bluuebunny/crossref_metadata_2025_split huggingface dataset:
Studies on the embryopathic effects of ethanolamine in Long‐Evans rats: Preferential embryopathy in pups contiguous with male siblings in utero
Authors: Mankes R. F. 
Published: February 2006

AbstractThe embryopathic effects of high doses of ethanolamine were evaluated in pregnant Long‐Evans rats during the “critical period” or organogenesis. Ethanolamine was given by gavage at levels of 0, 500, 300, or 50 mg/kg/day (24%, 14.4%, or 2.4% of the LD50 value). Ethanolamine caused dose‐dependent increases in intrauterine deaths, malformations, and intrauterine growth retardation. Embryolethality caused by 500 mg/kg of ethanolamine was not random: male pups contiguous to two male siblings (designated mMm) were almost quantitatively replaced by resorptions that were contiguous to two live male pups (designated mRm) (mMm pups constituted 6.7% of control implants and decreased to only 0.9% of group II implants while mRm resorptions increased from 0.3% in controls to 5.6% in group II dams). Intrauterine growth retardation and increases in gross structural anomalies (considered indicative of depressed fetal growth) more severely affected male than female offspring at all dose levels. Pups of either sex who were contiguous to male siblings were more adversely affected than those offspring contiguous to one or more female siblings. As ethanolamine was given prior to the period of greatest fetal growth and fetal sex steroidogenesis, it is suggested that intrauterine levels of female sex steroids (estradiol) enhance fetal repair of cellular damage while testosterone inhibits fetal repair or exacerbates previous embryonic damage by some unknown mechanism. Such interaction furthers the concept that intrauterine position affects the endpoints of developmental toxicity, as expressed at parturition.
Developmental effects of chemicals and the heat shock response in Drosophila cells
Authors: Bournias‐Vardiabasis Nicole , Buzin Carolyn H. 
Published: February 2006

AbstractExposure of prokaryotic and eukaryotic cells to heat shock (hyperthermia) or to a number of diverse environmental stresses such as teratogens, anoxia, and inhibitors of oxidative phosphorylation results in the enhanced synthesis of a number of proteins which have been previously referred to as heat shock proteins (hsps). More recently, in view of the diverse types of agents that can induce these proteins, they have also been referred to as stress proteins. This phenomenon is one of the most basic regulatory mechanisms in living organisms. Exposure of Drosophila embryos, larvae, or pupae to these types of stresses also results in a variety of developmental abnormalities in the ensuing adult. Although the function(s) of these heat shock proteins has yet to be determined, they are widely thought to play an important role in cell survival and protection following some types of environmental stress. In our laboratory, we have developed an in vitro assay for detecting agents that act as teratogens, utilizing Drosophila embryonic cultures. Drosophila embryonic cells differentiate in vitro to a number of functional cell types including myotubes and ganglia. A number of drugs that have been shown to act as teratogens in mammals have also been found to inhibit muscle and/or neuron differentiation in Drosophila embryonic cultures. We have examined, by twodimensional gel electrophoresis, the effects of such teratogens on protein synthesis in Drosophila embryonic cells. Inhibition of muscle and/or neuron differentiation correlates well with the induction of two proteins of about 20 kilodaltons. These are identical to two of the heat shock proteins (hsp 23, 22) as shown by electrophoretic mobilities and peptide mapping by partial proteolysis. Heat shock and other treatments such as exposure to some of the metal ions and ether induces the entire set of seven major heat shock proteins in the Drosophila embryonic cells. Dose‐response studies of several teratogens show a correlation between the degree of inhibition of differentiation and the level of induction of hsps. Since heat shock proteins have been suggested as possibly serving a protecting role, our present studies are aimed at identifying the role of hsps in teratogenesis and investigating the differential regulation of heat shock genes in response to different external stimuli.
Relationship between ossification and body weight of the CD‐1 mouse fetus exposed in utero to anticonvulsant drugs
Authors: Sucheston Martha E. , Hayes Thomas G. , Eluma Fabian O. 
Published: February 2006

