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PubMed1997

Developmental toxicity study in rats and rabbits administered an emulsion containing medium chain triglycerides as an alternative caloric source.

Triglyceride-containing lipid emulsions have been designed as caloric sources that can be administered intravenously to patients that cannot meet their nutritional needs by conventional parenteral therapies. In their study, we evaluate the developmental toxicity of a 20% lipid emulsion that contains a 3:1 ratio of medium chain triglyceride (MCT) to one long chain containing lipid emulsion (LCT). This emulsion was administered by intravenous infusion to rats and rabbits at dosages of 1 and 4.28 g lipid/kg body weight (g lipid/kg) at dose volumes of 5 and 21.4 mL/kg, respectively, once daily during organogenesis to assess the potential developmental toxicity of the test article. The control group received 0.9% saline at a dose volume of 21.4 mL/kg. Animals were observed for clinical signs of toxicity and adverse effects on body weights and feed consumption. On Day 20 (rats) or Day 29 (rabbits), females were necropsied and examined for maternal and embryo/fetal toxicity. Fetuses were removed, weighed, and examined for external, soft tissue, and skeletal abnormalities. Dosages of 4.28 g lipid/kg resulted in lower feed consumption for rats and rabbits, an expected finding based on the high-caloric nature of the test article. Potentially test article-related gross necropsy findings, including enlarged lymph nodes and spleen, small thymus, and enlarged renal pelvis, for rats given 4.28 g lipid/kg were present at a low incidence. There were no adverse effects on fetal parameters for rats even in the presence of some maternal toxicity. However, embryo and fetal toxicity (i.e., resorptions) and skeletal abnormalities were present for rabbits given 4.28 g lipid/kg. Under the conditions of this study, the no-observable-effect level for developmental toxicity was greater than or equal to 4.28 g lipid/kg for rats and greater than or equal to 1 g lipid/kg but less than 4.28 g lipid/kg for rabbits.

Abnormalities, Drug-Induced↗
PubMed1987

Application of the preliminary developmental toxicity screen for chemical hazard identification under the Toxic Substances Control Act.

The Office of Toxic Substances (OTS) within the U.S. Environmental Protection Agency (EPA) is authorized to carry forth the mandates of the Toxic Substances Control Act (TSCA). Included among the provisions of TSCA are the development of requirements for testing of "new" and "existing" chemicals that may present an unreasonable risk of injury to health or the environment. There are over 63,000 "existing" chemicals on the TSCA inventory, and EPA in recent years has been receiving an average of over 1,300 submissions for "new" chemicals a year. Since it is illogical and unrealistic to expect that all of these chemicals should be subjected to detailed testing for all potential adverse health and environmental effects, OTS views screening assays as highly useful tools to assign priorities to chemicals for further testing according to standard methodologies. The Chernoff/Kavlock assay (preliminary developmental toxicity screen) was specifically developed to address the need for a developmental toxicity assay to prioritize for further testing the large number of "new" and "existing" chemicals. OTS has been involved in seeking the development of data through the preliminary developmental toxicity screen for purposes of validating the screen and to obtain critical data necessary for evaluating chemicals. OTS believes that the screen has a role in the risk assessment process and has developed a testing protocol, which is included along with other OTS test guidelines; has provided internal guidance on when the screen may be recommended; and has discussed how the data may be applied in prioritizing chemicals for further study.

Animals↗
PubMed2000

Evaluation of the developmental toxicity of thalidomide using frog embryo teratogenesis assay-xenopus (FETAX): biotransformation and detoxification.

The developmental toxicity of thalidomide was evaluated using FETAX (Frog Embryo Teratogenesis Assay - Xenopus). Young X. Laevis embryos were exposed to this compound in each of two concentration-response experiments with and without differently induced exogenous metabolic activation systems (MASs) and/or inhibited MASs. Young male Sprague-Dawley rats were treated with either isoniazid or Aroclor 1254 to induce cytochrome P-450. Several of the rats were subsequently treated with diethyl maleate (DM) to deplete glutathione reserves. Specific aliquots of rat liver microsomes were treated with 3-amino-1,2,4-triazole (ATZ) or alpha-napthoflavone (alpha-N) to selectively inhibit P-450 activity. Bioactivation was indicated by increased developmental toxicity observed in MAS tests. Results obtained indicated that thalidomide was predominantly activated by P-450 isozyne CYP2E1, although weak cross-specificity between CYP1A1/A2 may have existed. Detoxification pathways for thalidomide were investigated by treatment of the MAS with cyclohexene oxide (CHO) and DM to inhibit the epoxide hydrolase and glutathione conjugation pathways, respectively. Results indicated that epoxide hydrolase was primarily responsible for the detoxification of bioactivated thalidomide. Teratogenesis Carcinog. Mutagen. 20:35-47, 2000.

