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PubMed2003

Evaluation of the developmental toxicities of ethanol, acetaldehyde, and thioacetamide using FETAX.

Potential mechanisms of the developmental toxicities of ethanol, acetaldehyde, and thioacetamide were evaluated using frog embryo teratogenesis assay-Xenopus (FETAX). Early X. laevis embryos were exposed to ethanol and thioacetamide in two separate definitive concentration-response tests with and without differentially induced exogenous metabolic activation systems (MAS) or selectively inhibited MAS. Two concentration-response tests were also performed with ethanol metabolites, acetaldehyde and acetic acid. The MAS was treated with 3,4-amino-1,2,4-triazole to modulate CYP2E1 activity, and heat to inactivate flavin containing monooxygenases (FMO) activity. Results from these studies suggested that thioacetamide may be bioactivated by both CYP2E1 and the FMO systems. Ethanol also appeared to be bioactivated by CYP2E1. Acetaldehyde was markedly more potent as a developmental toxicant than ethanol or acetic acid. Binary joint mixture studies conducted with ethanol and acetaldehyde indicated that the parent compound and metabolite acetaldehyde acted in a response additive manner. These results warrant the continued use of FETAX as a means of evaluating mechanisms of developmental toxicity in vitro.

Acetaldehyde↗
PubMed1991

Evaluation of Drosophila for screening developmental toxicants: test results with eighteen chemicals and presentation of a new Drosophila bioassay.

The objective of this study was to generate a comprehensive data set of chemically induced malformations in Drosophila using a detailed morphological examination of the entire fly (phase one). These data were analyzed, in blind, with the goal of developing a standardized set of criteria which could be used in a new, rapid, and economical Drosophila bioassay useful in the preliminary screening for potential developmental toxicants. After 32 chemicals were tested, formalized criteria were developed to form the basis of a new Drosophila bioassay. These criteria were then applied to the data from the same 32 chemicals (phase two). The data from only 18 of these chemicals met all requirements for evaluation, e.g., statistical significance, minimum fly numbers, sufficient challenge concentration administered, etc. In the new bioassay, rather than the detailed and time-consuming examination of the entire fly for a multitude of morphological defects, only two specific anatomical sites are examined. These sites are the humeral bristle and the wing blade, with focus placed on two structural defects--a bent bristle and a notch in the wing. These defects were the only two external malformations among the multitude of defects observed in flies treated in the first phase with the 32 chemicals which demonstrated the following characteristics: 1) A consistent concentration-response in flies treated with a variety of developmental toxicants; 2) a lack of response with most presumptive non-developmental toxicants; and 3) consistently low-background incidences in control flies. In both phases, developing Drosophila were exposed to the test agents from the egg through three larval stages by incorporating a range of concentrations of each chemical into the culture medium. Emerging adults were examined for an array of defects as part of a detailed morphological examination in the first phase, including bent bristles and wing notches. In the second phase, only bent bristle and wing notch data were evaluated. The incidences of bent humeral bristles and wing notches from flies exposed to each of the 18 chemicals were compared with those of concurrent controls. Of the 18 chemicals that could be evaluated using the new bioassay, 13 were known developmental toxicants while the remaining 5 were presumptive negative agents. Ten of the 13 mammalian developmental toxicants were correctly identified with this test (false negative rate of 23%). Four of five apparent non-developmental toxicants were correctly identified for a false positive rate of 20%.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormalities, Drug-Induced↗
PubMed1998

Calculation of benchmark doses for reproductive and developmental toxicity observed after exposure to isopropanol.

Reproductive, including developmental, toxicity risk assessment has typically relied on estimation of toxicity criteria values derived from no-observed-adverse-effect levels (NOAELs). The benchmark dose (BMD) approach has been proposed as an alternative that avoids problems with NOAELs. In this analysis of the reproductive and developmental toxicity observed in a multigeneration study of rats exposed to isopropanol, the BMD approach has been applied to all effects exhibiting significant dose-response relationships. The BMD estimates were very consistent across models and across end points; they were within the range of doses (100 to 500 mg/kg/day) that has been suggested as being the NOAEL. The use of the BMD approach for analysis of isopropanol reproductive toxicity is shown to avoid the experiment-specific argument of whether a particular treatment has induced statistically significant differences, compared to controls, in favor of the estimation of experiment-independent doses corresponding to risk levels of interest. The consistency of the BMD estimates, with values of about 420 mg/kg/day, suggests that, for isopropanol, the available multigeneration study data may provide a suitable basis for considering safe exposure.

