Subchronic feeding study of antimony trioxide in rats.

Diets containing antimony trioxide were fed to male and female Wistar rats of the Alpk:APSD strain over 90 days. Dose levels were 0 (control), 1000, 5000 and 20,000 ppm (equivalent to mean daily doses of 84, 421 and 1686 mg kg(-1) in males and 97, 494 and 1879 mg kg(-1) in females). There was no effect of compound on growth or growth rate, food consumption or clinical signs. Minor changes in haematology and urine biochemistry were considered incidental to treatment. Small reductions in plasma alkaline phosphatase activity and increases in aspartate aminotransferase activity at the high dose, together with a small (ca. 10%) increase in liver weight, could be indicative of a minor effect on the liver, but in the absence of any histological effects these changes are also considered incidental to treatment. This study confirms the inert nature of antimony trioxide.     

Cardiotoxic effects of arsenic trioxide/imatinib mesilate combination in rats

Cardiotoxicity is an important consideration in the evaluation of cancer chemotherapy, because chemotherapy-induced myocardial damage might be irreversible and lethal. This in-vivo study investigated the cardiotoxicity of either arsenic trioxide or imatinib mesilate, or a combination of both drugs, following repeated administration in male Wistar rats. Both arsenic trioxide and imatinib mesilate were administered daily at a dose of 5 mg kg(-1) intraperitoneally and 30 mg kg(-1) orally for 10 days, respectively. Cardiotoxicity was evaluated by biochemical and histopathological examination 48 h after the last dose. Treatment with either arsenic or imatinib, or both, resulted in significant increases in serum creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GPx), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activity levels. Cardiac tissue of rats treated with arsenic showed significant increases in levels of reduced glutathione (GSH) content, GPx activity, malondialdehyde (MDA) and total nitrate/nitrite (NOx), whereas imatinib treatment significantly increased cardiac GSH content and MDA production level and decreased GPx activity level and NOx content. A combination of arsenic and imatinib produced significant increases in cardiac GSH content, GPx activity and MDA production levels, in addition to a reduction in NOx content. Combination arsenic/imatinib treatment extensively increased GPx activity and MDA production levels compared with imatinib treatment alone. Moreover, rats treated with arsenic or imatinib, or both, showed a significant increase in serum bilirubin, creatinine and urea levels. Histopathological examination of cardiac tissue of the combination-treated group revealed fibroblastic proliferation, myocardial disorganization and myocardial necrosis. Liver peroxidative alterations revealed that treatment with either arsenic or imatinib, or the two combined, increased levels of reduced-GSH and MDA production levels. However, imatinib treatment depleted liver GPx activity level contrary to treatment with the combination. Rats treated with arsenic alone or arsenic/imatinib combination showed significant elevation in liver NOx. In conclusion, both arsenic trioxide and imatinib mesilate might have significant cardiotoxicity and cardiac function should be monitored during treatment with them alone or in combination, as well as in the presence of pre-existing cardiac dysfunction.     

Carcinogenic and toxicologic effects of inhaled ethylene oxide and propylene oxide in F344 rats

The chronic inhalation toxicity and carcinogenicity of ethylene oxide (EO) and propylene oxide (PO) were evaluated in a 2-year inhalation bioassay. Five groups of male weanling Fischer 344 rats, 80 per group, were exposed at 0 ppm (shared control; filtered air), 50 ppm EO, 100 ppm EO, 100 ppm PO, or 300 ppm PO (7 hr/day, 5 days/week) for 104 weeks. Body weights from rats exposed to EO and PO at all exposure concentrations were significantly reduced compared to controls. A statistically significant increase in mortality was observed in all groups of exposed rats compared to controls. Skeletal muscle atrophy in the absence of any sciatic nerve neuropathology was found in rats exposed at 100 ppm EO and 300 ppm PO. Statistically significant associations between EO exposure and an increased incidence of the following rat neoplasms were observed: mononuclear cell leukemia, peritoneal mesothelioma, and mixed cell brain glioma. Among rats exposed to PO there was a dose-dependent increase in the incidence of complex epithelial hyperplasia in the nasal passages, and two adenomas were detected in the nasal passages of rats exposed at 300 ppm PO. The incidence of adrenal pheochromocytomas was elevated in both PO exposure groups, but not in a dose-related manner. All rat groups were affected by an outbreak of Mycoplasma pulmonis infection which occurred about 16 months into the study. This infection alone and in combination with the epoxide exposures affected the survival of rats in this study, and influenced the development of the proliferative lesions in the nasal mucosa of the PO-exposed rats. No treatment-related changes in any clinical chemistry or urinalysis indices were detected. PO exposure did not increase the incidence of the three neoplasms associated with EO exposure; however, adrenal pheochromocytomas and proliferative lesions of the nasal cavity were increased in rats exposed to PO.     

