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PubMed2005

Developmental toxicity testing from animal towards embryonic stem cells.

Developmental toxicology is the study of undesirable effects on the development of the organism, which may result from exposure before conception, from the period of prenatal development, or postnatally during the time of sexual maturation. The principal manifestations of developmental toxicity include: embryolethality, malformations, growth retardation, and functional impairment. In 2001, the European Commission published the future chemicals policy entitled "White Paper: Strategy for a Future Chemicals Policy". The new regulation requires a toxicological evaluation with strong emphasis on reproductive toxicity, by using in vitro methods, especially for those chemicals marketed at more than 1 ton per year. For this reason, the establishment of in vitro models capable of detecting major undesirable manifestations in the fetus, are urgently required. The aim of the present review is to explore the capacity of existing in vitro systems, based on embryonic stem (ES) cells, to identify embryotoxicity with a focus on specific effects such as teratogenicity and growth retardation. In addition, we discuss the possibility to adapt the mouse ES cells based tests to human ES cells, avoiding inter-species variations in developmental toxicity studies and address related ethical issues. Considering the different manifestations of developmental toxicity, only a battery of in vitro tests will provide the necessary information for regulatory developmental toxicity assessment.

Animal Testing Alternatives↗
PubMed2001

Evaluation of the potential developmental toxicity of 3-aminopentanenitrile (3-APN) in the rat.

The potential developmental toxicity of 3-aminopentanenitrile (3-APN) was assessed in rats. Groups of 25 time-mated female Crl:CD(SD)IGS BR rats were orally gavaged at daily dose levels of 0, 5, 30, 100 or 300 mg/kg over days 6-20 of gestation (days 6-20G); the day of copulation plug detection was designated day 0G. The dams were euthanized on day 21G 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 and developmental toxicity was seen at 100 and 300 mg/kg. Regarding maternal toxicity, there were compound-related, statistically significant reductions in maternal body weight and food consumption at 100 and 300 mg/kg. The incidence of alopecia was significantly increased at these levels as well. Regarding developmental toxicity, mean fetal weight was slightly but significantly reduced at 100 and 300 mg/kg. In addition, at 300 mg/kg, there were significant increases in several skeletal variations (wavy ribs and skull, rib, and vertebral ossification delays) consistent with developmental delay. There was no evidence of either maternal or developmental toxicity at 5 or 30 mg/kg. Thus, the maternal and developmental no-observed-effect level (NOEL) was 30 mg/kg. Because developmental toxicity was observed only after administration of doses that also produced signs of maternal toxicity, 3-APN is not considered to be a selective developmental toxicant in the rat.

Animals↗
PubMed1997

Structural determinants associated with risk of human developmental toxicity.

OBJECTIVES: Identifying drugs or chemicals that represent hazards to human development is a continuous challenge. Of the approximately 60,000 chemicals in commercial use only 5% have been evaluated for developmental toxicity. Identification of inexpensive, rapid, validated techniques to demonstrate chemical hazards for the human embryo or fetus is the objective of this research. STUDY DESIGN: This research explored identification of structure activity predictors associated with human developmental toxicity by means of MULTICASE (multiple computer-automated structure evaluation), an algorithm that evaluates associations between chemicals and their constituent fragments and a biologic response. This algorithm allows identification of chemicals (and specific substructures) that may be human developmental toxicants. Developmental toxicity data were compiled from two sources (the Teratogen Information System and Food and Drug Administration guidelines) and analyzed to identify structural determinants (biophores) associated with human developmental toxicity. RESULTS: This analysis identified 17 biophores associated with human developmental toxicity. Testing the biophores against the learning set demonstrated 99% concordance, 100% sensitivity, and 98% specificity. Cross-validation studies were conducted, in which the original database was randomly separated into five learning and test sets; these demonstrated a mean concordance of 73%, with a mean sensitivity of 63% and a mean specificity of 79%. CONCLUSIONS: The MULTICASE structure-activity model is useful for identifying potential human developmental toxicants, as well as serving as a starting point for mechanistic investigations.

Algorithms↗
PubMed1993

Quaternary silsesquioxane: a developmental toxicity study in rats.