2-Propanol↗
PubMed2001

Developmental toxicity study of tetramethylurea (TMU) in rats.

The developmental toxicity of tetramethylurea (TMU) was assessed in rats by inhalation exposure of the test material over days 6-20 of gestation. Groups of 25 mated female Crl:CD BR rats were exposed whole-body for 6 hours/day to concentrations of either 0, 2, 20 or 100 ppm TMU. The dams were euthanized on day 21 and the offspring were weighted, sexed, and examined for external, visceral, and skeletal alterations. Maternal toxicity was demonstrated at both 20 and 100 ppm. Maternal body weights, weight changes, and food consumption were statistically significantly reduced at these concentrations; effects were more pronounced at 100 ppm. There was evidence of developmental toxicity only at 100 ppm. The only finding was a decrease in mean fetal weight. No fetal malformations or variations occurred in fetuses derived from rats exposed to all 3 test concentrations (up to 100 ppm). The maternal no-observed-effect-level (NOEL) was 2 ppm, the fetal NOEL was 20 ppm. Thus, TMU was not considered to be uniquely toxic to the rat conceptus.

Administration, Inhalation↗
PubMed2006

Adapting the medaka embryo assay to a high-throughput approach for developmental toxicity testing.

Chemical exposure during embryonic development may cause persistent effects, yet developmental toxicity data exist for very few chemicals. Current testing procedures are time consuming and costly, underlining the need for rapid and low cost screening strategies. While in vitro methods are useful for screening, these methods do not replicate all the intricacies of embryonic development and should ideally be complemented by an in vivo screening strategy. In this study, we modify a medaka fish embryo assay to meet the requirements of high-throughput, developmental toxicant testing in vivo. The Japanese medaka (Oryzias latipes) offers several advantages over traditional mammalian model systems, including economic husbandry, high fecundity, and rapid ex utero development. In most studies where fish eggs are exposed to a chemical, the exposure takes place in a common vessel, with many embryos being exposed to the same solution. This type of design is not amenable to high-throughput methodology, does not allow the investigator to follow the same embryo throughout gestation, and may confound statistical analysis of the results. Therefore, we developed a 96-well microtiter plate method to facilitate exposure of individual medaka embryos in single wells and compared this approach to the common vessel method using the industrial solvent dimethyl sulfoxide (DMSO) as the test compound. At lower DMSO concentrations (0% or 1%), the 96-well microtiter plate assay replicated results obtained using the common vessel exposure method. There was, however, increased lethality and decreased hatching rate in the bottle-reared embryos treated with the higher DMSO concentrations (5% or 10%). Because the embryos reared in the 96-well microtiter plates never showed increased adverse effects (as compared to the bottle-reared embryos) at any DMSO concentration, we conclude that the 96-well microtiter plate assay provides a rapid and efficient alternative for developmental toxicity screens that utilize fish embryos.

Age Factors↗
PubMed1995

Evaluation of chick embryo neural retinal cell culture as a screen for developmental toxicants.

This paper describes a study to evaluate the concordance with in vivo results of an in vitro screen for developmental toxicants. The screen is a primary culture of chick embryo neural retina cells (CERC) which undergo processes of cell-cell recognition and interaction, growth, and differentiation over a 7-day culture period. Each of these developmentally significant events is measured separately as formation of multicellular aggregates, protein content, and glutamine synthetase activity, respectively. A total of 45 chemicals, 24 of which have been shown to be teratogenic at some dosage to mammalian embryos in utero, 7 of which are embryotoxic (but not teratogenic) in utero at high dosage, and 14 of which have not produced developmental toxicity in vivo, were evaluated in this assay by investigators who were blinded to the identity of the chemicals. Chemicals were tested up to concentrations that were frankly cytolethal, or up to a maximum of 5 mg/ml. Chemicals were present only during the first 24 hr of culture. The chemicals were selected to be representative of a variety of chemical classes (e.g., solvents, metals, food additives, anticonvulsants, antineoplastics). In several cases, pairs of structurally similar compounds with different developmental toxic potencies (e.g., valproate and 2-en-valproate, formamide, and N,N-dimethylformamide) were tested. Of the 31 developmental toxicants, 25 affected at least one endpoint in the assay at concentrations which are achievable in vivo (i.e., below the systemic concentration at a lethal dose), yielding a false-negative rate of 19%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Reproductive and developmental toxicity of aluminum: a review.