Amitrole↗
PubMed1998

Assessment of the developmental toxicity, metabolism, and placental transfer of Di-n-butyl phthalate administered to pregnant rats.

The developmental toxicity and placental transfer of di-n-butyl phthalate (DBP) were evaluated in Sprague-Dawley rats given a single oral dose of DBP on Gestational Day 14. In the developmental toxicity study, dams were dosed with 0, 0.5, 1, 1.5, or 2 g DBP/kg and were necropsied on GD21. Increased incidence of resorptions and reduced fetal body weight were observed at 1.5 and 2 g/kg. Higher incidences of skeletal variations were found at doses > or = at 1 g/kg. No embryotoxic or teratogenic effects were observed at a dose of 0.5 g/kg. In the placental transfer study, dams were dosed with 0.5 or 1.5 g [14C]DBP/kg. Maternal and embryonic tissues were collected at intervals from 0.5 to 48 h. Embryonic tissues accounted for less than 0.12-0.15% of the administered dose. Levels of radiocarbon in placenta and embryo were one-third or less of those in maternal plasma. No accumulation of radioactivity was observed in the maternal or embryonic tissues. From HPLC analyses, it was shown that unchanged DBP and its metabolites mono-n-butyl phthalate (MBP) and MBP glucuronide were rapidly transferred to the embryonic tissues, where their levels were constantly lower than those in maternal plasma. MBP accounted for most of the radioactivity recovered in maternal plasma, placenta, and embryo. Unchanged DBP was found only in small amounts. These findings support the hypothesis that MBP, a potent teratogen, largely contributes to the embryotoxic effects of DBP.

Abnormalities, Drug-Induced↗
PubMed1990

Use of Frog Embryo Teratogenesis Assay-Xenopus and an exogenous metabolic activation system to evaluate the developmental toxicity of diphenylhydantoin.

The teratogenic potential of diphenylhydantoin (DPH) and hydroxylated metabolites (HPPH) was evaluated with the Frog Embryo Teratogenesis Assay--Xenopus (FETAX). Embryos of the South African clawed frog, Xenopus laevis were exposed to DPH and HPPH in two separate static-renewal experiments with and without the presence of an exogenous metabolic activation system (MAS) for 96 hr. Two separate dose-response tests were also conducted with DPH and HPPH with a MAS modulated by various mixed functional oxidase inhibitors [carbon monoxide (CO) (broad spectrum cytochrome P450), cimetidine (mainly cytochrome P450), and ellipticine (cytochrome P448)] and an epoxide hydrolase inhibitor (cyclohexene oxide). Assessment of the potential teratogenic hazard was based on teratogenic indices [TI = 96-hr LC50/96-hr EC50 (malformation)], types and severity of malformations, and embryo growth endpoints. Addition of the intact MAS to DPH increased the 96-hr LC50 and EC50 (malformation) from approximately 74.5 and 32.4 mg/liter to 126.4 and 62.9 mg/liter, respectively. The TI was reduced 1.2-fold. Both p-HPPH and m-HPPH were much less developmentally toxic than DPH. CO and cimetidine inhibition of cytochrome P450 maintained much of the developmental toxicity of DPH, whereas ellipticine inhibition of cytochrome P448 was much less effective in maintaining the developmental toxicity of DPH. Cyclohexene oxide inhibition of epoxide hydrolase markedly increased DPH-induced embryotoxicity decreasing the 96-hr LC50 from approximately 74.5 to 38.6 mg/liter. These results suggest that unmetabolized DPH and an embryotoxic epoxide intermediate may serve as the teratogenic species in FETAX.

Abnormalities, Drug-Induced↗
PubMed1984

Developmental toxicity and psychotoxicity of potassium iodide in rats: a case for the inclusion of behaviour in toxicological assessment.

