Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study.

OBJECTIVE: To examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis. DESIGN: Population based cohort study. SETTING: A cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14. PARTICIPANTS: Pregnancies of women enrolled in Medicaid from three or more months before the last menstrual period to one month after delivery, and infants enrolled for three or more months after birth. INTERVENTIONS: Use of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy. MAIN OUTCOME MEASURES: Risk of musculoskeletal malformations, conotruncal malformations, and oral clefts (primary outcomes), associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery, were examined. RESULTS: The study cohort of 1 969 954 pregnancies included 37 650 (1.9%) pregnancies exposed to oral fluconazole and 82 090 (4.2%) pregnancies exposed to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95% confidence interval 44.8 to 59.3) per 10 000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10 000 pregnancies exposed to topical azoles. The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10 000 pregnancies exposed to fluconazole and topical azoles, respectively; risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10 000 pregnancies, respectively. The adjusted relative risk after fine stratification of the propensity score was 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, the adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively. CONCLUSIONS: Oral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10 000 exposed pregnancies overall.

Selenomethionine exposure affects chondrogenic differentiation and bone formation in Japanese medaka (Oryzias latipes).

Excess selenium entering the aquatic environment from anthropogenic activities has been associated with developmental abnormalities in fish including skeletal deformities of the head and spine. However, mechanisms of this developmental toxicity have not been well-characterized. In this study, Japanese medaka (Oryzias latipes) embryos were exposed to seleno-l-methionine (Se-Met) in a range of concentrations. Gene expression was evaluated for sex-determining region Y (SRY)-related box (Sox9a and Sox9b), runt-related transcription factor 2 (Runx2), and melatonin receptor (Mtr). Alterations in the length of Meckel's cartilage, tail curvature, and decreased calcification were observed in skeletal stains at 10- and 22-days post-fertilization (dpf). Embryonic exposure of Osterix-mCherry transgenic medaka resulted in fewer teeth. Sox9a and Sox9b were up-regulated, while Runx2 and Mtr were down-regulated by Se-Met prior to hatch. Whole mount in situ hybridization (WISH) localized gene expression to areas observed to be affected in vivo. In addition, Se-Met exposures of a Mtr morpholino (Mtr-MO) as well as Luzindole exposed embryos developed similar skeletal malformations, supporting involvement of Mtr. These findings demonstrate that Se-Met modulates expression of key genes involved in chondrogenic differentiation and bone formation during development.

Video-based kinetic analysis of calcification in live osteogenic human embryonic stem cell cultures reveals the developmentally toxic effect of Snus tobacco extract.

Epidemiological studies suggest tobacco consumption as a probable environmental factor for a variety of congenital anomalies, including low bone mass and increased fracture risk. Despite intensive public health initiatives to publicize the detrimental effects of tobacco use during pregnancy, approximately 10-20% of women in the United States still consume tobacco during pregnancy, some opting for so-called harm-reduction tobacco. These include Snus, a type of orally-consumed yet spit-free chewing tobacco, which is purported to expose users to fewer harmful chemicals. Concerns remain from a developmental health perspective since Snus has not reduced overall health risk to consumers and virtually nothing is known about whether skeletal problems from intrauterine exposure arise in the embryo. Utilizing a newly developed video-based calcification assay we determined that extracts from Snus tobacco hindered calcification of osteoblasts derived from pluripotent stem cells early on in their differentiation. Nicotine, a major component of tobacco products, had no measurable effect in the tested concentration range. However, through the extraction of video data, we determined that the tobacco-specific nitrosamine N'-nitrosonornicotine caused a reduction in calcification with similar kinetics as the complete Snus extract. From measurements of actual nitrosamine concentrations in Snus tobacco extract we furthermore conclude that N'-nitrosonornicotine has the potential to be a major trigger of developmental osteotoxicity caused by Snus tobacco.

Induction of a thoracolumbar supernumerary rib in rat developmental toxicity studies: A short discussion on the critical window.

