Chromium is absorbed from oral, inhalation, or dermal exposure and distributes to nearly all tissues, with the highest concentrations found in kidney and liver. Bone is also a major storage site and may contribute to long-term retention. Hexavalent chromium's similarity to sulfate and chromate allow it to be transported into cells via sulfate transport mechanisms. Inside the cell, hexavalent chromium is reduced first to pentavalent chromium, then to trivalent chromium by many substances including ascorbate, glutathione, and nicotinamide adenine dinucleotide. Chromium is almost entirely excreted with the urine. (A12, L16)
IDENTIFICATION AND USE: Potassium dichromate forms bright orange-red crystals. It is used in In tanning leather, dyeing, painting, printing, decorating porcelain, photolithography, pigment-prints, staining wood, pyrotechnics, and safety matches. It is also used for bleaching palm oil; in wax and sponges; waterproofing fabrics; as an oxidizer in the manufacture of organic chemicals; in electric batteries; as a depolarizer for dry cells. It is also used as corrosion inhibitor and pharmaceutical aid (oxidizing agent). HUMAN EXPOSURE AND TOXICITY: In a population of 822 healthy adult volunteers, 2% of the 410 men & 1.5% of the 412 women showed a positive patch test reaction to 0.5% potassium dichromate in petroleum. In 2981 clinic patients tested during a 5-yr period, the frequency of chromate sensitivity was 6.8% in men & 2.8% in women among all patients tested, but 20% in men & 8% in women of the 499 patients with occupational hand eczema. Ulcers (chrome holes, chrome sores or acid bites) from contact with potassium dichromate in dust or liquid form commonly occur at breaks in the skin, nailroots, creases over knuckles, finger webs, backs of hands, and on forearms. Eye contact can cause severe damage with possible loss of vision. Potassium dichromate also quadrupled frequency of sister-chromatid exchanges in cultured human fibroblasts. ANIMAL STUDIES: Flare-up reactions were induced in potassium dichromate hypersensitive guinea pigs by a single oral dose of 55 mg/kg. This dose is systemically toxic and higher than the dose required to induce the same reactions in humans. A total oral dose of 90-115 mg/kg suppressed immunologic responsiveness for at least 6 wk. To guinea pigs, 10 mg administered subcutaneously in a single dose proved lethal, while 20 mg had the same effect on rabbits. To rabbits, 0.8-2 mg administered subcutaneously in a single dose produced nephritis. Sperm obtained from male mice were treated with potassium dichromate (0, 3.125, 6.25, 12.5, 25, or 50 uM) for 3 hr. Cr(VI) significantly decreased sperm viability and acrosome reaction with increasing dose. These Cr(VI)-treated sperms were further used for IVF of oocytes obtained from female mice. Results showed that Cr(VI)-treated sperm caused a significant reduction in IVF success, higher developmental arrest at the two-cell stage of embryos, and delayed blastocyst formation with increasing dose. In particular, most blastocysts from the Cr(VI)-treated sperm resulted in hatching failure as well as decreased inner cell mass and trophectoderm (TE). In male mice treated with potassium dichromate, a reduced number of sperm count and excessive destruction of testicular follicles, including destruction of spermatids, leydig cells, and sertoli cells was found. In female rat subacute treatment causes oxidative stress in rat uterus, leading to endometriotic stromal cells apoptosis. The exposure of pregnant female rabbits to trivalent (chromium chloride) or hexavalent (potassium dichromate) chromium compounds in drinking water (500 ppm) during the organogenesis period (6-18th day of gestation) revealed embryotoxic - and fetotoxic effects. Both trivalent and hexavalent compounds induced dwarfism, kinky and short tail and a significant reduction in the number of implantation sites and in the number of viable fetuses. The number of females with resorption was significantly increased in the hexavalent-exposed group. Visceral abnormalities in the form of lung hypoplasia, heart hypertrophy, intrathoracic hemorrhage and dilated nares and brain lateral ventricles were found in the fetuses of both chromium (III, VI) treated mothers. Skeletal anomalies (reduced number of sternal and caudal bones) were also recorded in both chromium groups. Furthermore, reduced ossification in parietal and interparietal bones was significantly increased in the hexavalent chromium exposed females. Potassium dichromate induced gene conversion in Schizosaccharomyces pombe. It is also induced forward mutations to 8-azaguanine resistance in Chinese hamster V79/4 cells. Potassium dichromate given chronically ip to rats 1 mg/kg body wt, caused significant increase in chromosomal aberrations in bone marrow cells. ECOTOXICITY STUDIES: Potassium dichromate blocked sea urchins embryo development. In acute Daphnia tests, the 24 hr EC50 was 0.35 mg/L for potassium dichromate, the EC0 was 0.11 mg/L. The nominal 21 day no observed effect concn was 0.018 mg/L. The 96-hour LC50 value for potassium dichromate was estimated to be 375.8 mg/L in a static system in Cyprinus carpio.
