Refining the Effects Observed in a Developmental Neurobehavioral Study of Ammonium Perchlorate Administered Orally in Drinking Water to Rats. I. Thyroid and Reproductive Effects

2005 ◽  
Vol 24 (6) ◽  
pp. 403-418 ◽  
Author(s):  
Raymond G. York ◽  
Elise Lewis ◽  
W. Ray Brown ◽  
Michael F. Girard ◽  
David R. Mattie ◽  
...  
Keyword(s):  
Drinking Water ◽  
Ammonium Perchlorate ◽  
Thyroid Stimulating Hormone ◽  
Gestation Length ◽  
Sprague Dawley ◽  
Cell Hyperplasia ◽  
Sprague Dawley Rats ◽  
Adaptive Effect ◽  
Effect Level ◽  
Maternal Thyroid

A recent study further investigated the potential effects of maternal thyroid function and morphology on fetal development upon maternal exposure to ammonium perchlorate during gestation and lactation. Female Sprague-Dawley rats (25/group) were given continual access to 0 (carrier), 0.01, 0.1, 1.0, and 30.0 mg/kg-day perchlorate in drinking water beginning 2 weeks prior to cohabitation through lactation day 10. Maternal, fetal, and pup serum thyroid hormone (thyroid-stimulating hormone [TSH], triiodo thyronine [T3], thyroxine [T4]) levels and thyroid histopathology were evaluated on gestation day 21, and lactation days 5, 10, and 22. No effects of exposure were observed on cesarean-sectioning, litter parameters, or fetal alterations. Reproductive parameters, including gestation length, number of implants, litter size, pup viability, and lactation indices, were comparable among all groups. Thyroid weights of dams sacrificed on gestation day 21, and lactation days 10 and 22 were significantly increased at 30.0 mg/kg-day. Increased thyroid weights were observed in male and female pups as early as postpartum days 5 and 10, respectively. Changes in maternal and neonatal thyroid histopathology were detectable at 1.0 mg/kg-day exposure. The maternal no-observable-effect level (NOEL) was 0.1 mg/kg-day (follicular cell hyperplasia was present at 1.0 and 30.0 mg/kg-day). The developmental NOEL was less than 0.01 mg/kg-day; thyroid weights of postpartum day 10 pups were increased at all exposures. Colloid depletion at 1.0 and 30.0 mg/kg-day exposures and changes of hormone levels at all exposures were considered an adaptive effect and appeared reversible in the rodent.

Oral (Drinking Water) Developmental Toxicity Study of Ammonium Perchlorate in Sprague-Dawley Rats

2003 ◽  
Vol 22 (6) ◽  
pp. 453-464 ◽  
Author(s):  
Raymond G. York ◽  
Kathleen A. Funk ◽  
Michael F. Girard ◽  
David Mattie ◽  
Joan E. Strawson
Keyword(s):  
Drinking Water ◽  
Ammonium Perchlorate ◽  
Developmental Toxicity ◽  
Thyroid Stimulating Hormone ◽  
Toxicity Study ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Maternal Thyroid

A developmental toxicity study was conducted with ammonium perchlorate (AP) in the drinking water at doses of 0.0, 0.01, 0.1, 1.0, and 30.0 mg/kg-day beginning 14 days before cohabitation and continuing through sacrifice. Twenty-four rats/group were cesarean-sectioned on day of gestation (DG) 21 and fetuses examined for visceral and skeletal alterations. An additional 16 litters/group were sacrificed on DG 21 for maternal and fetal serum TSH, T3, and T4 (thyroid-stimulating hormone, triiodothyronine, and thyroxine) levels and thyroid histopathology. Clinical and necropsy observations, body weights, feed and water consumption, and cesarean-sectioning parameters were comparable among the groups with only delays in ossification observed in the 30 mg/kg-day group. Maternal thyroid weights were increased in the 30.0 mg/kg-day group. Decreased colloid was present in male and female fetal thyroids in the 1.0 and 30.0 mg/kg-day groups. Maternal TSH was increased and T4 was decreased at all levels, and T3 was reduced at 30.0 mg/kg-day. Fetal TSH was increased at 1.0 and 30.0 mg/kg-day, T4 was reduced at 30.0 mg/kg-day, and T3 was decreased at all levels. The maternal no-observable-adverse-effect level (NOAEL) was 1.0 mg/kg-day; exposures of 30.0 mg/kg-day increased absolute and relative maternal thyroid weights and histopathology findings. The developmental NOAEL was 1.0 mg/kg-day; developmental delays in ossification occurred in the 30.0 mg/kg-day group. The colloid depletion in the thyroids and increased TSH and decreased T3 and T4 levels at lower exposures were considered adaptive and not adverse. No adverse effects on development at occurred levels that did not cause maternal toxicity. AP is not a selective developmental toxicant.

