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PubMed1997

Systemic and developmental toxicity of dermally applied syntower bottoms in rats.

Syntower bottoms (STB) was evaluated for subchronic and developmental toxicity. In the subchronic study, undiluted STB was applied on the shaved backs of male and female rats at dose levels of 0, 8, 30, 125, and 500 mg/kg for 13 weeks, 5 days per week. Exposure sites were not covered. In the developmental toxicity study, STB was similarly applied, but to pregnant rats at dose levels of 0, 8, 30, and 125 mg/kg on Gestation Days 0-19. In addition, 4 mg/kg was dosed as 8 mg/kg every other day, starting on Gestation Day 0, and 500 mg/kg was dosed on Gestation Days 10-12. Evidence of toxicity observed in the subchronic study included death, decreased body weights, aberrant serum chemistry and hematology values, altered organ weights, and histopathologic changes in a variety of organs. A no observed adverse effect level for systemic toxicity could not be established. Evidence of maternal toxicity was observed at all exposure levels in the development study. Regardless of the length of the exposure period, STB was toxic to the developing conceptus. Evidence of developmental toxicity observed included increased resorptions with a concomitant decrease in litter size and reduced fetal body weights. Cleft palate was observed in fetuses exposed in utero to STB during Gestation Days 10-12 at 500 mg/kg. No evidence of teratogenicity was observed when the exposure period was throughout gestation. Ossification delays were observed in fetuses exposed in utero to STB at doses in excess of 4 mg/kg. A no observed adverse effect level for maternal and developmental toxicity could not be established.

Abnormalities, Drug-Induced↗
PubMed1991

[A study on developmental toxicity of vanadium pentoxide in NIH mice].

There is no general agreement yet about the teratogenic effects or developmental toxicity of vanadium in animal studies. This is a report on developmental toxicity in NIH mice following injection of vanadium pentoxide (V2O5, 5 mg/kg body weight, i.p.) at different times of gestation (on days 1-5, 6-15, 7, 8, 9, 10, 11, 14-17 of gestation). No adverse effects of V2O5 on pre-implantation and implantation were noted, and neither were teratogenicity and premature birth. However, there was toxic effect on embryofetus. Increased frequency of resorption or fetal death on days 6-15, 7, 14-17 of gestation were observed. Delayed ossification of bones was noted on days 6-15, 8, 10, 14-17 of gestation. These results suggest that V2O5 may be a weak developmental toxicant but not a teratogen in NIH mice. In addition, this paper reports the developmental toxicity, especially teratogenicity of N, N'-methylene-bis (2-amino-1, 3, 4-thiadiazole) which was used as the positive control in NIH mice.

Animals↗
PubMedDate not supplied

Biodisposition of dibromoacetic acid (DBA) and bromodichloromethane (BDCM) administered to rats and rabbits in drinking water during range-finding reproduction and developmental toxicity studies.

