Molecular dynamics of the compensatory response to myocardial infarct.

Myocardial infarct via occlusion of the left anterior descending coronary in rats caused overriding depression in transcription, signal transduction, inflammation and extracellular matrix pathways in the infarct zone within 24 h. In contrast, remote zone gene expression was reciprocally activated during the immediate post-infarct period. Infarct zone signal transduction occurred primarily through TGFbeta1 induction while the remote zone exhibited elevated WNT, NOTCH, GPCR and transmembrane signaling. A minimal day 1 acute phase, inflammatory response was detected in the infarct zone while interleukins (IL1alpha, IL1beta, IL6, IL12alpha, IL18) and the TNFalpha superfamily were activated in the remote zone. Different cytochrome subsets were activated in each left ventricular region on day 1 while anti-oxidant genes were elevated only in the remote zone. The infarct zone exhibited mixed early transcription factor activation across all binding domains with a balance favoring constitutive gene activation and differentiation pathways as opposed to cell proliferation. In contrast, the remote zone exhibited activation of extensive developmental transcription factors involved in specification of cell phenotype, tissue-specific interactions and position-specific cell proliferation on day 1. The day 28 infarct zone response mirrored the day 1 remote zone response including activation of genes associated with matrix remodeling (metallothionein and metalloproteinase 9, 12, 23), as well as genes associated with cell proliferation and phenotype specification (MYC, EGR2, ATF3, HOXA1) recapitulating developmental histogenesis programs.

Prediction of ice skating performance with off-ice testing in women's ice hockey players.

Off-ice predictors of skating performance have not been investigated for women's hockey players. The purpose of this study was to identify the off-ice variables associated with high-performance skating acceleration, speed, agility, and on-ice anaerobic capacity and power in women's ice hockey players. Sixty-one women's ice hockey players between the ages of 8 and 16 years (x age = 12.18 +/- 2.05 years, x playing experience = 4.68 +/- 2.69 years) participated in the study. Subjects were 1-4 months postseason. Some players were continuing to play once per week during the off-season. Skating tests (ST) included (a) 6.10-m acceleration, (b) 47.85-m speed, (c) agility cornering S turn, and (d) modified repeat skate test (MRS). Two trials of each ST were measured with a photoelectric timing system (except MRS, which was measured with 1 trial). The off-ice variables that were evaluated included age, years of playing experience, height, body mass, predicted fat percentage, sit-and-reach flexibility, vertical jump height, 40-yd dash time, and 1-minute timed sit-ups and push-ups. The results of this study show that 40-yd dash time is the strongest predictor of skating speed in women's hockey players ages 8-16 years old. From the regression procedure the best prediction equation was speed = 4.913 - (0.0107 x kilograms) + (0.4356 x 40-yd dash time).

Stroke volume does not plateau during graded exercise in elite male distance runners.

UNLABELLED: Stroke volume (SV) responses during graded treadmill exercise were studied in 1) elite male distance runners (N = 5), 2) male university distance runners (N = 10), and 3) male untrained university students (N = 10). METHODS: Cardiac output (Q) and SV were determined by a modified acetylene rebreathing procedure. RESULTS: There were no differences in SV responses among the three groups during the transition from rest to light exercise (P > 0.05). However, the rates of change of SV during light to maximal exercise in untrained subjects (slope = -0.1544 mL x beat(-1)) and university distance runners (slope = 0.1041) did not change, whereas it dramatically increased (P < 0.001) in elite distant runners (slope = 0.6734). Moreover, the elite distance runners showed a further slope increase in SV when heart rate was above 160 bpm, which resulted in an average maximal SV of 187 +/- 14 mL x beat(-1) compared with 145 +/- 8 and 128 +/- 14 mL x beat(-1) in the university runners and untrained students, respectively (P < 0.001). Similarly, max Q reached 33.8 +/- 2.3, 26.3 +/- 1.7, and 21.3 +/- 1.5 L x min(-1) in the three groups, respectively (P < 0.001). On the other hand, there was a nonsignificant tendency for maximal arteriovenous oxygen content difference to be lower in the elite athletes compared with the other groups. CONCLUSION: Results from university distance runners and untrained university students support the classic observation that SV plateaus at about 40% of maximal oxygen consumption despite increasing intensity of exercise. In contrast, stroke volume in the elite athletes does not plateau but increases continuously with increasing intensity of exercise over the full range of the incremental exercise test.