Potassium iodide (KI) was fed to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through to day 90, at levels of 0, 0.025, 0.05 or 0.1% (w/w) of the diet. Dams in a fifth group (positive controls) were given 4 mg/kg ip of the anti-mitotic/cytotoxic drug 5-azacytidine on day 17 of gestation. All offspring were reared by their natural dams and were evaluated blind with respect to treatment in a battery of standardized behavioural tests between 3 and 90 days of age. KI produced no significant reductions in parental body weight or food consumption, though it significantly reduced litter size and increased offspring mortality at the highest dose, and decreased weight gain at the two highest doses throughout the first 90 days after birth. Functionally, KI delayed auditory startle at the two highest doses, delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels. In rats killed on day 90 after birth KI reduced brain and body weight at a dose of 0.1% of the diet, and reduced body but not brain weight at a dose of 0.05% of the diet. No significant effect was found on absolute or relative thyroid weight at 90 days of age. Several additional behavioural effects were observed in the low-dose KI group, but because these effects were not dose-dependent, they were not regarded as reliable. 5-Azacytidine produced evidence of substantially greater developmental toxicity than KI. It was concluded that KI produced evidence of developmental toxicity consistent with a picture of impaired thyroid function. The inclusion of tests of functional development added useful evidence to the overall picture of KI developmental toxicity.

Administration, Oral↗
PubMed1997

Study on the developmental toxicity of orally administered isobutylidenediurea in rats.

Developmental toxicity of isobutylidenediurea (IBDU) was determined by oral administration to Wistar rats. The substance was administered as an aqueous suspension to 22-24 pregnant rats per group by gavage in daily doses of 100, 400 and 1000 mg/kg body weight from day 6 post-coitum (p.c.) to day 15 p.c. The control group received the vehicle only (0.5% aqueous carboxymethyl cellulose solution). There were no substance-related effects in the dams concerning food consumption, body weight, body weight gain, uterine weights and clinical or autopsy observations even at the highest dose of 1000 mg/kg body weight/day. The reproduction data revealed no biologically relevant differences between the control and treated groups. The incidence and type of the foetal external, soft tissue and skeletal findings, which were classified as malformations, variations and/or retardations observed in the treated foetuses were similar to the concurrent and/or historical control data. Thus, under the conditions of this study, no signs of maternal toxicity or embryo/foetotoxicity were induced by IBDU and the no-observable-adverse-effect level on the maternal and developing organism was 1000 mg/kg body weight/day.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

The effect of maternal restraint on developmental toxicity of aluminum in mice.

Both aluminum (Al) and maternal restraint have been reported to cause developmental toxicity in mammals. This study assessed in pregnant mice the potential interaction between Al and maternal restraint. Four groups of plug-positive female mice were given IP injections of AlCl3 at 37.5 and 75 mg/kg/day on days 6-15 of gestation. Two of these groups were also subjected to restraint for 2 h/day during the same gestational days. Control groups included restrained and unrestrained pregnant mice nonexposed to Al. Cesarean sections were performed on gestation day 18, and the fetuses were weighed and examined for morphological defects. Maternal toxicity was significantly enhanced by restraint at 75 mg AlCl3/kg/day. No increases in the number of resorptions or dead fetuses per litter were observed following exposure to Al, maternal restraint, or combined Al and restraint. However, a significant decrease in fetal body weight, as well as a significant increase in the number of litters with morphologic defects, was observed in the group exposed to 75 mg AlCl3/kg/day plus maternal restraint. The current results suggest that maternal restraint could enhance the metal-induced developmental toxicity (reduced fetal body weight, increase in the number of litters with morphologic defects) only at high doses of the metal, which are also toxic to the dam.

Aluminum Chloride↗
PubMedDate not supplied

Evaluation of the developmental toxicity of benzo[a]pyrene and 2-acetylaminofluorene using Xenopus: modes of biotransformation. Stover Group.