Dibromoacetic acid (DBA) and bromodichloromethane (BDCM), by-products of chlorine disinfection of water, were provided in drinking water in range-finding reproductive/developmental toxicity studies (rats) and a developmental toxicity study (BDCM) in rabbits. Studies included absorption and biodisposition of DBA and BDCM, including passage into placentas, amniotic fluid, fetuses (rats and rabbits), or milk (rats). The DBA and BDCM range-finding reproductive/developmental toxicity studies each included 50 Sprague-Dawley rats/sex/group. DBA (0, 125, 250, 500, or 1000 ppm) or BDCM (0, 50, 150, 450, or 1350 ppm) was provided in drinking water 14 days premating through gestation and lactation (63 to 70 days). The developmental toxicity range-finding study included 25 time-mated New Zealand white rabbits/group given 0, 50, 150, 450, or 1350 ppm BDCM in drinking water on gestation days (GDs) 6 through 29. Satellite groups (6 male, 17 female rats/group/study and 4 rabbits/group) were used for bioanalytical sampling. Rats and rabbits had exposure-related reduced water consumption caused by apparent taste aversion to DBA or BDCM, especially in the parental animals at the two highest exposure levels (500 and 1000 ppm DBA; 450 and 1350 ppm BDCM). Female rats consumed slightly higher mg/kg/day doses of DBA than male rats, especially during gestation and lactation; weanling rats consumed the highest mg/kg/day doses. DBA produced detectable and quantifiable concentrations in plasma, placentas, amniotic fluid, and milk. Plasma samples confirmed that rats drink predominately during the dark; this drinking pattern, not accumulation, produced detectable plasma concentrations for 18 to 24 hours/day. No quantifiable concentrations of BDCM occurred in plasma, placentas, amniotic fluid, or milk, suggesting that BDCM is rapidly degraded or metabolized in vivo. DBA (500 and 1000 ppm, rats) and BDCM (450 and 1350 ppm, rats and rabbits) produced secondary toxicity in the parental generation by reducing water consumption, which caused severe exposure-related apparent dehydration, reduced feed intake and weight gain. Reproductive and developmental parameters were essentially unaffected (mating possibly reduced [DBA at 1000 ppm]; exposure-related decreases in body weights of pups secondary to reduced water and feed consumption [DBA at 250, 500, and 1000 ppm; BDCM at 150, 450, and 1350 ppm]). No effects on development of rabbit fetuses occurred at BDCM concentrations as high as 1350 ppm. Results from these preliminary studies, in which DBA and BDCM were provided in the drinking water at concentrations thousands of times higher than those to which humans are exposed, suggest that neither DBA nor BDCM are reproductive/developmental risks for humans.

Acetates↗
PubMed1996

Benchmark dose analysis of developmental toxicity in rats exposed to boric acid.

Developmental toxicity risk assessment has typically relied on the estimation of reference doses or reference concentrations based on the use of no-observed-adverse-effect levels (NOAELs) divided by uncertainty factors. The benchmark dose (BMD) approach has been proposed as an alternative basis for reference value calculations. In this analysis of the developmental toxicity observed in rats exposed to boric acid in their diet, BMD analyses have been conducted using two existing studies. By considering various end points (rib XIII effects, variations of the first lumbar rib, and fetal weight changes) and various modeling approaches for those end points, the best approach for incorporating all of the information available from those studies could be determined. Particular emphasis has been placed on methods for combining data across studies and for combining potentially related effects (on rib XIII and on the first lumbar rib). The issues of study and end point selection are ones that will arise frequently in the process of estimating reference values. This example of boric acid suggests that the BMD approach provides a reasonable basis for appropriately comparing and combining study data, as opposed to ad hoc combinations of study results. Moreover, it is shown that the BMD approach can be used with combinations of end points considered to differ in severity. In this case, the preferred approach involved combining the data from the two studies, which were similarly designed and were conducted in the same laboratory, to calculate BMDs that were more accurate and more precise than those that could be derived from either study alone. It was determined that decreased fetal body weight provided the best basis for BMD calculations; BMDs calculated for fetal body weight changes were less than those for all other relevant end points. The appropriate BMD to use as the basis for boric acid reference dose calculation appears to be 59 mg/kg/day, which is very similar to the NOAEL observed in the second of the two studies (55 mg/kg/day). Although the first study failed to establish a NOAEL, the BMD approach could have been applied to that study, thereby avoiding the need for a repeat study. Similar BMD results were obtained in both studies.

Animals↗
PubMed2006

Monomethylarsonic acid and dimethylarsinic acid: developmental toxicity studies with risk assessment.