Developmental toxicity evaluation of 1,2,3,4-butanetetracarboxylic acid in Sprague Dawley (CD) rats.

1,2,3,4-butanetetracarboxylic acid (BTCA), proposed as a formaldehyde substitute in the treatment of permanent press fabrics, was evaluated for developmental toxicity. Timed-mated CD rats (25 per group) received BTCA 250, 500, or 1000 mg/kg/day or vehicle (deionized/distilled water) by gavage on gestational days (gd) 6 through 19. Maternal feed and water consumption, body weight, and clinical signs were monitored throughout gestation. At termination (gd 20), confirmed-pregnant females (21 to 25 per group) were evaluated for clinical status and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations. One maternal death, reduced body weight, and reduced weight gain were noted at the high dose; confirmed pregnancy rates were 84 to 100% for each group. There were no treatment-related effects on fetal growth, survival, or morphologic development. The maternal toxicity NOAEL and LOAEL are 500 and 1000 mg/kg/day, respectively. The developmental toxicity NOAEL is > or = 1000 mg/kg/day, and the LOAEL was not established in this study.

Evaluation of the developmental toxicity of isoeugenol in Sprague-Dawley (CD) rats.

Isoeugenol, used as a perfumery and flavoring agent, was evaluated for developmental toxicity. Timed-pregnant CD((R)) outbred albino Sprague-Dawley rats received isoeugenol (250, 500, or 1000 mg/kg/day) or vehicle (5 ml/kg corn oil) by gavage on gestational days (gd) 6 through 19. Maternal food and water consumption, body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20), confirmed-pregnant females (23-25 per group) were evaluated for gestational outcome. All live fetuses were weighed and examined for external malformations, and approximately 50% were evaluated for visceral or skeletal malformations. There were no treatment-related maternal deaths. Clinical signs associated with isoeugenol exposure included dose-related evidence of sedation and aversion to treatment (rooting behavior) in all isoeugenol groups, as well as an increased incidence of piloerection at >/= 500 mg/kg/day. Maternal body weight, weight gain, and gestational weight gain (corrected for gravid uterine weight) were reduced at all doses in a dose-related manner. Gravid uterine weight was significantly decreased at the mid and high doses, whereas maternal relative liver weight was increased at all three dose levels. During treatment (gd 6 to 20), maternal relative food consumption was significantly decreased at the high dose, and maternal relative water consumption was elevated in the mid- and high-dose groups. Prenatal mortality (resorption or late fetal death) was unaffected. At 1000 mg/kg/day, average fetal body weight/litter was decreased by 7% (male) or 9% (female). Incidences of fetal morphological anomalies were statistically equivalent among groups, except for an increase in the incidence of unossified sternebra(e), a skeletal variation, at the high dose. In summary, the maternal toxicity lowest observed adverse effect level (LOAEL) was 250 mg/kg/day based primarily on reduced body weight and gestational weight gain (corrected for gravid uterine weight), and the maternal toxicity no observed adverse effect level (NOAEL) was not determined in this study. The developmental toxicity LOAEL was 1000 mg/kg/day based on intrauterine growth retardation and mildly delayed skeletal ossification. The developmental toxicity NOAEL was 500 mg/kg/day.

Evaluation of the developmental toxicity of formamide in Sprague-Dawley (CD) rats.