A Rat Neurodevelopmental Evaluation of Offspring, Including Evaluation of Adult and Neonatal Thyroid, from Mothers Treated with Ammonium Perchlorate in Drinking Water

2004 ◽  
Vol 23 (3) ◽  
pp. 191-214 ◽  
Author(s):  
Raymond G. York ◽  
John Barnett ◽  
W. Ray Brown ◽  
Robert H. Garman ◽  
David R. Mattie ◽  
...  
Keyword(s):  
Drinking Water ◽  
Motor Activity ◽  
Passive Avoidance ◽  
Ammonium Perchlorate ◽  
Thyroid Stimulating Hormone ◽  
Follicular Epithelium ◽  
Feed Consumption ◽  
Exposure Level ◽  
Exposure Group ◽  
Sprague Dawley

The purpose of this study was to evaluate the potential neurodevelopmental toxicity of perchlorate exposure during gestation and the first 10 days of lactation. Mated Sprague-Dawley rats (25/exposure group) were given continual access to 0, 0.1, 1.0, 3.0, or 10.0 mg/kg-day ammonium perchlorate (AP) in drinking water, starting gestation day 0 (mating) through lactation day 10 (DL 10). One pup/sex/litter/exposure group was assigned to (1) juvenile brain weights, morphometry, and neuropathology; (2) passive avoidance and watermaze testing; (3) motor activity and auditory startle habituation; and (4) adult regional brain weights, morphometry, and neuropathology. AP had no effect on body weights, feed consumption, clinical observations, or sexual maturation of pups at exposures as high as 10.0 mg/kg-day. There were no behavioral effects in the offspring exposed as high as 10.0 mg/kg-day as evaluated by passive avoidance, swimming watermaze, motor activity, and auditory startle. Increases in hypertrophy and hyperplasia of the thyroid follicular epithelium and a decrease in the thyroid follicle size were observed in culled male pups in the 10.0 mg/kg-day group on DL 5. The exposure level for effects on triiodothyroxine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) levels for pups were 0.1, 1.0, and 3.0 mg/kg-day, respectively. There was an apparent increase in the thickness of the corpus callosum of the 10 mg/kg-day group pups on DL 12. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was greater than 10.0 mg/kg-day. Based on the thyroid morphometric and histopathologic findings, the NOAEL for pup toxicity was 0.1 mg/kg-day.

Mineralocorticoid Receptor Activation by Aldosterone or Corticosterone Induces Hypertension, Myocardial Infarction and Proteinuria

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 723-723
Author(s):  
Qing-Feng Tao ◽  
Diego Martinez vasquez ◽  
Ricardo Rocha ◽  
Gordon H Williams ◽  
Gail K Adler
Keyword(s):  
Myocardial Infarction ◽  
Drinking Water ◽  
Mineralocorticoid Receptor ◽  
Critical Role ◽  
Weight Ratio ◽  
Myocardial Necrosis ◽  
Receptor Activation ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

P165 Aldosterone through its interaction with the mineralocorticoid receptor (MR) plays a critical role in the development of hypertension and cardiovascular injury (CVI). Normally, MR is protected by 11β-hydroxysteroid dehydrogenase (11β-HSD) which inactivates glucocorticoids preventing their binding to MR. We hypothesis that if activation of MR by either aldosterone or glucocorticoids induces hypertension and CVI, then the inhibition of 11β-HSD with glycyrrhizin (GA), a natural inhibitor of 11β-HSD, should induce damage similar to that observed with aldosterone. Sprague-Dawley rats were uninephrectomized, and treated for 4 weeks with 1% NaCl (in drinking water) for the control group, 1% NaCl + aldosterone infusion (0.75 μg/h), or 1% NaCl + GA (3.5 g/l in drinking water). After 4 weeks, aldosterone and GA caused significant increases in blood pressure compared to control rats ([mean ± SEM] 211± 9, 205 ± 12, 120 ± 9 mmHg, respectively, p<0.001). Both aldosterone- and GA-treated rats had a significant increase in proteinuria (152.2 ± 8.7 and 107.7 ± 19.5 mg/d, respectively) versus controls (51.2 ± 9.5 mg/d). There was a significant increase (p<0.001) in heart to body weight ratio in the rats treated with aldosterone or GA compared with control (3.92 ± 0.10, 3.98 ± 0.88, and 3.24 ± 0.92 mg/g, respectively). Hearts of GA and aldosterone treated rats showed similar histological changes consisting of biventricular myocardial necrosis and fibrinoid necrosis of small coronary arteries and arterioles. These data suggests that in rodents activation of MR by either aldosterone or corticosterone leads to severe hypertension, vascular injury, proteinuria and myocardial infarction. Thus, 11β-HSD plays an important role in protecting the organism from injury.