Hexavalent chromium's carcinogenic effects are caused by its metabolites, pentavalent and trivalent chromium. The DNA damage may be caused by hydroxyl radicals produced during reoxidation of pentavalent chromium by hydrogen peroxide molecules present in the cell. Trivalent chromium may also form complexes with peptides, proteins, and DNA, resulting in DNA-protein crosslinks, DNA strand breaks, DNA-DNA interstrand crosslinks, chromium-DNA adducts, chromosomal aberrations and alterations in cellular signaling pathways. It has been shown to induce carcinogenesis by overstimulating cellular regulatory pathways and increasing peroxide levels by activating certain mitogen-activated protein kinases. It can also cause transcriptional repression by cross-linking histone deacetylase 1-DNA methyltransferase 1 complexes to CYP1A1 promoter chromatin, inhibiting histone modification. Chromium may increase its own toxicity by modifying metal regulatory transcription factor 1, causing the inhibition of zinc-induced metallothionein transcription. (A12, L16, A34, A35, A36)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌性证据
癌症分类：不太可能对人类致癌
Cancer Classification: Not Likely to be Carcinogenic to Humans
WEIGHT OF EVIDENCE CHARACTERIZATION: Under the current guidelines (1986), Cr(VI) is classified as Group A - known human carcinogen by the inhalation route of exposure. Carcinogenicity by the oral route of exposure cannot be determined and is classified as Group D. Under the proposed guidelines (1996), Cr(VI) would be characterized as a known human carcinogen by the inhalation route of exposure on the following basis. Hexavalent chromium is known to be carcinogenic in humans by the inhalation route of exposure. Results of occupational epidemiological studies of chromium-exposed workers are consistent across investigators and study populations. Dose-response relationships have been established for chromium exposure and lung cancer. Chromium-exposed workers are exposed to both Cr(III) and Cr(VI) compounds. Because only Cr(VI) has been found to be carcinogenic in animal studies, however, it was concluded that only Cr(VI) should be classified as a human carcinogen. Animal data are consistent with the human carcinogenicity data on hexavalent chromium. Hexavalent chromium compounds are carcinogenic in animal bioassays, producing the following tumor types: intramuscular injection site tumors in rats and mice, intrapleural implant site tumors for various Cr(VI) compounds in rats, intrabronchial implantation site tumors for various Cr(VI) compounds in rats and subcutaneous injection site sarcomas in rats. In vitro data are suggestive of a potential mode of action for hexavalent chromium carcinogenesis. Hexavalent chromium carcinogenesis may result from the formation of mutagenic oxidatitive DNA lesions following intracellular reduction to the trivalent form. Cr(VI) readily passes through cell membranes and is rapidly reduced intracellularly to generate reactive Cr(V) and Cr(IV) intermediates and reactive oxygen species. A number of potentially mutagenic DNA lesions are formed during the reduction of Cr(VI). Hexavalent chromium is mutagenic in bacterial assays, yeasts and V79 cells, and Cr(VI) compounds decrease the fidelity of DNA synthesis in vitro and produce unscheduled DNA synthesis as a consequence of DNA damage. Chromate has been shown to transform both primary cells and cell lines. HUMAN CARCINOGENICITY DATA: Occupational exposure to chromium compounds has been studied in the chromate production, chromeplating and chrome pigment, ferrochromium production, gold mining, leather tanning and chrome alloy production industries. Workers in the chromate industry are exposed to both trivalent and hexavalent compounds of chromium. Epidemiological studies of chromate production plants in Japan, Great Britain, West Germany, and the United States have revealed a correlation between occupational exposure to chromium and lung cancer, but the specific form of chromium responsible for the induction of cancer was not identified ... Studies of chrome pigment workers have consistently demonstrated an association between occupational chromium exposure (primarily Cr(VI)) and lung cancer. Several studies of the chromeplating industry have demonstrated a positive relationship between cancer and exposure to chromium compounds. ANIMAL CARCINOGENICITY DATA: Animal data are consistent with the findings of human epidemiological studies of hexavalent chromium ... /Chromium (VI)/