Thoracolumbar supernumerary ribs (TSRs) are classified as less severe skeletal anomalies in rat developmental toxicity studies, although their incidence is relatively high in rodent studies. To investigate the characteristics of the critical window for chemically-induced TSR, in this study, rats were administered 5-fluorocytocine (5-FC) or sodium salicylate (SAL) at one of three time periods on gestational day (GD) 9, early morning (7:00 am), midday (12:00 pm to 1:00 pm), or late afternoon (4:00 pm or 7:00 pm). The incidence of TSR and other anomalies were assessed in GD20 fetuses. A single treatment with both chemicals on GD9-induced TSR, with the incidence highest when administered at 7:00 Am, decreasing gradually when administered later. This trajectory was clearer in rats treated with 5-FC than with SAL. The critical period of TSR induction is shorter in rats administered 5-FC than SAL. The characteristics of the critical window may cause variability in the incidence of TSR observed in developmental toxicity studies.

Repairability of skeletal alterations induced by sodium valproate in rats.

The present study aimed at examining postnatal repairability of sodium valproate-induced skeletal alterations in rats. Sodium valproate (400 mg/kg) or the vehicle (distilled water) was orally administrated to pregnant Sprague-Dawley rats from gestation days 9 to 11. Fetuses and pups were obtained on gestation day 21 and postnatal day 11, respectively, and their skeletons were stained with Alizarin red S and Alcian blue and examined. Sodium valproate-induced costal and vertebral alterations in the fetuses included discontinued rib cartilage, fused rib, full or short supernumerary rib, bipart ossification of thoracic centrum, supernumerary lumbar vertebrae, and lumbarization. In pups, however, discontinued rib cartilage was not observed, and the incidence of a short supernumerary rib was significantly lower than that in the fetuses, suggesting that these alterations are postnatally repairable.

Teratogenic effects of Mimosa tenuiflora in a rat model and possible role of N-methyl- and N,N-dimethyltryptamine.

Mimosa tenuiflora is a shrub/tree found in northeastern Brazil sometimes eaten by livestock and believed to be responsible for malformations observed in many animals from that region. The teratogenic compounds in M. tenuiflora are not known. This study used pregnant rats fed M. tenuiflora and components therefrom for bioassay and fractionation of possible teratogenic compounds. Rat pups were examined for cranial-facial defects and skeletal malformations. Experimental diets included M. tenuiflora leaf and seed material, extracts of leaf and seed, alkaloid extracts of leaf and seed, and N-methyltryptamine and N,N-dimethyltryptamine. Pups from mothers who received M. tenuiflora plant material, methanol extracts, alkaloid extracts, and purified N-methyltryptamines had a higher incidence of soft tissue cleft palate and skeletal malformations. Results are summarized as to the frequency of observed cleft palate and other noted malformations for each diet versus control.

Teratogenicity of asbestos in mice.

Possible teratogenicity of 3 different asbestos (crocidolite, chrysotile and amosite) was assessed in CD1(ICR) mice. Dams on day 9 of gestation were given a single intraperitoneal administration at dose of 40 mg/kg body weight of asbestos suspended in 2% sodium carboxymethyl cellulose solution in phosphate buffered saline, while dams in the control group were given vehicle (10 ml/kg body weight). Dams and fetuses were examined on day 18 of gestation. To compare with the control group, the mean percentage of live fetuses in implantations in the group given crocidolite and the incidence of dams with early dead fetuses in the groups given chrysotile or amosite were increased. While no external or skeletal malformation was observed in the control group, the incidence of external malformation (mainly reduction deformity of limb) in the group given amosite, and the incidences of skeletal malformation (mainly fusion of vertebrae) in the all dosed groups were significantly increased. The result indicated that asbestos (crocidolite, chrysotile and amosite) have fetotoxicity and teratogenicity in mice.

Using zebrafish as a model system for studying the transgenerational effects of dioxin.

2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD) has been associated with many disease states in humans. A rising concern is that exposure early in life can lead to adult toxicity and toxicity in subsequent generations. Juvenile zebrafish exposed to TCDD (50 pg/ml in water; 1 h exposure) at 3 and 7 weeks post fertilization showed toxicity only later in adulthood. We have maintained the offspring of these exposed F0 fish to determine whether we could find adverse affects in the next two generations of F1 and F2 offspring. TCDD exposure produced a significantly higher female:male ratio in all three generations. Scoliosis-like axial skeleton abnormalities, not normally observed in controls, were present in the F1 and F2 generations descended from the treated F0 founders. Egg release and fertilization success were reduced in the TCDD lineage F1 and F2 generations. This reduction in fertility in the TCDD lineage F2 generation could be attributed to alterations in the F2 males. Using zebrafish as a model allowed the simultaneous maintenance of different generations with relatively small space and costs. The zebrafish showed clear signs of transgenerational responses persisting into generations never directly exposed to TCDD.