AbstractThe anticonvulsant drugs carbamazepine, Na valproate, and phenytoin have been suspected as a cause of human congenital defects. The malformations produced may include cleft lip and/or palate, heart defects, skeletal defects, and low body weights. Since the toxic effects of these anticonvulsant drugs manifest themselves in terms of fetal growth retardation, evaluation of the state of ossification attained in the fetus is important. In the present study, pregnant CD‐1 mice received on gestational days 8–16 an oral dose of 375, 563, 938 mg/kg of carbamazepine; or 225, 338, 563 mg/kg of Na valproate; or 50, 75, 125 mg/kg of phenytoin. These groups were compared to two control groups. On day 17, the dams were killed by cervical dislocation and one‐third of the live fetuses were weighed and fixed for skeletal examination. Photographs were taken of the fore‐ and hindlimb skeletons. From these photographs, the length and width measurement of ossified regions of the humerus and femur were determined using a Zeiss Video‐Plan Morphometrics Computer. Of the three anticonvulsant drugs studied, the greatest correlation between reduced fetal weights and retarded ossification of the long bones was phenytoin at the 125 mg/kg dosage. Our results also showed that long bone ossification, when compared to the fetal weight, indicated that 59–66% of variability in weight is predictable by bone measurements.
Short‐term developmental toxicity testing: Considerations in the validation process
Authors: Kimmel G. L. 
Published: February 2006

AbstractThe development and validation of short‐term tests that assess developmental toxicity have received increased attention due to the large number of agents that need to be tested and the desirability to reduce the overall use of animals in research and safety evaluation. The Short‐Term In Vivo Reproductive Toxicity Test was developed to help meet this need and to provide a method for prioritizing agents for further testing. This report provides a brief overview of the risk assessment process and a focus on the aspects of test validation that should be considered when evaluating short‐term tests. It is intended to give the reader an appreciation for many of the considerations that must go into developing and validating a short‐term test, and to indicate areas within the risk assessment process where inclusion of such a test may be appropriate.
Further evaluation of an in vivo teratology screen
Authors: Kavlock Robert J. , Short Robert D. , Chernoff Neil 
Published: February 2006

AbstractThe in vivo teratology screening procedure described previously [Chernoff N, Kavlock RJ: J Toxical Environ Health 10:541–550, 1982] was further evaluated using a total of 46 chemicals in 50 different treatment regimens. Pregnant CD‐1 mice were generally treated by oral gavage on days 8–12 of gestation at a dose level predicted from a preliminary range finding study to induce a slight degree of maternal toxicity. The effects on early postnatal growth and viability were compared to results generated from standard mouse teratology bioassays as reported in the literature (there were nine regimens for which no valid comparisons could be made). The procedure correctly categorized 25 of the 30 treatment regimens which were considered developmentally toxic in the mouse, as well as nine of 11 which were considered to be nondevelopmentally toxic in the mouse. Thus, based upon the criteria used in the present study, the assay correctly classified 83% of the chemicals tested as to their effect in a standard mouse bioassay. The five nonconcurring negative findings were likely due to a combination of pharmacokinetic differences between the studies, as well as to the cessation of dosing on day 12, while critical events of organogenesis are still occurring. The assay achieves the requirements for a teratology screening system, but improved predictability would result from the addition of a lower dose level and extension of the dosing period to include later stages of organogenesis.
Currently used alternatives to the Chernoff‐Kavlock short‐term in vivo reproductive toxicity assay
Authors: Christian M. S. , Hoberman A. M. , Lochry E. A. 
Published: February 2006