The developmental toxicity of an antimicrobial organosilicon quaternary ammonium chloride (Quaternary Silsesquioxane) was evaluated in rats. Groups of 25 pregnant CD rats were administered 100, 300, or 1000 mg/kg/day of test material by gavage as a single daily dose on Days 6 through 15 of gestation at a volume of 10 ml/kg. The control group received only corn oil as the vehicle. Cesarean examinations were performed on all females on Gestation Day 20 followed by evaluation of the fetuses for teratogenicity. Maternal effects included a slight but statistically significant increase in relative liver weights at the 1000 mg/kg/day dose level. Using these hepatic changes as an adverse effect, the maternal no observable adverse effect level for this study was identified at 300 mg/kg/day. The number of corpora lutea, implantation sites, viable fetuses, and early and late resorptions, the fetal body weights, the crown-rump length, and the gravid uterine and corrected body weights were not affected by the administration of Quat-Silsesquioxane. The occurrence of external and internal soft tissue malformations and variations and the incidences of skeletal malformations and variations in the treated groups were not significantly different from those in the control group. These results demonstrated that oral administration of Quat-Silsesquioxane as high as 1000 mg/kg/day did not produce teratogenicity or other indications of developmental toxicity in the rat conceptus.

Animals↗
PubMed1996

The theoretical and empirical case for in vitro developmental toxicity screens, and potential applications.

In vitro assays for the screening of developmental toxicity potential have been under development for approximately 15 years. During that period, we have learned that assays consisting of primary cultures of embryonic tissues or cells, intact embryos in culture, or free-living embryos are capable of distinguishing between mammalian developmental toxicants and nondevelopmental toxicants with an accuracy of > or = 80%. Despite this level of performance, there is still considerable reluctance among the scientific community to employ these assays for preliminary screening. In this paper, I review the theoretical basis for the predictiveness of these assays, outline the empirical data indicating their utility in screening toxicants, discuss the major limitations of in vitro assays and how they can be managed, and suggest applications for in vitro pre-screens. The embryo-derived assays should work because they continue to develop in vitro, and the underlying cellular and molecular processes driving this development are the same as those in the mammalian embryo in situ, and therefore, susceptible to the same insults. The assays do work, as specific mechanisms of developmental toxicity have been demonstrated in vitro, and because extensive validation studies have shown them to be highly concordant with traditional in vivo screens. The assays are inherently limited by the fact that they do not include all the levels of complexity of the maternal-embryonic unit; however, these limitations can be minimized by thoughtful assay selection, study design, and interpretation. Potential applications are suggested that complement but do not replace in vivo testing. Pre-screens will make product development more efficient and add to our knowledge about the developmental toxicity of previously untested compounds. In vivo screening would still be conducted on all classes of substances that are currently tested for developmental toxicity; however, fewer chemicals with high likelihood of being developmentally toxic, and therefore not appropriate for further commercial consideration, would be evaluated in these costly screens.

Animals↗
PubMed1995

Developmental toxicity of dinitroaniline herbicides in rats and rabbits. I. Trifluralin.

The potential developmental toxicity of trifluralin was evaluated in rats and rabbits. Pregnant rats and rabbits were dosed once daily by gavage on Gestation Days 6-15 and 6-18, respectively. Doses for rats were 0, 100, 225, 475, or 1000 mg/kg; doses for rabbits were 0, 100, 225, or 500 mg/kg. Cesarean sections were performed on rats and rabbits on Gestation Days 20 and 28, respectively. In rats, maternal toxicity was indicated in the 475 and 1000 mg/kg treatment groups by depression of body weights and food consumption. Fetal viability and morphology were not adversely affected at any dose level. Developmental toxicity was indicated at the 1000-mg/kg dose level by depression of fetal weight. The NOAEL for maternal toxicity in the rat was 225 mg/kg; the NOAEL for developmental toxicity in the rat was 475 mg/kg. In rabbits, maternal toxicity was indicated at the 225 and 500 mg/kg dose levels by abortions and/or deaths in conjunction with anorexia and cachexia. Developmental toxicity was indicated at the 500 mg/kg dose level by depressed fetal viability and weight. Fetal morphology was not adversely affected at any dose level. The NOAELs for maternal and developmental toxicity in the rabbit were 100 and 225 mg/kg, respectively. Based on these data, trifluralin did not exhibit selective toxicity toward the developing conceptus.