BACKGROUND: The toxicity of arsenic compounds is highly dependent on the valence and methylation state of the compound. Although there is extensive published literature on the potential developmental toxicity of inorganic arsenic compounds, little exists on organic arsenic compounds and, in particular, studies conducted in accordance with conventional regulatory guidelines appropriate for risk assessment are rare. The organic arsenic compounds, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV, also called cacodylic acid), are the active ingredients in pesticide products that are used mainly for weed control. MMAV and DMAV are also metabolites of inorganic arsenic formed intracellularly by most living organisms (animals, plants and bacteria). In mammals, this occurs predominantly in liver cells. METHODS: Conventional developmental toxicity studies of orally administered MMAV and DMAV in the Sprague-Dawley rat and New Zealand White rabbit were conducted in commercial contract laboratories in the late 1980 s for regulatory compliance. The results of these studies are summarized and presented to broaden the data available in the public domain. RESULTS: In both species, data shows an absence of dose-related effects at organic arsenic exposures that were not maternally toxic. MMAV doses of 0, 10, 100, and 500 mg/kg/day (rat) and 0, 1, 3, 7, and 12 mg/kg/day (rabbit) and DMAV doses of 0, 4, 12, and 36 mg/kg/day (rat) and 0, 3, 12, and 48 mg/kg/day (rabbit) were administered by oral gavage daily during organogenesis (Gestation Day [GD] 6-15, rat; GD 7-19, rabbit) and the litters examined at maternal sacrifice (GD 20, rat; GD 29, rabbit). After treatment with MMAV, maternal and fetal toxicity were observed at the highest doses of 500 mg/kg/day (rat) and 12 mg/kg/day (rabbit), but no treatment-related developmental toxicity at the lower doses, even in the presence of minimal maternal toxicity in the rat at 100 mg/kg/d. There was no evidence of teratogenicity associated with MMAV treatment. With DMAV, maternal and developmental toxicity were observed in the rat at 36 mg/kg/day, with a higher than spontaneous incidence of fetuses with diaphragmatic hernia. In the rabbit at 48 mg/kg/day, there was marked maternal toxicity, culminating for most females in abortion and with no surviving fetuses for evaluation. There was no treatment-related maternal or developmental toxicity in the rat or rabbit at 12 mg/kg/day. Based on pregnancy outcome, the developmental toxicity no observed adverse effect level (NOAEL) for orally administered MMAV were 100 and 7 mg/kg/day in the rat and rabbit, respectively, and for DMAV were 12 mg/kg/day in both species. CONCLUSIONS: Margins of exposure estimated based on conservative estimates of daily intakes of arsenic in all of its forms indicate that exposure to MMAV or DMAV at environmentally relevant exposure levels, by the oral route (the environmentally relevant route of exposure) is unlikely to pose a risk to pregnant women and their offspring.

Abnormalities, Drug-Induced↗
PubMed1990

Developmental toxicity of hydroxylamine: an example of a maternally mediated effect.

Hydroxylamine (HA) is an important reducing agent that is used in several industries. HA is a moderate irritant and a powerful inducer of methemoglobinemia. HA has been shown to react readily with DNA in vitro. Several chemical derivatives of HA are potent developmental toxicants, whereas HA has been reported to cause no developmentally toxic effects. Since HA and its developmentally toxic derivatives share the presence of a terminal hydroxylamine functional group (-NHOH), and since that functional group has been proposed to be the biologically active portion of the molecule, it was deemed appropriate to re-examine the possible developmental toxicity of HA. Subcutaneous or intravenous injection of pregnant rabbits with 50-650 mg HA.HCl/kg on gestational day 12 caused the death or sacrifice of all rabbits within 30 hours. All maternally injected rabbits exhibited severe cyanosis, presumably due to methemoglobinemia. Histological examination of embryos revealed alterations of the cardiovascular system at 5 hours, but an absence of cell death in limb buds. At 8 hours, all embryos were dead. These effects appear to be secondary to the observed cyanosis in the maternal animals. In order to circumvent the powerful methemoglobinemia-inducing properties of HA, intracoelomic injections of 25-200 micrograms HA.HCl in 5-40 microliters of saline were made directly into the chorionic cavity of developing rabbit embryos, thereby bypassing the maternal system. Controls received similar volumes of saline. At doses of greater than or equal to 75 micrograms, HA.HCl killed 91 percent of injected embryos; among survivors, all exhibited reduced birth weights and 2/5 exhibited malformations in the craniofacial region and sternum. At doses of 25-50 micrograms, HA.HCl caused increased resorptions compared with controls; however, surviving fetuses displayed neither malformations nor reduced birth weights. Histological analysis at 4 hours after injection revealed cellular debris in the limb buds; when the antioxidant propyl gallate was co-administered with HA, cellular debris was absent at 4 hours. It is concluded that although HA is a directly acting developmental toxicant if it reaches the embryo, the observed embryolethality seen after subcutaneous injection of pregnant animals is a consequence of the powerful maternal toxicity of HA.