It is well known that aluminum is a developmental toxicant when administered parenterally. However, until recently, there was little concern about embryo/fetal consequences of aluminum ingestion because bioavailability was considered low. The importance of the route of exposure and the chemical form of the aluminum compound on the developmental toxicity of this element are now well established. Although no evidence of maternal and embryo/fetal toxicity was observed when high doses of aluminum hydroxide were given orally to pregnant rats and mice during organogenesis, signs of maternal and developmental toxicity were found in mice when aluminum hydroxide was given concurrently with citric or lactic acids. On the other hand, studies in rabbits have shown that aluminum-induced behavioral toxicity is greater in adult and aged animals than in young adults. However, maternal dietary exposure to excess A1 during gestation and lactation which did not produce maternal toxicity would be capable of causing permanent neurobehavioral deficits in weanling mice and rats. Adverse effects of parenteral aluminum administration on the mouse male reproductive system have also been reported. The embryo/fetal toxicity of aluminum administration, the potential reproductive toxicology of aluminum exposure, and the neurodevelopmental effects of aluminum are here reviewed.

Aluminum↗
PubMed1990

Structure-activity relationships in the developmental toxicity of substituted phenols: in vivo effects.

Hansch analysis, a quantitative approach relating the physical-chemical properties of molecules to biological effects, was applied to a series of substituted phenols tested for developmental toxicity. The physical-chemical properties included a hydrophobic parameter (log P), an electronic parameter (Hammett sigma), and a bulk parameter (molar refractivity (MR]. Biological activities (potencies) were obtained for 27 congeners in a Chernoff/Kavlock Assay performed in Sprague-Dawley rats exposed on day 11 of gestation. The potencies discussed in this report are the following: the dose to decrease maternal weight gain by 10 g at 24 and 72 hours after treatment (MTOX1 and MTOX2); the dose to increase postimplantation loss by 1 over the concurrent control value (PLOSS); and the dose required to decrease total litter weight by 10% on postnatal day 6 (BIO6). A quantitative structure-activity relationship QSAR was developed for the maternal data (1/MTOX1 = (0.0344*log P) + (-0.1503*sigma) + 0.1195; n = 22, r = 0.81, P less than .0001), which related increasing lipophilicity and decreasing electron-withdrawing ability of the substituent on 22 para-phenols to increasing toxicity. Another QSAR was developed from eight para-phenols that had the greatest postimplantation loss potencies (i.e., less than 100 mmol/kg). The model (1/PLOSS = (-0.2676*log P) + (-0.1827*sigma) + (0.0265*MR) + 0.4420; n = 8, r = 0.93, P less than .0298) related decreasing lipophilicity and electron-withdrawing ability and increasing bulk properties to the decreased viability of implantation sites. However, no descriptor was identified that distinguished the more potent from the less potent congeners for postimplantation loss, and no QSAR was found for litter weight on postnatal day 6 (even when limiting the analysis to the more potent congeners). Congeners were also grouped on a qualitative level according to whether they induced a biological effect below a dose of 6 mmol/kg (termed active), between 6 and 11 mmol/kg (moderately active), or greater than 11 mmol/kg (inactive). Overall, 14 of 27 congeners were classified as active in terms of maternal effects, but only 50% of these were active for developmental effects. Seven of the nine overall active developmental toxicants were active maternal toxicants. Four of the developmental toxicants produced a syndrome of effects that may be related to a similar mechanism of action or common metabolic pathway. Thus, from both quantitative and qualitative viewpoints, the properties of these phenolic congeners that promote maternal toxicity are different from those that contribute to developmental toxicity. It is therefore likely that the mechanisms of toxicity behind these effects are also different.

Animals↗
PubMedDate not supplied

Reproductive and developmental toxicity of arsenic in rodents: a review.

