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Environmental Health Perspectives Jan 1994Two-year animal carcinogenicity experiments are used to evaluate the potential carcinogenicity from exposure to chemicals. The choice of exposure levels, the allocation... (Review)
Review
Two-year animal carcinogenicity experiments are used to evaluate the potential carcinogenicity from exposure to chemicals. The choice of exposure levels, the allocation of animals to doses, the length of exposure, and the choice of interim sacrifice times all affect the power of statistical tests for carcinogenic effects and the variance of interpolated estimates of carcinogenic risk. In this paper, one aspect of this problems is considered: the ability of tumor incidence data to provide information on carcinogenic mechanism and the optimal choice of design parameters with which to achieve this purpose. The direct application of biochemical data to the estimation of carcinogenic risk is also discussed in detail.
Topics: Animals; Biometry; Carcinogenicity Tests; Incidence; Models, Biological; Neoplasms, Experimental; Research Design; Risk Factors; Rodentia; Time Factors
PubMed: 8187725
DOI: 10.1289/ehp.94102s15 -
Regulatory Toxicology and Pharmacology... Dec 2014The subchronic (90-day) toxicity of a "core" version of EPG was assessed in rats. Crl:CD-1®(ICR)BR rats (70/sex) received diets containing a constant level of 5% EPG...
The subchronic (90-day) toxicity of a "core" version of EPG was assessed in rats. Crl:CD-1®(ICR)BR rats (70/sex) received diets containing a constant level of 5% EPG (w/w) or adjusted to deliver 0 (control), 0.5, 1, or 2g/kg of body weight/day (g/kg bw/day). Subsets of animals from each group (20/sex) were evaluated after 30 days (interim sacrifice); the remainder after 90 days. EPG intake at all dose levels was associated with lower mean liver vitamin E levels; liver vitamin A and serum vitamin D were also lower, but less consistently. Animals given 5% EPG had higher fecal output (males) and cholesterol (males and females) without corresponding changes in serum cholesterol. Urinary pH was also mildly lower in males given 5% EPG. However, detailed evaluation of general health and assessment of blood, organs and tissues showed no evidence that EPG administration compromised the nutritional requirements of the animals, caused a state of fat-soluble vitamin deficiency, or caused' toxicity to any organ system. Based on the results of this study, it was not possible to establish a no-observable-effect level (NOEL). The possible effect of EPG on vitamin levels in the absence of any clinical signs of deficiency was not considered "adverse" per se. As such, the 2g/kg and 5% EPG level were considered to represent a no-observable-adverse-effect levels (NOAELs).
Topics: Animals; Cholesterol; Diet; Fat Substitutes; Fatty Acids; Feces; Female; Glycerides; Liver; Male; No-Observed-Adverse-Effect Level; Rats; Toxicity Tests, Subchronic; Vitamin A; Vitamin D; Vitamin E
PubMed: 25497991
DOI: 10.1016/j.yrtph.2014.11.017 -
International Journal of Toxicology 2021Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotective biologic in Parkinson's disease models. Adeno-associated viral vector serotype 2...
Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotective biologic in Parkinson's disease models. Adeno-associated viral vector serotype 2 (AAV2)-human GDNF safety was assessed in rats treated with a single intracerebral dose of vehicle, 6.8 × 10, 6.8 × 10, or 5.2 × 10 vector genomes (vg)/dose followed by interim sacrifices on day 7, 31, 90, and 376. There were no treatment-related effects observed on food consumption, body weight, hematology, clinical chemistry, coagulation parameters, neurobehavioral parameters, organ weights, or serum GDNF and anti-GDNF antibody levels. Increased serum anti-AAV2 neutralizing antibody titers were observed in the 5.2 × 10 vg/dose group. Histopathological lesions were observed at the injection site in the 6.8 × 10 vg/dose (day 7) and 5.2 × 10 vg/dose groups (days 7 and 31) and consisted of gliosis, mononuclear perivascular cuffing, intranuclear inclusion bodies, and/or apoptosis on day 7 and mononuclear perivascular cuffing on day 31. GDNF immunostaining was observed in the injection site in all dose groups through day 376 indicating no detectable impacts of anti-AAV2 neutralizing antibody. There was no evidence of increased expression of calcitonin gene-related peptide or Swann cell hyperplasia in the cervical and lumbar spinal cord or medulla oblongata at the 5.2 × 10 vg/dose level indicating lack of hyperplastic effects. In conclusion, no systemic toxicity was observed, and the local toxicity observed at the injection site appeared to be reversible demonstrating a promising safety profile of intracerebral AAV2-GDNF delivery. Furthermore, an intracerebral dose of 6.8 × 10 AAV2-GDNF vg/dose was considered to be a no observed adverse effect level in rats.