Animals↗
PubMedDate not supplied

Developmental toxicity evaluation of inhaled tertiary amyl methyl ether in mice and rats.

This evaluation was part of a much more comprehensive testing program to characterize the mammalian toxicity potential of the gasoline oxygenator additive tertiary amyl methyl ether (TAME), and was initiated upon a regulatory agency mandate. A developmental toxicity hazard identification study was conducted by TAME vapor inhalation exposure in two pregnant rodent species. Timed-pregnant CD(Sprague-Dawley) rats and CD-1 mice, 25 animals per group, inhaled TAME vapors containing 0, 250, 1500 or 3500 ppm for 6 h a day on gestational days 6-16 (mice) or 6-19 (rats). The developmental toxicity hazard potential was evaluated following the study design draft guidelines and end points proposed by the United States Environmental Protection Agency. Based on maternal body weight changes during pregnancy, the no-observable-adverse-effect level (NOAEL) was 250 ppm for maternal toxicity in rats and 1500 ppm for developmental toxicity in rats using the criterion of near-term fetal body weights. In mice, more profound developmental toxicity was present than in rats, at both 1500 and 3500 ppm. At the highest concentration, mouse litters revealed more late fetal deaths, significantly reduced fetal body weights per litter and increased incidences of cleft palate (classified as an external malformation), as well as enlarged lateral ventricles of the cerebrum (a visceral variation). At 1500 ppm, mouse fetuses also exhibited an increased incidence of cleft palate and the dam body weights were reduced. Therefore, the NOAEL for the mouse maternal and developmental toxicity was 250 ppm under the conditions of this study.

Abnormalities, Drug-Induced↗
PubMed1992

Developmental toxicity of nondepolarizing muscle relaxants in cultured rat embryos.

Evidence of developmental toxicity of clinically used nondepolarizing muscle relaxants was sought in rat embryos grown in culture. Embryos were explanted at 8 AM on day 9 of gestation (presomite stage, plug day = day 0), and were cultured in rotating bottles with medium containing various concentrations of d-tubocurarine, pancuronium, atracurium, and vecuronium. At 10 AM on day 11 of gestation (forelimb bud stage), culture was terminated and embryos were examined for general morphology. Treatment with tested agents resulted in dose-dependent developmental toxicity; namely, growth retardation seen as decreased crown-rump length, decreased number of somite pairs, and morphologic abnormalities. However, the concentrations that caused toxicity were at least 30-fold greater than serum concentrations clinically achieved in the mother. We conclude that these muscle relaxants have a low potential for causing developmental toxicity during organogenesis.

Animals↗
PubMed1995

Comparison of two approaches to analyzing correlated binary data in developmental toxicity studies.

Recently developed statistical methodology is presented for analyzing correlated developmental toxicity data where multiple measures are obtained on individual units such as rat pups. Of particular interest is the assessment of the homogeneity of effects from chemical exposure across different outcomes such as malformation types or non-ossification of forepaw digits. Such contrasts are referred to as within-cluster effects, as they represent differences between observations within a cluster (e.g., pup). Between-cluster effects correspond to comparison of observations from different clusters, e.g., pups exposed to varied doses of chemicals or carcinogens. Two classes of statistical models are available for estimation of these distinct types of effects: (1) cluster-specific models in which regression adjustments are made for cluster effects, and hence all parameters are interpreted as within-cluster effects; and (2) population-averaged models in which no explicit adjustments are made for cluster, and thus all parameters are interpreted as group differences without regard to whether they represent between- or within-cluster effects. Many models in the developmental toxicity literature are population-averaged logistic regression models ignoring variation among clusters which may be significant under strong influences of genetic and environmental factors. Under such conditions, confidence interval-based inference for effect homogeneity will depend upon the class of models. These issues are illustrated with data from two developmental toxicity studies: (1) a National Toxicology Program study of the effects of in utero exposure to di(2ethylhexyl)phthalate among three malformation outcomes in mouse pups; and (2) a study conducted by Hartsfield to investigate the effects of anticonvulsant phenytoin on the risk of non-ossification among digits of the left and right forepaws in rat pups.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Subchronic and developmental toxicity studies in rats with Ac-Di-Sol croscarmellose sodium.

