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.     

Effect of pH on the acute toxicity of hexavalent chromium to rainbow trout (Salmo gairdneri)

The acute toxicity of hexavalent chromium, Cr(VI). to rainbow trout (Salmo gairdneri) increased with decreasing pH in the range from 7.8 to 6.5. Morphological changes that could be associated with acute Cr(VI) poisoning at pH 7.8 were found in gills, kidney and stomach, whereas those at pH 6.5 appeared to be restricted to the gills only. At both pH values, however, similar alterations in plasma osmolality and hematocrit values of blood were found in fish surviving an exposure to acute toxic concentrations.To explain the observed effects, hydroehromate (HCrO₄^?) and chromate (CrO^2?₄) were considered as the toxic species of Cr(VI). An attempt was made to calculate the relative toxicities of these ionic species from empirical toxicity relationships for weak acids in fish, as described in the literature.     

Mechanisms of chromium toxicity in mammalian cell cultures

Our observations about the cytotoxic and cytogenetic effects of hexavalent and trivalent chromium compounds in mammalian cells cultured in vitro are reviewed. Additional data concerning the induction of chromosomal aberrations and sister chromatid exchanges, the inhibition of nucleic acid and protein synthesis, the interference with nucleotide metabolism, and the modification of membrane-linked enzyme activity are reported. A possible mechanism of chromium action is proposed.     

A physiologically based model for the ingestion of chromium(III) and chromium(VI) by humans.

A physiologically based model of human chromium kinetics has been developed, based on an existing physiologically based model of human body and bone growth (O'Flaherty, 1993, Toxicol. Appl. Pharmacol. 118, 16-29; 1995a, Toxicol. Appl. Pharmacol. 131, 297-308; 2000, Toxicol. Sci. 55, 171-18) and an existing physiologically based model of chromium kinetics in rats (O'Flaherty, 1996, Toxicol. Appl. Pharmacol. 138, 54-64). Key features of the adapted model, specific to chromium, include differential absorption of Cr(VI) and Cr(III), rapid reduction of Cr(VI) to Cr(III) in all body fluids and tissues, modest incorporation of chromium into bone, and concentration-dependent urinary clearance consistent with parallel renal processes that conserve chromium efficiently at ambient exposure levels. The model does not include a physiologic lung compartment, but it can be used to estimate an upper limit on pulmonary absorption of inhaled chromium. The model was calibrated against blood and urine chromium concentration data from a group of controlled studies in which adult human volunteers drank solutions generally containing up to 10 mg/day of soluble inorganic salts of either Cr(III) (chromic chloride, CrCl(3)) or Cr(VI) (potassium dichromate, K(2)Cr(2)O(7)) (Finley et al., 1997, Toxicol. Appl. Pharmacol. 142, 151-159; Kerger et al., 1996, Toxicol. Appl. Pharmacol. 141, 145-158; Paustenbach et al., 1996, J. Toxicol. Environ. Health 49, 453-461). In one of the studies, in which the chromium was ingested in orange juice, urinary clearance was observed to be more rapid than when inorganic chromium was ingested. Chromium kinetics were shown not to be dependent on the oxidation state of the administered chromium except in respect to the amount absorbed at these ambient and moderate-to-high exposures. The fraction absorbed from administered Cr(VI) compounds was highly variable and was presumably strongly dependent on the degree of reduction in the gastrointestinal tract, that is, on the amount and nature of the stomach contents at the time of Cr(VI) ingestion. The physiologically based model is applicable to both single-dose oral studies and chronic oral exposure, in that it adequately reproduced the time dependence of blood plasma concentrations and rates of urinary chromium excretion in one of the subjects who, in a separate experiment, ingested daily 4 mg of an inorganic Cr(VI) salt in 5 subdivided doses of 0.8 mg each for a total of 17 days. The high degree of variability of fractional absorption of Cr(VI) from the gastrointestinal tract leads to uncertainty in the assignment of a meaningful value to this parameter as applied to single Cr(VI) doses. To model chronic oral chromium exposure at ambient or moderately above-ambient levels, the physiologically based model in its present form should be usable with urinary clearance set to a constant value of 1-2 liters/day and the gastrointestinal absorption rate constants set at 0.25/day for Cr(III) and 2.5/day for Cr(VI). The model code is given in full in the Appendix.     