Aniline Compounds↗
PubMed2004

Developmental toxicity study of dimethylpiperidone.

The potential maternal and developmental toxicity of dimethylpiperidone (DMPD) was assessed in rats. Groups of 25 mated female Crl:CD (SD)IGS BR rats were exposed by inhalation (whole-body exposures) for approximately six hours per day over days 7-21 of gestation (G); day 1G was the day of copulation plug detection. The exposure levels were 0, 52, 260, or 340 (vapor plus aerosol) mg/m3 DMPD. During the in-life portion, body weights, food consumption, and clinical observation data were collected. On day 22G, the dams were euthanized and examined for gross external and internal alterations. The uterine contents were described and the fetuses were weighed and examined for external, visceral, and skeletal alterations. Maternal toxicity was seen at both 260 and 340 mg/m3. At 340 mg/m3, evidence of maternal toxicity included mortality, increased clinical observations, and decreased body weight and food consumption. At 260 mg/m3, maternal toxicity was limited to increased clinical observations and decreased food consumption. Developmental toxicity was also produced at 260 and 340 mg/m3. At 340 mg/m3, evidence of developmental toxicity included decreased fetal weight, increased embryofetal lethality with concomitant reductions in litter size, and increased fetal malformations and variations. At 260 mg/m3, effects in fetuses were limited to slightly decreased fetal weight and increased fetal variations; additionally, one litter from this level consisted entirely of resorptions. There were no compound-related effects in either dams or fetuses at 52 mg/m3. It was, therefore, concluded that DMPD was not selectively toxic to the rat conceptus.

Abnormalities, Drug-Induced↗
PubMed2006

Understanding dioxin developmental toxicity using the zebrafish model.

Zebrafish (Danio rerio) have advantages over mammals as an animal model for investigating developmental toxicity. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin, TCDD), a persistent global contaminant, is the most comprehensively studied developmental toxicant in zebrafish. The hallmark responses of TCDD developmental toxicity manifested in zebrafish larvae include edema, anemia, hemorrhage, and ischemia associated with arrested growth and development. Heart and vasculature development and function are severely impaired, and jaw malformations occur secondary to inhibited chondrogenesis. The swim bladder fails to inflate, and the switch from embryonic to adult erythropoiesis is blocked. This profile of developmental toxicity responses, commonly referred to as "blue sac syndrome" because the edematous yolk sac appears blue, is observed in the larval form of all freshwater fish species exposed to TCDD at the embryonic stage of development. Components of the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator (AHR/ARNT) signaling pathway in zebrafish have been identified and functionally characterized. Their role in mediating TCDD toxicity has been determined using morpholinos to specifically knockdown the translation of zfAHR1, zfAHR2, zfARNT1, and zfARNT2 mRNAs, respectively, and a line of zfARNT2 null mutant zebrafish has provided further insight. These studies have shown that zfAHR2 and zfARNT1 mediate TCDD developmental toxicity. In addition, the growing use of molecular and genomic tools for research on zebrafish have led to advances in our understanding of the mechanism of TCDD developmental toxicity at the molecular level, including the recent finding that toxicity is not mediated by increased cytochrome P4501A (zfCYP1A) expression.

Animals↗
PubMed2005

Evaluation of the developmental toxicity of 8-2 telomer B alcohol.

