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PubMed1990

Ethoxyquin and nordihydroguaiaretic acid reduce hydroxyurea developmental toxicity.

Hydroxyurea (HU) is a potent teratogen that causes a characteristic, rapidly occurring episode of embryonic cell death 2 to 4 h after subcutaneously injecting 650 mg/kg of HU into pregnant New Zealand White rabbits on gestational day 12. Previous studies documented the ability of the phenolic antioxidant, propyl gallate, to delay the onset of embryonic cell death and to decrease the number and severity of defects seen at term. The present study investigated the ability of the structurally different antioxidants, ethoxyquin (ETX) and nordihydroguaiaretic acid (NDGA), to also ameliorate HU developmental toxicity. Injection of pregnant rabbits with either ETX or NDGA at 950 mg/kg, 15 to 30 min prior to HU injection, resulted in reduced developmental toxicity seen at term. The reduction was manifested by fewer malformed fetuses with increased body weights compared with fetuses from HU-only treated litters, greatly reduced incidences of specific malformations, and diminished severity of some HU-induced defects. Microscopic analysis of HU, HU-ETX, and HU-NDGA embryos was performed at 4 or 8 h after treatment. HU caused cell death in the limb bud mesenchyme, clearly evident at 4 h. In contrast, HU-NDGA embryos exhibited no signs of cell death until 8 h after treatment. Although most HU-ETX embryos exhibited little or no cell death at 4 h after treatment, in about 20% the level of cell death was indistinguishable from that in HU-treated embryos. The amelioration of HU developmental toxicity in the present study is consistent with the results of previous studies utilizing propyl gallate. The results suggest that the antioxidant properties of these substances interfere with the rapidly occurring toxic effects of HU and that this may account for amelioration of HU developmental toxicity.

Abnormalities, Drug-Induced↗
PubMed1999

Structural determinants of developmental toxicity in hamsters.

A CASE/MULTICASE structure activity relationship (SAR) model of developmental toxicity of chemicals in hamsters (HaDT) was developed. The model exhibited a predictive performance of 74%. The model's overall predictivity and informational content were similar to those of an SAR model of mutagenicity in Salmonella. However, unlike the Salmonella mutagenicity model, the HaDT model did not identify overtly chemically reactive moieties as associated with activity. Moreover, examination of the number and nature of significant structural determinants suggested that developmental toxicity in hamsters was not the result of a unique mechanism or attack on a specific molecular target. The analysis also indicated that the availability of experimental data on additional chemicals would improve the performance of the SAR model.

Algorithms↗
PubMed2002

Developmental toxicity but no immunotoxicity in the rat after prenatal exposure to diethylstilbestrol.

Studies with dioxins and PCB's have shown that the developing immune system may be especially vulnerable to xenobiotics during the perinatal period. However, current guidelines for reproductive toxicity testing do not include immune parameters. In the present study, we have explored the usefulness of including immune parameters within the prenatal developmental toxicity study in rats, using the treatment protocol as described in the OECD 414 developmental toxicity test guideline. In addition, the experimental protocol was enhanced by including ten dose groups to facilitate dose-response analysis. Diethylstilbestrol (DES) was used as the model compound, as it is known to be toxic both for embryofetal development and for the immune system. The results show developmental toxicity in terms of decreased fetal survival and decreased pup body weight in the presence of reduced maternal food consumption and reduced body weight gain. However, immune parameters, including histopathology, hematology, and antibody responses to sheep red blood cells (SRBC) in pups at 4 weeks of age were uncompromised. It is speculated that rather than the prenatal exposure protocol used here, the generation study design with both pre- and postnatal exposure may be preferable as a general screen to detect developmental immunotoxic injury after xenobiotic exposure.

Abnormalities, Drug-Induced↗
PubMed1990

Further validation of FETAX: evaluation of the developmental toxicity of five known mammalian teratogens and non-teratogens.

