bluuebunny/crossref_metadata_2025_split huggingface dataset:
A summary of the results of 55 chemicals screened for developmental toxicity in mice
Authors: Seidenberg Janice M. , Becker Richard A. 
Published: February 2006

AbstractFifty‐five chemicals, including known teratogens, known embryotoxins, equivocal teratogens, nonembryotoxins, and nonteratogens, as well as compounds of unknown teratogenic or embryotoxic potential, were evaluated in the Chernoff/Kavlock developmental toxicity screen. All chemicals were administered by gavage to pregnant ICR/SIM mice on gestation days 8 through 12. The mice were allowed to deliver, and several neonatal growth and viability parameters were measured in the offspring. Comparative statistical analysis of these parameters between treated animals and concurrent (vehicle‐treated) controls provided a data base to evaluate the validity of the developmental toxicity screen as an assay to detect teratogens and embryotoxins. Of the 26 compounds reported in the literature to be teratogenic or embryotoxic in mice following oral administration, 24 were positive in the developmental toxicity screen. Of the compounds previously tested in conventional assays and found to be devoid of teratogenic or embryotoxic activity in mice, 93% were negative in the developmental toxicity screen. The importance of experimental design, dose selection, and neonatal growth and viability measurements as they relate to interpretation and evaluation of the results of the developmental toxicity assay are discussed.
The Chernoff‐Kavlock assay: Its validation and application in rats
Authors: de S. Wickramaratne G. A. 
Published: February 2006

AbstractAs the rat is the preferred species for teratogenicity studies in our laboratories, the Chernoff‐Kavlock assay was modified and validated for use in this species. The Alpk:AP (Wistar‐derived) strain, which is also used routinely for toxicology studies, was used, under standard SPF conditions. Twenty‐six chemicals have been assayed to demonstrate the utility of the system as a predictor of rat teratogens and to develop a set of rules for interpretation of the results. Routes of chemical administration were largely gavage, with some dermal, subcutaneous, inhalation, and intraperitoneal applications. The use of the assay in five modes to assist the toxicological evaluation or understanding of chemicals is displayed. These modes are (1) as a pre‐screen, (2) to compare analogues/homologues, (3) to provide a rapid hazard estimate, (4) to generate a dose‐response, and (5) to test a hypothesis.
Overview and summary: Workshop on the Chernoff/Kavlock preliminary developmental toxicity test
Authors: Hardin Bryan D. , Becker Richard A. , Kavlock Robert J. , Seidenberg Janice M. , Chernoff Neil 
Published: February 2006

AbstractThe Chernoff/Kavlock assay, proposed as a preliminary screen for teratogenic potential, was the subject of a 2‐day workshop sponsored by the National Institute for Occupational Safety and Health. Data from three large testing programs were presented, representing tests of 165 chemicals, of which 33 were tested at least twice. Applications of the test in industrial laboratories and product development, hazard identification, and risk assessment were discussed. Workshop participants recognized the assay as one of several valid ways to preliminarily evaluate chemicals with unknown developmental toxicity. Other preliminary tests were also discussed in terms of their relationship to this test, which was seen as having the advantage of providing information on neonatal viability. Other techniques, particularly an abbreviated conventional teratology study, were also recognized as appropriate screens. The preferred test in a particular laboratory will be dependent upon the particular skills and objectives of that laboratory. Standardized protocols were suggested, but flexibility in experimental design was considered necessary, and many variations on the basic test could be appropriate. This preliminary test has been used most often as a single‐dose test in mice, but might provide more generally useful data if conducted in rats using two dose levels. Workshop participants viewed the test as highly reliable in correctly identifying developmentally toxic chemicals and suggested that a negative finding in a properly conducted Chernoff/Kavlock test could be a sufficient basis for regulatory agencies to determine that conventional teratology tests in the same species are not warranted.
An evaluation system for ranking chemicals with teratogenic potential
Authors: Wang G. M. , Schwetz B. A. 
Published: February 2006