The potential maternal and developmental toxicity of 8-2 Telomer B Alcohol was assessed in rats. Groups of 22 time-mated female Crl:CD (SD)IGS BR rats were administered oral gavage doses as suspensions of 8-2 Telomer B Alcohol in aqueous 0.5% methylcellulose from day 6 through 20 of gestation (G) at daily doses of either 0, 50, 200, or 500 mg/kg. Under the conditions of this study, adverse maternal toxicity was produced at 500 mg kg(- 1) day(- 1) and consisted of maternal mortality, decreased body weights and body weight gains, and increased clinical observations of toxicity. One litter at 500 mg kg(- 1) day(- 1) consisted of one early resorption and was believed to be secondary to overt maternal toxicity, although single conceptus litters occur historically in this strain of rats. Developmental toxicity at 500 mg kg(- 1) day(- 1) consisted of increased fetal skeletal variations (delayed pelvic bone ossification and wavy ribs). At 200 and 500 mg kg(- 1) day(- 1), there were transient reductions in maternal feed consumption. In addition, there were slight increases in the incidence of delayed fetal skull bone ossification at 200 and 500 mg kg(- 1) day(- 1). The no-observed-adverse-effect level (NOAEL), defined as the highest dose at which adverse effects attributable to the test substance were not detected, for both maternal and developmental toxicity, is considered to be 200 mg kg(- 1) day(- 1). Thus, 8-2 Telomer B Alcohol is not considered to be a selective developmental toxicant in rats. The transient and quantitative nature of the observations in the 200 mg/kg group supports the conclusion that these findings were not adverse.

Abnormalities, Drug-Induced↗
PubMed1996

Prospects for the development of validated screening tests that measure developmental toxicity potential: view of one skeptic.

Humans are exposed to a variety of potential developmental toxicants. This fact, combined with the knowledge that human development can be disrupted by "environmental" agents, has led to the development of methods designed to identify potential developmental toxicants. Currently, the principal method used to screen drugs and chemicals that are potential human developmental toxicants is the segment II study (i.e., a study in which prospective drugs and chemicals are tested in pregnant animals). Because of the cost and time involved in such studies and the pressure to reduce the number of animals used in such testing, alternative methods for developmental toxicity testing have been sought. This has resulted in a number of in vitro tests whose aim is to screen large numbers of agents quickly and inexpensively. Although numerous in vitro tests of developmental toxicity have been developed during the last 15 years, no one system or combination of tests have been validated for the purpose intended. Nonetheless, two systems--the limb bud/CNS micromass, and the chick embryo neural retina cell culture (CERC)--continue to be advanced as viable in vitro developmental toxicology tests. The purpose of this commentary is to evaluate the prospects for the development of an in vitro test system(s) that can screen the universe of drugs and chemicals and reliably identify those that require further study and those that do not. The conclusion of this investigator is that the prospects for validating such in vitro tests are not promising. This conclusion is based primarily on the lack of basic knowledge regarding the relevance of end points assayed in the micromass and CERC test systems to those end points known or thought to be critical for normal development.

Animals↗
PubMed1992

Assessment of a short-term reproductive and developmental toxicity screen.

Short-term tests for reproductive and developmental toxicity are needed to provide preliminary data on the toxicity of chemicals about which little or no data exist. An ideal design would test all aspects of reproduction and identify the target process in a short time period. One potential design has been evaluated using four chemicals of varying reproductive/developmental toxicity. Swiss mice were mated for 3 days prior to chemical exposure to produce time-mated females for gestational exposure and to ascertain fertility of the untreated males. The group of time-mated females was treated during Gestation Days 8-14 and allowed to litter for observations through Postnatal Day (PND) 4. Endpoints observed included pup number and body weights on PND 0, 1, and 4 and number of uterine implantation sites on PND 4. A second group of females was dosed daily for 19 days. After 7 days, these females (n = 10/group) were cohabited with male mice who had been treated for 5 days prior to this second mating. Daily chemical dosing continued during the 5-day cohabitation. This second group of females was killed after 19 days of treatment and the number of live and dead fetuses and implantation sites was recorded. After 17 days of dosing, male mice were killed and the reproductive system evaluated by organ weights, total epididymal sperm counts and motility, and testicular histology. All four chemicals tested, boric acid, ethylene glycol, ethylene glycol monomethyl ether, and theophylline, were found to be toxic to development or reproduction when tested previously by conventional developmental toxicity or continuous breeding protocols. This short-term (21 day) design correctly identified three of these four chemicals as reproductive and developmental toxicants and distinguished the potent toxicants from the less effective compounds. This design can be used to prioritize chemicals for further study, or to delineate the relative toxicities of structurally related chemicals, and to identify the proper dose range for subsequent toxicity studies.