六价铬对作业工人生殖功能影响的调查

目的:探讨六价铬对作业工人的生殖毒性.方法:采用职业流行病学方法,对电镀和皮革行业中六价铬作业81名工人生殖功能进行了调查.结果:作业环境铬浓度平均为0.0135(0.001～0.086)mg/m3;女工月经异常发生率明显增高,以痛经和月经周期异常为主,自然流产率和死产率均高于对照组;男工精浆铬含量高于血液5倍.精子数量减少,精子存活率下降,精浆锌含量明显下降,精浆LDH和LDHx活性及其比率也显著降低,结论:六价铬对男、女作业工人的生殖功能均可产生不良影响,同时也危及胚胎发育.     

Mechanisms underlying methotrexate-induced pulmonary toxicity

Background: Methotrexate (MTX) has been widely used for the treatment of inflammatory diseases and rheumatoid arthritis, as well as a variety of tumors. However, MTX-induced pulmonary toxicity is a serious and unpredictable side effect of the therapy, which includes allergic, cytotoxic or immunologic reactions, and is a major clinical problem. Objective: To summarize the mechanisms of action involved in MTX-induced pulmonary toxicity. Methods: We reviewed the literature describing MTX-induced adverse pulmonary effects and the mechanisms of action underlying MTX-induced pulmonary toxicity. Conclusion: The mechanisms underlying MTX toxicity are complex. The clinical effects may be attributable to both the anti-inflammatory and immunosuppressive effects of MTX. The mechanisms causing the side effects of MTX include mutation of the genotype, inhibition of transport, MTX-polyglutamates and P-glycoprotein binding with MTX. The p38 MAPK-signaling pathway is especially associated with a pulmonary inflammatory response. These mechanisms can be applied to optimize drug treatment.     

Mechanisms of toxicity by carbon nanotubes

Abstract

Carbon nanotubes (CNTs) consist of a family of carbon built nanoparticles, whose biological effects depend on their physical characteristics and other constitutive chemicals (impurities and functions attached). CNTs are considered the twenty first century material due to their unique physicochemical characteristics and applicability to industrial product. The use of these materials steadily increases worldwide and toxic outcomes need to be studied for each nanomaterial in depth to prevent adverse effects to humans and the environment. Entrance into the body is physical, and usually few nanoparticles enter the body; however, once there, they are persistent due to their limited metabolisms, so their removal is slow, and chronic cumulative health effects are studied. Oxidative stress is the main mechanism of toxicity but size, agglomeration, chirality as well as impurities and functionalization are some of the structural and chemical characteristic contributing to the CNTs toxicity outcomes. Among the many toxicity pathways, interference with cytoskeleton and fibrous mechanisms, cell signaling, membrane perturbations and the production of cytokines, chemokines and inflammation are some of the effects resulting from exposure to CNTs. The aim of this review is to offer an up-to-date scope of the effects of CNTs on biological systems with attention to mechanisms of toxicity.     

Variations in Prkdc and susceptibility to benzene-induced toxicity in mice.

Benzene, a carcinogen that induces chromosomal breaks, is strongly associated with leukemias in humans. Possible genetic determinants of benzene susceptibility include proteins involved in repair of benzene-induced DNA damage. The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), encoded by Prkdc, is one such protein. DNA-PKcs is involved in the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break (DSB) repair. Here we compared the toxic effects of benzene on mice (C57BL/6 and 129/Sv) homozygous for the wild-type Prkdc allele and mice (129/SvJ) homozygous for a Prkdc functional polymorphism that leads to diminished DNA-PK activity and enhanced apoptosis in response to radiation-induced damage. Male and female mice were exposed to 0, 10, 50, or 100 ppm benzene for 6 h/d, 5 d/week for 2 weeks. Male mice were more susceptible to benzene toxicity compared with females. Hematotoxicity was evident in all male mice but was not seen in female mice. We observed similar, large increases in both micronucleated erythrocyte populations in all male mice. Female mice had smaller but significant increases in micronucleated cells. The p53-dependent response was induced in all strains and genders of mice following benzene exposure, as indicated by an increase in p21 mRNA levels in bone marrow that frequently corresponded with cell cycle arrest in G2/M. Prkdc does not appear to be a significant genetic susceptibility factor for acute benzene toxicity. Moreover, the role of NHEJ, mediated by DNA-PK, in restoring genomic integrity following benzene-induced DSB remains equivocal.     