AbstractAn evaluation system has been developed which permits comparison of the relative toxicity of chemicals based on their potential to alter embryonal and early‐stage fetal development. It was considered necessary, from a regulatory standpoint, to develop a system for ranking chemicals which possess teratogenic potential. A detailed discussion of the various parameters selected and their relative importance is provided.
Effect of ethylene glycol monomethyl ether on spermatogenesis, dominant lethality, and F1 abnormalities in the rat and the mouse after treatment of F0 males
Authors: Anderson Diana , Brinkworth M. H. , Jenkinson P. C. , Clode S. A. , Creasy D. M. , Gangolli S. D. 
Published: February 2006

AbstractAdult male CD rats and CD‐1 mice were given a single oral dose of ethylene glycol monomethyl ether (EGM) at 0, 500, 750, 1,000, or 1500 mg/kg. Groups of 10 were killed at weekly intervals after dosing for analysis of sperm counts and morphology or testicular histology; further groups of 10 were sequentially mated to pairs of virgin females to test for dominant lethality or gross foetal malformations in the F1 generation (F1 abnormalities).EGM was found to deplete the spermatocytes of both species severely, principally pachytene cells, but with other stages affected with increasing dose. A delay in the progression of spermatogenesis may account for a discrepancy between the apparent stage‐specificity of damage deduced from lowered sperm counts and that observed histologically. In the rat, morphological abnormalities were observed in sperm that had been exposed as spermatocytes; in the mouse, however, the sensitive cells were the late spermatocytes and early spermatids. In all these parameters there was an indication of a dose‐response relationship in both rats and mice. In the mating studies EGM induced a dose‐related decrease in fertility 5 weeks after dosing in the rat, but complete sterility in all but the lowest dose after 6 weeks. In contrast, EGM had no effect on the reproductive capacity of the mouse. There was no statistically significant evidence for the induction of dominant lethal mutations or F1 abnormalities in either species.A single oral dose of cyclophosphamide (CTX) at 100 mg/kg induced a significant increase in dominant lethality in both species. CTX reduced the number of total implants in the rat and induced a nonsignificant increase in the number of abnormal offspring sired by treated male mice.
Potentiating effect of caffeine on embryotoxicity of cyclophosphamide treatment in vivo during the preimplanation period
Authors: Vogel Richard , Spielmann Horst 
Published: February 2006

AbstractSince it is unknown if chemicals which are generally safe in pregnancy can potentiate the embryotoxicity of cytotoxic drugs before implantation, the combined effects of cyclophosphamide (CPA) and caffeine (CF) were studied in the mouse (day 2) with CPA at 20 mg/kg, which induces a 18% resorption rate, and CF at 100 mg/kg, which does not increase embryolethality. The embryotoxicity of CPA did not increase when CF was either given 6 h before or simultaneously with CPA on day 2. However, when CF was given 6 h after CPA, a potentiated increase of embryolethality was observed at term and of structural chromosomal aberrations in embryos even before implantation, while sister chromatid exchange (SCE) frequency was less increased than after single CPA treatment. The results demonstrate the importance of pharmacokinetics in pregnancy even before implantation. Furthermore, since SCE may not only indicate DNA damage but also repair, the reduced SCE rate and the increase in structural chromosome aberrations suggest that CF can inhibit the repair of CPA‐induced DNA damage in preimplantation embryos. Finally, for the first time the data are providing evidence that CF at subthreshold doses can potentiate the embryotoxicity of an alkylating agent in vivo even before implantation.
Cyclophosphamide‐induced cytogenetic effects in mouse bone marrow and spleen cells in in vivo and in vivo/in vitro assays
Authors: Krishna G. , Nath J. , Petersen M. , Ong T. 
Published: February 2006

AbstractSister chromatid exchange (SCE) and chromosomal aberration studies have been used to monitor human populations for genotoxic exposure to chemical substances. These monitoring techniques involve collection of blood and/or bone marrow from the exposed subjects and culturing cells for one or two cell cycles with various treatments in culture. The results obtained from such in vivo/in vitro studies may lead to an over‐or underestimation of the damage that could occur in vivo. In the present study, which uses a mouse model, the in vivo/in vitro cytogenetic assays (SCEs and chromosomal aberrations) have been compared with similar in vivo systems in bone marrow and spleen cells treated with various doses of cyclophosphamide (CPA). The results indicate a significant difference in CPA‐induced cytogenetic endpoints between in vivo and in vivo/in vitro conditions in both organs. However, linear relationships were found between CPA dose and cytogenetic end point analyzed under both conditions. Based on these results it appears that the in vivo/in vitro assay is a useful technique for indicating potential in vivo damage of chemicals.
Problems facing the decision‐maker in the risk assessment process
Authors: Moore John A. 
Published: February 2006