Topics: Animals; Disease Models, Animal; Female; Glial Cell Line-Derived Neurotrophic Factor; Humans; Male; Neuroprotective Agents; Parkinson Disease; Rats; Rats, Sprague-Dawley
PubMed: 33131343
DOI: 10.1177/1091581820966315 -
Biomaterials Apr 2013The evaluation of candidate materials and designs for soft tissue scaffolds would benefit from the ability to monitor the mechanical remodeling of the implant site...
The evaluation of candidate materials and designs for soft tissue scaffolds would benefit from the ability to monitor the mechanical remodeling of the implant site without the need for periodic animal sacrifice and explant analysis. Toward this end, the ability of non-invasive ultrasound elasticity imaging (UEI) to assess temporal mechanical property changes in three different types of porous, biodegradable polyurethane scaffolds was evaluated in a rat abdominal wall repair model. The polymers utilized were salt-leached scaffolds of poly(carbonate urethane) urea, poly(ester urethane) urea and poly(ether ester urethane) urea at 85% porosity. A total of 60 scaffolds (20 each type) were implanted in a full thickness muscle wall replacement in the abdomens of 30 rats. The constructs were ultrasonically scanned every 2 weeks and harvested at weeks 4, 8 and 12 for compression testing or histological analysis. UEI demonstrated different temporal stiffness trends among the different scaffold types, while the stiffness of the surrounding native tissue remained unchanged. The changes in average normalized strains developed in the constructs from UEI compared well with the changes of mean compliance from compression tests and histology. The average normalized strains and the compliance for the same sample exhibited a strong linear relationship. The ability of UEI to identify herniation and to characterize the distribution of local tissue in-growth with high resolution was also investigated. In summary, the reported data indicate that UEI may allow tissue engineers to sequentially evaluate the progress of tissue construct mechanical behavior in vivo and in some cases may reduce the need for interim time point animal sacrifice.
Topics: Animals; Biocompatible Materials; Collagen; Elasticity; Female; Image Processing, Computer-Assisted; Models, Animal; Polyesters; Polyurethanes; Porosity; Rats; Rats, Inbred Lew; Tissue Engineering; Tissue Scaffolds; Ultrasonics
PubMed: 23347836
DOI: 10.1016/j.biomaterials.2013.01.036 -
The Journal of Toxicological Sciences Dec 2005General toxicity studies on 2,2'-isobutylidenebis(4,6-dimethylphenol)(IBBMP) were conducted using male and female Wistar rats. In the acute test, the oral LD50 values... (Comparative Study)
Comparative Study
General toxicity studies on 2,2'-isobutylidenebis(4,6-dimethylphenol)(IBBMP) were conducted using male and female Wistar rats. In the acute test, the oral LD50 values were 119 mg/kg BW in males and 103 mg/kg BW in females. Hypersensitivity, loss of righting reflex and abdominal position were observed. In the subchronic test, rats were fed a diet containing IBBMP at levels of 0, 20, 100 or 500 ppm for 13 weeks with interim sacrifice at 4 weeks (equal to 0, 1.1, 5.5 or 27.9 mg/kg BW/day in males and 0, 1.1, 5.9 or 29.6 mg/kg BW/day in females). In both sexes, there were no changes in general condition, body weight gains and food intakes in all groups. No deaths were observed in all groups. Significant increase in AST was observed in 500 ppm males at Week 4. However, the change was not observed at Week 13. Slight but significant decreases in creatinine were also observed in 100 ppm females at Week 13 and 500 ppm males and females at Weeks 4 and 13. Total cholesterol (T-CHO) was significantly elevated in females of the 500 ppm group at Weeks 4 and 13. Absolute and relative liver weights were increased in 500 ppm of both sexes at Week 4. In females, the increases were also observed at Week 