Carcinogenic effects of bis(2,3-dibromopropyl)-phosphate in Wistar rats.

Four groups of 40 Wistar rats of each sex per dose level were fed diets containing 0, 80, 400 or 2000 ppm of the magnesium salt of bis(2,3-dibromopropyl)phosphate (Bis-BP) for 24 months. A high incidence of tumours was induced, in both sexes, in the digestive system. Tumours included papillomas and adenocarcinomas of the tongue, oesophagus and forestomach, adenocarcinomas of the intestine and hepatocellular adenomas (neoplastic nodules) and carcinomas. Pre-terminal mortalities were associated with an increased incidence of forestomach papillomas in both sexes, adenocarcinomas of the small intestine in male rats and increased incidence of hepatocellular carcinomas in females. The data suggest that Bis-BP is a more potent proximate carcinogen than tris-(2,3-dibromopropyl)phosphate (Tris-BP).     

Toxicity of antimony trioxide nanoparticles on human hematopoietic progenitor cells and comparison to cell lines

Nanoparticles (NPs) are materials with one dimension in the range of 1–100 nm. The toxicity of NPs remains widely unknown and still poses concerns, due to the peculiar characteristics of materials in the nano-size range. We analyze the toxicity of seven NPs (Fe₂O₃, Fe₃O₄, Sb₂O₃, Au, TiO₂, Co, and Ag) on primary cultures of human hematopoietic progenitor cells from the bone marrow of healthy donors with CFU assays, and show that antimony oxide (Sb₂O₃) NPs and cobalt (Co) NPs have a toxic effect, while the other NPs have no effect at the tested concentrations (5, 25 and 100 μg/ml). While Co NPs suspension is toxic to both erythroid and granulocytic–monocytic precursors, Sb₂O₃ NPs at 5 μg/ml are specifically toxic to erythroid colony development, suggesting a highly selective type of toxicity. With liquid culture assays we show that Sb₂O₃ NPs impair the proliferation of erythroid progenitors, while no toxic effect is observed when Sb₂O₃ NPs are added during erythroid differentiation. CFU assays and liquid culture assays on seven human cell lines of hematopoietic origin (K562, HL-60, CEM, CEM-R, Thp-1, Jurkat, and Molt-4) show that, contrary to what observed on primary cultures of bone marrow progenitors, Sb₂O₃ NPs have no toxic effect on proliferation of any of the cell lines, raising concerns about the use of immortalized cell lines for nanotoxicology tests.     

Carcinogenic effects of low-level ionizing radiation: problems and prospects

For public health purposes, the overall risks of cancer are assumed to increase in proportion to the dose of ionizing radiation, without a threshold. Assessment of the risks that may be attributable to doses below the range in which empirical data are available, however, entails the use of models, the credibility of which depends on the extent to which the models are consistent with what is known about the occurrence and mechanisms of the effects in question. Although the weight of existing evidence is consistent with the hypothesis that the risks of genetic and carcinogenic effects of ionizing radiation increase as linear-nonthreshold functions of the dose, this concept is challenged by some observers in view of growing evidence that low doses of radiation may elicit adaptive responses that enhance the repair of DNA damage and protect in other ways as well. Further research is needed to resolve the issue.     

Subacute toxicity of pentavalent antimony compounds in rats.

A subacute toxicity study of pentavalent antimony (Sb) compounds, sodium stibogluconate (SSG) and meglumine antimoniate (MA) was carried out in rats. Three groups of 10 rats each were treated with saline (control group), 300 mg Sb kg-1 d-1 or 900 mg Sb kg-1 d-1 of SSG for 30 d. A parallel study of similar type was conducted for MA. Compared with controls, drug-treated rats showed an impairment of feeding habits and retardation of weight gain (P less than 0.01) during the treatment period. In both SSG- and MA-treated rats there was a dose-related reduction in haemoglobin concentration (P less than 0.001), and hematocrit (P less than 0.001). Red cell count was reduced in SSG-treated rats only. Both drugs, however, significantly raised the white cell count (P less than 0.05). These changes were more pronounced with SSG them with MA. There was no change in MCV, MCH and MCHC. SSG, 900 mg Sb kg-1 d-1, significantly raised AST (P less than 0.005), ALT (P less than 0.01) and alkaline phosphatase activity (P less than 0.01). SSG-treated rats also had raised BUN (P less than 0.01) and creatinine (P less than 0.001), but no significant change in bilirubin levels. MA significantly raised AST (P less than 0.01), ALT (P less than 0.01), BUN (P less than 0.001) and serum creatinine levels (P less than 0.001), but had no appreciable effect on bilirubin and alkaline phosphatase levels. Both SSG and MA decreased blood glucose levels (P less than 0.01) and induced proteinuria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Subchronic inhalation toxicity of soluble hexavalent chromium trioxide in rats