AbstractThis paper presents an overview of the U.S. Environmental Protection Agency's risk assessment process, describes problems that the Agency faces in conducting risk assessment, in general, and identifies some specific problems that the Agency confronts when conducting risk assessments on suspected developmental toxicants. As noted by the NAS (National Research Council: “Risk Assessment in the Federal Government: Managing the Process.” Washington, DC: National Academy Press, 1983, pp 17–83), improving the quality and comprehensiveness of knowledge is the most effective way to improve risk assessment, but some limitations are inherent and may remain unresolvable. Therefore, inferences will always be required. The Agency's challenge is to ensure that these inferences are as soundly based as possible.
Maternal factors in developmental toxicity
Authors: DeSesso John M. 
Published: February 2006

AbstractThe maternal organism provides the developing embryo with its physical environment, nutrients, and a mechanism for eliminating metabolic wastes. Since the physiological state of the pregnant female affects her ability to provide those requirements for the developing embryo, it is not surprising that there are maternal factors that can affect the wellbeing of the embryo. Extremes of maternal age in both humans and animals have been implicated in growth retardation, as well as autosomal trisomies. The influence of maternal size on fetal size is more pronounced among larger species with longer gestation periods such as humans and domestic animals. A clear relationship between the parity of the mother and potential developmental toxicity in humans has not been established due to the confounding influences of maternal age. Among laboratory rodents, however, it appears that offspring of multiparous animals are at increased risk of developmental toxicity. A variety of infectious agents, particularly viruses, have either been demonstrated or implicated as causes of developmental toxicity. In addition, hyperthermia is a possible confounding factor inherent with maternal infection. Although under experimental conditions hyperthermia is teratogenic in laboratory animals, a causative role for transient hyperthermia, which occurs during febrile states concomitant with infections, cannot be clearly established. Chronic maternal vascular disease states including essential hypertension, heart disease, or diabetes mellitus are likely to contribute to uteroplacental insufficiency and developmental toxicity. Poor maternal nutrition among humans contributes to growth retardation, but not to malformations. The production of “abnormal” maternal antibodies, such as are present in Rh incompatibility, can cause fetal wastage. An important maternal factor in humans is uteroplacental insufficiency, which can occur in normal states like twinning, as well as in abnormal conditions including reduced placental size, chronic maternal hypoxia, or uterine ischemia. Although all these maternal factors can contribute to developmental toxicity, they do not necessarily occur as isolated events. Some developmental toxicants exert deleterious effects within both the embryo and the maternal system.
Maternal toxicity in humans and animals: Effects on fetal development and criteria for detection
Authors: Khera K. S. 
Published: February 2006

AbstractEvaluation of published human and animal teratology data revealed associations between maternal toxicity and congenital malformations and embryofetal death. This has been reported elsewhere in detail and is herein summarized. Regarding human data, intrauterine deaths were observed to occur in association with (1) maternal homeostatic changes due to phenylketonuria and diabetes and (2) maternal toxicity resulting from alcohol abuse, use of aminopterin, and, possibly, trimethadione. A pattern of malformations that was similar and thus suggestive of a common cause was noticed among malformations attributed to phenylketonuria, diabetes mellitus, aminopterin, alcohol, warfarin, phenytoin, phenobarbital, trimethadione, and valproic acid. On reviewing 234 studies of agents tested in hamsters, mice, rats and rabbits, a fairly strong association between maternal toxicity and embryo‐fetal mortality was observed. Further, a consistent pattern of fetal malformations associated with maternotoxic effects was discovered in a survey of 476 studies of agents tested in these four species. In these reviews, it was postulated that maternal toxicity per se could possibly cause such fetal effects. For evaluating maternotoxic effects in experimental studies, the minimum maternal data required would be frequent measurements of maternal body weight and food consumption, signs of altered behavior, death, and gross lesions at necropsy.
Effect of prenatal reserpine exposure on development of the postnatal rat heart
Authors: Harmon James R. , Kimmel Gary L. , Webb Peggy J. , Delongchamp Robert R. 
Published: February 2006