AbstractThe Chernoff‐Kavlock assay was initially designed to identify developmental toxins within a relatively short time frame, using a mammalian system. Although it has been used for initial prioritization of multiple agents studied concurrently or for dosage‐range evaluations, it has not gained wide usage in a commercial setting. As proposed, use of the Chernoff‐Kavlock assay in an industrial setting is relatively inefficient, in terms of animal usage and data produced, when compared with available alternative study designs. Only a single dosage level was studied, and the data obtained from the assay do not provide sufficient information to meet the minimum requirements of safety evaluations submitted for regulatory review. For these reasons, other methods of prioritization are generally used. Alternate methods used for initial screening and prioritization at our laboratory are: (1) the hydra developmental toxicity assay; and (2) a dosage‐range study in rats. When the results of several pilot and definitive developmental toxicity assays performed in rats were compared, it appeared that the described pilot study served the dual functions of predicting and prioritizing the developmental hazard of the test agent and providing a dosage‐range study that identified the appropriate dosages to be tested in the definitive study.
Assessment of adult toxicity in developmental versus prechronic toxicology studies
Authors: Schwetz B. A. , Moorman M. P. 
Published: February 2006

AbstractThere is no general agreement at the present time regarding the role of maternal toxicity in the manifestation of teratogenic effects or developmental toxicity in animal studies designed to identify the teratogenic potential of chemicals. A survey of 90 teratology studies published in the recent literature revealed wide differences in the amount and nature of maternal toxicity data collected in teratology studies. In addition, the use of the maternal toxicity data in the process of interpreting developmental toxicity varied widely between authors. In comparison with teratology studies, there is more uniformity in the collection of toxicity data in prechronic toxicity studies. The guidance provided by various government agencies on the parameters to be observed in prechronic toxicity studies is much more explicit than that provided regarding the collection of maternal toxicity data in teratology studies. Because of the likely importance of maternal toxicity in the conduct and interpretation of teratology studies, it is recommended that more maternal toxicity data be collected in teratology studies and the parameters be standardized between laboratories so that data are comparable. Guidelines should be established for the use of maternal toxicity data in the interpretation of the results of teratology studies.
Approaches to defining the relationship of maternal and developmental toxicity
Authors: Schardein James L. 
Published: February 2006

AbstractMaternal and developmental toxicities reported in the literature were examined in an attempt to define more clearly their relationship. Relationships were difficult to ascertain because maternal toxicity end points are not clearly defined, or even assessed, in every study. However, maternal toxicity accompanied by developmental toxicity is the most common outcome of in vivo testing. Approaches to define these associations have included assessment of acute maternal toxicity and teratogenicity; evaluation of maternal toxicity and its association to developmental toxicity in general, and to malformations, specifically; and examination of developmental variations, embryolethality, and altered growth. None has demonstrated an unequivocal relationship between specific maternal and developmental toxicities: Developmental disruption appears not to result unconditionally from maternal toxicity. Maternal “stress” appears to have some impact on development but resists further definition at this time. Variations in association may be due to the extent to which maternal homeostasis has been compromised. Several quantitative approaches to relating maternal toxicity and developmental toxicity in animal systems (ie, relative teratogenic index, adult/developmental toxicity ratio) may provide the most satisfactory means of evaluating developmental toxicity testing for assessment of hazard.
Comparison of maternal and fetal toxic dose responses in mammals
Authors: Rogers John M. 
Published: February 2006

AbstractThe role of maternal toxicity in adverse developmental outcome and the importance of maternal toxicity as a factor in developmental risk assessment have received increasing attention in the recent literature. This paper reviews these concepts and some of the experimental approaches that have been used to assess their importance. The often non‐parallel nature of maternal and fetal toxic dose response curves makes specific comparisons of maternal and fetal toxic doses quite difficult. The use of specific ratios of maternal to fetal toxic doses, such as the A/D ratio and the Relative Teratogenic Index is discussed, including some of the difficulties encountered in assigning such ratios, and a compilation of A/D ratios for compounds for which this ratio could be estimated in more than one mammalian species is included. Results of our studies on the fungicide, dinocap, for which the A/D ratio does not seem to be consistent across species, are briefly reviewed. Maternal toxicity is usually evaluated only on the basis of significant mortality, dose‐related weight loss, or obvious external observations. Some examples of other more specific indications of maternal toxicity that may be involved in teratogenesis are presented.
Developmental toxicity of dinocap in the mouse is not due to two isomers of the major active ingredients
Authors: Rogers John M. , Gray L. Earl , Carver Brenda D. , Kavlock Robert J. 
Published: February 2006