13. However, no remarkable histopathological findings were observed in all treated groups. In the chronic test, rats were fed a diet containing IBBMP at levels of 0, 100, 500 and 1500 ppm for 18 months with interim sacrifices at 6 and 12 months (equal to 0, 3.8, 19.4 or 59.4 mg/kg BW/day in males and 0, 4.3, 20.9 or 67.5 mg/kg BW/day in females). No remarkable changes in general appearance were observed in any rats. Body weight gains, food intakes and survival rates in all treated animals were comparable to those of the control. No remarkable changes in the hematological parameters were observed. T-CHO was significantly elevated in females of the 1500 ppm groups throughout the experiment. Significant increases or tendencies for increase in relative liver weights were observed in the 500 and 1500 ppm animals of both sexes. Increased incidences of swelling in liver cells were observed in 1500 ppm males at 6 months and 1500 ppm females at 12 and 18 months. At 18 months, dose-dependent increases in thickness of basement membrane of renal tubules and Bowman's capsule and cell infiltration to the interstitium of the kidney were observed in males. Significant increases of hyaline cast and basophilic change were also observed in 1500 ppm males. In females, increased incidences of hyaline cast were observed at 500 ppm and higher at 18 months. No other toxicity was apparent. No neoplastic lesions that could be attributed to IBBMP were observed in any organs of either sex. From the result of the chronic toxicity test, the no-observed-adverse-effect level (NOAEL) for IBBMP was concluded to be 100 ppm in the diet (4.26 mg/kg BW/day) in female rats on the basis of induction of hyaline cast in renal tubules at 500 ppm, whereas, in males, only a lowest-observed-adverse-effect level (LOAEL) was given as 100 ppm (3.84 mg/kg BW/day) on the basis of induction of thickening of basement membrane in renal tubules at 100 ppm.
Topics: Animals; Antioxidants; Body Weight; Diet; Female; Hematologic Tests; Kidney; Kidney Tubules; Liver; Male; Organ Size; Rats; Rats, Wistar; Sex Factors; Time Factors; Toxicity Tests, Acute; Toxicity Tests, Chronic; Xylenes
PubMed: 16404136
DOI: 10.2131/jts.30.275 -
American Journal of Translational... 2020Experiments were conducted on the assumption that vivid chondrogenesis would be boosted in vivo following previously preliminary chondrogenesis in a mesenchymal stem...
BACKGROUND
Experiments were conducted on the assumption that vivid chondrogenesis would be boosted in vivo following previously preliminary chondrogenesis in a mesenchymal stem cell (MSC)-rich entire umbilical cord (UC) in vitro.
METHODS
Virtual 3-D tracheal grafts were generated by using a profile obtained by scanning the native trachea of the listed porcine. Although the ultimate goal was the acquisition of a living specimen beyond a 3-week survival period, the empirical results did not meet our criteria until the 10 experiment, ending with the sacrifice of the animal. The categories retrospectively evolved from post-transplant modification due to porcine death using 4 different methods of implantation in chronological order. For each group, we collected details on graft construction, clinical outcomes, and results from both gross and histology examinations.
RESULTS
Three animals died due to tracheal complications: one died from graft crush, and two died secondary to erosion of the larger graft into the great vessels. It appeared that the remaining 7 died of tracheal stenosis from granulation tissue. Ectopic de novo growth of neocartilage was found in three porcine subjects. In the nearby tissues, we detected neocartilage near the anastomosis containing interim vesicles of the vascular canals (VCs), perichondrial papillae (PPs) and preresorptive layers (PRLs), which were investigated during the infancy of cartilage development and were first unveiled in the tracheal cartilage.