Arsenic is a recognized reproductive toxicant in humans and induces malformations, especially neural tube defects, in laboratory animals. Early studies showed that murine malformations occurred only when a high dose of inorganic arsenic was given by intravenous or intraperitoneal injection in early gestation. Oral gavage of inorganic arsenic at maternally toxic doses caused reduced fetal body weight and increased resorptions. Recently, arsenic reproductive and developmental toxicity has been studied in situations more similar to human exposures and using broader endpoints, such as behavioral changes and gene expression. For the general population, exposure to arsenic is mostly oral, particularly via drinking water, repeated and prolonged over time. In mice and rats, methylated or inorganic arsenic via drinking water or by repeated oral gavage induced male and female reproductive and developmental toxicities. Furthermore, at nonmaternally toxic levels, inorganic arsenic given to pregnant dams via drinking water affected fetal brain development and postnatal behaviors. However, arsenic given by repeated oral gavage to pregnant mice and rats was not morphologically teratogenic. In this review of arsenic reproductive and developmental toxicity in rats and mice, the authors summarize recent in vivo studies and discuss possible underlying mechanisms. The influences of folate, selenium, zinc, and arsenic methylation on arsenic reproductive and developmental toxicity are also discussed.

Animals↗
PubMed1987

Maternal factors in developmental toxicity.

The 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.

Animals↗
PubMedDate not supplied

Developmental toxicity evaluation of unleaded gasoline vapor in the rat.

To evaluate the potential of unleaded gasoline vapor for developmental toxicity, a sample was prepared by slowly heating API 94-02 (1990 industry average gasoline) and condensing the vapor. The composition of this vapor condensate, which comprises 10.4% by volume of the starting gasoline, is representative of real-world exposure to gasoline vapor encountered at service stations and other occupational settings and consists primarily of volatile short chain (C4-C6) aliphatic hydrocarbons (i.e. paraffins) with small amounts of cycloparaffins and aromatic hydrocarbons. A preliminary study in rats and mice resulted in no developmental toxicity in either species. However, a slight reduction in maternal body weight gain in rats led to the selection of rats for this guideline study. Groups of pregnant rats (n = 24/group) were exposed to unleaded gasoline vapor at concentrations of 0, 1000, 3000, or 9000 (75% lower explosive limit) ppm equivalent to 0, 2653, 7960, or 23,900 mg/m3, for 6 h/day on gestation days 6-19. All rats were sacrificed on gestation day 20. No maternal toxicity was observed. Developmentally, there were no differences between treated and control groups in malformations, total variations, resorptions, fetal body weight, or viability. The maternal and developmental NOAEL is 9000 ppm. Under conditions of this study, unleaded gasoline vapors did not produce evidence of developmental toxicity.

Administration, Inhalation↗
PubMed1994

Dose-response assessment for developmental toxicity. I. Characterization of database and determination of no observed adverse effect levels.

Developmental toxicity risk assessment currently relies on the estimation of reference doses (RfDDTs) or reference concentrations (RfCDTS) based on the use of no observed adverse effect levels (NOAELs) and uncertainty factors. The benchmark dose (BMD) has been proposed as an alternative basis for reference value calculations. A large database of 246 developmental toxicity experiments (Segment II-type studies) representing 1825 data subsets for various endpoints was compiled for use in comparing NOAEL and BMD approaches to developmental toxicity risk assessment. This paper describes the characteristics of the database used and the estimation of NOAELs using several approaches. For each endpoint evaluated, two NOAELs were calculated using the NOSTASOT procedure (Tukey et al., 1985). The first NOAEL calculation, the QNOAEL, was based on a quantal response where a litter was defined as "affected" if one or more fetuses or implants in the litter had the endpoint of interest. The second NOAEL calculation, the CNOAEL, was based on the proportion of fetuses or implants affected within each litter and was treated as a continuous response variable. Fifty-seven percent of the 246 experiments had at least one endpoint that showed a significant trend with dose. A total of 386 data sets were significant with respect to both the quantal and continuous test of trend. An additional 44 data sets were identified with significant trend only by the quantal approach whereas 177 additional data sets were identified with significant trend tests only by the continuous approach. Thus, the continuous approach appeared to be more powerful in detecting dose-related toxicity, but the patterns detected by the two approaches differed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Ethanol- and acetaldehyde-mediated developmental toxicity in zebrafish.