Animals↗
PubMed1993

Evaluation of the developmental toxicity of trichloroethylene and detoxification metabolites using Xenopus.

Potential mechanisms of trichloroethylene-induced developmental toxicity were evaluated using FETAX (Frog Embryo Teratogenesis Assay--Xenopus). Early Xenopus laevis embryos were exposed to trichloroethylene for 96 h in two separate definitive concentration-response assays with and without an exogenous metabolic activation system (MAS) and inhibited MAS. The MAS was treated with either carbon monoxide or cyclohexene oxide to modulate mixed-function oxidase (MFO) or epoxide hydrolase activity, respectively. Trichloroethylene metabolites: dichloroacetic acid, trichloroacetic acid, trichloroethanol, and oxalic acid were also evaluated in two separate definitive, static renewal tests. Addition of the MAS decreased the 96 h LC50 and EC50 (malformation) of trichloroethylene 1.8-fold and 3.8-fold, respectively. Addition of the carbon monoxide inhibited MAS decreased the developmental toxicity of activated trichloroethylene to levels approximating that of the parent compound. Cyclohexene oxide-inhibited MAS substantially increased the developmental toxicity of trichloroethylene. In addition, each of the metabolites tested were significantly less developmental toxic than the parent compound, trichloroethylene. Results indicate that a highly embryotoxic epoxide intermediate, trichloroethylene oxide, formed as the results of MFO mediated metabolism may play a significant role in the developmental toxicity of trichloroethylene in vitro.

Animals↗
PubMed1991

Relationship between fetal weight and malformation in developmental toxicity studies.

Exposure to developmental toxicants may cause fetal malformations, increase prenatal death rates and reduce fetal weight at term. However, there has been little formal study of the relationship among these effects. Certainly, no statistical methods are currently available to jointly analyze these effects of exposure. As a preliminary step in developing such methods, simple exploratory analyses were conducted using a series of ten studies conducted for the National Toxicology Program. Because fetal weight and malformation status were both reported for all live fetuses, the data permitted an exploration of the correlation between these two outcomes. The data show a clear pattern wherein malformed fetuses tended to be lighter at term than nonmalformed fetuses. While these patterns cannot be used to draw inferences regarding the biological relationship between fetal weight and malformation, they do suggest the potential value in developing statistical models for the joint effect of exposure on fetal weight and malformations.

Animals↗
PubMed1995

Effects of maternal stress on methylmercury-induced developmental toxicity in mice.

The developmental toxicity of combined exposure to maternal restraint stress and methylmercury chloride (MMC) was assessed in Swiss mice. On day 10 of gestation, four groups of plug-positive female mice were treated (p.o.) with a single dose of 12.5 or 25 mg MMC/kg. Immediately after MMC exposure, two of those groups were subjected to restraint for 14 hr. Control groups included restrained and unrestrained pregnant mice nonexposed to MMC. Combined exposure to 25 mg MMC/kg and restraint enhanced MMC-induced maternal toxicity, which included deaths and decreased body weight gain and food consumption. The number of nonviable implants was also increased significantly following concurrent exposure to MMC (25 mg/kg) and restraint, with the percentage of postimplantation loss increased from 64% (MMC alone) to 100% (MMC plus restraint). However, the types and incidence of internal and skeletal anomalies observed after administration of 12.5 mg MMC/kg were not increased by maternal restraint. These results suggest that maternal stress would enhance the MMC-induced maternal and embryo/fetal toxicity at doses of MMC that are highly toxic to the dams, whereas at doses that are less acutely toxic the role of maternal stress would not be significant.

Abnormalities, Drug-Induced↗
PubMed1999

Preliminary validation of tumor cell attachment inhibition assay for developmental toxicants with mouse S180 cells.