AbstractTechnical‐grade dinocap, a complex‐mixture fungicide, is teratogenic in the CD‐1 mouse, causing cleft palate and otolith defects. In this study we compared the developmental toxicities of 2,4‐dinitro‐6‐(1‐methylheptyl)phenyl crotonate and 2,6‐dinitro‐4‐(1‐methylheptyl)phenyl crotonate, model isomers of the major active ingredients of technical dinocap, to the known teratogenicity of the technical compound. Individual isomers, both isomers combined, or technical dinocap were administered to pregnant mice on days 7–16 of gestation. Some dams were killed at term and litters were removed, dead fetuses and resorptions were counted, and live fetuses were weighed and preserved in Bodian's fixative for examination for cleft palate. Other treated dams were allowed to give birth: postnatal viability and growth, development of swimming behavior, and otolith formation were evaluated. As in previous studies, technical‐grade dinocap caused cleft palate and weight deficits in fetuses at term and increased neonatal mortality and abnormal swimming behavior, torticollis, and deficient otolith formation in surviving pups. Neither of the purified isomers exhibited any developmental toxicity when administered under identical conditions. Thus, it is concluded that these isomers are not the active teratogenic component(s) in technical‐grade dinocap.
Late‐onset cerebellar degeneration in mice induced transplacentally by methylnitrosourea
Authors: Smith Sylvia B. , Brown Cathy B. , Wright Mary E. , Yielding K. Lemone 
Published: February 2006

AbstractA late‐onset degenerative disease in the cerebellum was produced in the offspring of mice exposed to 1 mg/kg of the direct‐acting DNA alkylating agent methylnirosourea (MNU) on day 16 of gestation. This intrauterine exposure to MNU also provoked a progressive retinal degeneration that was described elsewhere. Mild ataxia in the MNU‐exposed animals was expressed by 20 weeks of age. Although animals appeared normal in the immediate post‐natal period, quantitative histological evaluation of cerebellar coronal sections indicated that MNU‐exposed animals had a significantly greater number of pyknotic Purkinje cells than age‐matched controls. The number of pyknotic Purkinje cells declined with age in the drug exposed animals; however, the percentage of pyknotic Purkinje cells to total number of Purkinje cells still was greater in MNU‐induced animals at 36 weeks than in controls, suggesting that a slow degenerative process was ongoing in the MNU‐exposed animals. Furthermore, the folia were grossly disrupted in 90% of the older MNU‐exposed animals (ages greater than 12 weeks), suggesting permanent cerebellar disruption macroscopically. Such intrauterine exposure to low doses of alkylating agents may be potentially useful in modeling degenerative neuronal diseases.
Variable patterns in anticonvulsant drug‐induced malformations in mice: Comparisons of phenytoin and phenobarbital
Authors: Finnell Richard H. , Shields Heidi E. , Chernoff Gerald F. 
Published: February 2006

AbstractAnticonvulsant drugs are known to induce a varied pattern of malformation in both humans and in experimental rodent models. Often the clinical overlap between the pattern of defects induced by different anticonvulsant drugs is so striking that many clinicians question the role these compounds play relative to the existing maternal seizure disorder in the etiology of the observed malformations. In three inbred mouse strains exposed to phenytoin or phenobarbital in utero, the pattern of malformation differed markedly. From the types of anomalies observed, it is apparent that phenobarbital induced more malformations, while phenytoin produced a higher frequency of anomalies related to incomplete development. Thus, while there exists a certain degree of similarity between some of the minor features characteristic of each drug‐induced syndrome, there are distinct differences in pregnancy outcome in experimental animals exposed to these drugs. Given the fact that phenobarbital induces more malformations that can be traced to exposure during early organogenesis, it may be wise to consider a therapeutic strategy in which phenytoin is utilized only during organogenesis, and is then replaced with phenobarbital for the remainder of the pregnancy.
Regulatory decision making and the need for and the use of exposure data on pesticides determined to be teratogenic in test animals
Authors: Wang G. M. 
Published: February 2006