Timed-pregnant CD(R) outbred albino Sprague-Dawley rats received formamide (50, 100, or 200 mg/kg/day) or vehicle (5 ml/kg deionized/distilled water, po) on gestational days (gd) 6 through 19. Maternal food and water consumption (absolute and relative), body weight, and clinical signs were monitored at regular intervals throughout gestation. At termination (gd 20), confirmed-pregnant females (21-23 per group) were evaluated for clinical status and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations and variations. There were no maternal deaths and no dose-related clinical signs. At 200 mg/kg/day, maternal body weight on gd 20, weight gain, and gravid uterine weight were significantly decreased. Maternal weight gain, corrected for gravid uterine weight, liver weight (absolute or relative), and food and water consumption (absolute or relative), were not affected. Formamide did not affect prenatal viability or incidences of fetal malformations or variations. Average fetal body weight/litter was decreased at 100 and 200 mg/kg/day. Fetal body weight was affected at lower daily doses than in previously published studies, possibly due to the longer total exposure period and/or lack of a recovery period between cessation of exposure and termination. In summary, the maternal toxicity no-observed-adverse-effect level (NOAEL) was 100 mg/kg/day and the low observed adverse effect level (LOAEL) was 200 mg/kg/day under the conditions of this study. Similarly, the developmental toxicity NOAEL was 50 mg/kg/day and the LOAEL was 100 mg/kg/day.

Coincident resection-recession (tenectomy-recession) of the medial rectus muscle, bilaterally, for the treatment of esotropia: results in 18 cases.

PURPOSE: To study the effect of preceding tenectomy of the medial rectus tendon on the results of medial rectus muscle recession. SUBJECTS AND METHODS: Eighteen consecutive cases of incomitant esotropia were retrospectively reviewed. The average preoperative esotropia was 35 PD with an incomitant deviation between 10 PD and 30 PD. All patients underwent 7 mm bilateral medial rectus muscle recession after 4 mm tenectomy of the anterior medial rectus muscle. RESULTS: Fourteen patients (78%) had "satisfactory" results (within 10 PD static esodeviation and 12 PD dynamic deviation [incomitance]). Four (22%) were undercorrected. One showed a postoperative consecutive exotropia of 4 PD at distance only. CONCLUSIONS: Tenectomy of the anterior muscle tendon preceding large recessions of the medial rectus was effective in reducing the frequency of overcorrection (consecutive exotropia). Undercorrection did not appear to be more common.

Formamide and dimethylformamide: reproductive assessment by continuous breeding in mice.

Reproductive toxicity in Swiss mice, during chronic exposure to formamide (FORM) or dimethylformamide (DMF), was evaluated using the Reproductive Assessment by Continuous Breeding Protocols. FORM administered in drinking water at 0, 100, 350, and 750 ppm (approximately 20 to 200 mg/kg/d) reduced fertility and litter size in F0 animals without generalized toxicity at 750 ppm FORM. Crossover matings suggested that females were the affected sex. After F1 mating, FORM reduced F2 litter size, increased days to litter, reduced relative ovarian weight, and lengthened estrous cycles at 750 ppm. The No-Observed-Adverse-Effect-Level for generalized toxicity was 750 ppm for the F0 and 350 ppm for the F1 generation. Reproductive performance was normal at 350 ppm for both F0 and F1 mice. Chronic exposure to DMF in drinking water at 0, 1000, 4000, and 7000 ppm (approximately 200 to 1300 mg/kg/d) reduced fertility by the first litter at 4000 ppm, reduced body weight in F0 females at 7000 ppm, and increased liver weights at all doses in both sexes. A crossover mating at 7000 ppm identified F0 females as the affected sex. F1 postnatal survival was reduced at > or =4000 ppm DMF. F1 mating reduced F2 litter size and live pup weight at > or =1000 ppm. At necropsy, body weight of F1 males and females was reduced at > or =4000 ppm. DMF-treated pups (both F1 and F2) and F1 adults had cranial and sternebral skeletal malformations. Only DMF caused overt developmental toxicity. A No-Observed-Adverse-Effect-Level for DMF was not established.

Evaluation of the developmental toxicity of methacrylamide and N,N'-methylenebisacrylamide in Swiss mice.