We performed a 90-day repeated-dose inhalation toxicity study of soluble hexavalent chromium trioxide (CrO₃ (VI)). Male Sprague-Dawley (SD) rats were exposed to doses of CrO₃ in the form of 0.55.0 m aerosol at 0.00, 0.20, 0.50, and 1.25 mg/m³ for 6 h/day, 5 days/week for 13 weeks using inhalation chamber. CrO₃ induced decrease of activity, alopecia and nasal hemorrhage. Body weights of the high-dose 1.25-mg/m³ exposure group were significantly lower than those of the control group. Hematological results revealed the reduction of the number of red blood cell and hematocrit values in the 1.25-mg/m³ exposure group. In addition, the hemoglobin values in the 0.50- and 1.25-mg/m³ exposure groups were significantly decreased compared with those of the control group. Clinical biochemical measurements revealed the reduction in total protein, albumin and alanine aminotransferase (ALT) level of the 0.50- and 1.25-mg/m³ exposure groups. Microscopic examination of the lung showed inflammation reactions caused by Cr exposure. In conclusion, the 13-week repeated exposure with soluble CrO₃ demonstrated the injury in SD rats with the no observed adverse effect level (NOAEL) under 0.20 mg/m³.     

联用维甲酸和三氧化二砷对APL细胞作用机制的初步研究

目的 探讨联用维甲酸(RA)和三氧化二砷(ATO)对急性早幼粒细胞白血病(APL)细胞的作用机制.方法 单用或联用生理和药理浓度RA和ATO作用于NB4细胞(APL细胞株),于不同时相进行分化抗原CD11b以及凋亡早期指标膜联蛋白-Ⅴ(annexin-Ⅴ)的测定,同时绘制细胞生长曲线.结果 在细胞分化方面,ATO和生理浓度RA之间存在协同作用,促进NB4细胞的分化;然而ATO对药理浓度RA诱导的NB4细胞分化却具有抑制作用;在生长抑制和早期凋亡方面,在联用组未表现出明显的协同作用.结论 联用RA和ATO在临床治疗APL上的协同作用机制比较复杂,需要进一步研究.     

Evaluation of dietary rapeseed protein concentrate flours in rats and dogs.

Graded doses of dietary aflatoxin (1.25, 2.5 and 5 μg/g) fed to broiler chicks for 3 weeks did not affect subsequent in vitro absorption of methionine and glucose by the intestine, compared with contol birds receiving no aflatoxin. A dietary level of 10 μg/g produced a significant increase in the absorption rate of both nutrients. Inhibition studies showed that both the mediated and diffusion components of absorption were increased with 10 μg/g. A prolonged exposure to aflatoxin was necessary for the effect since birds fed toxin for 1 week only (2 to 3 weeks of age) absorbed methionine and glucose at the same rate as controls receiving no aflatoxin.     

Absence of prenatal developmental toxicity from inhaled arsenic trioxide in rats.

A review of the literature revealed no published inhalational developmental toxicity studies of arsenic performed according to modern regulatory guidelines and with exposure throughout gestation. In the present study, inorganic arsenic, as arsenic trioxide (As(+3), As2O3), was administered via whole-body inhalational exposure to groups of twenty-five Crl:CD(SD)BR female rats for six h per day every day, beginning fourteen days prior to mating and continuing throughout mating and gestation. Exposures were begun prior to mating in order to achieve a biological steady state of As(+3) in the dams prior to embryonal-fetal development. In a preliminary exposure range-finding study, half of the females that had been exposed to arsenic trioxide at 25 mg/m3 died or were euthanized in extremis. In the definitive study, target exposure levels were 0.3, 3.0, and 10.0 mg/m3. Maternal toxicity, which was determined by the occurrence of rales, a decrease in net body weight gain, and a decrease in food intake during pre-mating and gestational exposure, was observed only at the 10 mg/m3 exposure level. Intrauterine parameters (mean numbers of corpora lutea, implantation sites, resorptions and viable fetuses, and mean fetal weights) were unaffected by treatment. No treatment-related malformations or developmental variations were noted at any exposure level. The no-observed-adverse-effect level (NOAEL) for maternal toxicity was 3.0 mg/m3; the NOAEL for developmental toxicity was greater than or equal to 10 mg/m3, 760 times both the time-weighted average threshold limit value (TLV) and the permissible exposure limit (PEL) for humans. Based on the results of this study, we conclude that arsenic trioxide, when administered via whole-body inhalation to pregnant rats, is not a developmental toxicant.     