AbstractMajor efforts have been made in the development of a system that takes the reviewer step‐by‐step by the use of the developmental toxicity and exposure assessment data to a recommended risk assessment and risk management position. Thereupon a set of regulatory decisions can be arrived at that are backed up by sound scientific analysis. Examples of pesticides that have been found to be teratogenic in animal testing are provided to demonstrate the process of use of exposure data in making risk assessment and management decisions.
Quantitative risk assessment: Qualms and questions
Authors: Karstadt Myra 
Published: February 2006

AbstractWithin the past ten years, quantitative risk assessment has come to play a central role in the federal regulation of carcinogens. Federal agencies use quantitative risk both to set priorities and to establish exposure levels. The use of quantitative risk assessment is mandated by Executive Orders requiring performance of cost‐benefit analysis, although performance of assessments has often been ascribed to the Supreme Court decision in the 1980 “benzene” case.Quantitative risk assessment is a deeply flawed methodology with results that give a false sense of certainty and objectivity. Also, the nature of quantitative risk assessment methodologies currently in use makes it difficult for members of the public to scrutinize and assess regulatory actions.Quantitative risk assessment should not be used for regulation of carcinogens, especially not for establishing exposure levels. Instead, alternative methodologies should be utilized, which are appropriately reflective of uncertainty and which are more readily accessible to public scrutiny and participation.
Effects of the antioxidant butylated hydroxytoluene (BHT) on retinal degeneration induced transplacentally by a single low dosage of n‐methyl‐N‐nitrosourea (MNU)
Authors: Smith Sylvia B. , Cooke Carol Beck , Lemone Yielding K. 
Published: February 2006

AbstractA 1 mg/kg dose of the DNA alkylating agent, N‐methyl‐N‐nitrosourea (MNU), when administered on day 16 of gestation provokes a progressive retinal degeneration in CD‐1 albino mice reared under standard fluorescent lighting conditions (12 hr light : 12 hr dark); this degeneration begins at about 4 weeks post‐natally and worsens with age. It is accelerated by constant fluorescent light exposure but is retarded greatly by constant darkness, suggesting the importance of secondary insults in the post‐natal period for development of the degenerative disease. To determine whether the secondary photochemical damage might be specifically blocked, MNU‐exposed and control animals in the present study were fed an antioxidant‐enriched diet of Purina mouse chow supplemented with 0.75% butylated hydroxytoluene (BHT). A second group of MNU‐exposed and control animals were fed a non‐BHT supplemented standard Purina mouse chow diet. Systematic measurements of the number of rows of photoreceptor cell nuclei, the thickness of the inner/outer segment layer, and the thickness of the whole retina were made, to quantify any degenerative changes in animals 2, 4, 6, and 8 weeks of age. By 8 weeks, retinas of BHT‐fed, MNU‐exposed animals were significantly thicker and had more rows of photoreceptor cell nuclei than regular‐diet, MNU‐exposed animals. Moreover, the retinas of BHT‐fed animals, both for MNU‐exposed and controls, demonstrated sporadic morphologic changes in the form of circular configurations composed of ganglion cells, arcades of nuclear and plexiform layers, and, in one control animal, a hyperplastic nodule. These experiments suggested that MNU‐induced retinal degeneration may be retarded by a BHT‐enriched diet; however, continuous high doses of this compound pre‐ and post‐natally may induce other retinal abnormalities.