Evaluation: There is sufficient evidence in humans for the carcinogenicity of chromium(VI) compounds. Chromium(VI) compounds cause cancer of the lung. Also positive associations have been observed between exposure to Chromium(IV) compounds and cancer of the nose and nasal sinuses. There is sufficient evidence in experimental animals for the carcinogenicity of chromium(VI) compounds. Chromium(VI) compounds are carcinogenic to humans (Group 1). /Chromium(VI) compounds/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
几种Cr(III)和Cr(VI)化合物（三价铬氯化物、三价铬硝酸盐、三价铬硫酸盐、三氧化铬、重铬酸钾）在新西兰白兔和(CxO)小鼠中的急性和亚急性毒性已经确定，通过腹腔注射给药。在处理后10天以上的中位致死剂量平均为(17.9 + 或 - 1.8) X 10(-6) g铬/g体重，不论注射的Cr化合物的氧化状态如何（三价铬硫酸盐可能是个例外），但是Cr(VI)化合物的急性毒性（3天）要大得多。将整个雄性小鼠进行酸消化，这些小鼠曾腹腔注射1/6的中位致死剂量，无论是单次给药还是每周一次重复给药，并进行分析以确定Cr在全身的持久性和清除动力学。单次给予Cr(III)的小鼠在21天时保留的铬量是有Cr(VI)处理的6.5倍。当每周给予Cr(III)时，小鼠在8周内积累的Cr是有Cr(VI)处理的6倍，尽管只有后者表现出铬中毒的症状。随着进一步给予Cr(III)，全身Cr浓度继续上升，而Cr(VI)则缓慢下降。对粪便和尿液排泄的分析证实，Cr(VI)处理的小鼠在尿液和粪便中排泄的铬要比给予Cr(III)的小鼠快得多。Cr(III)和Cr(VI)化合物的不同储存和清除动力学在实验性铬致癌研究中以及在工业暴露于潜在致癌含铬尘埃或气溶胶的工人铬的毒理学中可能是重要的。
The acute and subacute toxicities of several Cr(III) and Cr(VI) compounds (chromium(3+) chloride, chromium(3+) nitrate, chromium(3+) sulfate, chromium trioxide, potassium dichromate) were determined in NZC and (CxO) mice injected ip. The distal median lethal doses (> 10 days after treatment) averaged (17.9 + or - 1.8) X 10(-6) g chromium/g body wt regardless of the oxidation state of the Cr compound injected (chromium(3+) sulfate may be an exception), but acute toxicity (3 days) was much greater with Cr(VI) compounds. Acid digests of entire male mice that were administered ip 1/6 of the distal LD50, either once or repeatedly at weekly intervals, were analyzed to determine the whole body persistence and clearance kinetics of Cr. Mice dosed once with Cr(III) retained 6.5 times more chromium at 21 days than mice treated with Cr(VI). When Cr(III) was given at weekly intervals mice accumulated 6 times more Cr by 8 wk than Cr(VI)-treated mice, though only the latter showed symptoms of chromic toxicity. Whole body Cr concentrations continued to rise with further Cr(III) treatments, but slowly declined with Cr(VI). Analyses of fecal and urinary excretion confirmed that most of the urinary Cr excretion from Cr(VI)-treated animals was much faster in both urine and feces than from mice given Cr(III). The differential storage and clearance kinetics of Cr(III) and Cr(VI) compounds may be significant in experimental Cr carcinogenesis studies and in the toxicology of Cr in workers exposed industrially to potentially carcinogenic chromium-containing dusts or aerosols.
The interaction of potassium dichromate (Cr(VI)) with bovine serum albumin (BSA) was investigated by fluorescence, synchronous fluorescence, resonance light scattering (RLS), ultraviolet-visible absorption, and circular dichroism (CD) spectroscopies under simulated physiological conditions. The experimental results showed that Cr(VI) could quench the intrinsic fluorescence of BSA following a static quenching process, which indicates the formation of a Cr(VI)-BSA complex. The binding constant (KA) and binding site (n) were measured at different temperatures. The spectroscopic results also revealed that the binding of Cr(VI) to BSA can lead to the loosening of the protein conformation and can change the microenvironment and skeleton of BSA.