The developmental toxicity of five compounds was evaluated with the Frog Embryo Teratogenesis Assay: Xenopus (FETAX). Late Xenopus laevis blastulae were exposed to 5-azacytidine, methotrexate, pseudoephedrine, aspartame, and amaranth for 96 h. Three separate static-renewal assays were conducted for each compound. Based on Teratogenic Index [LC50/EC50 (malformation)] values, types and severity of induced malformations, and embryo growth, 5-azacytidine and methotrexate tested as having strong teratogenic potential. Pseudoephedrine scored as having moderate teratogenic potential, but amaranth and aspartame had little or no teratogenic potential. Results support the use of FETAX for the screening of developmental toxicants.

Abnormalities, Drug-Induced↗
PubMed2006

The maternal combined supplementation of folic acid and Vitamin B(12) suppresses ethanol-induced developmental toxicity in mouse fetuses.

Maternal ethanol consumption during pregnancy can induce developmental defects in the fetus. The objective of this study was to assess whether combined supplementation of folic acid (FA) and Vitamin B(12) (VB(12)) in dams would suppress ethanol-induced developmental toxicity in CD-1 mice. Ethanol (5.0 g/kg) was given intragastrically from gestational day (GD) 6 to GD15. Vitamin supplementation groups were additionally given 60.0 mg/kg FA, 1.0 mg/kg VB(12), or 60.0 mg/kg FA+1.0 mg/kg VB(12) during GD1-16. The control group received distilled water only. Results of litter evaluation on GD18 showed that combined supplementation of FA and VB(12) ameliorated many of the adverse effects of ethanol. In contrast, the single vitamin supplementation groups showed little or no amelioration. These results suggest that combined supplementation of FA and VB(12) was more effective than each vitamin toward suppressing ethanol-induced developmental toxicity in CD-1 mice.

Abnormalities, Drug-Induced↗
PubMed2003

Influence of maternal stress on uranium-induced developmental toxicity in rats.

It has been demonstrated that uranium is an embryo/fetal toxicant when given orally or subcutaneously to pregnant mice. On the other hand, maternal stress has been shown to enhance the developmental toxicity of a number of metals. In this study, maternal toxicity and developmental effects of a concurrent exposure to uranyl acetate dihydrate (UAD) and restraint stress were evaluated in rats. Four groups of pregnant animals were given subcutaneous injections of UAD at 0.415 and 0.830 mg/kg/day on Days 6 to 15 of gestation. Animals in two of these groups were also subjected to restraint for 2 hr/day during the same gestational days. Control groups included restrained and unrestrained pregnant rats not exposed to UAD. Cesarean sections were performed on gestation Day 20, and the fetuses were weighed and examined for malformations and variations. Maternal toxicity and embryotoxicity were noted at 0.830 mg/kg/day of UAD, while fetotoxicity was evidenced at 0.415 and 0.830 mg/kg/day of UAD by significant reductions in fetal body weight and increases in the total number of skeletally affected fetuses. No teratogenic effects were noted in any group. Maternal restraint enhanced uranium-induced embryo/fetal toxicity only at 0.830 mg/kg/day, a dose that was also significantly toxic to the dams. As in previous studies with other metals, maternal stress enhances uranium-induced developmental toxicity at uranium doses that are highly toxic to the dams; however, at doses that are less acutely toxic the role of maternal stress would not be significant.

Abnormalities, Drug-Induced↗
PubMed1994

Dose-response assessment for developmental toxicity. III. Statistical models.