This study was designed to explore the possibility of using ascitic mouse sarcoma cell line (S180) to validate the mouse tumor cell attachment assay for developmental toxicants, and to test the inhibitory effects of various developmental toxicants. The results showed that 2 of 3 developmental toxicants under consideration, sodium pentobarbital and ethanol, significantly inhibited S180 cells attachment to Concanavalin A-coated surfaces. Inhibition was dependent on concentration, and the IC50 (the concentration that reduced attachment by 50%), of these 2 chemicals was 1.2 x 10(-3) mol/L and 1.0 mol/L, respectively. Another developmental toxicant, hydrocortisone, did not show inhibitory activity. Two non-developmental toxicants, sodium chloride and glycine were also tested and these did not decrease attachment rates. The main results reported here were generally similar to those obtained with ascitic mouse ovarian tumor cells as a model. Therefore, this study added further evidence to the conclusion that cell specificity does not limit attachment inhibition to Con A-coated surfaces, so S180 cell may serve as an alternative cell model, especially when other cell lines are unavailable. Furthermore, after optimal validation, it can be suggested that an S180 cell attachment assay may be a candidate for a series of assays to detect developmental toxicants.

Animals↗
PubMed2003

Significance of 2-methoxypropionic acid formed from beta-propylene glycol monomethyl ether: integration of pharmacokinetic and developmental toxicity assessments in rabbits.

Commercial grade propylene glycol monomethyl ether (PGME), which is composed of > 99.5% alpha-isomer and < 0.5% beta-isomer, has been shown in several studies to have a low potential for developmental toxicity. Nonetheless, questions have been raised about potential human developmental toxicity due to beta-PGME, because it can be metabolized to 2-methoxypropionic acid (MPA), a compound bearing structural similarity to the teratogen, methoxyacetic acid (MAA). Accordingly, a series of in vivo developmental toxicity, whole embryo culture, and in vivo pharmacokinetic experiments were conducted in New Zealand White rabbits (highly sensitive to these compounds) to better understand the developmental toxicity potential of MPA and the kinetics of its formation from beta-PGME. For the in vivo developmental toxicity studies, groups of 20 inseminated rabbits were gavaged with 0, 10, 26, or 78 mg/kg/day of MPA on gestation day (GD) 7-19, followed by fetal evaluation on GD 28. Results with MPA were compared with those of rabbits similarly dosed with 0, 2.5, 7.5, or 15 mg/kg/day of MAA. Developmental toxicity no-observable-effect levels (NOEL) were approximately 10-fold higher for MPA (26 mg/kg/day) than for MAA (2.5 mg/kg/day). Also, the severity of effects caused by MPA was less than that of MAA, and unlike MAA, MPA was not selectively toxic to the fetus. This differential toxicity was also seen in whole embryo cultures of GD 9 rabbit embryos, in which there were no adverse effects of MPA (1.0, 5.0 mM) or its parent compound, beta-PGME (0.5, 2.0 mM), but severe dysmorphogenesis in 100% of embryos cultured in 5.0 mM MAA. The pharmacokinetics study showed rapid and complete conversion of beta-PGME to MPA, with a relatively long elimination half-life (33-44 h) for MPA. However, peak and AUC concentrations of MPA in blood associated with the MPA LOEL dose of 78 mg/kg/day were 1.3 mM and 52.9 mM-h/l, respectively, suggesting a relatively high threshold based on internal dosimetry. Taken together, these data indicate a negligible risk of developmental toxicity due to MPA formation from the small amounts of beta-isomer present in commercial PGME.

Abnormalities, Drug-Induced↗
PubMed1999

Relative developmental toxicities of acrylates in rats following inhalation exposure.

The developmental toxicities of seven acrylates were studied in Sprague-Dawley rats after inhalation exposure for 6 h/day, during days 6 to 20 of gestation. The exposure concentrations were: for acrylic acid, 50, 100, 200, or 300 ppm; for methyl acrylate, 25, 50, or 100 ppm; for ethyl acrylate, 25, 50, 100, or 200 ppm; for butyl acrylate, 100, 200, or 300 ppm; for ethylhexyl acrylate, 50, 75, or 100 ppm; for hydroxyethyl acrylate, 1, 5, or 10 ppm; and for hydroxypropyl acrylate, 1, 5, or 10 ppm. No treatment-related increases in embryo/fetal mortality or fetal malformations were observed after exposure to any of these acrylates. Fetal toxicity, indicated by reduced fetal body weight, was observed after exposure to 300 ppm acrylic acid, 100 ppm methyl acrylate, 200 ppm ethyl acrylate, and 200 or 300 ppm butyl acrylate in the presence of overt signs of maternal toxicity. While there was evidence of maternal toxicity, no significant developmental toxic effects were observed after exposure to ethylhexyl acrylate, hydroxyethyl acrylate, or hydroxypropyl acrylate at any concentration. These results indicate that inhaled acrylic acid, methyl acrylate, ethyl acrylate, butyl acrylate, ethylhexyl acrylate, hydroxyethyl acrylate, and hydroxypropyl acrylate are not selectively toxic to the embryo or fetus.