CONCLUSIONS
3-D-printed anatomically precise grafts could not provide successful transplantation with stent-sparing anastomosis; nonetheless, de novo cartilage regeneration in situ appears to be promising for tracheal graft adaptability. Further graft refinement and strategies for managing granulated tissues are still needed to improve graft outcomes.
PubMed: 32774730
DOI: No ID Found -
Environmental Health Perspectives Oct 1994This article describes the relationship between fiber biopersistence and the chronic toxicity of different chemical compositions of man-made vitreous fibers (MMVF) in... (Comparative Study)
Comparative Study
This article describes the relationship between fiber biopersistence and the chronic toxicity of different chemical compositions of man-made vitreous fibers (MMVF) in the lung. Rats were exposed in "nose-only" inhalation chambers, 6 hr/day, 5 days/week, for 24 months to aerosol concentrations of 30 mg/m3 containing comparable fiber numbers and similar dimensions of fibrous glass (FG) or refractory ceramic fiber (RCF). Interim sacrifices were performed periodically to monitor fiber number and dimensions in the lung and the progression of pulmonary alterations. At each interim sacrifice, three to six recovery animals were removed from each exposure group and held until two years to determine the biopersistence of fibers after different exposure times. Fibers were recovered from the ashed lungs, counted, and measured using optical and scanning electron microscopy (SEM). Fiber chemistry was assessed in 91-week recovery lungs using energy dispersive spectroscopy (EDS) analysis. RCF induced lung fibrosis and an elevation in lung tumors and pleural mesotheliomas. FG exposure resulted in no lung fibrosis, no statistically significant increase in the lung tumor incidence, and no mesotheliomas. After two years of continuous exposure, the number of World Health Organization fibers per milligram dry lung recovered from RCF and FG exposed lungs was comparable. EDS analysis of recovery lungs showed that most of the alkalis and alkaline earths had leached from the FG fibers over time. A slight change in RCF chemistry was observed. These findings indicate that the change in the chemical composition of fibers may be an important determinant of the chronic toxicity of MMVFs.
Topics: Administration, Inhalation; Animals; Asbestos, Serpentine; Body Burden; Ceramics; Glass; Lung; Male; Rats; Rats, Inbred F344; Time Factors; World Health Organization
PubMed: 7882917
DOI: 10.1289/ehp.94102s5133 -
Environmental Health Perspectives Oct 1994Lifetime "nose-only" inhalation studies were conducted in rats using four types of refractory ceramic fibers (FCF), 1 micron in diameter x 22 to 26 microns length: High...
Lifetime "nose-only" inhalation studies were conducted in rats using four types of refractory ceramic fibers (FCF), 1 micron in diameter x 22 to 26 microns length: High Purity, Kaolin, Zirconia, and After-Service; and on hamsters using Kaolin RCF. For comparison, animals also were exposed to chrysotile fibers. Rats were exposed 6 hr/day, 5 days/week for 24 months to concentrations ranging between 3 and 30 mg/m3. Time- and dose-dependent lesions in the rat included the development of interstitial fibrosis, pleural fibrosis, pulmonary tumors, and mesothelioma. Exposure to 3, 9 or 16 mg/m3 produced no excess lung tumors; no fibrosis was seen at 3 mg/m3. A significant increase in lung tumors and interstitial fibrosis was observed at 30 mg/m3. A single mesothelioma was observed in rats exposed to 9 mg/m3, while two occurred at 30 mg/m3. Hamsters were similarly exposed to 30 mg/m3 Kaolin RCF for 18 months; no lung tumors were induced, but pulmonary and pleural fibrosis were observed and there was a 42% incidence of mesothelioma. Multiple interim sacrifices together with recovery animals allowed detailed assessment of the lung burden of RCF, which was found to be dose related and, at the high doses, exceeded 10(5) fibers/mg of dry lung. During the various recovery periods there was a clear reduction in fiber burden. Mathematical modeling of these data for deposition, clearance, and retention and for species is currently underway.
Topics: Administration, Inhalation; Animals; Body Burden; Ceramics; Cricetinae; Kaolin; Lung; Mesocricetus; Rats; Rats, Inbred F344; Time Factors
PubMed: 7882933
DOI: 10.1289/ehp.94102s5207