Refining the Effects Observed in a Developmental Neurobehavioral Study of Ammonium Perchlorate Administered Orally in Drinking Water to Rats. II. Behavioral and Neurodevelopment Effects

2005 ◽  
Vol 24 (6) ◽  
pp. 451-467 ◽  
Author(s):  
Raymond G. York ◽  
John Barnett ◽  
Michael F. Girard ◽  
David R. Mattie ◽  
Marni V. K. Bekkedal ◽  
...  
Keyword(s):  
Drinking Water ◽  
Ammonium Perchlorate ◽  
Brain Regions ◽  
Male Rats ◽  
Male Rat ◽  
Sprague Dawley ◽  
Continuous Access ◽  
Brain Morphometry ◽  
The Central Nervous System ◽  
The Right

A developmental neurotoxicity study was conducted to generate additional data on the potential functional and morphological hazard to the central nervous system caused by ammonium perchlorate in offspring from in utero and lactation exposure. Female Sprague-Dawley rats (23 to 25/group) were given continuous access to 0 (carrier), 0.1, 1.0, 3.0, and 10.0 mg/kg-day perchlorate in the drinking water beginning 2 weeks prior to mating and continuing through day 10 of lactation for the behavioral function assessment or given continuous access to 0 (carrier), 0.1, 1.0, 3.0, and 30.0 mg/kg-day beginning on gestation day 0 and continuing through day 10 of lactation for neurodevelopment assessments. Motor activity was conducted on postpartum days 14, 18, and 22 and juvenile brain weights, neurohistopathological examinations, and regional brain morphometry were conducted on postpartum days 10 and 22. This research revealed a sexually dimorphic response, with some brain regions being larger in perchlorate-treated male rats than in comparable controls. Even so, there was no evidence of any obvious exposure-related effects on male rat brain weights or neuropathology. The most consistent exposure-related effect in the male pups was on the thickness of the corpus callosum, with both the right- and left-sided measures of the thickness of this white matter tract being significantly greater for the male pups in the 0.1 and 1.0 mg/kg-day exposure groups. The behavioral testing suggests prenatal exposure to ammonium perchlorate does not affect the development of gross motor movements in the pups.

scholarly journals A 4-Week Repeated Oral Dose Toxicity Study of Ssanghwa-Tang in Crl:CD Sprague Dawley Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Sae-Rom Yoo ◽  
Hyekyung Ha ◽  
Mee-Young Lee ◽  
Hyeun-kyoo Shin ◽  
Su-Cheol Han ◽  
...  
Keyword(s):  
Safety Information ◽  
Experimental Period ◽  
Serum Biochemistry ◽  
Toxicity Study ◽  
Herbal Formula ◽  
Sprague Dawley ◽  
Organ Weights ◽  
Sprague Dawley Rats ◽  
Adverse Effect Level ◽  
Effect Level

Ssanghwa-tang (SHT), a traditional herbal formula, has been widely used to recover fatigue or consumptive disease after an illness. Along with much attention to herbal formula, the concerns about the safety and toxicity have arisen. To establish the safety information, SHT was administrated in Crl:CD Sprague Dawley rats at a daily dose of 0, 1000, 2000, and 5000 mg/kg for 4 weeks. During the test periods, we examined the mortality, clinical observation, body weight change, food consumption, organ weights, hematology, serum biochemistry, and urinalysis parameters. No changes of mortality and necropsy findings occurred in any of the groups during the experimental period. In either sex of rats treated with SHT at 5000 mg/kg/day, changes were observed in food intake, reticulocyte, total bilirubin, some urinalysis parameters, and relative organ weights. The results indicated that SHT did not induce toxic effects at a dose level up to 2000 mg/kg in rats. This dosage was considered no observed adverse effect level (NOAEL) and was appropriate for a 13-week subchronic toxicity study.

scholarly journals Safety Assessment of Ubiquinol Acetate: Subchronic Toxicity and Genotoxicity Studies

2019 ◽  
Vol 2019 ◽  
pp. 1-25
Author(s):  
Gajanan Deshmukh ◽  
Suresh B. Venkataramaiah ◽  
Chandrashekar M. Doreswamy ◽  
Mohan C. Umesh ◽  
Rajesh B. Subbanna ◽  
...  
Keyword(s):  
Biologically Active ◽  
High Dose ◽  
Sprague Dawley ◽  
Subchronic Toxicity ◽  
Sprague Dawley Rats ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Endogenous Antioxidant ◽  
In Vitro Genotoxicity