Studies were conducted to evaluate the subchronic and developmental toxicity of Ac-Di-Sol (croscarmellose sodium). In the subchronic study, groups of Sprague-Dawley rats (20/sex/group) received 0 (control), 10000, or 50000 ppm Ac-Di-Sol in the diet for 90 consecutive days (equivalent to 757 and 893 mg/kg/day for males and females fed 10000 ppm, respectively, and to 3922 and 4721 mg/kg/day for males and females fed 50000 ppm, respectively). No mortality, clinical signs of toxicity, or adverse toxicological effects on hematology or serum chemistry parameters, feed consumption, or ophthalmologic examinations were noted in any treatment group. Body weight gain was depressed in high-dose males during the final 3 weeks. The only treatment-related histological lesion noted was moderate renal mineralization at the corticomedullary junction in one high-dose female. This lesion was not considered a specific effect of Ac-Di-Sol, but rather a secondary effect resulting from a potential increase in urinary pH and renal excretion of sodium due to the high intake of sodium associated with Ac-Di-Sol. In the developmental toxicity study, groups of pregnant Sprague-Dawley rats (25/group) received 0 (control), 10000, or 50000 ppm Ac-Di-Sol in the diet on gestational days 6 to 15. No evidence of maternal, fetal, or embryo toxicity was noted. The no-observed-adverse-effect level (NOAEL) for Ac-Di-Sol in both studies exceeds 50000 ppm in the diet, which represents doses of 3922 and 4712 mg/kg/day, for males and females, respectively. The results of these studies demonstrate the low subchronic oral toxicity and developmental toxicity of Ac-Di-Sol, and support the safe use of Ac-Di-Sol in oral applications such as pharmaceuticals, dietary supplements, and sweetener tablets.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Guidelines for developmental toxicity testing of chemicals in Japan.

With the definition of teratogenicity expanded in terms of the developmental stages when an agent acts and the types of developmental anomalies induced, the concept of developmental toxicity has been established. The examination of functional developmental disorders including behavior has become one of the most important items for the evaluation of developmental toxicity of chemicals, especially pharmaceutical drugs. The guidelines for developmental toxicity testing of drugs in Japan stress the need for examination of growth and development including behavior and fertility on the postweaning offspring. The outline of the Japanese guidelines is presented and it is emphasized that studies should be done as research and include self evaluation of the scientific truth of the experiment and extrapolation to humans. In addition, the activities of the Behavioral Teratology Meeting, a satellite meeting to the Japanese Teratology Society, are introduced and enquête surveys of the Japan Pharmaceutical Manufacturers Association and collaborative studies for the standardization of learning tests in Japan are briefly presented.

Animals↗
PubMed2003

Developmental toxicity and genotoxicity studies of 1,1,1,3,3,3-hexachloropropane (HCC-230fa) in rats.

The potential developmental toxicity and the in vitro and in vivo genotoxicity of HCC-230fa were assessed. In the developmental toxicity study, groups of 25 mated Crl:CD(R)(SD)BR rats were exposed (whole body) by inhalation to HCC-230fa over days 7-21 of gestation; the day of confirmed mating was designated as gestation day 1 (GD1). Exposures were 6 h per day at concentrations of 0, 0.5, 2.5, or 25 ppm. Body weight, food consumption, and clinical observation data were collected during the study. On day 22 of gestation, the dams were euthanized and examined grossly. The fetuses were removed and subsequently weighed, sexed, and examined for external, visceral, head, and skeletal alterations. Evidence of maternal and developmental toxicity was observed at 25 ppm and was noted as significant, compound-related reductions in mean maternal body weight, weight change, and food consumption. Significant fetal effects also were observed at 25 ppm as compound-related reductions in mean fetal weight and increased fetal malformations (filamentous tail, situs inversus, absent vertebrae) and variations (rudimentary cervical ribs, delayed sternebral ossification). There was no evidence of either maternal or developmental toxicity at 0.5 or 2.5 ppm. The genotoxicity of HCC-230fa was examined in a bacterial reversion assay and in erythrocyte micronucleus studies in two species by different routes of administration. No increases in the number of revertants were observed in the bacterial reversion assay. In one micronucleus study, HCC-230fa was administered by inhalation to rats as part of a 90-day study at doses indicated above. For the second study, ICR mice were given a single ip dose at 0, 166, 330, or 660 mg/kg. In both micronucleus studies, a significant increase in micronucleated erythrocytes was observed. The results of these studies suggest that HCC-230fa affects rapidly dividing cells and may have long-term consequences for occupational exposures.