Effects of maternal administration of aluminum chloride on the development of the skeletal system of albino rat fetuses - protective role of saffron

Aluminum is widely used in food packaging and additives. Aluminum chloride (AlCl3) was known to cause maternal toxicity and embryolethality. Previous studies have demonstrated the antioxidant effects of saffron. The purpose of the present study was to assess the effect of maternal administration of aluminum chloride during the period of embryogenesis on the development of the skeletal system of albino rat fetuses and the protective role of saffron. Twenty four virgin female albino rats were used throughout this study. One male rat was introduced into a cage with two females for mating. Once the pregnancy was confirmed, pregnant rats were divided into the following groups: Control, AlCl3 treated (200 mg/kg) and AlCl3+S treated (AlCl3 200 mg/kg and saffron 200 mg/kg in water extract). Rats received treatments daily from the 6th to 15th day of gestation intragastrically and sacrificed on the 20th day. The fetuses were obtained through Caesarian section, stained with Alizarin red and examined for skeletal development. AlCl3 treated rats showed toxic manifestations and decreased weight gain and their fetuses revealed increased embryolethality and a higher number of bones showed delayed ossification. AlCl3 +S treated animals revealed improvement in maternal weight gain, embryolethality and bone ossification. We conclud that AlCl3 induces delay in bone development, and saffron ameliorates its effects (AU)

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Oral and dermal developmental toxicity studies of phenylethyl alcohol in rats.

Phenylethyl alcohol (PEA) was tested for developmental toxicity. Pregnant rats were fed 0, 83, 266, or 799 mg/kg/d PEA on gestation days (GDs) 6 to 15; only minimal, nonsignificant effects were observed. In dermal studies, PEA (neat) was applied to the skin on GDs 6 to 15 at dosages of 0, 140, 430, or 1400 mg/kg/d and at 0, 70, 140, 280, 430, or 700 mg/kg/d in a corroborative study. Observations included maternal and embryo-fetal toxicity/abnormalities at 1400 mg/kg/d, increased incidences of rudimentary cervical ribs at ≥430 mg/kg/d, and reduced fetal body weights at ≥140 mg/kg/d. Dermal maternal and developmental no-observed-adverse-effect levels are 70 mg/kg/d, based on dermal irritation and reductions (nonsignificant) in fetal body weights. Human exposure from fragrances is 0.02 mg/kg/d, resulting in a margin of safety >2600, when marked differences in dermal absorption between rats and humans are considered. Under normal fragrance use conditions, PEA is not a developmental toxicity hazard for humans.

Risk of congenital anomalies in relation to the uptake of trihalomethane from drinking water during pregnancy.

OBJECTIVES: Congenital anomalies have been inconsistently associated with maternal crude estimated exposure to drinking water trihalomethane (THM). We investigated the relationship between individual THM uptake during the first trimester of pregnancy and congenital anomalies. METHODS: We estimated maternal THM uptake for 3074 live births using residential tap water concentrations, drinking water ingestion, showering and bathing, and uptake factors of THM in the blood. Multiple logistic regression was used to investigate the association of THM exposure with congenital anomalies. RESULTS: We observed no statistically significant relationships between congenital anomalies and the total THM internal dose. We found little indication of a dose-response relationship for brominated THM and congenital heart anomalies. The relationship was statistically significant for bromodichloromethane (BDCM) (OR=2.16, 95% CI 1.05 to 4.46, highest vs lowest tertile) during the first month of pregnancy. During the first trimester of pregnancy, the probability of developing heart anomalies increased for every 0.1 µg/d increase in the BDCM and for every 0.01 µg/d increase in the internal dibromochloromethane (DBCM) dose (OR 1.70, 95% CI 1.09 to 2.66, and OR 1.25, 95% CI 1.01 to 1.54, respectively). A dose-response relationship was evident for musculoskeletal anomalies and DBCM exposure during the first and second months of pregnancy, while BDCM exposure tended to increase the risk of urogenital anomalies. CONCLUSIONS: This study shows some evidence for an association between the internal dose of THM and the risk of congenital anomalies. In particular, increased prenatal exposure to brominated THM might increase the risk of congenital heart and musculoskeletal anomalies.

