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PubMed1989

An overview of maternal toxicity and prenatal development: considerations for developmental toxicity hazard assessments.

The objective of testing xenobiotics for potential developmental toxicity is to extrapolate laboratory animal information to the human species, thereby deriving biologically rational regulatory policies. One of the problems that significantly contributes to the difficulty of this task is the possibility that general effects on the maternal organism could affect the developing conceptus. Published data have indicated that factors intrinsic to the maternal organism affect developmental outcome. This overview examines factors which may bear directly or indirectly upon developmental outcome, with emphasis on those of greatest relevance to the hazard assessment process. Standard teratology testing protocols often call for dose levels that induce overt maternal toxicity, and the developmental effects of this toxicity (both alone, and with concurrent embryo/fetal insult) continue to present regulators with considerable interpretive difficulties. In response to these problems there have been both research and literature review efforts dealing with the relationship of maternal and developmental toxicity. Relevant studies are reviewed here, and suggestions for avenues of future research are offered including the identification of any syndromes of developmental effects occurring at maternally toxic levels irrespective of the causative agent, and experimental approaches for the characterization of maternal toxicity.

Animals↗
PubMed1989

A perspective on the significance of maternally mediated developmental toxicity.

The significance of maternally mediated developmental toxicity has been controversial from both a biological and a regulatory point of view. The open literature has at times been interpreted to mean that a number of the effects seen in fetuses from dams exposed to maternally toxic doses of chemicals were secondary consequences of maternal toxicity rather than direct effects on the conceptus. Recent experimental studies, however, indicate that although certain relatively species-specific manifestations of developmental toxicity may at times be maternally mediated, most are not. On occasion, even severe maternal toxicity can apparently occur without causing readily discernible effects on the embryo/fetus. The most important concern of a regulatory agency with regard to developmental toxicity is the possibility of the causation of significant, irreversible harm to the offspring. In practical terms, the margin of safety for exposure to a developmental toxicant is of much more importance than whether or not the agent's effects are maternally mediated. For protection of the unborn, it is obviously the end result that matters, regardless of the mechanism. Safeguarding the conceptus from specific developmental toxicants (i.e., agents with relatively high A/D ratios) requires the use of safety factors based on the developmental toxicity NOEL. Protecting the conceptus against agents with A/D ratios near unity could be based on the maternal toxicity NOEL, however, as the true NOEL for developmental toxicity may be near that for the mother, but the adult NOEL is likely to be more readily determinable.

Animals↗
PubMed2001

Evaluation of developmental toxicity in rats exposed to the environmental estrogen bisphenol A during pregnancy.

Bisphenol A (BPA) is an essential component of epoxy resins used in the lacquer lining of metal food cans, as a component of polycarbonates, and in dental sealants. The present study was conducted in an attempt to evaluate the adverse effects of the environmental estrogen BPA on initiation and maintenance of pregnancy and embryofetal development after maternal exposure during the entire period of pregnancy in Sprague-Dawley rats. The test chemical was administered by gavage to mated females from days 1 to 20 of gestation (sperm in varginal lavage = day 0) at dose levels of 0, 100, 300, and 1000 mg/kg. All females were subjected to caesarean section on day 21 of gestation and their fetuses were examined for external, visceral and skeletal abnormalities. In the 1000 mg/kg group, significant toxic effects including abnormal clinical signs, decreased maternal body weight and body weight gain, and reduced food consumption were observed in pregnant rats. An increase in pregnancy failure was also found in the successfully mated females. In addition, increased number of embryonal deaths, increased postimplantation loss, reduced litter size and fetal body weight, and decreased number of fetal ossification centers of several skeletal districts were seen. On the contrary, no significant changes induced by BPA were detected in the number of corpora lutea and implantation sites and by fetal morphological examinations. In the 300 mg/kg group, suppressed maternal body weight and body weight gain, decreased food intake and reduced body weight of male fetuses were seen. There were no adverse signs of either maternal toxicity or developmental toxicity in the 100 mg/kg group. It was concluded that BPA administration during the entire period of pregnancy in rats produced pregnancy failure, pre- and postimplantation loss, fetal developmental delay and severe maternal toxicity, but no embryo-fetal dysmorphogenesis at an oral exposure level of 1000 mg/kg.