Although quantitative modeling has been central to cancer risk assessment for years, the concept of dose-response modeling for developmental effects is relatively new. The benchmark dose (BMD) approach has been proposed for use with developmental (as well as other noncancer) endpoints for determining reference doses and reference concentrations. Statistical models appropriate for representing the unique features of developmental toxicity testing have been developed and applied (K. Rai and J. Van Ryzin, 1985, Biometrics 41, 1-9; L. Kupper, C. Portier, M. Hogan, and E. Yamamoto, 1986, Biometrics 42, 85-98; R. Kodell, R. Howe, J. Chen, and D. Gaylor, 1991, Risk Anal. 11, 583-590). Generalizations of those models (designated the RVR, LOG, and NCTR models, respectively) account for the correlations among observations in individual fetuses or implant within litters; the potential for variables other than dose, such as litter size, to affect the probability of adverse outcome; and the possibility of a threshold dose below which background response rates are unaltered. The generalized models were applied to a database of 607 endpoints with significant dose-related increases in response rate. It was determined that the models were generally capable of fitting the observed dose-response patterns, with the LOG model appearing to be superior with respect to fit. A significant contributor to the ability of the LOG model to fit the data was its flexibility with respect to the representation of the dependence of response probability on litter size, a trait not shared by the other two models. Litter size appeared to be a significant covariable for predicting response rates, even when intralitter correlation was accounted for by assuming a beta-binomial distribution for the observations among individual fetuses. In contrast, a threshold dose parameter did not appear to be necessary to adequately describe the observed dose-response patterns. BMD estimates (corresponding to 5% additional risk) from all three models were similar to one another and to BMDs estimated from other, generic dose-response models (not specifically designed for developmental toxicity testing) that modeled average proportion of fetuses affected. The BMDs at the 5% level of risk were similar to no observed adverse effect levels determined by statistical tests of trend. Greater emphasis on and further examination of dose-response modeling for developmental toxicity testing are needed; biologically based approaches that consider the continuum of developmental effects induced in such tests should be encouraged.

Animals↗
PubMedDate not supplied

Developmental toxicity of di-isodecyl and di-isononyl phthalates in rats.

The developmental toxicity of di-isodecyl phthalate (DIDP; CAS RN 68515-49-1) and di-isononyl phthalate (DINP; CAS RN 68515-48-0) were investigated in Sprague-Dawley rats. DIDP and DINP were administered by gavage to mated rats at doses of 0, 100, 500, and 1000 mg/kg/d on Gestation Days (GD) 6 through 15. Cesarean sections were performed on GD 21 and the fetuses removed for evaluation. Maternal weight gain and food consumption were significantly reduced at 1000 mg/kg/d during the exposure period. No treatment-related effects were noted at cesarean section, nor were there any fetal morphologic observations except for an increased frequency of seventh cervical and rudimentary lumbar ribs at the maternally toxic exposure level of 1000 mg/kg/d. Under these study conditions, mild maternal and developmental effects were observed at 1000 mg/kg/d. Both maternal and developmental NOAELs were therefore established at 500 mg/kg/d. The results indicate that neither DIDP nor DINP is teratogenic or a selective developmental toxicant.

Abnormalities, Drug-Induced↗
PubMed1998

Effect of environmental temperature on the interactive developmental toxicity of radiofrequency radiation and 2-methoxyethanol in rats.

OBJECTIVE: This research was conducted to determine if altered environmental temperatures would affect the interactive developmental toxicity of radiofrequency (RF) radiation and the industrial solvent, 2-methoxyethanol (2ME). This is important because RF radiation is used in a variety of workplaces that have poorly controlled environmental temperatures, and many workers are concurrently exposed to various chemicals. Furthermore, we have previously demonstrated that combined exposure to RF radiation (10 MHz) and 2ME produces enhanced teratogenicity in rats. METHODS: RF radiation sufficient to maintain colonic temperatures at the control value (38degrees ), 39.0degrees or 40.0 degrees C for 2 or 4 h combined with either 0 or 100 mg/ kg 2ME at environmental temperatures of 18 degrees , 24 degrees and 30 degrees C (65 degrees , 75 degrees , and 85 degrees F) were given on gestation day 13 to Sprague-Dawley rats. Dams were killed on gestation day 20, and the fetuses were examined for external malformations. RESULTS AND CONCLUSIONS: Environmental temperature does affect the specific absorption rate (SAR) necessary to maintain a specific colonic temperature but does not affect the interactive developmental toxicity of RF radiation and 2ME in rats. These results, consistent with the literature, add to the evidence that the developmental toxicity of RF radiation (combined or alone) is associated with colonic temperature, not with SAR.