Abnormalities, Drug-Induced↗
PubMed2005

[Significance of laboratory studies of neurobehavioral and developmental toxicities--transgenerational effects of styrene exposure].

Recently, health problems caused by environmental chemical substances present in daily life have been increasing, particularly developmental toxicities, the effects of which often become apparent only after a long developmental period. It is difficult to determine adverse transgenerational effects. Therefore, we must recognize important indices to measure neurobehavioral and developmental effects. The assessment of such effects indices, is difficult and few neurobehavioral data are available compared to teratological data. Thus, through studies using laboratory animals, analyses of the mechanisms, exposure periods, doses and neurobehavioral effects are necessary. We have reviewed studies of the volatile monomer of the organic solvent styrene with regard to reproductive and developmental toxicities in laboratory animals. The styrene monomer crosses through the placenta; however, fetal excretion is less than maternal excretion. Therefore, it seems that a dose of styrene that does not affect the mother may be toxic for the fetus. We reported that exposure to low-dose styrene results in physical and neurobehavioral developmental delays, as well as decreases in enzyme activity and neurotransmitter secretion level. To prevent neurobehavioral toxicity, we need further studies to obtain precise data on chemical-biological interactions developmental toxicity and dose-response relationships. A key step towards effective prevention can also be obtained from studies in which animals are continuously exposed to chemicals for one or more generations. Thereafter, we must extrapolate developmental toxicity data from animals to humans. In this paper, we provide the information on developmental toxicity.

Animals↗
PubMed2002

Developmental toxicity of N-methyl-2-pyrrolidone administered orally to rats.

The developmental toxicity of N-methyl-2-pyrrolidone (NMP) was studied in Sprague-Dawley rats after oral administration. Pregnant rats were given NMP at doses of 0 (distilled water), 125, 250, 500, and 750 mg/kg/day, by gavage, on gestational days (GD) 6 through 20. Significant decreases in maternal body weight gain and food consumption during treatment, and a reduction in absolute weight gain were observed at 500 and 750 mg/kg. The incidence of resorptions per litter was significantly higher than control at 500 mg/kg, and rose to 91% at 750 mg/kg. Examination of the foetuses revealed treatment-related malformations, including imperforate anus and absence of tail, anasarca, and malformations of the great vessels and of the cervical arches. The incidence of malformed foetuses per litter, and of litters with malformed foetuses was significantly increased at 500 and 750 mg/kg. At 250 mg/kg, one foetus showed malformations similar to those recorded at higher dosages. There was a dose-related decrease in foetal body weights (male, female, and total) that reached statistical significance at 250 mg/kg. A significant increase in incomplete ossification of skull bones and of sternebrae was also present at 500 and 750 mg/kg. In summary, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 250 and 125 mg/kg/day, respectively. Thus, oral administration of NMP produced developmental toxicity below maternally toxic levels.

Abnormalities, Drug-Induced↗
PubMed1992

Methotrexate-induced developmental toxicity in rabbits is ameliorated by 1-(p-tosyl)-3,4,4-trimethylimidazolidine, a functional analog for tetrahydrofolate-mediated one-carbon transfer.