Air Pollutants↗
PubMed1991

Chick embryo neural retina cell culture as a screen for developmental toxicity.

An in vitro screen for developmental toxic potential of chemicals using primary cultures of chick embryo neural retina cells is described. The neural retinas of incubation Day 6.5 White Leghorn chick embryos are dissociated into single cells, which are subsequently maintained in a rotating suspension culture. Under normal circumstances, neural retina cells form spheroidal aggregates of a consistent size over the first 24 hr of culture, an event which is dependent on competent cell-cell interactions. Over the remaining 7-day period of culture, cells continue to divide and grow, and differentiation takes place. Each of these developmentally important events--aggregation, growth, and differentiation--is objectively and quantitatively measured as aggregate size and number, aggregate protein content, and glutamine synthetase (a marker of differentiation) activity, respectively. The effects on each developmental endpoint of 22 chemicals, 14 of which have been demonstrated to be developmentally toxic in one or more mammalian species in vivo, and 8 of which are not developmentally toxic, were evaluated. Chemicals were tested up to a concentration of 40 mM, or until marked cytolethality was observed. Of the known developmental toxicants, all but one, 2-methoxyethanol, affected one or more endpoints in the assay. The teratogenic metabolite of 2-methoxyethanol, 2-methoxyacetic acid, was active in the assay. None of the 8 nondevelopmental toxicants had any effect up to a concentration of 40 mM, or at biologically achievable concentrations (e.g., in vivo systemic concentrations at the LD50). Thus, the assay is 95% concordant with in vivo results for this set of chemicals. Quantitative comparisons were made (1) between developmentally toxic ip dosages in rats or mice in vivo and effective concentrations in the chick retina cell culture, and (2) between effective concentrations in chick retina cell culture and rodent whole embryo culture. In the first instance, 71% of the comparisons, and in the second instance, 89% of the comparisons, were within the same order of magnitude (and usually within a factor of two), indicating that the chick retina cell culture is also concordant with developmental toxic potency. Last, it was observed that test agents differentially affect developmental endpoints. Because the assay's endpoints are measured separately and objectively, it may be possible to use the assay to evaluate the effects of test agents on cellular development.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Developmental toxicity assessment of the new fluoroquinolone antibacterial DW-116 in rabbits.

DW-116 is a newly developed fluoroquinolone antibacterial with a broad spectrum against both Gram-positive and Gram-negative bacteria. We have reported recently that DW-116 is embryotoxic and teratogenic in rats. The present study was conducted to investigate the teratogenicity of DW-116, together with maternal toxicity and developmental toxicity using New Zealand White rabbits. The test chemical was administered by gavage to pregnant rabbits from gestational day (GD) 6 through to GD 18 at dose levels of 0, 5, 19.5 and 76.1 mg kg(-1) day(-1). All does were subjected to caesarean section on day 28 of gestation and their foetuses were examined for external, visceral and skeletal abnormalities. In the 76.1 mg kg(-1) group, a minimal maternal toxicity, as evidenced by decreased body weight gain during treatment period, was observed in pregnant rabbits. Significant embryo-foetal toxicity, including increased number of foetal deaths and delayed foetal ossification, was seen. However, no treatment-related morphological changes were detected in foetal external, visceral and skeletal examinations. There were no adverse effects on either pregnant dams or embryo-foetal development at 19.5 and 5 mg kg(-1). It was concluded that administration of DW-116 during the major organogenetic period in rabbits produced decreased maternal body weight gain, increased number of foetal deaths and foetal developmental delay but no evidence of teratogenicity. The no-observed-adverse-effect levels (NOAELs) of DW-116 are considered to be 19.5 mg kg(-1) day(-1) for does and embryo-foetuses, respectively.