Abnormalities, Drug-Induced↗
PubMed2000

Developmental toxicity of Spinosad administered by gavage to CD rats and New Zealand white rabbits.

The insecticide Spinosad was administered by gavage to pregnant CD(R) rats at 0, 10, 50 or 200 mg/kg/day on gestation days (gd) 6-15 and to New Zealand White rabbits at 0, 2.5, 10 or 50 mg/kg/day on gd-7-19. Rats and rabbits were monitored for clinical signs of toxicity and body weight gains. At gd-21 (rats) or gd-28 (rabbits), maternal organ weights, reproductive parameters, fetal body weights, and fetal external, visceral and skeletal structures were evaluated. Rats given 200 mg/kg/day exhibited a 4% lower body weight on gd-12 and decreased body weight gains on gd-6-16 relative to controls. There was no maternal toxicity at 10 or 50 mg/kg/day, and no developmental toxicity in rats at any dose level. Rabbits given 50 mg/kg/day exhibited decreased feed consumption, reduced fecal output, body weight loss during the initial dosing period (gd-7-10) and a non-statistically significant decrease (31%) in body weight gain during the dosing period (gd-7-20). Two litters aborted due to maternal inanition. There were no maternal effects at lower doses, and no signs of developmental toxicity at any dose. Thus, the maternal no-observed-effect levels (NOEL) were 50 and 10 mg/kg/day in rats and rabbits, respectively, and the embryonal/fetal NOELs were 200 mg/kg/day in rats and 50 mg/kg/day in rabbits.

Abnormalities, Drug-Induced↗
PubMed2007

Developmental toxic effects of antifungal flusilazole administered by gavage to mice.

BACKGROUND: The developmental toxicity of flusilazole was studied in CD-1 mice after oral administration. METHODS: Pregnant mice were given flusilazole at doses of 0 (corn oil), 10, 20, and 40 mg/kg/day, by gavage, on gestational days (GD) 6-15. RESULTS: Maternal toxicity, as evidenced by reduction in body weight gain and signs of toxicity, was observed at the middle- and high-dose groups. No significant incidence of resorptions or death was observed in any of dose groups. There was a pronounced reduction in fetal weight, which was significantly lower than control from 20 and 40 mg/kg/day. There was no significant increase in the incidence of fetuses with external or visceral malformations in any of dose groups, but there was a significant increase in the incidence of skeletal malformations was observed at 20 and 40 mg/kg/day. CONCLUSIONS: The results of this study reported marked maternal toxicity, growth retardation, and skeletal abnormalities in the mid- and high-dose groups. It seems likely that marked maternal toxicity contributed to the observed alterations in fetal growth retardation and skeletal development. The no-observed-effect level in the present study for maternal and developmental toxicity was 10 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMed1996

The developmental toxicity of boric acid in rabbits.

Boric acid (BA), an ingredient of many pharmaceutical, cosmetic, and pesticide products, was previously shown to induce reproductive and developmental toxicity in laboratory rodents. In this study, BA (0, 62.5, 125, or 250 mg/kg/day, po) was administered on Gestational Days (GD) 6-19 to New Zealand White rabbits (18-23 pregnant/group). Maternal body weight, food consumption, and clinical condition were monitored at regular intervals throughout gestation. At termination (GD 30), the numbers of uterine implantations, resorptions, dead fetuses, and live fetuses were determined. Fetuses were weighed, and live fetuses examined for external, visceral, and skeletal defects. Maternal food intake decreased during treatment at 250 mg/kg/day and increased at >/=125 mg/kg/day after treatment. Maternal body weight (GD 9-30), weight gain during treatment, gravid uterine weight, and number of ovarian corpora lutea decreased at 250 mg/kg/day. In contrast, maternal corrected gestational weight gain increased at >/=125 mg/kg/day. Maternal liver weight was not affected. Relative (but not absolute) maternal kidney weight increased at 250 mg/kg/day, and microscopic evaluation revealed no treatment-related renal pathology. At 250 mg/kg/day, prenatal mortality was increased (90% resorptions/litter vs 6% for controls), the proportion of pregnant females with no live fetuses was increased (73% vs 0%), and live litter size was reduced (2.3 fetuses/litter vs 8.8). As a result, there were only 14 live fetuses (6 live litters) available for evaluation in the high-dose group, compared to 153-175 live fetuses (18-23 live litters) in the other groups. The percentage malformed fetuses/litter was increased at 250 mg/kg/day, primarily due to cardiovascular defects in 72% of high-dose fetuses vs 3% of controls. The most prevalent cardiovascular malformation (interventricular septal defect) was observed in 57% of high-dose fetuses compared to 0.6% among controls. At 250 mg/kg/day, average fetal body weight/litter was 92% of the average control weight (not statistically significant). In summary, no definitive maternal or developmental toxicity was observed at 62.5 or 125 mg/kg/day BA. Mild maternal effects and severe developmental toxicity were observed at 250 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMed1992