AbstractPrevious studies have suggested that reserpine treatment may result in altered heart development. In order to more fully investigate this possibility, reserpine was administered s.c. at 0,0.375, or 0.75 mg/kg/day to pregnant rats on gestation days 12–15. Maternal weight gain, as well as pup weight on postnatal day (PND) 1, was significantly reduced in a dose‐dependent manner. Litter size was unaffected, but reserpine‐treated dams had more dead pups than did control dams. On PND 1, litters were randomly standardized at ten pups each for analysis on PNDs 5, 8, 15, and 22. Pup body weight and heart weight were reduced in a doserelated manner at all ages measured. The decreased heart weights were probably due to decreases in cell number. Beta‐adrenergic receptor concentration was significantly reduced only on PND 5, at the low reserpine dose, and was not considered to be a treatment effect. Prenatal reserpine exposure had no effect on levels of basal cardiac ornithine decarboxylase (ODC), an enzyme associated with growth and development. Cardiac ODC stimulation by insulin and isoproterenol also showed no effects of maternal reserpine treatment. The results suggest that maternal reserpine treatment may lead to adverse effects in the developing offspring.
Müllerian remnants of male mice exposed prenatally to diethylstilbestrol
Authors: Newbold Retha R. , Bullock Bill C. , McLachlan John A. 
Published: February 2006

AbstractPrenatal exposure of males to diethylstilbestrol (DES) results in reproductive tract teratogenesis, ie, retention of Müllerian duct remnants. The potential of these remnants to develop pathological changes has not been studied. Therefore, pregnant outbred CD‐1 mice were subcutaneously injected with daily doses of DES (100 μg/kg) on days 9 through 16 of gestation. DES‐exposed male offspring and age‐matched control male mice were sacrificed at 10 to 18 mo of age and examined for reproductive tract abnormalities. Prominent Müllerian remnants were observed in 268 out of 277 (97%) of the DES‐exposed male mice. These remnants differentiated into “femalelike structures” homologous to oviduct and uterus. The Müllerian remnants were often enlarged and cystic and shared supporting connective tissue with adjacent male structures. Previously reported lesions, termed “epididymal cysts,” were determined histologically to be cystic “oviductlike” structures and were, therefore, considered a Müllerian duct abnormality. Pathological changes in these male oviductal and uterine homologs included benign and malignant lesions.In addition, epididymal structures were altered. Inflammation and sperm granulomas were prevalent in DES‐treated mice as young as 10 mo old but were only observed in control mice at 18 mos. Cysts of epididymal duct origin, hyperplasia, and adenoma of the epididymal duct were also observed. No comparable abnormalities were noted in 122 control males of corresponding ages.The data presented in this report demonstrated that transplacental exposure to DES affected the differentiation and normal development of the male genital tract involving both the Müllerian (paramesonephric) and Wolffian (mesonephric) ducts. The long‐term changes in these tissues include lesions, some of which resembled neoplasia although the natural history of the lesions is not known. Moreover, some previously described abnormalities referred to as “epididymal cysts” were associated with tissues derived from embryonic female origin.
Investigation of the teratogenic effects of exercise on pregnancy outcome in mice
Authors: Boehnke William H. , Chernoff Gerald F. , Finnell Richard H. 
Published: February 2006

AbstractSwiss Webster female mice were arbitrarily assigned to a heavily exercised group (HE), a moderately exercised group (ME), or a sedentary group (S). Exercised groups were subjected to a progressive treadmill training routine, 6 days a week (60 min per day) for a total of 9 wk. Following mating after 6 wk of training, treatment groups continued to exercise at preconceptual intensities. Pregnant mice were sacrificed on the 19th day of pregnancy, and the fetuses were recovered. A positive training effect was demonstrated by a significant increase in succinate dehydrogenase activity in the gastrocnemius muscles of exercising dams. The numbers of implants, resorptions, live fetuses, mean fetal weight, and developmental stage were unaffected by the exercise treatment. A detailed fetal examination revealed no significant skeletal or gross tissue abnormalities in any of the experimental groups.
Cyclophosphamide: Interstrain differences in the production of mutagenic metabolites by S9‐fractions from liver and kidney in different mutagenicity test systems in vitro and in the teratogenic response in vivo between CBA and C 57 BL mice
Authors: Winckler K. , Obe G. , Madle S. , Kocher‐Becker U. , Kocher W. , Nau H. 
Published: February 2006