Timed-pregnant CD-1 outbred albino Swiss mice received either methacrylamide (MAC; 0, 60, 120, or 180 mg/kg/day) or N,N'-methylenebisacrylamide (BAC; 0, 3, 10, or 30 mg/kg/day) p.o. in distilled water on gestational days (GD) 6 through 17. Maternal clinical status was monitored daily. At termination (GD 17), confirmed-pregnant females (27-30 per group, MAC; 24-25 per group, BAC) were evaluated for clinical status and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations. For MAC, no treatment-related maternal mortality was observed. Maternal body weight on GD 17, maternal weight gain during treatment and gestation, and corrected maternal weight gain were reduced at the high dose. Relative maternal food and water intake was not adversely affected; neurotoxicity was not observed. Relative maternal liver weight was increased at > or = 120 mg/kg/day; gravid uterine weight was decreased at 180 mg/kg/day. The maternal no-observed adverse effect level (NOAEL) was 60 mg/kg/day. The NOAEL for developmental toxicity was also 60 mg/kg/day. At > or = 120 mg/kg/day, mean fetal body weight was reduced. At 180 mg/kg/day, increased postimplantation death per litter was observed. Morphological development was not affected. The maternal NOAEL for BAC was 10 mg/kg/day. At 30 mg/kg/day, decreased maternal body weight on GD 17, maternal body weight change during treatment and gestation, corrected maternal body weight, and gravid uterine weight were observed. Relative maternal liver weight increased at 30 mg/kg/day. The developmental NOAEL was 3 mg/kg/day BAC. Mean fetal body weight was reduced at 30 mg/kg/day. At > or = 10 mg/kg/day, an increased incidence of fetal variations (extra rib) was observed, although fetal malformation rate was unaffected. MAC and BAC were not teratogenic to Swiss mice at the doses tested. BAC was more potent than MAC in causing adverse maternal and developmental effects.

Non-exercise VO2max estimation for physically active college students.

This study sought to develop a maximal oxygen consumption (VO2max) regression model derived strictly from self-reported non-exercise (N-EX) predictor variables. The VO2max (mean +/- SD; 44.05 +/- 6.6 ml.kg-1.min-1) of 100 physically active college students (50 females, 50 males), aged 18 to 29 yr, was measured using a treadmill protocol and open circuit calorimetry. Questionnaire-based predictor variables used in the N-EX regression model included (a) the subject's perceived functional ability (PFA) to walk, jog, or run given distances, (b) habitual physical activity (PA-R) data, (c) body mass index (BMI), and (d) gender. BMI (kg.m-2) was computed from self-reported body weight in pounds and self-reported body height in feet and inches. The questionnaire-based N-EX regression model (R = 0.85, SEE = 3.44 ml.kg-1.min-1) developed in this study exceeded the accuracy of previously developed N-EX regression models and is comparable to many exercise-based regression models in the literature. Cross-validation using PRESS (predicted residual sum of squares) statistics demonstrated minimal shrinkage (R = 0.84, SEE = 3.60 ml.kg-1.min-1) of the present regression model. The PFA data were useful in explaining observed VO2max variance (squared partial r2 = 0.155, P < 0.0001) and enhanced the ability of the N-EX regression model to accurately predict criterion VO2max. These results suggest that a questionnaire-based N-EX regression model provides a valid and convenient method for predicting VO2max in physically active college students.

Evaluation of the developmental toxicity of methacrylonitrile in Sprague-Dawley rats and New Zealand white rabbits.