The developmental toxicities of benzo[a]pyrene (BAP) and 2-acetylaminofluorene (AAF) were evaluated using FETAX (Frog Embryo Teratogenesis Assay-Xenopus). Young X. laevis embryos were exposed to these two compounds in each of two separate concentration-response experiments with and without an exogenous metabolic activation system (MAS) and/or inhibited MAS. The MAS was treated with cimetidine (CIM), ellipticine (ELL), or alpha-napthoflavone (alpha-N) to selectively modulate cytochrome P-450 activity. Bioactivation of both of these compounds was indicated by increased developmental toxicity observed in MAS tests. Results obtained in treated MAS tests indicated that BAP was predominantly activated by Cytochrome P-450 isozyme CYP1A1. AAF bioactivation was shown to be only partly mediated by CYP1A1/2. Detoxification pathways for these two compounds were investigated by treatment of the MAS with cyclohexene oxide (CHO) and diethyl maleate (DM) to inhibit the epoxide hydroxylase and glutathione conjugation pathways, respectively. Results indicated that epoxide hydroxylase was primarily responsible for the detoxification of BAP, with glutathione conjugation playing a secondary role. Detoxification of AAF by these two pathways was not indicated.

2-Acetylaminofluorene↗
PubMed1993

Using historical controls in the analysis of developmental toxicity data.

Historical control data can often aid in the interpretation of the results from laboratory dose-response experiments. For example, formal statistical methods for using historical data are well established for carcinogenicity studies. In that case, a score test derived from a beta-binomial model yields a simple modification of the standard Cochran-Armitage test for trend. However, this test cannot be used for developmental toxicity studies since it does not allow for the additional correlation structure induced by the presence of litter effects. In this paper, quasi-likelihood methods are used to incorporate historical control information into a trend test for the types of correlated binary outcomes that typically arise in developmental toxicity studies. The proposed test is asymptotically equivalent to the beta-binomial score test in the special case when all the litter sizes are equal to 1. Malformation data from a series of developmental toxicity studies illustrate the results.

Abnormalities, Drug-Induced↗
PubMed1991

Assessment of the developmental toxicity of ascorbic acid, sodium selenate, coumarin, serotonin, and 13-cis retinoic acid using FETAX.

The developmental toxicity of five compounds was evaluated with the Frog Embryo Teratogenesis Assay: Xenopus (FETAX) and the results were compared to mammalian literature. Small cell Xenopus laevis blastulae were exposed to ascorbic acid, sodium selenate, coumarin, serotonin and 13-cis retinoic acid for 96 hr. Three separate static-renewal assays were conducted for each compound. Teratogenic potential of the test materials was determined based on Teratogenic Index values [TI = LC50/EC50 (malformation)], types and severity of induced malformations and embryo growth. Ascorbic acid had little or no teratogenic potential. Sodium selenate and coumarin tested as having moderately positive teratogenic potential. Serotonin scored as having moderately strong teratogenic potential and 13-cis retinoic acid scored as having strong teratogenic potential. Results were consistent with mammalian data and support the use of FETAX for the screening of developmental toxicants.

Abnormalities, Drug-Induced↗
PubMed1990

Arsine: absence of developmental toxicity in rats and mice.

Arsine gas is a potent hemolytic agent but the effects of exposure to tolerated concentrations on pregnancy and prenatal development have not been reported. In the present evaluation, groups of bred mice and rats were exposed to arsine at concentrations of 0.025, 0.5, or 2.5 ppm on Gestation Days (gd) 6 through 15. Animals were killed on gd 17 (mice) or on gd 20 (rats) and endpoints of maternal and developmental toxicity were evaluated. In rats, maternal spleens were enlarged in the 2.5 ppm group and there was a decrease in packed red cell volume in pregnant rats. Fetuses weighed more than in the control group but other endpoints of developmental toxicity were not affected by arsine exposure. In another experiment involving separate groups of rats, the arsenic content of maternal blood and fetal livers increased with increasing atmospheric arsine concentrations, as assessed on gd 20. In mice, maternal spleen size was significantly increased in the 2.5 ppm group. The number of live fetuses, mean fetal body weight, and percentages of resorptions or malformations per litter were not affected by arsine exposure. In conclusion, arsine at atmospheric concentrations that caused increases in maternal spleen size and measurable levels of arsenic in maternal blood and fetal livers did not adversely affect endpoints of developmental toxicity.

Air Pollutants, Occupational↗
PubMedDate not supplied

A new threshold dose-response model including random effects for data from developmental toxicity studies.