A study of developmental toxicity of hydroquinone in the rabbit.

To obtain information on potential developmental toxicity, hydroquinone (HQ) was administered to pregnant New Zealand White rabbits (18 mated per dose group) in aqueous solution (0, 25, 75, or 150 mg HQ/kg/day) by gavage on Gestation Days (GD) 6 to 18. Caesarean sections were performed on GD 30. Doses of 75 and 150 mg/kg/day adversely affected feed consumption and/or body weights of dams during the treatment period. At these doses, however, treatment-related effects were not evident from physical observations, liver and kidney weights, premature delivery incidence, and caesarean sectioning data. The NOEL for maternal toxicity was 25 mg/kg/day. In the 150 mg/kg/day dose group, total incidences of external, visceral, and skeletal findings for fetuses did not differ statistically from controls. Slight, statistically insignificant, increases were found, however, in the incidences of ocular and minor skeletal malformations (micro-ophthalmia, vertebral/rib defects, angulated hyoid arch) on both a per fetus and a per litter basis. Under the conditions of this study, HQ at 150 mg/kg/day produced minimal developmental alterations in the presence of maternal toxicity. The NOEL for developmental toxicity was 75 mg/kg/day.

Animals↗
PubMed1996

Developmental toxicity study in rats exposed dermally to clarified slurry oil for a limited period of gestation.

Clarified slurry oil (CSO, CAS number 64741-62-4), a refinery stream produced by processing crude oil, is a developmental toxicant when administered dermally throughout gestation to pregnant rats. The manifestations of developmental toxicity observed included embryolethality and growth retardation; evidence of teratogenicity was limited, and not conclusive. The present study was undertaken to further explore the teratogenic potential of CSO. In an attempt to limit embryolethality and thereby promote detection of terata, CSO was administered once daily for a limited period of gestation [gestation days (GD) 9-12], via dermal application, to pregnant Sprague-Dawley rats at doses of 0, 10, 100, and 1000 mg/kg. All animals were sacrificed on GD 20. Detailed examination of the dams was performed. Due to the screening nature of this investigation, fetal evaluations were limited to body weight measurements, external examinations, and evaluation of select visceral endpoints. In the dams exposed to CSO, significant decreases in body weight [absolute and gain (GD 9-13, GD 0-20)] and in the amount of food consumed were observed at 100 and 1000 mg/kg. Additional evidence of maternal toxicity observed at 1000 mg/kg included decreased absolute and relative thymus weights, increased absolute and relative liver weights, and aberrant serum chemistry. Ingestion of the test material was evident at the high dose. Developmental toxicity was observed at 1000 mg/kg and included increased embryolethality, decreased body weight, and anomalous development (cleft palate, brachydactyly, edema). Although a low incidence of abnormal fetal development was observed at 100 mg/kg, it was not conclusive that the alterations were due to CSO exposure. It is likely that three to seven-ring polycyclic aromatic compounds present in CSO were responsible for the toxic effects observed.

Administration, Cutaneous↗
PubMed1980

Developmental toxicity of methoxyflurane in mice.