Timed-pregnant Sprague-Dawley (CD) outbred rats and New Zealand White rabbits were dosed by gavage with methacrylonitrile (MACR) in distilled water during major organogenesis. Rats were dosed on Gestational Days (GD) 6 through 15 (0, 5, 25, or 50 mg MACR/kg/day) and rabbits on GD 6 through 19 (0, 1, 3, or 5 mg MACR/kg/day). Maternal clinical status was monitored daily during treatment. At termination (GD 20, rats; GD 30, rabbits), confirmed-pregnant females (25-26 per group, rats; 17-22 per group, rabbits) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In rats, no treatment-related maternal clinical signs or mortality were observed, nor was there any adverse effect on maternal body weight or food or water consumption. At necropsy, absolute, relative, and adjusted maternal liver weight was increased at the mid- and high-dose groups, an effect that may be indicative of induction of hepatic enzymes rather than toxicity. In the absence of any indication of maternal toxicity, the no-observed-adverse-effect level (NOAEL) for maternal toxicity in this study was >/=50 mg MACR/kg/day. The NOAEL for developmental toxicity in rats was also >/=50 mg MACR/kg/day. There was no effect of treatment on postimplantation loss, mean fetal body weight per litter, or morphological development. In rabbits, maternal mortality and clinical signs were not dose related. Maternal food consumption, body weight, and liver weight were not adversely affected by treatment. Thus, the maternal NOAEL was >/=5 mg MACR/kg/day. Maternal toxicity, including death, was observed >/=7.5 mg/kg/day in preliminary studies. The developmental NOAEL was also >/=5 mg MACR/kg/day. There was no adverse effect of treatment on postimplantation loss or fetal body weight. A significant decrease in the percentage male fetuses per litter was observed, although there was no effect on total live litter size, suggesting that the reduction in the ratio of live male fetuses in the high-dose group was not biologically significant. MACR had no adverse effect on morphological development. In summary, oral administration of MACR to rats and rabbits during organogenesis, at doses that did not cause persistent maternal toxicity (50 mg MACR/kg/day, rats; 5 mg MACR/kg/day, rabbits), also did not cause any adverse developmental effects.

Nitrofurazone: reproductive assessment by continuous breeding in Swiss mice.

Nitrofurazone (NTFZ), a nitrofuran antibiotic, was evaluated for reproductive toxicity in Swiss CD-1 mice using the Reproductive Assessment by Continuous Breeding protocol. Male and female mice were cohabited for 15 weeks and exposed to NTFZ in feed at concentrations of 0, 100, 375, and 750 ppm (14-102 mg/kg/day). Fzero 750-ppm breeding pairs had significantly reduced fertility after 7 days of exposure to NTFZ (17% fertile compared to 98% for control pairs) and were infertile after the second litter. Fzero mid-dose pairs had progressively decreasing fertility (47% by the fifth litter), reduced litter size, and reduced proportion of pups born alive. Crossover breeding of control and high-dose Fzero animals confirmed infertility in high-dose males and reduced litter size and pup weight in high-dose females when compared to the control x control group. At necropsy, there were no effects on body weight, but Fzero males had reduced testis weight at the high dose and reduced epididymal sperm concentration and abnormal sperm morphology at all doses of NTFZ. Increased liver as well as kidney and adrenal weights (combined) were observed at 375 and 750 ppm; hepatic hypertrophy was noted microscopically at 750 ppm. Fzero females had reduced body weight, hepatic hypertrophy, and altered estrous cycles at 750 ppm and reduced ovarian weight at all doses. In the second generation, F1 mice at 375 ppm had reduced postnatal survival and body weight and produced smaller F2 litters compared to control mice. At necropsy, F1 males had reduced testes weight and epididymal sperm concentration, abnormal sperm morphology, hepatic hypertrophy at 375 ppm, and borderline nephropathy at 100 and 375 ppm. F1 females had decreased body, liver, and ovarian weight at 375 ppm and altered estrous cycles at 100 and 375 ppm. Thus, NTFZ at > or = 100 ppm (> or = 14 mg/kg/day) caused adverse reproductive effects in Fzero male and female and F1 female mice in the presence of relatively mild systemic toxicity.

ATSDR evaluation of health effects of chemicals. IV. Polycyclic aromatic hydrocarbons (PAHs): understanding a complex problem.