Protein Kinase Inhibitors (Variants), Use Thereof in Treating Oncological Diseases and a Pharmaceutical Composition Based Thereon
申请人：Obshchestvo s ogranichennoy otvetstvennostyou "Fusion Pharma"
公开号：US20140213592A1
公开（公告）日：2014-07-31
The present invention relates to the treatment of oncological, chronic inflammatory and similar diseases with the aid of new families of chemical compounds having improved efficiency with regard to the inhibition of Abl kinase and mutant forms thereof, as well as other therapeutically significant kinases. It describes protein kinase inhibitors in the form of compounds of general formula (I) and compounds of general formula (II), or a tautomer, an individual isomer, a mixture of isomers, a pharmaceutically acceptable salt, a solvate or a hydrate thereof.
A polymerisation catalyst comprising (1) a transition metal compound of Formula A, and optionally (2) an activating quantity of a Lewis acid activator, Formula (A), wherein Z is a five-membered heterocyclic group containing at least one carbon atom, at least one nitrogen atom and at least one other hetero atom selected from nitrogen, sulphur and oxygen, the remaining atoms in the ring being nitrogen or carbon; M is a metal from Group 3 to 11 of the Periodic Table or a lanthanide metal; E
1
and E
2
are divalent groups from (i) aliphatic hydrocarbon, (ii) alicyclic hydrocarbon, (iii) aromatic hydrocarbon, (iv) alkyl substituted aromatic hydrocarbon (v) heterocyclic groups and (vi) heterosubstituted derivatives of groups (i) to (v); D′ and D
2
are donor groups; X is an anionic group, L is a neutral donor group; n=m=zero or
1
; y and z are zero or integers. The catalysts are useful for polymerising or oligomerising
1
-olefins.
Antiviral compositions containing bis-basic ketones of xanthene and
申请人：Richardson-Merrell Inc.
公开号：US03957989A1
公开（公告）日：1976-05-18
Novel bis-basic ketones of xanthene and xanthen-9-one have antiviral activity when administered orally and parenterally. The compounds are represented by the following formula: ##SPC1## Wherein Z is oxygen or H.sub.2 ; each A is a straight or branched alkylene chain having from 1 to about 6 carbon atoms; and each Y is A. the group ##EQU1## wherein R.sup.1 and R.sup.2 are individually hydrogen, lower alkyl having from 1 to about 6 carbon atoms, cycloalkyl having from 3 to 6 carbon atoms, alkenyl of from 3 to 6 carbon atoms and having the vinyl unsaturation in other than the 1-position of the alkenyl group; or B. the group ##EQU2## WHEREIN N IS A WHOLE INTEGER FROM 4 TO 6, AND R.sup.3 is hydrogen, lower alkyl of from 1 to about 4 carbon atoms and can be linked to any one of the carbon atoms of the heterocyclic group; or C. the group ##EQU3## wherein X is oxygen or NR.sup.4, and R.sup.4 is hydrogen or lower alkyl of from 1 to about 4 carbon atoms; Or a pharmaceutically acceptable acid addition salt thereof. These compounds can be prepared by several different methods.
A process for the preparation of trialkyl and trialkenyl phosphates. The process involves oxidation of the corresponding phosphite with oxygen or an oxygen-containing gas. The oxidation is catalyzed by a metal catalyst such as a transition metal carboxylate, for example, and is carried out at relatively low temperatures.
Novel metal-micelle asbestos and treatment of asbestos and other
申请人：Flow General, Inc.
公开号：US04401636A1
公开（公告）日：1983-08-30
Silicate minerals, including asbestos fibres, are rendered less harmful by forming metal-micelle polymer coatings on the silicate. A metal-micelle polymer coating is formed on a silicate by contacting a silicate mineral, such as asbestos, with a metal-weak base-strong acid aqueous ion system, or a metal-strong base-weak acid ion system. In these systems the metal is selected from the group consisting of manganese, chromium, cobalt, iron, copper, aluminum and mixtures of these metals. The product of reacting asbestos fibres with these systems is less irritating to living cells than asbestos fibres and also has substantially the same physical and chemical properties as asbestos fibres and can thus be substituted for asbestos fibres in most technological applications.