Prenatal effects of natural calcium supplement on Wistar rats during organogenesis period of pregnancy.

The potential of oral exposure to calcium and magnesium citrate, a natural product obtained from dolomite, to initiate teratogenesis was analyzed in Wistar rats. Animals received calcium and magnesium citrate oral doses of 250, 500 and 1000 mg/kg during the period of gestation from day 6 to 17 post conception. Maternal, embryo and fetal toxicity was evaluated. Calcium and magnesium citrate exposure did not produce maternal toxicity assessed by clinical observations, body weight gain, food intake, hematology, biochemical parameters and necropsy finding. Signs of embryo-fetal toxicity were not observed. Skeletal and visceral malformations were seen occasionally in all drug-treated and control groups. Skeletal and visceral variations were similar in control and drug-treated groups except for incomplete ossification rib. These finding was spontaneous and unrelated to the drug. In conclusion, in this study we found that the oral exposure to rats of up to 1000 mg/kg of calcium and magnesium citrate during organogenesis did not induce significant maternal and embryo-fetal toxicity. The experimentally derived NOAEL for developmental toxicity was 1000 mg/kg.

Major malformations following exposure to nonsteroidal antiinflammatory drugs during the first trimester of pregnancy.

OBJECTIVE: Nonsteroidal antiinflammatory drugs (NSAID) are among the most common medicines used by pregnant women. Published data are controversial regarding fetal safety following intrauterine exposure to NSAID. We investigated exposure to NSAID in the first trimester in a large cohort of infants and fetuses. METHODS: A computerized database of medications dispensed from 1998 to 2009 to all women registered in the "Clalit" health maintenance organization in Southern Israel was linked with 2 computerized databases containing maternal and infant hospitalization records. Pregnancy terminations for medical reasons were analyzed. The following confounders were controlled for: parity, maternal age, ethnicity, maternal pregestational diabetes, maternal inflammatory disease, and year of birth or pregnancy termination. First trimester exposure to nonselective cyclooxygenase (COX) inhibitors and to selective COX-2 inhibitors as groups and to individual drugs was analyzed. RESULTS: There were 110,783 pregnancies during the study period: 109,544 singleton births and 1239 pregnancy terminations for medical reasons. In total, 5267 mothers were exposed to NSAID during the first trimester of pregnancy: 5153 to nonselective COX inhibitors and 114 to COX-2 selective inhibitors. Exposure to NSAID in the first trimester, as groups (nonselective COX and selective COX-2 inhibitors) and as individual drugs, was not associated with an increased risk of major congenital malformations in general (adjusted OR 1.07, 95% CI 0.96-1.21 for nonselective; and adjusted OR 1.40, 95% CI 0.70-2.78, for selective COX-2 inhibitors), although an increased risk for musculoskeletal malformations was found following exposure to COX-2 selective inhibitors (adjusted OR 3.39, 95% CI 1.37-8.34). CONCLUSION: Intrauterine exposure to NSAID was not associated with increased risk for major congenital malformations. Further studies are needed to assess the risk for malformations after exposure to COX-2 selective inhibitors.

Nitric oxide rescues thalidomide mediated teratogenicity.

Thalidomide, a sedative drug given to pregnant women, unfortunately caused limb deformities in thousands of babies. Recently the drug was revived because of its therapeutic potential; however the search is still ongoing for an antidote against thalidomide induced limb deformities. In the current study we found that nitric oxide (NO) rescues thalidomide affected chick (Gallus gallus) and zebrafish (Danio rerio) embryos. This study confirms that NO reduced the number of thalidomide mediated limb deformities by 94% and 80% in chick and zebrafish embryos respectively. NO prevents limb deformities by promoting angiogenesis, reducing oxidative stress and inactivating caspase-3 dependent apoptosis. We conclude that NO secures angiogenesis in the thalidomide treated embryos to protect them from deformities.