Polycyclic Aromatic Hydrocarbons (PAHs) are a group of chemicals that are formed during the incomplete burning of coal, oil, gas, wood, garbage, or other organic substances, such as tobacco and charbroiled meat. There are more than 100 PAHs. PAHs generally occur as complex mixtures (for example, as part of products such as soot), not as single compounds. PAHs are found throughout the environment in the air, water, and soil. As part of its mandate, the Agency for Toxic Substances and Disease Registry (ATSDR) prepares toxicological profiles on hazardous chemicals, including PAHs (ATSDR, 1995), found at facilities on the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) National Priorities List (NPL) and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). These profiles include information on health effects of chemicals from different routes and durations of exposure, their potential for exposure, regulations and advisories, and the adequacy of the existing database. Assessing the health effects of PAHs is a major challenge because environmental exposures to these chemicals are usually to complex mixtures of PAHs with other chemicals. The biological consequences of human exposure to mixtures of PAHs depend on the toxicity, carcinogenic and noncarcinogenic, of the individual components of the mixture, the types of interactions among them, and confounding factors that are not thoroughly understood. Also identified are components of exposure and health effects research needed on PAHs that will allow estimation of realistic human health risks posed by exposures to PAHs. The exposure assessment component of research should focus on (1) development of reliable analytical methods for the determination of bioavailable PAHs following ingestion, (2) estimation of bioavailable PAHs from environmental media, particularly the determination of particle-bound PAHs, (3) data on ambient levels of PAHs metabolites in tissues/fluids of control populations, and (4) the need for a critical evaluation of current levels of PAHs found in environmental media including data from hazardous waste sites. The health effects component should focus on obtaining information on (1) the health effects of mixtures of PAHs particularly their noncarcinogenic effects in humans, and (2) their toxicokinetics. This report provides excerpts from the toxicological profile of PAHs (ATSDR, 1995) that contains more detailed information.

Navy review of nasopharyngeal radium treatments of submarine candidates.

From approximately 1945 through 1960 nasopharyngeal radium treatments were used to treat barotrauma incurred during submarine escape training by submarine candidates. Concern has been expressed that the treatments placed submarine candidates at significantly increased risk of having brain cancer develop. The concern is based on brain cancer incidence rates reported in a study of Washington County children. Using comparable populations' risk coefficients and secondary brain tumor incidence rates, the excess number of brain cancers per 10,000 subjects during the 42.5 years after treatment was calculated to be 0.5 to 2.8 cases and 1 case, respectively. Personnel records of a sample of those treated and others whose treatment status was unknown were reviewed to determine the feasibility of an epidemiologic study to confirm the cancer risk. The records indicated treatments were not consistently documented to confirm who was treated. In addition, social security numbers are not known to aid in determination of vital status. In conclusion, nasopharyngeal irradiation does not appear to pose a significant risk to submariners, and it is not feasible to use the submariner population to do a meaningful epidemiologic study to clarify the cancer risk.

The reproductive and neural toxicities of acrylamide and three analogues in Swiss mice, evaluated using the continuous breeding protocol.

Acrylamide is a known genetic, reproductive, and neural toxicant, although it is not known if one effect is predominant. The toxicities of several structural analogues of acrylamide have been incompletely characterized, and the relative sensitivity of the second generation is not known. The present studies were designed to explore the relationship between neurotoxicity and reproductive toxicity, to further characterize the toxicities of three acrylamide analogues, and to evaluate the relative sensitivity of a second generation to these compounds. For the F0 generation, male and female Swiss CD-1 mice were provided drinking water containing acrylamide (ACR; 3, 10, 30 ppm), N,N'-methylenebisacrylamide (MBA; 10, 30, 60 ppm), N-(hydroxymethyl)acrylamide (HMA; 60, 180, 360 ppm), or methacrylamide (MACR; 24, 80, 240 ppm) during and after a 14-week cohabitation. The last litter was reared and dosed after weaning until mating at 74 +/- 10 days of age with the same level of compound given to the parents Neurotoxicity was assessed at several times in both generations by measuring forelimb and hindlimb grip strength. In the F0 generation, ACR caused an 11% decrease in pup number without measurable neurotoxicity; female fertility was not affected. Although both generations consumed the same amount of ACR, there were larger changes in the fertility-related endpoints in the F1 mice than in the F0's, with no concomitant change in organ weights or sperm parameters. In F0 mice, MBA reduced the number of live pups and their adjusted weight, with no neurotoxicity and no change in F0 female reproduction. MBA caused greater adverse effects in the second generation, concomitant with increased consumption. In the F0 generation, HMA caused the largest decrease in pup number during cohabitation (26%) together with a small effect on grip strength. Female reproduction was not affected. The second generation consumed more HMA and showed slightly greater toxic effects. In both generations, MACR was negative for both neurotoxicity and reproductive toxicity. Dominant-lethal studies showed that the fertility effects for ACR, MBA, and HMA could be explained by a male-mediated increase in postimplantation loss. These studies found that dominant lethality occurred without structural effects on the reproductive system in the presence of only minor effects on grip strength and without detectable neural histopathology. Female reproduction was not significantly affected by these compounds at the doses used. Thus, these data confirm the male as the affected gender and that the reproductive toxicity was greater than motoneuron toxicity when measured as grip strength.