六价铬对肝细胞内活性氧和腺苷酸转运体1转录水平的影响

目的探讨重金属六价铬[Cr(Ⅵ)]的体外肝毒性。方法 L-02肝细胞经Cr(Ⅵ)0,2,4,8,16和32μmol.L-1分别染毒12,24或36 h后,采用逆转录-荧光定量聚合酶链反应(RT-qPCR)和荧光光度法分别对腺苷酸转运体1(ANT1)mRNA表达水平和活性氧簇(ROS)水平进行检测。结果 Cr(Ⅵ)32μmol.L-1处理细胞12和24 h后,ROS水平明显升高,而处理36 h后,ROS水平明显下降。Cr(Ⅵ)2～32μmol.L-1处理细胞12和24 h后,细胞内ANT1 mRNA呈明显低表达水平,而处理36 h后,细胞内ANT1 mRNA表达水平明显增高,达正常对照组的2倍左右。结论 Cr(Ⅵ)在早期(12,24 h)可使L-02肝细胞内ROS水平升高,发生氧化应激,在后期(36 h)可诱导ANT1 mRNA表达水平升高,发生能量代谢应激,可能是Cr(Ⅵ)诱导细胞线粒体损伤的分子毒性机制之一。     

Assessment of genotoxic and mutagenic potential of hexavalent chromium in the freshwater fish Labeo rohita (Hamilton, 1822)

The present study was undertaken to investigate the genotoxicity and mutagenicity of sublethal concentrations of hexavalent chromium (potassium dichromate) in the Indian major carp, Labeo rohita. The 96?h LC₅₀ value of potassium dichromate estimated was 118?mg?L^?1 by probit analysis using SPSS (version 16.0) software. Based on 96?h LC₅₀ value, three sublethal test concentrations of potassium dichromate (29.5, 59.0 and 88.5?mg?L^?1) were selected and specimens were exposed in vivo to these test concentrations for 96?h. The mutagenic and genotoxic effects of potassium dichromate were evaluated in gill and blood cells using micronucleus (MN) test and comet assay. In general, significant (p?相似文献   

Mechanisms of toxicity associated with six tyrosine kinase inhibitors in human hepatocyte cell lines

Tyrosine kinase inhibitors have revolutionized the treatment of certain cancers. They are usually well tolerated, but can cause adverse reactions including liver injury. Currently, mechanisms of hepatotoxicity associated with tyrosine kinase inhibitors are only partially clarified. We therefore aimed at investigating the toxicity of regorafenib, sorafenib, ponatinib, crizotinib, dasatinib and pazopanib on HepG2 and partially on HepaRG cells. Regorafenib and sorafenib strongly inhibited oxidative metabolism (measured by the Seahorse‐XF24 analyzer) and glycolysis, decreased the mitochondrial membrane potential and induced apoptosis and/or necrosis of HepG2 cells at concentrations similar to steady‐state plasma concentrations in humans. In HepaRG cells, pretreatment with rifampicin decreased membrane toxicity (measured as adenylate kinase release) and dissipation of adenosine triphosphate stores, indicating that toxicity was associated mainly with the parent drugs. Ponatinib strongly impaired oxidative metabolism but only weakly glycolysis, and induced apoptosis of HepG2 cells at concentrations higher than steady‐state plasma concentrations in humans. Crizotinib and dasatinib did not significantly affect mitochondrial functions and inhibited glycolysis only weakly, but induced apoptosis of HepG2 cells. Pazopanib was associated with a weak increase in mitochondrial reactive oxygen species accumulation and inhibition of glycolysis without being cytotoxic. In conclusion, regorafenib and sorafenib are strong mitochondrial toxicants and inhibitors of glycolysis at clinically relevant concentrations. Ponatinib affects mitochondria and glycolysis at higher concentrations than reached in plasma (but possibly in liver), whereas crizotinib, dasatinib and pazopanib showed no relevant toxicity. Mitochondrial toxicity and inhibition of glycolysis most likely explain hepatotoxicity associated with regorafenib, sorafenib and possibly pazopanib, but not for the other compounds investigated.     