Dihydrofolate reductase reduces folic acid to tetrahydrofolate as a prerequisite to one-carbon metabolism, which is required for normal embryonic de novo DNA synthesis. The developmental toxicity of methotrexate (MTX) has been attributed to MTX's ability to inhibit the activity of dihydrofolate reductase and thereby indirectly suppress one-carbon metabolism. The compound 1-(p-tosyl)-3,4,4-trimethylimidazolidine (TTI), which is structurally unrelated to folate, reestablishes one-carbon metabolism by the biomimetic transfer of single carbon units. Whether the developmental toxicity of MTX is indeed caused via suppressed one-carbon metabolism was tested in New Zealand white rabbits following concurrent maternal treatment with MTX and TTI. TTI reduced MTX developmental toxicity judged by increased mean fetal body weights, decreased percentage of malformed fetuses, and reduced incidences of major malformations. Two doses of TTI (90 mg/kg, each) at 1 hr prior to and 1 hr after MTX also reduced the developmental toxicity, but was no more effective than the single-injection regimen. Treatment with TTI alone caused no developmental toxicity. Histologically, MTX caused enlarged intercellular spaces in limb bud mesenchyme that began at 6-8 hr and increased in size until 16 hr. Mesenchymal nuclei appeared basophilic, with angular contours. Pretreatment with TTI delayed MTX-induced histological changes until 20-24 hr after MTX in 36-50% of embryos and completely protected the remainder. The sequence of MTX-induced changes was not altered among affected embryos, although the severity of the lesions did not appear as great. Saline-only or TTI-only treatments caused no alterations in limb buds. These data are consistent with the concept that impaired one-carbon metabolism is indeed the fundamental process underlying MTX developmental toxicity.

Animals↗
PubMed2002

Concordance across species in the reproductive and developmental toxicity of tetrachloroethylene.

Reproductive and developmental toxicities resulting from exposure to tetrachloroethylene include delayed or impaired conception, sperm quality, death during development, developmental neurotoxicity, and growth retardation. In most cases there was concordance between rodents and humans. The risk assessments indicated that neurotoxicity was the most sensitive endpoint for inhalation, whereas growth retardation was the most sensitive endpoint when exposure was by the oral route. The reference concentration (RfC) of 0.01 ppm was based on neurotoxicity among human subjects. The reference dose (RfD) of 0.0006 mg/kg per day was based on small for gestation age infants. In both cases, studies in rodents supported the credibility of these assessments. For the RfD, similar findings for other trihalomethanes have been reported. The latter part of pregnancy and early life may constitute a susceptible period for alterations leading to behavioral deficits. During this period, the capacity to metabolize tetrachloroethylene is reduced and may further contribute to the sensitivity during this phase of development. Studies suggest that an effect on dopamine metabolism is a plausible mode of action for some types of neurotoxicity. In addition, it has been suggested that this alteration may affect reproductive integrity by influencing prolactin levels.

Abortion, Spontaneous↗
PubMed1991

Developmental toxicity of bromoxynil in mice and rats.

The developmental toxicity of the wide-spectrum herbicide bromoxynil (bromoxynil phenol; 3,5-dibromo-4-hydroxyphenyl cyanide) was evaluated in Sprague-Dawley rats and Swiss-Webster mice, and the developmental toxicity of its octanoate ester (2,6-dibromo-4-cyanophenyl octanoate) was evaluated in Sprague-Dawley rats. Animals were treated from Day 6 to Day 15 of gestation [presence of sperm or semen plug = 0 of gestation]. The doses administered were as follows: bromoxynil phenol in the mouse, 342, 114, and 38 mumol/kg/day; bromoxynil phenol and bromoxynil octanoate in the rat, 54, 18, and 6 mumol/kg/day. Some animals were killed on selected days during treatment for measurement of organ weights sensitive to stress. In mice treated with bromoxynil phenol, maternal mortality was noted at 114 and 342 mumol/kg/day, but surviving females gained weight normally. Liver to body weight ratios increased with increasing dose, but no consistent effect was seen on adrenal, thymus, or spleen weights. Fetuses of mice treated with the highest dose of bromoxynil phenol were of lower weight and had a higher incidence of supernumerary ribs than controls. In rats, bromoxynil phenol and its octanoate ester at the highest doses used caused no mortality but resulted in only transient decreases in maternal weight gain and significantly increased the liver to body weight ratio, but did not significantly alter adrenal, thymus, or spleen weight in the dams. No significant maternal effects were seen at lower doses. The highest doses of both compounds increased the incidence of supernumerary ribs in fetuses of treated rats, but did not induce other anomalies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

A summary of the results of 55 chemicals screened for developmental toxicity in mice.

Fifty-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.

Animals↗