Animals↗
PubMed2003

Developmental toxicity evaluation of ELF magnetic fields in Sprague-Dawley rats.

To identify possible effects of horizontally polarized magnetic field (MF) exposure on maintenance of pregnancy and embryo-fetal development, an MF exposure system was designed and constructed and 96 time-mated female Sprague-Dawley (SD) rats (24/group) received continuous exposure to 60 Hz MF at field strengths of 0 (sham control) and 5, 83.3, or 500 microT (50, 833, or 5000 mG). Dams received MF or sham exposures for 22 h/day on gestational day 6-20. MF was monitored continuously throughout the study. There were no evidences of maternal toxicity or developmental toxicity in any MF exposed groups. Mean maternal body weight, organ weights, and hematological and serum biochemical parameters in groups exposed to MF did not differ from those in sham control. No exposure related differences in fetal deaths, fetal body weight, and placental weight were observed between MF exposed groups and sham control. External, visceral, and skeletal examination of fetuses demonstrated no significant differences in the incidence of fetal malformations between MF exposed and sham control groups. In conclusion, exposure of pregnant rats to 60 Hz at MF strengths up to 500 microT during gestation day 6-20 did not produce any biologically significant effect in either dams or fetuses.

Abnormalities, Radiation-Induced↗
PubMed1990

Proceedings of the Workshop on the Acceptability and Interpretation of Dermal Developmental Toxicity Studies.

The workshop on The Acceptability and Interpretation of Dermal Developmental Toxicity Studies, held April 13-14, 1988, was organized by the U.S. EPA's Office of Research and Development and Office of Toxic Substances and was supported by the Agency's Risk Assessment Forum. The purpose of the workshop was to review the current state of knowledge on the use of the dermal route of exposure in developmental toxicity studies. In evaluating this area, three major issues were considered by the participants: (1) the evaluation of maternal toxicity in dermal developmental toxicity studies, (2) what types of pharmacokinetic data are necessary or desirable for the appropriate design and interpretation of these studies, and (3) what factors are important to consider in the design of dermal developmental toxicity studies. The participants concluded: (1) dermal developmental toxicity studies without any indication of maternal or developmental toxicity are inadequate for risk assessment unless accompanied by absorption data, (2) absorption data and limited pharmacokinetic data should be collected in every dermal developmental toxicity study, and (3) dermal developmental toxicity studies in which skin irritation is too marked should be considered inadequate for risk assessment. General recommendations made for all developmental toxicity studies regardless of the route of exposure were: signs of local irritation should be examined, and absorption/pharmacokinetic data should be developed. Areas in which additional research is needed to permit more complete assessment of dermal developmental toxicity studies were also identified.

Absorption↗
PubMed1987

The role of metabolism in the testing of developmental toxicants.

The delivery of potential developmental toxicants to the conceptus is dependent on several metabolic and pharmacokinetic factors. Within the maternal-embryo/fetal unit, maternal, placental, and embryo/fetal factors must be considered. These factors include blood flow, permeability, biotransformation, and elimination. Pharmacokinetic models based on data gathered from appropriate in vivo and in vitro studies may be used to describe the effect of these factors on toxicant delivery to the conceptus. Several known human developmental toxicants are discussed in terms of the metabolic and pharmacokinetic factors controlling their delivery to the conceptus. Metabolic events, including activation and/or detoxification, have been reported for the majority of the toxicants examined. Thus it would appear that the role of metabolism should be considered during the testing of potential developmental toxicants.

Animals↗
PubMed2003

Evaluation of the potential developmental toxicity of cyclododecatriene (CDDT).