Comparing anti-hyperglycemic activity and acute oral toxicity of three different trivalent chromium complexes in mice

Three different ligands (rutin, folate and stachyose) of chromium(III) complexes were compared to examine whether they have similar effect on anti-hyperglycemic activity as well as the acute toxicity status. Anti-hyperglycemic activities of chromium rutin complex (CrRC), chromium folate complex (CrFC) and chromium stachyose complex (CrSC) were examined in alloxan-induced diabetic mice with daily oral gavage for a period of 2 weeks at the dose of 0.5–3.0 mg Cr/kg. Acute toxicities of CrRC and CrFC were tested using ICR mice at the dose of 1.0–5.0 g/kg with a single oral gavage and observed for a period of 2 weeks. Biological activities results indicated that only CrRC and CrFC could decrease blood glucose level, reduce the activities of aspartate transaminase, alanine transaminase, alkaline phosphatase, and increase liver glycogen level. In acute toxicity study, LD₅₀ values for both CrRC and CrFC were above 5.0 g/kg. The minimum lethal dose for CrFC was above 5.0 g/kg, while that for CrRC was 1.0 g/kg. Anti-diabetic activity of those chromium complexes was not similar and their acute toxicities were also different. CrFC represent an optimal chromium supplement among those chromium complexes with potential therapeutic value to control blood glucose in diabetes and non-toxicity in acute toxicity.     

Chronic toxicity and carcinogenicity studies of chromium picolinate monohydrate administered in feed to F344/N rats and B6C3F1 mice for 2 years

Trivalent chromium (Cr(III)) has been proposed to be an essential element, which may increase sensitivity to insulin and thus participate in carbohydrate and lipid metabolism. Humans ingest Cr(III) both as a natural dietary constituent and in dietary supplements taken for weight loss and antidiabetic effects. Chromium picolinate (CP), a widely used supplement, contains Cr(III) chelated with three molecules of picolinic acid and was formulated in an attempt to improve the absorption of Cr(III). In order to examine the potential for CP to induce chronic toxicity and carcinogenicity, the NTP conducted studies of the monohydrate form (CPM) in groups of 50 male and female F344/N rats and B6C3F1 mice exposed in feed to concentrations of 0, 2000, 10,000 or 50,000 ppm for 2 years; exposure concentrations were selected following review of the data from NTP 3-month toxicity studies. Exposure to CPM did not induce biologically significant changes in survival, body weight, feed consumption, or non-neoplastic lesions in rats or mice. In male rats, a statistically significant increase in the incidence of preputial gland adenoma at 10,000 ppm was considered an equivocal finding. CPM was not carcinogenic to female rats or to male or female mice.     

Metallothionein protection of cadmium toxicity

The discovery of the cadmium (Cd)-binding protein from horse kidney in 1957 marked the birth of research on this low-molecular weight, cysteine-rich protein called metallothionein (MT) in Cd toxicology. MT plays minimal roles in the gastrointestinal absorption of Cd, but MT plays important roles in Cd retention in tissues and dramatically decreases biliary excretion of Cd. Cd-bound to MT is responsible for Cd accumulation in tissues and the long biological half-life of Cd in the body. Induction of MT protects against acute Cd-induced lethality, as well as acute toxicity to the liver and lung. Intracellular MT also plays important roles in ameliorating Cd toxicity following prolonged exposures, particularly chronic Cd-induced nephrotoxicity, osteotoxicity, and toxicity to the lung, liver, and immune system. There is an association between human and rodent Cd exposure and prostate cancers, especially in the portions where MT is poorly expressed. MT expression in Cd-induced tumors varies depending on the type and the stage of tumor development. For instance, high levels of MT are detected in Cd-induced sarcomas at the injection site, whereas the sarcoma metastases are devoid of MT. The use of MT-transgenic and MT-null mice has greatly helped define the role of MT in Cd toxicology, with the MT-null mice being hypersensitive and MT-transgenic mice resistant to Cd toxicity. Thus, MT is critical for protecting human health from Cd toxicity. There are large individual variations in MT expression, which might in turn predispose some people to Cd toxicity.     

The problem of maternal toxicity in developmental toxicity studies

Guidelines for developmental toxicity studies require that the highest dose(s) should induce some signs of maternal toxicity. However, the interpretation of the results is often difficult when developmentally toxic effects are recorded only at maternotoxic doses, as it is impossible to ascertain whether the developmental effects are maternally mediated or not. In order to avoid this source of misinterpretation we suggest to use in developmental toxicity tests for environmental chemicals the maximum dose unable to produce maternal toxic effects extrapolated by previous short term toxicity studies.     