Usually, in teratological dose finding studies, there are not only threshold effects but also extra variations that cannot be accounted for by the beta-binomial model alone. The beta-binomial model assumes correlation between fetuses in the same litter. The general random effect threshold (RE) model allows the additional variability that arises due to correlation and between litter variability to be modeled, in combination with threshold in the model. The goal of this research was to investigate a threshold dose-response model with random effects (RE) to model the variability that exists between litters of animals in studies of toxic agents. Data from a developmental toxicity study of a toxic agent were analysed, using the proposed RE threshold dose-response model, which is an extension of logit in form. Also, an approximate likelihood function was used to derive parameter estimates from this model, and tests were performed to determine the significance of the model parameters, in particular, the RE parameter. A simulation study was conducted to assess the performance of the RE threshold model in estimating the model parameters.

Algorithms↗
PubMed1993

Developmental toxicity of bromohydroquinone (BHQ) and BHQ-glutathione conjugates in vivo and in whole embryo culture.

Glutathione conjugates of 2-bromohydroquinone (GSyl-BHQ) cause renal proximal tubular necrosis that is dependent upon the activity of gamma-glutamyl transferase (GGT). GGT is present in embryonic yolk sac and its activity increases with gestational age, suggesting that the developing embryo might be at risk from maternal exposure to glutathione conjugates or compounds which are shown to form glutathione conjugates. Studies in pregnant rats exposed on Day 9 of gestation to 400 or 800 mumol/kg BHQ or 20 mumol/kg 2-Br-(di-GSyl)HQ and examined on Day 11 of gestation suggested that the parent compound (BHQ) or a metabolite was nephrotoxic in the adult and dysmorphogenic in the embryo and that 2-Br-(di-GSyl)HQ was nephrotoxic but not dysmorphogenic at the dose tested (20 mumol/kg). We therefore exposed Day 9 rat embryos to BHQ, 2-Br-6-(GSyl)HQ, or 2-Br-(di-GSyl)HQ in vitro for 48 hr to determine the relative dysmorphogenic activity of the parent compounds and the two conjugates. In vitro exposure to BHQ (0-40 microM) resulted in dose-related decreases in somite number (SN), total protein, and developmental score (DEVSC), with no effect on yolk sac diameter (YSD), crown rump length (CR), head length (HL), or percentage abnormal embryos (%AE); 60 microM BHQ was embryolethal. Embryos exposed to 2-Br-6-(GSyl)HQ (0-120 microM) were not affected at concentrations below 120 microM, at which dose there were significant effects on protein, YSD, CR, HL, DEVSC, SN, and %AE. Embryos exposed to 2-Br-(di-GSyl)HQ had a significantly lower DEVSC at the 80 microM concentration and significantly lower YSD, protein, and DEVSC and significantly higher %AE at the 10, 25, and 120 microM concentrations. CR, HL, and SN were not affected at any exposure level with this compound. In conclusion, BHQ was found to be developmentally toxic in vitro and in vivo at doses which also produced severe maternal renal necrosis. The doses of 2-Br-(di-GSyl)HQ in vivo which caused only mild maternal renal necrosis did not produce developmental toxicity. Conjugation of BHQ with either one or two molecules of GSH decreased the embryolethality of BHQ. The conjugates appeared to be of comparable toxicity as measured by the incidence of abnormal embryos in vitro. The role of maternal toxicity and GSH conjugation in 2-BHQ-mediated developmental toxicity remains to be determined.

Animals↗
PubMed1994

Reproductive and developmental toxicity studies of silicone gel Q7-2159A in rats and rabbits.

Studies reported here assessed the potential adverse effects of silicone gel, Dow Corning Q7-2159A, on general reproduction and fetal development in male and female Charles River CD rats and New Zealand white rabbits. Two control and three treatment groups of 30 male and 30 female rats and 25 female rabbits per group were used in the one-generation reproduction and developmental toxicity studies, respectively. The silicone gel was implanted subcutaneously in two flank sites at dosage levels of 3, 10, and 30 ml/kg. The highest dose was selected on the basis of likely human body burden. Control groups received either sterile saline or carboxymethylcellulose solution in two flank implantation sites. The control and test articles were implanted in male and female rats 61 and 47 days, respectively, prior to mating (in the rat reproduction study) and approximately 42 days prior to insemination of female rabbits (in the rabbit developmental toxicity study). There were no treatment-related effects on F0 parental general conditions and reproductive performance, F1 neonatal viability, or growth in the rat reproduction study. No maternal nor developmental effects, including teratogenicity, were observed in rabbits in the groups implanted with Q7-2159A gel in the developmental toxicity study.