Carpal tunnel syndrome and musculoskeletal symptoms in postmenopausal women with early breast cancer treated with exemestane or tamoxifen after 2-3 years of tamoxifen: a retrospective analysis of the Intergroup Exemestane Study.

BACKGROUND: Aromatase inhibitors are more effective than is tamoxifen in prevention of breast-cancer recurrence, but at the expense of increased musculoskeletal side-effects, such as carpal tunnel syndrome. The aim of this study was to assess risk factors and the prognostic value of musculoskeletal symptoms during treatment with the steroidal aromatase inhibitor exemestane or with tamoxifen after 2-3 years of tamoxifen. METHODS: In the Intergroup Exemestane Study, postmenopausal women treated for early invasive breast cancer who remained disease free and on treatment after 2-3 years of tamoxifen were randomised to switch to exemestane or to continue tamoxifen for the remainder of the 5-year period of endocrine treatment. The primary endpoint for this retrospective analysis was occurrence of carpal tunnel syndrome and any musculoskeletal events, analysed in the safety population, which consisted of all patients who had received any trial treatment. As well as case-report forms, questionnaires were distributed retrospectively to gain more details of cases of carpal tunnel syndrome. The relation between musculoskeletal symptoms reported by 6 months from randomisation and survival from 9 months onwards was assessed by Cox proportional hazards models. The trial is registered, number ISRCTN11883920. It has completed accrual and follow-up is continuing for enrolled participants. FINDINGS: After a median follow-up of 91·0 months (IQR 83·0-99·2), carpal tunnel syndrome had been reported for 66 (2·8%) of 2319 patients in the exemestane group compared with 13 (0·6%) of 2338 in the tamoxifen group (odds ratio [OR] 5·23, 99% CI 2·39-11·49; p<0·0001). More events occurred during treatment in the exemestane group than in the tamoxifen group (66 [2·8%] vs seven [0·3%], adjusted OR 9·90, 99% CI 3·52-27·82; p<0·0001). There was no significant difference between groups in events in the post-treatment period (ten with exemestane [0·4%] vs seven with tamoxifen [0·3%]; p=0·46). More patients in the exemestane group (1082 of 2319 patients, 46·7%) had musculoskeletal symptoms than in the tamoxifen group (901 of 2338, 38·5%; OR 1·48, 99% CI 1·32-1·67, p<0·0001). More events occurred during treatment in the exemestane group than in the tamoxifen group (984 [42·4%] vs 776 [33·2%], adjusted OR 1·59, 99% CI 1·32-1·91; p<0·0001), with this difference persisting to some extent in the post-treatment period (449 [19·4%] vs 390 [16·7%]; p=0·017). Of 73 on-treatment cases of carpal tunnel syndrome, 58 (79·5%) completed questionnaires were available. 27 patients (46·6%) had bilateral carpal tunnel syndrome and 31 (53·4%) had unilateral disease; 40 (69·0%) underwent surgical release. The disorder greatly affected daily-life activities in 21 (36·2%) cases. Occurrence of musculoskeletal symptoms, including carpal tunnel syndrome, was associated with improved disease-free survival in unadjusted analysis (p=0·023), but not with overall survival (p=0·36). However, after adjustment for possible confounding factors, musculoskeletal symptoms were not associated with disease-free survival (hazard ratio [HR] 0·96, 95% CI 0·82-1·14, p=0·67) or overall survival (HR 1·02, 95% CI 0·84-1·25, p=0·82). INTERPRETATION: Occurrence of carpal tunnel syndrome is higher in patients with breast cancer given exemestane than in those treated with tamoxifen, and surgical release might be necessary in most cases. Development of musculoskeletal symptoms in the first 6 months of treatment is not an independent biomarker of improved disease outcome. Further investigation is warranted into the relation between treatment-emergent musculoskeletal symptoms and clinical outcome in patients with breast cancer receiving hormonal therapy. FUNDING: Pfizer.

TCDD disrupts hypural skeletogenesis during medaka embryonic development.