The developmental toxicity of trace, subanesthetic, and anesthetic exposure to methoxyflurane was examined in Swiss/ICR mice. No adverse effects on reproduction or fetal development were demonstrated following exposure to trace (2 ppm) and subanesthetic (60 ppm) concentrations of methoxyflurane for 4 hours daily on days 6 through 15 of pregnancy. Exposure to an anesthetic concentration (2000 ppm; 0.2%) for the same period resulted in decreased fetal weight, decreased ossification, and delayed renal maturation. Additionally, the incidence of minor skeletal anomalies was increased. It is concluded that gestational exposure of mice to trace of subanesthetic concentrations of methoxyflurane does not result in reproductive loss or morphologic abnormalities in their offspring.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Developmental toxicity of cysteamine in the rat: effects on embryo-fetal development.

The reproductive and developmental safety of cysteamine has become an important issue to children with cystinosis because renal transplants and treatment with cysteamine reduce the complications associated with cystinosis and increase the lifespan of the affected children. In addition, there is the potential to decrease the severity or the incidence of renal Fanconi syndrome with administration of cysteamine to pregnant women carrying fetuses with cystinosis, and to ease significantly the burden of this disease throughout their lives. If cysteamine increases significantly the risk of fetal death, growth retardation or birth defects at doses used to treat women with cystinosis, treatment of the affected female should cease during pregnancy and would not be considered for fetal treatment. The goal of this study was to assess the developmental safety of exposure in utero to cysteamine in the rat. Pregnant rats were given cysteamine (as phosphocysteamine) from day 6.5 through day 18.5 postconception and fetuses were assessed for survival, growth, and structural abnormalities on day 20.5. Cysteamine was administered orally in doses of 0, 37.5, 75, 100, or 150 mg/kg/day. Cysteamine produced dose-dependent developmental toxicity with an apparent no adverse effect observed level of 75 mg/kg/day. Specific malformations were associated with this effect (cleft palate, kyphosis), as well as intrauterine growth retardation and fetal death at 100-150 mg/kg/day, without signs of maternal toxicity. Investigations continue into the mechanism for the developmental toxicity of cysteamine.

Administration, Oral↗
PubMed1989

Characterization of a developmental toxicity dose-response model.

The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included developmental evaluations of ethylene glycol, diethylhexyl phthalate, di- and triethylene glycol dimethyl ethers, and nitrofen in rats, mice, or rabbits. Graphic examination and statistical evaluation demonstrate that this model is sensitive to the data when compared to directly measured experimental outcomes. The model was used to interpolate to low-risk dose levels, and comparisons were made between the values obtained and the no-observed-adverse-effect levels (NOAELs) divided by an uncertainty factor. Our investigation suggests that the Rai and Van Ryzin model is sensitive to the developmental toxicity end points, prenatal deaths, and malformations, and appears to model closely their relationship to dose.

Abnormalities, Drug-Induced↗
PubMed2005

Dichloroacetate-induced developmental toxicity and production of reactive oxygen species in zebrafish embryos.

Dichloroacetate (DCA) is one of the toxic by products that are formed during the chlorine disinfection process of drinking water. In this study, the developmental toxicity of DCA has been determined in zebrafish (Danio rerio) embryos. Embryos were exposed to different concentrations (4, 8, 16, and 32 mM) of the compound at the 4 h postfertilization (hpf) stage of development, and were observed for different developmental toxic effects at 8, 24, 32, 55, 80, and 144 hpf. Exposure of embryos to 8-32 mM of DCA resulted in significant increases in the heart rate and blood flow of the 55 and 80 hpf embryos that turned into significant decreases at the 144 hpf time point. At 144 hpf, malformations of mouth structure, notochord bending, yolk sac edema and behavioral effects including perturbed swimming and feeding behaviors were also observed. DCA was also found to produce time- and concentration-dependent increases in embryonic levels of superoxide anion (O2*-) and nitric oxide (NO), at various stages of development. The results of the study suggest that DCA-induced developmental toxic effects in zebrafish embryos are associated with production of reactive oxygen species in those embryos.

Animals↗