The selective estrogen receptor modulator, raloxifene: a segment II/III delivery study in rats.

Raloxifene is a nonsteroidal, selective estrogen receptor modulator developed by Eli Lilly and Company as a therapeutic agent for postmenopausal osteoporosis. Raloxifene was administered orally by gavage at doses of 0, 0.1, 1, or 10 mg/kg/d to female CD rats (25/group) on Gestation Day 6 (GD 6) through Postpartum Day 20 (PD 20).

The selective estrogen receptor modulator, raloxifene: reproductive assessments following preimplantation exposure in mated female rats.

Raloxifene is a nonsteroidal, selective estrogen receptor modulator being developed for postmenopausal osteoporosis. As part of an integrated reproductive toxicity assessment, two studies were conducted in which raloxifene was administered orally to CD rats during Gestation Days (GD) 0 through 5. In each study, animals received daily raloxifene doses of 0, 0.

The selective estrogen receptor modulator, raloxifene: reproductive assessments following premating exposure in female rats.

Raloxifene HCl is a nonsteroidal, selective estrogen receptor modulator developed as a therapeutic agent for postmenopausal osteoporosis. Two studies were conducted that examined the effects of premating exposure to raloxifene HCl. In the first study, adult female CD rats (20/group) were given diets containing 0, 0.

The selective estrogen receptor modulator, raloxifene: an overview of nonclinical pharmacology and reproductive and developmental testing.

Raloxifene is a nonsteroidal, selective estrogen receptor modulator being developed by Eli Lilly and Company as a therapeutic agent for postmenopausal osteoporosis. In the ovariectomized (OVX) rat, raloxifene prevents the loss of bone at the distal metaphysis of the femur, proximal tibia, and vertebrae; reduces cancellous bone resorption; and reduces serum cholesterol, but does not cause any significant changes in stromal eosinophilia or uterine epithelium. In estrogen-stimulated OVX rats, raloxifene prevents the morning lowering of serum luteinizing hormone levels, produces a reduction in afternoon serum prolactin levels, antagonizes pituitary weight increase, and antagonizes stimulation of mammary gland development.

A developmental neurotoxicity evaluation of the effects of prenatal exposure to fluoxetine in rats.

Fluoxetine is a widely used serotonin reuptake inhibitor effective in the treatment of depression. This experiment assessed the potential developmental neurotoxicity of fluoxetine. Sprague-Dawley CD rats were treated once per day on Days 7-20 of gestation with 0, 1, 5, or 12 mg/kg of fluoxetine (free base) dissolved in distilled water.

The use of repeated measures analyses in developmental toxicology studies.

In many toxicology studies, it is common to take the same measurements on an individual animal at several time points (e.g., body weight across days or weeks, activity levels either within a single test session or across days).

Developmental toxicity of the dopamine agonist pergolide mesylate in CD-1 mice. II: Perinatal and postnatal exposure.

Pergolide mesylate is a dopamine agonist and, therefore, reduces prolactin secretion. In Experiment I, pregnant mice were given oral doses of 0, 0.1, 0.

Developmental toxicity of the dopamine agonist pergolide mesylate in CD-1 mice. I: Gestational exposure.

Pergolide was given by oral gavage to mated CD-1 female mice at doses of 0, 1, 20, or 60 mg/kg/day on gestation days (GD) 6-15. Animals assigned to the teratology segment were killed on GD 18 for evaluation of maternal organ weights, and fetal viability, weights and morphology. Animals assigned to the postnatal segment were allowed to deliver and physical development and behavioral performance of the progeny were monitored until weaning.

Workshop on the qualitative and quantitative comparability of human and animal developmental neurotoxicity, Work Group II report: testing methods in developmental neurotoxicity for use in human risk assessment.

The Work Group addressed the design and content of a basic screening battery for detecting or flagging developmental neurotoxicity. It was agreed that a basic screening battery should be incorporated routinely into any developmental or reproductive toxicity study conducted for risk assessment purposes, and that a "triggered" stand-alone developmental neurotoxicity study, as exemplified by the current EPA proposal, should include greater in-depth evaluation of CNS function and pathology. Time constraints did not permit the group to address the design or content of such a stand-alone study.

Postnatal function following prenatal reserpine exposure in rats: neurobehavioral toxicity.

Behavioral and neurochemical analyses were conducted on preweanling CD rats prenatally exposed to either 0, 0.375 or 0.750 mg/kg/day reserpine SC on gestation days 12-15.

Practical considerations in establishing reliable and sensitive neurobehavioral test methods.

The use of animal models in the safety assessment of compounds requires that the methods employed be established as reliable, sensitive and valid indicators of toxicity. Neurobehavioral toxicology is in a unique position due to recent efforts in this area prior to incorporation into routine screening systems. Aspects of study design and general implications of results are discussed from the Collaborative Behavioral Teratology Study, a large-scale effort specifically undertaken to evaluate the reliability and sensitivity of a standardized behavioral teratology test protocol.

Prenatal reserpine exposure in rats decreases caudate nucleus dopamine receptor binding in female offspring.

The effects of prenatal exposure to reserpine on [3H]spiroperidol binding in caudate nucleus at postnatal day (PND) 21 were investigated. Pregnant rats were dosed with 0, 0.375 or 0.

Early neurobehavioral and neurochemical alterations in rats prenatally exposed to imipramine.

