induced increases in brain lipid peroxidation and impaired social recognition memory in female rats

There is increasing concern about the neurodegenerative and behavioral consequences of ozone pollution in industrialized urban centers throughout the world and that women may be more susceptible to brain neurodegenerative disorders. In the present study we have investigated the effects of chronic (30 or 60 days) exposure to ozone on olfactory perception and memory and on levels of lipid peroxidation, α and β estrogen receptors and dopamine β-hydroxylase in the olfactory bulb in ovariectomized female rats. The ability of 17β-estradiol to prevent these effects was then assessed. Results showed that ozone exposure for 30 or 60 days impaired formation/retention of a selective olfactory recognition memory 120 min after exposure to a juvenile stimulus animal with the effect at 60 days being significantly greater than at 30 days. They also showed impaired speed in locating a buried chocolate reward after 60 days of ozone exposure indicating some loss of olfactory perception. These functional impairments could all be prevented by coincident estradiol treatment. In the olfactory bulb, levels of lipid peroxidation were increased at both 30- and 60-day time-points and numbers of cells with immunohistochemical staining for α and β estrogen receptors, and dopamine β-hydroxylase were reduced as were α and β estrogen receptor protein levels. These effects were prevented by estradiol treatment. Oxidative stress damage caused by chronic exposure to ozone does therefore impair olfactory perception and social recognition memory and may do so by reducing noradrenergic and estrogen receptor activity in the olfactory bulb. That these effects can be prevented by estradiol treatment suggests increased susceptibility to neurodegenerative disorders in aging women may be contributed to by reduced estrogen levels post-menopause.

Comparative juvenile safety testing of new therapeutic candidates: Relevance of laboratory animal data to children

Differences in drug response in patients of various ages including children and the elderly are common, often leading to challenges in optimizing dosages and duration of use. For example, developmental changes in renal function can dramatically alter the plasma clearance of compounds with extensive renal elimination and thus can enhance renal and systemic toxicity of these drugs. Preclinical and clinical research of new therapeutics is initially focused on adults, and provides little relevant information for children especially those who are still going through skeletal and organ development. The organ systems in the pediatric population that can be most susceptible are lungs, brain, kidneys, immune, skeletal, and reproductive systems. Considering that significant differences can exist between adult and juvenile populations that may affect drug safety, major regulatory agencies around the world are encouraging and sometimes requiring companies to generate preclinical juvenile animal data to predict for potential drug toxicity in children. However, data generated from such studies are useful only if obtained using the most appropriate species at the most relevant age considering comparability of specific organ system development in question. Other factors in the design of juvenile safety studies should include the indication, existing toxicological data and likely route of human exposure. This report will discuss these factors with a focus on reviewing species-specific developmental schedules for specific target organs and relevance of preclinical data in the design and conduct of clinical pediatric studies. Specific examples will be used to discuss the relationship of preclinical juvenile toxicity observations to risk assessment in humans.