The potential maternal and developmental toxicity of cyclododecatriene (CDDT) was assessed in rats. Groups of 22 time-mated female Crl:CD (SD) BR rats were exposed by inhalation (whole-body, 6 h/day) to either 0 (control), 10, 25, or 67 ppm CDDT over days 6-20 of gestation (days 6-20 G); the day of copulation plug detection was designated day 0 G. The dams were euthanized on day 21 G, and their abdominal and thoracic viscera were examined grossly. The fetuses were weighed, sexed, and examined for external, visceral, and skeletal alterations. Evidence of maternal toxicity was seen at 25 and 67 ppm. There were compound-related reductions in maternal body weight and food consumption parameters as well as increased occurrences of wet and stained fur at these exposure levels. Developmental toxicity evident as reduced mean fetal weight and delayed skeletal ossification was seen only at 67 ppm. There was no evidence of either maternal or developmental toxicity at 10 ppm. Thus, the no-observed-effect level (NOEL) for maternal toxicity was 10 ppm, and the NOEL for developmental toxicity was 25 ppm. Because developmental toxicity was observed only after exposures that also produced signs of maternal toxicity, CDDT was not considered to be a selective developmental toxicant in the rat.

Abnormalities, Drug-Induced↗
PubMed1996

Light catalytically cracked naphtha: subchronic toxicity of vapors in rats and mice and developmental toxicity screen in rats.

Both a subchronic inhalation study and a developmental toxicity screen were performed with vapors of light catalytically cracked naphtha (LCCN). In the subchronic study, four groups of mice and rats (10 animals per sex per species) were exposed for approximately 13 wk (6 h/d, 5 d/wk) to concentrations of LCCN vapors of 0, 530, 2060, or 7690 mg/m3. An untreated control group was also included. Animals were observed daily and body weights were taken weekly. No significant treatment-related changes were found in clinical signs, body weight, serum chemistry, hematology, histopathology of 24 tissues, or weights of 12 organs. A marginal decrease was noted in the number of sperm per gram of epididymis. In the developmental toxicity screen, presumed-pregnant Sprague-Dawley rats were exposed to 0, 2150, or 7660 mg/m3 of LCCN vapors, 6 h/d on d 0-19 of gestation. Females were sacrificed on d 20; dams and fetuses were examined grossly and fetuses were later evaluated for skeletal and visceral effects. The number of resorptions was increased by approximately 140% in the group receiving 7660 mg/m3; no other definite treatment-related changes were observed. Overall, the effects of exposure to partially vaporized LCCN were minimal.

Administration, Inhalation↗
PubMed1991

The role of metallothionein induction and altered zinc status in maternally mediated developmental toxicity: comparison of the effects of urethane and styrene in rats.

We hypothesize that maternal metallothionein (MT) induction by toxic dosages of chemicals may contribute to or cause developmental toxicity by a chain of events leading to a transient but developmentally adverse decrease in Zn availability to the embryo. This hypothesis was tested by evaluating hepatic MT induction, maternal and embryonic Zn status, and developmental toxicity after exposure to urethane, a developmental toxicant, or styrene, which is not a developmental toxicant. Pregnant Sprague-Dawley rats were given 0 or 1 g/kg urethane ip, or 0 or 300 mg/kg styrene in corn oil po, on Gestation Day 11 (sperm positive = Gestation Day 0). These were maternally toxic dosages. As both treatments decreased food consumption, separate pair-fed control groups were also evaluated for effects on MT and Zn status and development. In addition, Gestation Day 11 rat embryos were exposed to urethane in vitro in order to determine whether urethane has the potential to be directly embryotoxic. Urethane treatment induced hepatic MT 14-fold over control; styrene treatment induced MT 2.5-fold. The MT induction by styrene could be attributed to decreased food intake, as a similar level of induction was observed in a pair-fed untreated control group. However, the level of MT induction by urethane was much greater than that produced by decreased food intake alone. Hepatic Zn concentration, particularly in the cytosol, was increased in the presence of increased hepatic MT concentration. Plasma Zn concentration was significantly decreased (approximately 30%) by urethane treatment, but not by styrene or food restriction (pair-feeding). Distribution of 65Zn to the liver of urethane-treated dams was significantly greater (by 30%), while distribution to embryonic tissues was significantly lower (by at least 50%) than in pair-fed or ad lib.-fed controls. Styrene treatment had no effect on 65Zn distribution. Urethane was developmentally toxic, causing an 18% decrease in fetal weight and a significant delay in skeletal ossification, but was not toxic to rat embryos in vitro. Styrene was not developmentally toxic. The changes observed after urethane treatment, namely substantial hepatic MT induction and altered maternal and embryonic Zn status, along with the lack of direct embryotoxicity of urethane in vitro, support the hypothesis that these maternal effects contribute to developmental toxicity. The lack of similar changes in styrene-intoxicated dams provides one explanation for its low developmental toxicity at maternally toxic dosages.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Developmental toxicity risk assessment: consensus building, hypothesis formulation, and focused research.