Pregnant CD rats were treated subcutaneously with 0, 5 or 10 mg/kg/day of imipramine (IMI) on days 8-20 of gestation. Behavioral and neurochemical endpoints were measured at different postnatal days (PND). Three behavioral tests were conducted: negative geotaxis on PNDs 7-9; auditory startle habituation (ASH) on PNDs 14, 16 and 18; locomotor activity before and after intraperitoneal (i.

Collaborative Behavioral Teratology Study: programmed data entry and automated test systems.

The automated laboratory systems described in this paper were developed for use at the National Center for Toxicological Research (NCTR) and each of five collaborating laboratories. These laboratories participated in a study designed to evaluate the intra- and interlaboratory reliability and sensitivity of several behavioral test methods used in developmental toxicity studies. This paper describes two microcomputer systems.

d-Amphetamine as a behavioral teratogen: effects depend on dose, sex, age and task.

Reports on the behavioral effects of prenatal exposure to d-amphetamine in rodents are inconsistent. Activity levels have been variously reported to increase, decrease, or show no change (as in the Collaborative Study) following such exposure. As a follow-up to the Collaborative Behavioral Teratology Study, 3 experiments have been conducted at the NCTR to examine the behavioral teratogenicity of this compound following SC dosing on days 12-15 of gestation.

Collaborative Behavioral Teratology Study: implications, current applications and future directions.

The general conclusions from the Collaborative Behavioral Teratology Study (CBTS) and the implications for research and testing in the field of behavioral teratology are discussed. The results of the CBTS indicate that behavioral teratology data are reproducible, if appropriate attention to study design and testing procedures is maintained. The statistical detection sensitivity of most of the test procedures was excellent, requiring no more than a 5-20% change from control values to detect an effect.

Collaborative Behavioral Teratology Study: results.

Behavioral measures used in the Collaborative Behavioral Teratology Study (CBTS) were negative geotaxis (PNDs 7-10), olfactory discrimination (PNDs 9-11), auditory startle habituation (PNDs 18-19 and 57-58), 1-hr activity (PNDs 21, 60, 100 and 120), 23-hr activity (PND 100), activity following a pharmacological challenge (PND 120), and an operant, discrete trial visual discrimination task. Maternal and offspring body weights and the appearance of certain physical landmarks of development were also monitored. The design of the CBTS allowed evaluation of the reproducibility and detection sensitivity of these behavioral test methods, as well as the impact of early testing experience on later behavioral assessment, offspring sex differences in response levels and variability, and the contribution of litter-to-litter and animal-to-animal variation to behavioral measures in a standardized test protocol.

Collaborative Behavioral Teratology Study: statistical approach.

The design of the Collaborative Behavioral Teratology Study included six laboratories and two test compounds, d-amphetamine sulfate and methylmercuric chloride. For each lab-compound combination, there were four doses, four replicates (reps), four litters within each dose-rep combination, and eight pups per litter (four males and four females). Two males and two females per litter had early experience testing, the other pups in each litter were naive until day 21 of age.

Collaborative Behavioral Teratology Study: protocol design and testing procedures.

This paper presents background information on the methods used in the Collaborative Behavioral Teratology Study (CBTS), the rationale behind the experimental design, and the design and specific procedures used in the CBTS. Each of the following methods is discussed: negative geotaxis, olfactory discrimination, auditory startle habituation, one-hour activity in the figure-8 maze, visual discrimination learning, 23-hour activity in the figure-8 maze, and amphetamine-stimulated activity. The CBTS was designed to determine the intra- and interlaboratory reliability of these test methods and the detection sensitivity of each method, as well as to determine the importance of several major variables (early test experience, gender, litter).

Collaborative Behavioral Teratology Study: preliminary research.

Prior to the beginning of the Collaborative Behavioral Teratology Study (CBTS), extensive preliminary experiments were conducted. Several experiments were conducted to permit the selection and verification of dosage levels of d-amphetamine sulfate and methylmercuric chloride to be used in the CBTS. These studies included evaluations of any teratogenic effects produced by selected concentrations of the chemicals, the potential pathology produced in the dams and offspring, and the postnatal behavioral consequences of the prenatal exposures.

Collaborative Behavioral Teratology Study: background and overview.

Organization of the Collaborative Behavioral Teratology Study began in 1978 because of concern about potential postnatal dysfunction following developmental chemical exposure. The study design was focused primarily on the evaluation of reliability of behavioral testing methods, the sensitivity of these methods to alterations produced by prenatal chemical exposure, and the effects of litter, sex of the animals and prior testing experience on behavioral responses. The test methods and chemicals used were selected from the literature available at that time using certain specific criteria.

Postnatal toxicity following prenatal reserpine exposure in rats: effects of dose and dosing schedule.

Pregnant CD rats were treated subcutaneously with 0, 0.1, 0.33, or 1.

Sex and strain differences in the developmental activity profile of rats prenatally exposed to sodium salicylate.

Pregnant Sprague-Dawley (CD) and Long-Evans (LE) rats were treated by gavage on days 8-10 of gestation with either 0, 125 or 175 mg/kg/day sodium salicylate. Locomotor activity was monitored repeatedly for 30 min in the offspring on postnatal days 12, 16, 20, 24, 30, 60, 90 and 120 in the presence or absence of olfactory cues from home cage bedding. Prenatal exposure during organogenesis to the doses of sodium salicylate used here resulted in subtle alterations in developmental locomotor activity, the pattern of which was dependent on sex, strain and bedding condition during testing.