The evaluation of the developmental toxicity of hydrochlorothiazide in mice and rats.

Timed-pregnant CD-1 outbred albino Swiss mice and CD Sprague-Dawley rats were administered hydrochlorothiazide (HCTZ, USP) in corn oil by gavage during major organogenesis, Gestational Days (GD) 6 through 15. The doses administered were 0, 300, 1000, or 3000 mg/kg/day for mice and 0, 100, 300, or 1,000 mg/kg/day for rats. Maternal clinical status was monitored daily during treatment. At termination (GD 17, mice; GD 20, rats), confirmed pregnant females (20-27 per group, mice; 36-39 per group, rats) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In mice, no maternal mortality was observed. However, clinical signs including dehydration, piloerection, lethargy, and single-day weight loss appeared to be dose-related. HCTZ had no effect on maternal weight gain or water consumption, gravid uterine weight, relative maternal liver weight, or relative maternal kidney weight. There was no definitive evidence of embryotoxicity or fetal toxicity for mice on GD 17. Thus, the no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was 3000 mg/kg/day. In rats, HCTZ had no effect on maternal survival, clinical signs, or water consumption. Clinical signs were not dose-related. Maternal weight gain during treatment was depressed at 1000 mg/kg/day. Gravid uterine weight and relative maternal liver weight were unaffected. Relative maternal kidney weight was slightly (7-8%) increased at all dose levels, but there was no evidence of a dose response. Thus, the maternal NOAEL for rats was 300 mg/kg/day, based on decreased maternal weight gain during treatment at 1000 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Carisoprodol: reproductive assessment by continuous breeding in Swiss mice.

Carisoprodol (CARI), a commonly prescribed neuromuscular relaxant, was evaluated for reproductive toxicity in Swiss CD-1 mice using the Reproductive Assessment by Continuous Breeding (RACB) protocol. Male and female mice were given CARI in corn oil suspension by daily gavage at doses of 0, 300, 750, and 1200 mg/kg body wt/day. Clinical signs of general toxicity in F0 animals included sedation, primarily in the high-dose group during the first week of exposure, and reduced body weight in high-dose females. CARI administration for 14 weeks did not affect the ability of the F0 animals to produce litters. However, decreases in proportion of pups born alive (4%) and absolute (5%) and adjusted live pup weight (7%) were observed at 1200 mg/kg CARI when compared to controls. In a crossover mating trial to determine the affected sex, there were no significant differences in the measured reproductive parameters. CARI at the high dose increased the proportion of time spent in proestrus and estrus, but cycle length was unaffected. At F0 necropsy (Week 27 of treatment), all sperm parameters were normal. Right epididymis and liver weights, relative to body weight, were increased (12 and 23%, respectively) over the control group for high-dose males. A mating trial to determine the fertility and reproductive competence of the F1 generation showed no effect of CARI on indices of mating, pregnancy, or fertility, the proportion of F2 pups born alive, the sex ratio of live F2 pups, live F2 pup weight, or gestation length.(ABSTRACT TRUNCATED AT 250 WORDS)