三氧化二砷及顺铂对乳腺癌裸鼠移植瘤生长的抑制作用

目的 了解三氧化二砷(As2O3)、顺铂(DDP)单独及联合应用对人乳腺癌裸鼠移植瘤生长的抑制作用. 方法 建立裸鼠人乳腺癌MCF-7细胞移植瘤动物模型,成瘤后动物随机分为4组,每组4只:(1)阴性对照组,(2)As2O3组,(3)DDP组,(4)As2O3 DDP组.疗程结束后,观察3 d,处死裸鼠.治疗期间观察并记录各组裸鼠移植瘤的生长情况及肿瘤体积和裸鼠体重的变化,计算肿瘤生长抑制率,用流式细胞仪法、透射电镜观察体内瘤体的细胞凋亡情况. 结果 As2O3组、DDP组和As2O3 DDP组治疗后肿瘤体积减少,与对照组相比,差异均有显著性(P＜0.01);与As2O3及DDP组单独用药组比较,As2O3 DDP联合用药组肿瘤体积明显减少(P＜0.01),抑瘤率明显增高(P＜0.01);而阴性对照组肿瘤体积增加.各组裸鼠体重无明显变化.As2O3 DDP联合用药组细胞凋亡率为36.9%,明显高于其他2组,差异有显著性(P＜0.01). 结论 As2O3与DDP联合用药比2药单独应用抑制肿瘤生长的作用更强,二者具有协同抗癌作用.     

Carcinogenic potential of cooked food mutagens (IQ and MeIQ) in Wistar rats after short-term exposure

Two potent cooked food mutagens, 2-amino-3-methylimidazo/4,5-f/quinoline (IQ) and 2-amino-3,4-dimethylimidazo/4,5-f/quinoline (MeIQ), were examined in an initiation-promotion assay in the male wistar rat. Fourteen doses of 10 mg IQ or 10 mg MeIQ/kg b.wt. were given during initiation, followed by promotion with 500 p.p.m. phenobarbital sodium (PB) in the drinking water up to week 58. A small number of tumours of Zymbal's gland were seen in all groups treated with IQ or MeIQ, irrespective of PB-treatment. Though the promotional regimen failed to produce the expected number of liver tumours, it did induce a significant amount of gamma-glutamyltranspeptidase (GGT) activity. These results suggest that even short exposures to low doses of IQ or MeIQ produce persistent procarcinogenic lesions in the rat, and that secondary factors, e.g. promoters or high cell turnover, may over time develop these lesions into cancer.     

西红花酸对三氧化二砷诱导大鼠心肌损伤的保护作用

目的 探讨西红花酸对三氧化二砷(As203)所致大鼠心肌损伤的保护作用.方法 40只SD大鼠随机均分为对照组,模型组和西红花酸25、50 mg ? kg-1组,分别每日上午腹腔注射生理盐水或相应剂量西红花酸,6h后模型组和西红花酸组腹腔注射As203 5 mg·kg-1诱导心肌损伤模型,连续10 d.检测心电图,观察心...     

Evaluation of the prenatal developmental toxicity of orally administered arsenic trioxide in rats.

A thorough review of the literature revealed no published repeated-dose oral developmental toxicity studies of inorganic arsenic in rats. In the present study, which was conducted according to modern regulatory guidelines, arsenic trioxide was administered orally beginning 14 days prior to mating and continuing through mating and gestation until gestational day 19. Exposures began prior to mating in an attempt to achieve a steady state of arsenic in the bloodstream of dams prior to embryo-foetal development. Groups of 25 Crl:CD(SD)BR female rats received doses of 0, 1, 2.5, 5 or 10mg/kg/day by gavage. The selection of these dose levels was based on a preliminary range-finding study, in which excessive post-implantation loss and markedly decreased foetal weight occurred at doses of 15 mg/kg/day and maternal deaths occurred at higher doses. Maternal toxicity in the 10mg/kg/day group was evidenced by decreased food consumption and decreased net body weight gain during gestation, increased liver and kidney weights, and stomach abnormalities (adhesions and eroded areas). Transient decreases in food consumption in the 5mg/kg/day group caused the maternal no-observed-adverse-effect level (NOAEL) to be determined as 2. 5mg/kg/day. Intrauterine parameters were unaffected by arsenic trioxide. No treatment-related foetal malformations were noted in any dose group. Increased skeletal variations at 10mg/kg/day were attributed to reduced foetal weight at that dose level. The developmental NOAEL was thus 5mg/kg/day. Based on this study, orally administered arsenic trioxide cannot be considered to be a selective developmental toxicant (i.e. it is not more toxic to the conceptus than to the maternal organism), nor does it exhibit any propensity to cause neural tube defects, even at maternally toxic dose levels.     

