In order to understand the possible role of reactive intermediates in the formation of tissue-specific DNA damage by chromium(VI), electron paramagnetic resonance spectroscopy was used to study the in vivo formation of chromium(V) in the liver and red blood cells of 14 day chick embryos following treatment with chromium(VI). In vivo administration of sodium dichromate onto the inner shell membrane of 14 day chick embryos resulted in the formation of a persistent chromium(V) species in liver cells (g = 1.987). The intensity of the chromium(V) signal in liver cells plateaued at 70 min and persisted for 240 min after treatment with chromium(VI). The dependence of chromium(V) formation on the dose of sodium dichromate administered to the embryo was clearly different in liver versus red blood cells. Chromium(V) was detected in red blood cells only at high doses of sodium dichromate (0.50-0.60 mmol/kg), whereas chromium(V) was undetectable in red blood cells at lower doses of sodium dichromate (0.10-0.30 mmol/kg) which produced clear evidence for chromium(V) in liver. Uptake studies showed that total chromium levels in red blood cells were 10-fold greater than in liver cells, and that up to 10% of the total chromium existed as chromium(V) in liver and red blood cells in vivo. Depletion of glutathione by pretreatment of embryos with L-buthionine-S,R-sulfoximine (BSO) for 24 hr prior to treatment with a high dose of sodium dichromate (0.60 mmol/kg) caused both a decrease in the levels of chromium(V) species produced and a decrease of chromium uptake into red blood cells 50 min after treatment. At this high dose of chromium(VI), BSO pre-treatment had no effect on the level of the chromium(V) or on chromium uptake into liver cells after a 70 min incubation period. Thus, the concentration of chromium(V) inside the cell correlated with the levels of chromium taken up into the cell. Chromium(V) may be the form of chromium which is responsible for induction of DNA damage following in vivo administration of sodium dichromate.
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: Sodium dichromate is a red or red-orange crystalline solid. It is used as oxidizing agent in the manufacture of dyes, many other synthetic organic chemicals, and inks; in chrome-tanning of hides; in electric batteries; bleaching fats, oils, sponges, resins; refining petroleum; in corrosion-inhibitors, corrosion-inhibiting paints; in many metal treatments; electroengraving of copper; mordant in dyeing; for hardening gelatin; for the defoliation of cotton plants and other plants and shrubs. It is also used as veterinary medication. HUMAN EXPOSURE AND TOXICITY: Eye contact can cause severe damage with possible loss of vision. In clinical course and toxicological findings in 18 patients intoxicated with ingested chromium salts, 17 patients ingested potassium and sodium dichromate while the remaining patients ingested chromic acid. The first stage of 6-valent chromium is characterized by its irritating effect on the gastrointestinal mucous membrane manifested by diarrhea, vomiting often with blood, leading to severe water-electrolyte disorders, acidosis and shock. Lesions to kidneys, liver and myocardium may develop in the next stage. Probably endothelium is also in injured with resulting increase in its permeability. Acute renal failure is not seen even with high levels of chromium in the urine provided, that the recovery from the shock is prompt, and adequate diuresis induced with mannitol and/or furosemide is maintained. All patients with blood chromium concentration exceeding 1 mg/100 g died. This level is of prognostic and diagnostic value indicating an ingestion and absorption of the high doses of this metal. Increased chromosome aberrations were detected in human peripheral lymphocytes cultured in vitro for 72 hr in water soluble compounds containing chromium (6+) (as sodium dichromate). Nanomolar concentrations of sodium dichromate cause DNA base oxidation in human white blood cells. ANIMAL STUDIES: In the rat, a single subcutaneous injection of sodium dichromate (20 mg/kg) causes acute renal injury and significant polyuria, proteinuria, and glycosuria (peaking 2-3 days after treatment, and returning to normal by day 5) without any changes in the plasma levels of protein, glucose, and glycated hemoglobin. Groups of 20 male and 19 female rats received 16 monthly intrapleural injections of 2 mg sodium dichromate(VI) in gelatin and were observed for up to 2 yr. One Adenocarcinoma of lung was observed, and no tumors at injection site were observed in 60 control rats. Chronic ingestion of high concentrations of sodium dichromate in drinking water induced intestinal tumors in mice. Sister chromatid exchanges and chromosome aberrations increased in CHO cells. Salmonella typhimurium strain TA102, particularly suited to the detection of oxidative mutagens, was the most sensitive out of 9 strains of S. typhimurium his- in revealing the mutagenicity of Cr(VI) compounds (sodium dichromate, calcium chromate and chromium trioxide). The rank of sensitivity was the following: TA102, TA100, TA97, TA92, TA1978, TA98, TA1538 and TA1537, TA1535 being the only insensitive strain. ECOTOXICITY STUDIES: Sodium dichromate (25 uM) increased the frequency of chromosome aberrations in the root cells using Allium anaphase-telophase test.