Coenzyme Q10 (CoQ10) is a lipid soluble, endogenous antioxidant present at highest levels in the heart followed by the kidney and liver. The reduced CoQ10 ubiquinol is well known for its chemical instability and low bioavailability. The present study was designed to synthesize ubiquinol acetate, which is more stable and biologically active, and further evaluate its safety and genotoxic potential. Synthesized ubiquinol acetate showed better stability than that of ubiquinol at the end of 3 months. In vitro genotoxicity studies (AMES test, in vitro micronucleus and chromosomal aberration) showed ubiquinol acetate as nongenotoxic with no clastogenic or aneugenic effects at high dose of 5000 and 62.5 μg/mL, respectively. In subchronic toxicity study, ubiquinol acetate was administered orally to Sprague Dawley rats at 150, 300, and 600 mg/kg/day for 90 days. No treatment related adverse effects were observed in males at 600 mg/kg/day; however, females showed treatment related increase in AST and ALT with small focal irregular white-yellow spots in liver on gross necropsy examination. Histopathological evaluation revealed hepatocellular necrosis in high dose females which was considered as adverse. Based on the results, the No-Observed-Adverse-Effect Level (NOAEL) of ubiquinol acetate in males and females was determined as 600 and 300 mg/kg/day, respectively.

Subchronic Toxicity of S-111-S-WB in Sprague Dawley Rats

2010 ◽  
Vol 29 (4) ◽  
pp. 358-371 ◽  
Author(s):  
Jozef J. W. M. Mertens ◽  
Daniel W. Sved ◽  
Gary B. Marit ◽  
Nichole R. Myers ◽  
Phil L. Stetson ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Steady State ◽  
Ammonium Salts ◽  
Serum Concentrations ◽  
Sprague Dawley ◽  
Subchronic Toxicity ◽  
Lower Serum ◽  
Sprague Dawley Rats ◽  
Steady State Serum ◽  
Effect Level

S-111-S-WB, a mixture of perfluoro fatty acid ammonium salts (C6-C13), was administered orally to Crl:CD (SD)IGS-BR rats. Higher hepatic β-oxidation and liver weights with hepatocellular hypertrophy were present at the 0.125 and 0.6 mg/kg/d dosage. The 0.6 mg/kg/d males developed hepatocellular degeneration and necrosis. Lower serum protein and higher bilirubin and BUN were seen in the 0.6 mg/kg/d males and lower globulin and higher alkaline phosphatase in the 0.125 mg/kg/d males and 0.6 mg/kg/d animals. After 2 weeks, serum concentrations of pentadecafluorooctanoic acid (C8), heptadecafluorononanoic acid (C9), perfluoroundecanoic acid (C11), and perfluorotridecanoic acid (C13) were constant for at least 8 hours. After 90 days, only C9 in the 0.025 mg/kg/d females had reached steady state. Serum C8 and C9 concentrations in the males were 10-fold higher than in the females, whereas C11 and C13 were similar for both genders. The main elimination was via the urine for C8 (males) and C9 (females), and via the feces for C11 and C13. The no-observed-effect level (NOEL) was 0.025 mg/kg/d for the males and 0.125 mg/kg/d for the females.

Subchronic Hepatotoxicity Evaluation of 1,2,4-Tribromobenzene in Sprague-Dawley Rats

2012 ◽  
Vol 31 (3) ◽  
pp. 250-256 ◽  
Author(s):  
Darol E. Dodd ◽  
Linda J. Pluta ◽  
Mark A. Sochaski ◽  
Kathleen A. Funk ◽  
Russell S. Thomas
Keyword(s):  
Adverse Effect ◽  
Body Weight ◽  
Exposure Time ◽  
Clinical Signs ◽  
Liver Weight ◽  
Sprague Dawley ◽  
Significant Incidence ◽  
Sprague Dawley Rats ◽  
Adverse Effect Level ◽  
Effect Level

Male Sprague-Dawley rats were exposed to 1,2,4-tribromobenzene (TBB) by gavage for 5 days, 2, 4, and 13 weeks at 0, 2.5, 5, 10, 25, or 75 mg/kg per d. There were no TBB exposure-related clinical signs of toxicity or changes in body weight. Liver weight increases were dose and exposure time related and statistically significant at ≥10 mg/kg per d. Incidence and severity of centrilobular cytoplasmic alteration and hepatocyte hypertrophy were dose and time related. The 75 mg/kg per d group had minimally increased mitoses within hepatocytes (5 days only). Hepatocyte vacuolation was observed (13 weeks) and was considered TBB exposure related at ≥25 mg/kg per d. Concentrations of blood TBB increased linearly with dose and at 13 weeks, ranged from 0.5 to 17 µg/mL (2.5-75 mg/kg per d). In conclusion, rats administered TBB doses of 10-75 mg/kg per d for 13 weeks had mild liver effects. A no observed adverse effect level of 5 mg/kg per d was selected based on the statistically significant incidence of hepatocyte hypertrophy at doses ≥10 mg/kg per d.

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