Carcinogenic activity of benzo[a]pyrene in a 2 year oral study in Wistar rats

Because of the relatively high human oral exposure to polycyclic aromatic hydrocarbons (PAHs) compared to the inhalation exposure, the known carcinogenicity of this type of compounds and the limited data from oral studies available with polycyclic aromatic hydrocarbons, an oral carcinogenicity study was performed using benzo[a]pyrene (B[a]P) as a PAH representative. Wistar rats, 52 animals per sex and group were exposed daily (5 days a week) to 0, 3, 10 or 30 mg B[a]P/kg bw/day by gavage for 104 weeks and were subject to gross- and histopathology. The main tumours observed were hepatocellular carcinomas and forestomach tumours. Other tumours induced in this study were tumours of the auditory canal, skin and appendages, oral cavity, small intestine, kidney, and soft tissue sarcomas. For hepatocellular carcinomas and forestomach tumours, the BMDL10 were 3 and 1 mg/kg bw/day, respectively. The incidence of altered hepatic foci was increased in the 3mg/kg bw/day group. The increase in liver tumours is considered the most relevant effect for human risk assessment in terms of pathogenesis and sensitivity, and is proposed as the basis for human cancer risk assessment for oral PAH exposure.     

Carcinogenic potential of o-nitrotoluene and p-nitrotoluene

The potential of o-nitrotoluene and p-nitrotoluene to cause cancer in mammalian species was studied in male and female F344/N rats and B6C3F1 mice. These chemicals are on the EPA list of high production chemicals and there is potential for human exposure (High Production Volume Chemical List (2000) http://oaspub.cpa.gov/opptintr/chemrtk/volchall.htm.). o-Nitrotoluene, administered in the feed for up to 2 years, caused clear evidence for cancer at multiple sites in rats and mice. Male rats, receiving o-nitrotoluene in the feed ( approximately 0, 25, 50, or 90 mg/kg per day), developed treatment-related mesotheliomas, subcutaneous skin neoplasms, mammary gland fibroadenomas, and liver neoplasms. By 2 years, mesotheliomas, skin, liver, mammary gland and liver tumors also occurred in 'stop-study' male rats that received o-nitrotoluene at 125 or 315 mg/kg per day for only the first 3 months of study. These 'stop-studies' showed that the critical events leading to tumor formation occurred after 3 months of dosing, and these events were irreversible and eventually led to cancer at multiple sites. o-Nitrotoluene given in the feed to female rats (approximately 0, 30, 60, or 100 mg/kg per day) and to male and female mice (approximately 0, 150, 320, or 700 mg/kg per day) also caused a carcinogenic response. In female rats, treatment-related subcutaneous skin neoplasms and mammary gland fibroadenomas occurred. Hemangiosarcomas and carcinomas of the large intestine (cecum) were seen in treated male and female mice. In contrast to o-nitrotoluene, p-nitrotoluene given in the feed over approximately the same exposure levels caused only equivocal evidence of carcinogenic activity in male rats (subcutaneous skin neoplasms); some evidence of carcinogenic activity in female rats (clitoral gland neoplasms); equivocal evidence of carcinogenic activity in male mice (lung neoplasms); and no evidence of carcinogenic activity in female mice. Differences in the o-nitrotoluene and p-nitrotoluene carcinogenic activity may be due to differences in the metabolism of the parent compound to carcinogenic metabolites.     

Safety evaluation of fish protein concentrate over five generations of rats

Fish protein concentrate (FPC), prepared from whole red hake (Urophycis chuss), was fed as the sole source of protein to five generations of rats; observations on growth, reproduction and lactation of these groups were compared to control groups fed either laboratory chow or a semisynthetic diet containing casein as the protein source. Selected biochemical parameters were also evaluated and tissues from all groups were assessed for histopathologic alterations. Major differences noted were better reproduction and decreased food efficiency in the chow group, compared to either FPC or casein groups; toxicologic and pathologic data were essentially the same for all groups. Based on this evidence, FPC prepared according to methods developed by the Bureau of Commercial Fisheries can be considered nutritious, safe and wholesome.