Metabolism and hemoglobin adduct formation of acrylamide in humans.

Acrylamide (AM), used in the manufacture of polyacrylamide and grouting agents, is produced during the cooking of foods. Workplace exposure to AM can occur through the dermal and inhalation routes. The objectives of this study were to evaluate the metabolism of AM in humans following oral administration, to compare hemoglobin adduct formation on oral and dermal administration, and to measure hormone levels. The health of the people exposed under controlled conditions was continually monitored. Prior to conducting exposures in humans, a low-dose study was conducted in rats administered 3 mg/kg (1,2,3-13C3) AM by gavage. The study protocol was reviewed and approved by Institute Review Boards both at RTI, which performed the sample analysis, and the clinical research center conducting the study. (1,2,3-13C3) AM was administered in an aqueous solution orally (single dose of 0.5, 1.0, or 3.0 mg/kg) or dermally (three daily doses of 3.0 mg/kg) to sterile male volunteers. Urine samples (3 mg/kg oral dose) were analyzed for AM metabolites using 13C NMR spectroscopy. Approximately 86% of the urinary metabolites were derived from GSH conjugation and excreted as N-acetyl-S-(3-amino-3-oxopropyl)cysteine and its S-oxide. Glycidamide, glyceramide, and low levels of N-acetyl-S-(3-amino-2-hydroxy-3-oxopropyl)cysteine were detected in urine. On oral administration, a linear dose response was observed for N-(2-carbamoylethyl)valine (AAVal) and N-(2-carbamoyl-2-hydroxyethyl)valine (GAVal) in hemoglobin. Dermal administration resulted in lower levels of AAVal and GAVal. This study indicated that humans metabolize AM via glycidamide to a lesser extent than rodents, and dermal uptake was approximately 6.6% of that observed with oral uptake.     

Modulatory effect of Turnera diffusa against testicular toxicity induced by fenitrothion and/or hexavalent chromium in rats

Oxidative stress and increased production of reactive oxygen species have been implicated in pesticides and heavy metals toxicity. The objective of this study was to investigate the efficacy of Turnera diffusa Willd (damiana) on counteracting fenitrothion (FNT) and/or potassium dichromate (CrVI)‐induced testicular toxicity and oxidative injury in rats. FNT and/or CrVI intoxicated animals revealed a significant increase in thiobarbituric acid reactive substances and hydrogen peroxide levels. While, reduced glutathione and protein content, as well as antioxidant enzymes, phosphatases, and aminotransferases activities, were significantly decreased. In addition, significant changes in testosterone and follicle‐stimulating hormone levels were detected. Furthermore, histological and immunohistochemical alterations were observed in rat testes and this supported the observed biochemical changes. On the other hand, rats treated with damiana alone decreased lipid peroxidation and increased most of the examined parameters. Moreover, damiana pretreatment to FNT and/or CrVI‐intoxicated rats showed significant improvement in lipid peroxidation, enzyme activities, and hormones as compared with their respective treated groups. Conclusively, rats treated with both FNT and/or CrVI showed pronounced hazardous effect especially in their combination group in addition, Turnera diffusa had a potential protective role against FNT and/or CrVI induced testicular toxicity.     

薏苡仁多糖急性毒性及遗传毒性试验研究

目的了解薏苡仁多糖的毒理学安全性。方法小鼠急性毒性试验和遗传毒性试验（Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验）。结果薏苡仁多糖的小鼠经口LD50〉20g·kg^-1;在Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验中均呈阴性反应,未显示有遗传毒性作用。结论薏苡仁多糖基本无毒性。     

The Microtox as an alternative assay in the acute toxicity assessment of water pollutants

The toxicity of 15 chemicals was determined with the Microtox Assay System (MAS). Subsequently the sensitivity of the MAS was compared with that of standard aquatic toxicity tests, comprising 20 different species including recommended test species. The MAS yielded fairly replicable results which were comparable with those obtained with the standard tests. As the MAS does not require the culturing of test organisms and takes about 5% of the actual work involved in the standard procedures, it is suggested to use the MAS as a prescreening tool in the hazard assessment of chemicals.