Defective bone and cartilage development account for a large number of human birth defects annually. Normal skeletogenesis involves cartilage development in early morphogenesis through a highly coordinated and orchestrated series of events involving commitment and differentiation of mesenchymal cells to chondrocytes followed by a highly programmed process of structural maturation. Recent developmental studies with laboratory model fish demonstrate that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in cartilage and skeletal abnormalities. In this study, we exposed embryonic medaka to TCDD to induce developmental modification(s) of both cartilage and bone formation. Emphasis is placed on cell-rich hyaline cartilage of the hypural plate where both chondrogenesis and osteogenesis are impaired by TCDD exposure. In this model, TCDD exposure results in a concentration-dependent impairment of mesenchymal cell recruitment, chondrocyte cell proliferation, differentiation, and progression to hypertrophy. Gene expression of ColA2, a marker of chondrocyte terminal differentiation in hypural structures, is markedly attenuated consistent with hypural dysmorphogenesis. Assessment of hypural structure using a transgenic medaka expressing mCherry under control of the osterix promoter illustrated significant attenuation in expression of the osteoblast gene marker and lack of formation of a calcified perichondral sheath surrounding hypural anlage. Overall, these studies illustrate that TCDD impacts terminal differentiation and growth of cartilage and bone in axial structures not likely derived from neural crest progenitors in medaka hypurals.

Impact of strontium on skeletal deformities in Baltic cod (Gadus morhua callaris L.).

A study was conducted to examine spinal deformities such as lordosis, scoliosis, and dwarfism in cod (Gadus morhua callaris L.) that were caught in the southern Baltic. The bone tissue of the spine and the muscle of the deformed cod were analyzed for concentration of macroelements (Sr, Ca and P) and toxic metals (Cd, Pb and Hg). Healthy specimens of the same body length that were caught in the same hauls were also tested, and these comprised the reference material. The study was undertaken to verify the hypothesis that lowered values of Ca/Sr and P/Sr ratios caused skeletal deformities. Toxic metals were also tested to determine whether they had an impact on the deformities of cod inhabiting Baltic waters. In cod with deformities, a significant decrease in Ca/Sr ratios were noted in 86% of the spine and 97% of the muscle. Decreases in the values of the P/Sr ratios were confirmed in 57% of the bone tissue and 78% of the muscle tissue of individuals with skeletal deformities. Toxic metals (Cd, Pb and Hg) occurred in the bone and muscle tissues of deformed and healthy cod on the low levels. It was not differences in concentrations of these elements, and thus could not have had an impact on the occurrence of deformities. Skeletal deformities could have resulted from lowered values of the Ca/Sr and P/Sr ratios of the spinal bone and muscle tissues of cod. Lower values of these coefficients should be linked to the varied salinity (5-21‰) and strontium (5-15Bqm(-3)) concentrations of Baltic waters.

The impact of dose rate on ethylene glycol developmental toxicity and pharmacokinetics in pregnant CD rats.

High-dose bolus exposure of rats to ethylene glycol (EG) causes developmental toxicity mediated by a metabolite, glycolic acid (GA), whose levels increase disproportionately when its metabolism is saturated. However, low-level exposures that do not saturate GA metabolism have a low potential for developmental effects. Toward the goal of developing EG risk assessments based on internal dose metrics, this study examined the differences between fast (bolus) and slow (continuous infusion) dose-rate exposures to EG on developmental outcome and pharmacokinetics. Time-mated female CD rats received sc bolus injections of 0, 1000, or 2000 mg/kg/day of EG on gestation day (GD) 6-15 once daily, whereas three corresponding groups were given the same daily doses as an infusion administered continuously from GD 6-15 via an sc implantable pump. In the sc bolus groups, increases in 11 fetal malformations (major defects) and 12 variations (minor alterations) were seen at the 2000 mg/kg/day dose level, whereas increases in 2 malformations and 2 variations occurred at 1000 mg/kg/day. In contrast, equivalent daily doses of EG given slowly via infusion did not cause any developmental effects. A pharmacokinetics time course was then conducted to compare GD 11-12 kinetics from oral bolus (gavage) exposure versus sc infusion of EG. Although dose rate had a modest impact (8- to 11-fold difference) on peak EG levels, peak levels of GA in maternal blood, kidney, embryo, and exocoelomic fluid were 59, 100, 49, and 56 times higher, respectively, following gavage versus the same dose given by infusion. These data illustrate how high-dose bolus exposure to EG causes a dramatic shift to nonlinear GA kinetics, an event which is highly unlikely to occur following exposures to humans associated with consumer and worker uses.