Risk assessment for developmental toxicity has become more defined over the last decade and the most recent EPA guidelines for developmental toxicity risk assessment were published in 1991. Development of approaches for risk assessment in this area have relied on building of consensus opinion among experts about the interpretation of developmental toxicity data. These discussions have aided in strengthening the scientific basis for risk assessment for developmental toxicity, including the default assumptions that must be used when more complete information on mechanisms of action and pharmacokinetics are unavailable. Such discussions continue on both a national and international basis. The EPA risk assessment guidelines outlined several major areas of research needed to strengthen risk assessment for developmental toxicity and led to the formulation of hypotheses to be tested in focused research projects. Several major research efforts have focused on dose-related mechanisms and biologically based modeling of specific agents, physiologically based pharmacokinetic models of pregnancy that can be scaled across species, and the influence of dose and duration of exposure on developmental outcomes, as well as the delineation of specific biomarkers of adverse developmental effects. Although such research initiatives will require a long-term effort, it is important that attention be focused now on those approaches that can improve the risk assessment process to avoid continued reliance on default approaches that have been used for the past 30 years or more. The impact of the EPA Guidelines for Developmental Toxicity Risk Assessment has been widespread. One of the main purposes for developing risk assessment guidelines by EPA was to communicate procedures to risk assessors inside the agency in an effort to promote consistency. In addition, the guidelines were to communicate to those outside the agency in private industry and other regulatory agencies how EPA would evaluate and interpret data. The developmental toxicity guidelines have standardized terminology used in developmental toxicity risk assessments. They also have influenced the revision of testing guidelines and the writing of new guidelines, such as the developmental neurotoxicity testing guidelines. More extensive use of developmental toxicity data within the RfD/RfC process was influenced by the guidelines, as well. More recently, the risk assessment guidelines have had a major impact on the harmonization of international testing and risk assessment guidelines through cooperative efforts with the World Health Organization under the auspices of the International Program on Chemical Safety (IPCS) and the Organization for Economic Cooperation and Development (OECD). We foresee these types of interagency and international cooperative efforts continuing as we attempt to make more efficient use of the limited resources available for testing, risk assessment, and research to better understand and prevent developmental toxicity.

Child↗
PubMed1999

Developmental toxicity of indium in cultured rat embryos.

Developmental toxicity of indium was examined using rat embryo culture with reference to toxicokinetics. Rat embryos at day 9.5 of pregnancy were cultured for 48 h under various exposure conditions to indium trichloride. Indium was embryotoxic to cultured rat embryos at concentrations ranging from 25 to 50 microM for 24 h exposure according to the embryonic age, and the exposure concentration was more critical than the exposure time. The embryotoxic concentrations were comparable to the serum concentration at a developmentally toxic dose by intravenous administration in an in vivo experiment. It was considered from these results that the developmental toxicity of indium is a direct effect on the embryo or yolk sac and that weak developmental toxicity of indium by oral administration was due to low exposure concentrations in the embryo.

Animals↗
PubMed1998

Evaluation of the developmental toxicities of coumarin, 4-hydroxycoumarin, and 7-hydroxycoumarin using FETAX.