Ethanol is a well-established developmental toxicant; however, the mechanism(s) of this toxicity remains unclear. Zebrafish are becoming an important model system for the evaluation of chemical and drug toxicity. In this study, zebrafish embryos were utilized to compare the developmental toxicity resulting from either ethanol or acetaldehyde exposure. Embryos were exposed to waterborne ethanol concentrations for various lengths of time but encompassed the earliest stages of embryogenesis. The waterborne ethanol concentration that causes 50% mortality (LC(50)) following a 45-h ethanol exposure was approximately 340 mM (1.98% v/v). A number of reproducible endpoints resulted from ethanol exposure and included pericardial edema, yolk sac edema, axial malformations, otolith defects, delayed development, and axial blistering. When the exposure period was reduced, similar signs of toxicity were produced at nearly identical ethanol concentrations. To estimate the embryonic dose following a given waterborne ethanol concentration, a kinetic alcohol dehydrogenase (ADH) assay was adapted. The average embryonic ethanol dose was calculated to be a fraction of the waterborne concentration. Embryos exposed to waterborne acetaldehyde resulted in similar, but not identical, endpoints as those induced by ethanol. Embryos were however, almost three orders of magnitude more sensitive to acetaldehyde than to ethanol. Ethanol and acetaldehyde both negatively impact embryonic development; however, ethanol is more teratogenic based on teratogenic indices (TIs). These results demonstrate that the zebrafish model will provide an opportunity to further evaluate the mechanism of action of ethanol on vertebrate development.

Abnormalities, Multiple↗
PubMed2003

Decision tree SAR models for developmental toxicity based on an FDA/TERIS database.

Humans are exposed to thousands of environmental chemicals for which no developmental toxicity information is available. Structure-activity relationships (SARs) are models that could be used to efficiently predict the biological activity of potential developmental toxicants. However, at this time, no adequate SAR models of developmental toxicity are available for risk assessment. In the present study, a new developmental database was compiled by combining toxicity information from the Teratogen Information System (TERIS) and the Food and Drug Administration (FDA) guidelines. We implemented a decision tree modeling procedure, using Classification and Regression Tree software and a model ensemble approach termed bagging. We then assessed the empirical distributions of the prediction accuracy measures of the single and ensemble-based models, achieved by repeating our modeling experiment many times by repeated random partitioning of the working database. The decision tree developmental SAR models exhibited modest prediction accuracy. Bagging tended to enhance the accuracy of prediction. Also, the model ensemble approach reduced the variability of prediction measures compared to the single model approach. Further research with data derived from animal species- and endpoint-specific components of an extended and refined FDA/TERIS database has the potential to derive SAR models that would be useful in the developmental risk assessment of the thousands of untested chemicals.

Abnormalities, Drug-Induced↗
PubMed2006

Developmental toxicity evaluation of berberine in rats and mice.

BACKGROUND: Berberine, a plant alkaloid, is found in some herbal teas and health-related products. It is a component of goldenseal, an herbal supplement. Berberine chloride dihydrate (BCD) was evaluated for developmental toxicity in rats and mice. METHODS: Berberine chloride dihydrate was administered in the feed to timed-mated Sprague-Dawley (CD) rats (0, 3,625, 7,250, or 14,500 ppm; on gestational days [GD] 6-20), and Swiss Albino (CD-1) mice (0, 3,500, 5,250, or 7,000 ppm; on GD 6-17). Ingested doses were 0, 282, 531, and 1,313 mg/kg/day (rats) and 0, 569, 841, and 1,155 mg/kg/day (mice). RESULTS: There were no maternal deaths. The rat maternal lowest observed adverse effect level (LOAEL), based on reduced maternal weight gain, was 7,250 ppm. The rat developmental toxicity LOAEL, based on reduced fetal body weight per litter, was 14,500 ppm. In the mouse study, equivocal maternal and developmental toxicity LOAELs were 5,250 ppm. Due to scattering of feed in the high dose groups, a gavage study at 1,000 mg/kg/day was conducted in both species. CONCLUSIONS: In rats, maternal, but not fetal adverse effects were noted. The maternal toxicity LOAEL remained at 7,250 ppm (531 mg/kg/day) based on the feed study and the developmental toxicity NOAEL was raised to 1,000 mg/kg/day BCD based on the gavage study. In the mouse, 33% of the treated females died. Surviving animals had increased relative water intake, and average fetal body weight per litter decreased 5-6% with no change in live litter size. The maternal toxicity LOAEL remained at 5,250 ppm (841 mg/kg/day) BCD, based on increased water consumption. The developmental toxicity LOAEL was raised to 1,000 mg/kg/day BCD based on decreased fetal body weight.

Animals↗
PubMed1990

Ethylene glycol monopropyl ether: a developmental toxicity study in rabbits.