AbstractThe formation of mutagenic compounds from cyclophosphamide (CPA) by S9‐fractions from liver (S9L) or kidney (S9K) of pregnant CBA and C 57 BL mice was investigated, using point mutations in Salmonella typhimurium (TA 1535) and the induction of sister chromatid exchanges (SCE) in human peripheral lymphocytes (HPL) or Chinese hamster ovary (CHO) cells as end points. In addition, the teratological response of CBA and C 57 BL mice to CPA on day 11 of pregnancy was analysed in vivo.The results are as follows: (1) S9L from CBA mice was more effective than S9L from C 57 BL mice in metabolizing CPA to products inducing mutations in Salmonella and SCEs in HPL and CHO cells. (2) S9L was more effective than S9K from both strains of mice. (3) In vivo pretreatment of mice with a single dose of CPA (20 mg/kg) reduced the in vitro metabolizing capacity of S9L and S9K significantly and led to the disappearance of the interstrain difference. (4) The embryolethal and teratogenic effects of CPA were stronger in C 57 BL than in CBA mice; the types of teratological effects were partially different in the two strains.
Routine teratogenicity test that uses chick embryos in vitro
Authors: Kučera Pavel , Burnand Marie‐Beatrice 
Published: February 2006

AbstractAn in vitro culture of chicken embryo is described: the embryos at the stage of gastrulation are explanted from eggs into transparent silicone chambers where they continue to develop normally under controlled conditions for additional 3 d. This period corresponds to 2‐5 wk of postconceptional age in the human embryo. In both the chick and man, this period is very sensitive to physicochemical perturbations which can lead to surviving malformations.Six chemical agents were tested with this culture: methotrexate, cadmium chloride, caffeine, phenobarbital, aspirin, and saccharin. Survival scores, growth perturbations, and early signs of anomalies of the nervous, skeletomotor, and cardiovascular systems were analyzed with respect to the used concentrations. The dose‐response curves were obtained with good precision and allowed a discrimination between the teratogenetic and unspecific toxic effects and a comparison of the toxic potency of the six drugs. The evaluation of one drug took, roughly, 3 wk, one technician, and about 150 eggs.The advantages (simplicity, rapidity, reproducibility, specificity, economy, no suffering, and no use of mature animals) and disadvantages (nonmammalian species, absence of detoxicating organs) of the method are discussed. The method is proposed as a routine teratogenicity and embryotoxicity test which allows primary screening of many compounds and which can thus substantially reduce the ultimate experiments that use pregnant mammalian females.
Analysis of diurnal difference in teratogen (Ara‐C) susceptibility in mouse embryos by a progressive phase‐shift method
Authors: Endo Akira , Sakai Nobuyoshi , Ohwada Kazuo 
Published: February 2006

AbstractOur objectives were to determine whether the embryotoxic and teratogenic potential of cytosine arabinoside (Ara‐C) differs depending on the time of day. Pregnant CD‐1 (ICR) mice were placed in an environment where the phases of lighting and darkness were reversed by progressive phase‐delay or phase‐advance methods—2 h every day from day of gestation (dg) 2 to dg 7 (or 6). After it was confirmed that these progressive phase‐shifting methods had no effect on embryonic growth and pregnancy outcome, 5 mg/kg body weight (bt) of Ara‐C was injected intraperitoneally into these animals at 1000 or 1600 on dg 11, and the incidence of gross fetal malformations was compared with that in control dams treated similarly but under a regular lighting regimen (0600–1800). In contrast to previous reports on other teratogens, no diurnal difference was observed in fetal susceptibility to the teratogenic potential of Ara‐C. The possible usefulness of the progressive phase‐shifting method in the field of chronoteratology is proposed.