The developmental toxicities of coumarin and hydroxycoumarin metabolites were evaluated using FETAX. Young X. laevis embryos were exposed to coumarin, 4-hydroxycoumarin, and 7-hydroxycoumarin 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 carbon monoxide (CO), cimetidine (CIM), or ellipticine (ELL) to selectively modulate cytochrome P-450 activity. The MAS was also treated with cyclohexene oxide (CHO) to selectively modulate epoxide hydrolase activity. Without the MAS or inhibited MAS, coumarin and 7-hydroxycoumarin were nearly equitoxic, whereas 4-hydroxycoumarin was nearly 2-fold less developmentally toxic than coumarin on an equimolar basis. Addition of the MAS and CIM-MAS increased the developmental toxicities of coumarin and, particularly, 4-hydroxycoumarin. Addition of the CHO-MAS greatly increased the developmental toxicity of coumarin and, especially, 4-hydroxycoumarin. Addition of the ELL- or CO-inhibited MAS did not increase the developmental toxicity of coumarin. However, addition of the intact MAS did not alter the developmental toxicity of 7-hydroxycoumarin. Results from these studies suggested that P-450; specifically ELL-inhibited P-450 (arylhydrocarbon hydroxylase) may have been responsible for increasing the developmental toxicity of coumarin. Furthermore, the increased toxicity of coumarin or 4-hydroxycoumarin following co-incubation with CHO-treated microsomes indicated that highly toxic epoxide intermediates may be produced from oxidative P-450 metabolism and that epoxide hydrolase may play a role in detoxification of the reactive intermediates.

4-Hydroxycoumarins↗
PubMed2000

Inhalation developmental toxicity and reproduction studies with cyclohexane.

The reproductive and developmental toxicity of cyclohexane was assessed in a two-generation reproduction study with Crl:CD BR rats and in developmental toxicity studies with Crl:CD BR rats and Hra:(NZW)SPF rabbits. The animals were exposed whole-body to atmospheric concentrations of 0, 500, 2000, or 7000 ppm cyclohexane. In the two-generation reproduction study, parental effects included statistically significantly lower mean body weight, overall mean body weight gain, and overall mean food efficiency for P1 and F1 females of the 7000 ppm level and statistically significantly lower mean body weight for F1 males of that level. Adult rats exposed to 2000 ppm cyclohexane and above exhibited a transient diminished or absent response to a sound stimulus while in the chambers during exposure. Mean pup weight was statistically significantly lower than control from lactation day 7 throughout the remainder of the 25-day lactation period for both F1 and F2 7000 ppm litters. Changes observed at 500 ppm were either considered not to be compound related or not adverse. Therefore, the systemic-toxicity no-observed-effect level (NOEL) was 500 ppm and the reproductive NOEL was 2000 ppm. The reproductive NOEL was based solely on the decreased pup weights in both the F1 and F2 generations observed at 7000 ppm. In the developmental toxicity studies, only the rats showed evidence of maternal toxicity. For rats in the 7000 ppm group, statistically significant reductions were observed in overall maternal body weight gain and overall maternal food consumption for the treatment period. Rats exposed to 2000 ppm cyclohexane and above again exhibited a transient diminished or absent response to a sound stimulus while in the chambers during exposure. Therefore, for rats, the maternal no-observed-effect level (NOEL) was 500 ppm. In the rabbit developmental toxicity study, no compound-related maternal effects were observed at concentration levels of 7000 ppm and below. Therefore, the maternal NOEL for rabbits was 7000 ppm. No compound-related evidence of developmental toxicity was observed at any test concentration in either species. Therefore, the developmental NOEL for both species was 7000 ppm, the highest concentration tested.

Acoustic Stimulation↗
PubMed1999

Developmental toxicity study of glycolic acid in rats.