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：经吸入途径为A类人类致癌物；经口服途径为D类，无法归类为人类致癌物
Cancer Classification: Group A Human Carcinogen by Inhalation; Group D Not Classifiable as to Human Carcinogenicity by Oral Route
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/
1. Intratracheal instillation of sodium dichromate (CrVI) and chromium acetate hydroxide (CrIII) to male Wistar rats gave rise to increased chromium concentrations in whole blood, plasma and urine up to 72 hr post exposure; peak concentrations were reached at 6 hr after exposure. 2. The ratio of whole blood chromium to plasma chromium concentrations was significantly different for Cr(VI) and Cr(III) treatments. Both blood chromium and plasma chromium assays should therefore be used for the assessment of chromium exposure. 3. Chromium was also detected in peripheral lymphocytes. Cr(VI), but not Cr(III) accumulated significantly in the lymphocytes after treatment. These cells have potential to be used for biomarkers of the assessment of exposure to chromium compounds.
Ethyl campholenates and dihydro derivatives thereof as flavorants and
申请人：Givaudan Corporation
公开号：US05164364A1
公开（公告）日：1992-11-17
The ethyl esters of .beta.- and .gamma.-campholenic acids and of .gamma.-campholenic acid in admixture with .alpha.-campholenic acid and the ethyl esters of the corresponding dihydro derivatives have organoleptic properties which make them useful for preparing fragrances and flavors.
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.
Processes for preparing vanadium- and chlorine-free sodium bichromate which comprises concentration of a sodium chromate liquor so as to cause formation of crystals of neutral sodium chromate tetrahydrate, separation of these crystals from their mother liquor, treatment thereof with sulfuric acid, concentration of the acid solution obtained, and after separation of insoluble sodium sulfate so formed, crystallization of sodium bichromate.
Bis-basic substituted aromatic polycyclic compounds of the following structure are useful in treating conditions of delayed hypersensitivity: ##SPC1## Wherein [W] represents an aromatic polycyclic nucleus selected from fluoranthene, fluorene, fluoren-9-ol, fluoren-9-one, dibenzofuran, dibenzothiophene, carbazole, N-(lower)alkyl carbazole, xanthene, xanthone, thioxanthene, phenoxathiin, or anthraquinone; Y represents carbonyloxy, carbonylthio, oxygen, divalent sulfur or carbonyl with the provisos that when Y is carbonyloxy or carbonylthio, [W] is other than thioxanthene, phenoxathiin or anthraquinone, when Y is oxygen or divalent sulfur, [W] is other than thioxanthene or phenoxathiin, and when Y is carbonyl, [W] is other than fluoren-9-ol or anthraquinone; A represents a straight or branched alkylene chain of from 1 to 6 carbon atoms with the proviso that when Y is carbonyloxy or carbonylthio, A contains at least 2 straight chain carbon atoms, that is, an ethylene radical; R represents hydrogen, a straight or branched lower alkyl group of from 1 to 4 carbon atoms, phenyl or benzyl; and pharmaceutically useful acid addition salts.
Certain fluorenone and anthraquinone compounds, each of which is 2-substituted by a carboxyl group or a salt, ester or optionally substituted amide thereof and each of which is optionally substituted in the 5,6-,7- or 8- position, by a second carboxyl group, salt, ester or optionally substituted amide thereof, the substitutent in the 5,6-7- or 8- position of the fluorenone compounds, also being selected from cyano, halogen, nitro, alkyl, alkoxy and acyl, are useful for the relief or prophylaxis of allergic conditions.