To determine the potential developmental toxicity of ethylene glycol monopropyl ether (EGPE), groups of pregnant New Zealand white rabbits were exposed to target concentrations of 0, 125, 250, or 500 ppm EGPE vapors for 6 hr a day on Days 6-18 of gestation. Maternal effects included a slight reduction in feed consumption during the first week of treatment at the 250- and 500-ppm exposure levels and slightly reduced body weight gain at the 500-ppm level compared to those of the controls, but the differences were not statistically significant. One doe exposed to 500 ppm had red-colored urine during the 24-hr period following the second exposure. Hematologic determinations, absolute and relative organ weights, and observations at necropsy revealed no treatment-related maternal effects. Reproductive indices, i.e., pregnancy rate, number of corpora lutea, implantation sites, viable fetuses, early and late resorptions, fetal body weights, fetal sex ratio, and the gravid uterine and corrected body weights, were not affected by exposures to EGPE. The occurrences of external and internal soft tissue malformations and variations and the incidences of skeletal malformations in the EGPE-exposed groups were not significantly different from those in the control group. Common skeletal variations, in many instances, were seen less frequently in EGPE-exposed fetuses than in control fetuses. In those cases where the incidence of fetuses with a skeletal variation was greater for EGPE-exposed fetuses than that for control fetuses, the number of litters involved was not significantly different from that of the control group. Thus, EGPE vapor concentrations as high as 500 ppm did not produce teratogenicity or other developmental toxicity in the rabbit conceptus.

Abnormalities, Drug-Induced↗
PubMed2006

Evaluation of developmental toxicity of amitraz in Sprague-Dawley rats.

This study investigated the potential adverse effects of amitraz on the initiation and maintenance of pregnancy in Sprague-Dawley rats as well as its effects on embryo-fetal development after maternal exposure during the entire pregnancy period. Amitraz was administered to pregnant rats by gavage from days 1 to 19 of gestation at dose levels of 0, 3, 10, and 30 mg/kg/day. All dams underwent a caesarean section on day 20 of gestation and their fetuses were examined for any external, visceral, and skeletal abnormalities. At 30 mg/kg, maternal toxicity manifested as an increase in the incidence of abnormal clinical signs and a lower body weight gain and food intake. Developmental toxicity included an increase in the fetal death rate, a decrease in the litter size, and a reduction in the fetal body weight. In addition, there was an increase in the incidence of fetal external, visceral, and skeletal abnormalities. At 10 mg/kg, maternal toxicity observed included a decrease in the body weight gain and a decrease in food intake. In addition, minimal developmental toxicity, including a decrease in the fetal body weight, an increase in the visceral and skeletal aberrations, and a delay in fetal ossification. There were no signs of either maternal toxicity or developmental toxicity at 3 mg/kg. These results show that amitraz administered during the entire pregnancy period in rats is embryotoxic and teratogenic at the maternally toxic dose (i.e., 30 mg/kg/day) and is minimally embryotoxic at a minimally maternally toxic dose (i.e., 10 mg/kg/day). Under these experimental conditions, the no-observed-adverse-effect level of amitraz for both dams and embryo-fetal development is estimated to be 3 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMed2000

Modifications of the topical Japanese medaka (Oryzias latipes) embryo larval assay for assessing developmental toxicity of pentachlorophenol and p, p'-dichlorodiphenyltrichloroethane.

One method currently available for investigating developmental toxicity in teleost species is the Japanese medaka embryo larval assay (MELA). In the present study, the MELA was modified to evaluate repeated topical exposures to pentachlorophenol (PCP) and p, p'-dichlorodiphenyltrichloroethane (DDT) and to identify sensitive stages of embryonic development. A single topical exposure using embryos at 48 h postfertilization resulted in a statistically significant increase in embryo mortality at 688 and 1250 ng PCP/egg compared with controls. In contrast, the toxicity following exposure to 11, 36, 78, 120, 208, and 400 ng DDT/egg was expressed only in larvae after hatching. Results further demonstrate that the MELA can be optimized to accommodate repeated daily topical exposures starting at 48 h postfertilization and ending at 120 h postfertilization. In addition, the neurula stage (24 h postfertilization) represented the most sensitive embryonic stage following a single topical exposure of PCP. However, no differences were observed in the sensitivity of embryonic stages following DDT exposure. The modified MELA was also used to evaluate sediment extracts contaminated with DDT metabolites obtained from the Tensas River, Louisiana. Results indicate that there is a low potential for developmental toxicity using the present extraction and exposure scenario even though elevated levels of DDE and toxaphene currently exist in several adult fish species at this site. The MELA as a screen for evaluating the potential for developmental toxicity of contaminated sediments is discussed.

Administration, Topical↗