The developmental toxicity of glycolic acid was assessed in rats by orally administering solutions of the test material in water over days 7-21 of gestation (the day of copulation plug detection was defined as day 1 of gestation). Groups of 25 mated female Crl: CD BR rats were gavaged at daily dose levels of 0, 75, 150, 300 or 600 mg/kg. The dams were euthanized on day 22 and the offspring were weighed, sexed, and examined for external, visceral, and skeletal alterations. Clear evidence of maternal toxicity was demonstrated at 600 mg/kg; adverse clinical observations were statistically significantly increased (wheezing/lung noise, abnormal gait/staggering, lethargy). In addition, maternal body weights, weight changes, and food consumption were statistically significantly reduced at this dose level. Marginal evidence of maternal toxicity was demonstrated at 300 mg/kg; wheezing/lung noise similar to that seen at 600 mg/kg was observed in 2 of 25 dams. This increase approached statistical significance (p = 0.0553). There was marked evidence of developmental toxicity at 600 mg/kg. Mean fetal weight was statistically significantly reduced while the incidences of skeletal (ribs, vertebra, and sternebra) malformations and variations were statistically significantly increased. At 300 mg/kg/day, there was a slight (2 affected fetuses from 2 litters) increase in the incidence of two skeletal malformations: fused ribs and fused vertebra. Although these increases were not statistically significant (p = 0.0555), they were consistent with findings seen at 600 mg/kg/day and thus were considered relevant. There was no other evidence of developmental toxicity at 300 mg/kg/day nor was any developmental toxicity seen at 150 or 75 mg/kg/day. Thus, the maternal and developmental no-observed-effect level (NOEL) was considered 150 mg/kg.

Abnormalities, Drug-Induced↗
PubMed1996

Evaluation of the developmental toxicity of theophylline, dimethyluric acid, and methylxanthine metabolites using Xenopus.

The developmental toxicities of theophylline and theophylline metabolites were evaluated using FETAX (Frog Embryo Teratogenesis Assay - Xenopus). Young X. laevis embryos were exposed to theophylline, 1-methylxanthine, 3-methylxanthine, or 1, 3-dimethyluric acid 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 carbon monoxide (CO), cimetidine (CIM), or ellipticine (ELL) to selectively modulate cytochrome P-450 activity. Addition of the MAS and CIM-MAS reduced the developmental toxicity of theophylline. Addition of the ELL- or CO-inhibited MAS did not reduce the developmental toxicity of theophylline. Addition of the intact MAS did not alter the developmental toxicity of 1-methyl- or 3-methylxanthine which were slightly more developmentally toxic on an equimolar basis than theophylline itself. 1, 3-dimethyluric acid was not developmentally toxic at maximum soluble concentrations in 1% (V/V) DMSO. Results from these studies suggested that P-450, specifically ELL-inhibited P-450 (aryl hydrocarbon hydroxylase) may have been responsible for detoxification of theophylline and that 1, 3 dimethyluric acid represented the primary detoxification metabolite of theophylline.

Abnormalities, Drug-Induced↗
PubMed1992

Evaluation of acetaminophen-induced developmental toxicity using FETAX.

Potential mechanisms of acetaminophen-induced developmental toxicity were evaluated using FETAX (Frog Embryo Teratogenesis Assay-Xenopus). Early Xenopus laevis embryos were exposed to acetaminophen for 96-h in two definitive concentrations-response assays with and without an exogenous metabolic activation system (MAS). Two static renewal tests of acetaminophen and the MAS treated with carbon monoxide, cimetidine, ellipticine, diethyl maleate, and supplemented with glutathione were also performed. Addition of the MAS decreased the 96-h LC50 and EC50 (malformation) values of unactivated acetaminophen 3.9-fold and 7.1-fold, respectively. Addition of the carbon monoxide- and ellipticine-inhibited MAS, as well as the glutathione-supplemented MAS decreased the developmental toxicity of activated acetaminophen to levels near that of the unactivated parent compound. Cimetidine-inhibited MAS also reduced the developmental toxicity of acetaminophen, but not to the extent observed with the carbon monoxide- and ellipticine-inhibited, or glutathione-supplemented MAS. Addition of the diethyl maleate-treated MAS substantially increased the developmental toxicity of acetaminophen. Results indicate that a highly reactive intermediate formed as the result of MFO-mediated metabolism (possibly P-448) significantly increased the developmental toxicity of acetaminophen. Glutathione was also found to play a major role in intermediate detoxification in vitro.

Abnormalities, Drug-Induced↗