Acrylates↗
PubMed2003

Analysis of the nonsteroidal anti-inflammatory drug literature for potential developmental toxicity in rats and rabbits.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed to pregnant women. Some case-control studies have linked the NSAIDs aspirin and indomethacin with a risk of congenital abnormalities and low birthweight. High doses of aspirin produce developmental toxicity in rats (e.g., gastroschisis/umbilical hernia, diaphragmatic hernia [DH]) when administered during sensitive windows of development. Unlike other NSAIDs, aspirin irreversibly inhibits cyclooxygenases (COXs) 1 and 2. Hence, the developmental toxicity seen in rats after exposure to aspirin may be due to the irreversible inhibition of COX-1 and/or COX-2. If so, other NSAIDs, which act through a reversible inhibition of COX, may produce a weak developmental toxicity signal or no developmental toxicity signal when tested in preclinical models. To investigate this relationship, a comprehensive analysis of the NSAID developmental toxicity literature was undertaken to determine whether NSAIDs other than aspirin induce developmental anomalies similar to those elicited by aspirin. METHODS: Developmental toxicity studies were identified through literature searches of PubMed and TOXNET, and pregnancy outcome data were extracted and tabulated. By using a set of defined criteria, each study was evaluated for quality and assigned to one of five tiers. The relation between certain malformations and NSAID treatment was analyzed for the best studies (tiers 1-4) by using concurrent control data (Mantel-Haenszel and permutation tests) and by combining the concurrent control data with historical control data (chi2 test and permutation tests). RESULTS: A qualitative analysis of these data led to a focus on three types of malformations: DH, ventricular septal defects (VSDs), and midline defects (MDs). In rats, the incidences of VSD and MD were increased among fetuses treated with NSAIDs when compared with the concurrent controls. The extent of the increase was attenuated when the data from the aspirin studies were excluded from the analysis. There were no qualifying (i.e., tiers 1-4) aspirin studies conducted in rabbits, but the incidences of the three defects were increased over control incidences among non-aspirin NSAID-treated animals. Statistical analysis of these data was subsequently conducted. When tiers 1-4 were combined and compared with concurrent controls plus the most appropriate historical control database, the strongest associations were between NSAID treatment and VSD in rats, VSD in rabbits, and MD in rabbits. There also was some suggestion of an association between NSAID treatment and DH in rabbits. CONCLUSIONS: This analysis of the non-clinical NSAID literature demonstrated a possible association between exposure to NSAIDs and developmental anomalies. The anomalies were similar for aspirin and for other NSAIDs, but effects occurred at a much lower incidence with non-aspirin NSAIDs than previously reported with aspirin. Such a finding is consistent with the concept that reversible inhibition of COX-1 and/or COX-2 by other NSAIDs would produce weaker developmental toxicity signals than aspirin. However, there were limitations of the evaluated studies: (1) there were very few robust International Conference on Harmonization-compliant studies conducted with NSAIDs in the published literature; (2) many of the studies were conducted at doses well below the maximum tolerated dose (MTD), where effects are rarely seen; and (3) numerous studies were conducted above the MTD, where reduced numbers of fetuses hampered detection of low-incidence findings. Although weak associations were observed, these limitations prevented us from definitively determining the presence or absence of a developmental toxicity signal from the existing body of NSAID data. Further exploration of this hypothesis will require assessing the potential association in animal models by using dose levels centered around the MTD.

Abnormalities, Drug-Induced↗