Abnormalities, Drug-Induced↗
PubMed2004

Endocrine-disrupting activity in carbendazim-induced reproductive and developmental toxicity in rats.

This study was designed to investigate the endocrine-disrupting activity of carbendazim-induced reproductive and developmental toxicity in Sprague-Dawley rats treated orally with the fungicide. Cotreatment of male rats with 675 mg/kg carbendazim and 50 or 100 mg/kg flutamide, an androgen receptor antagonist, once daily for 28 d blocked decrease of testis weight induced by treatment with carbendazim alone. The cotreatment prevented losses of spermatozoa and cell morphology and decrease of sperm concentration induced by carbendazim. Premating treatment of male and female rats with 200 mg/kg carbendazim for 28 d produced androgenic effects including incomplete development of uterine horn, enlargement of uretha, absence of vagina, and induction of seminal vesicles in female offspring, without marked effects in male offspring. Premating treatment with 100mg/kg benomyl, the parent compound of carbendazim, resulted in incomplete development of uterine horn and absence of vagina in female offspring and produced testis and epidydimis atropy in male offspring. Treatment of male rats with 25, 50, 100, 200, 400, and 800 mg/kg carbendazim for 56 d produced dose-dependent increases of androgen receptor concentrations in testis and epididymis. Additions of 5, 50, and 500 microM carbendazim to testis extract from untreated rats replaced binding of [3H]-5 alpha-dihydrotestosterone to androgen receptor in a concentration-dependent manner. The present study demonstrates that reproductive toxicity induced by carbendazim is blocked by an androgen receptor antagonist in male rats and developmental toxicity of the fungicide shows androgenic properties in female offspring. These results suggest that androgen- and androgen receptor-dependent mechanisms are possibly involved in carbendazim-induced toxicity.

Abnormalities, Drug-Induced↗
PubMed1989

The developmental toxicity of an isolate from the plant Solanum dimidiatum (potato-weed) in Syrian golden hamsters.

The developmental toxicity of an ethanol extract from Solanum dimidiatum was investigated in date-bred Syrian golden hamsters. Neural tube defects were seen in three Syrian golden hamster fetuses, from one litter out of 12, at a maternal dose of 1.52 mg of plant isolate per g of body weight. Other malformations observed were syndactyly in a single fetus, from one litter out of ten, in the 0.45 mg/g dose group and gastroschisis in a single fetus, from one litter out of nine, in the 1.01 mg/g dose group. These findings suggest minimal developmental toxicity for this plant isolate.

Animals↗
PubMed1993

[A study on developmental toxicity of vanadium pentoxide in Wistar rats].

Timed-pregnant Wistar rats were injected intraperitoneally with V2O5 at 0.33, 1.0 and 3.0 mg/kg/day on days 6-15 of gestation. Maternal toxic symptoms, decreased of weight gain during treatment and placenta weight, increased incidence of embryo-fetus mortality and external or skeletal malformation and fetal growth retardation were observed in the 3.0 mg/kg group. Increased incidence of embryo-fetus mortality and external or skeletal malformation, delayed ossification of bone and decreased placenta weight were observed in the 1.0 mg/kg group. These results indicate that V2O5 is a developmental toxicant with or without obvious maternal toxicity in Wistar rats. Although vanadium can be accumulated in placenta, it could passed through placenta. In this study, vanadium could induce a decrease of placenta weight without obvious maternal toxicity, and an A/D ratio of 3 was noted. These results suggest that vanadium may exert a direct effect on embryo-fetues or a "double effect" on the placenta function and embryo-fetus both. It has been reported that vanadium does not increase mal formation in NIN, Kunming, Swiss, NMRI mice or Syrian golden hamster. The dose for inducing developmental toxicity of vanadium in mice is higher than that in rats. This suggests that rats be more sensitive than mice to the developmental toxicity of vanadium.

Abnormalities, Drug-Induced↗