Zinc can enter the body through the lungs, skin, and gastrointestinal tract. Intestinal absorption of zinc is controlled by zinc carrier protein CRIP. Zinc also binds to metallothioneins, which help prevent absorption of excess zinc. Zinc is widely distributed and found in all tissues and tissues fluids, concentrating in the liver, gastrointestinal tract, kidney, skin, lung, brain, heart, and pancreas. In the bloodstream zinc is found bound to carbonic anhydrase in erythrocytes, as well as bound to albumin, _2-macroglobulin, and amino acids in the the plasma. Albumin and amino acid bound zinc can diffuse across tissue membranes. Zinc is excreted in the urine and faeces. 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, L49)
IDENTIFICATION AND USE: Zinc chromate is a lemon-yellow powder. Zinc chromates are employed primarily in priming paints used for metals, for which they provide resistance against corrosion. HUMAN EXPOSURE AND TOXICITY: Development of dermatitis from exposure to zinc chromate has been reported, but such instances are rare. An outbreak of hand dermatitis was reported amongst employees working on a new assembly line of an electronics factory. Twenty-four out of 41 employees had signs of irritant contact dermatitis. The fingertips and the dorsal parts of the hands were especially affected. In 1975, five manufacturers of chromate pigment (including zinc chromate) in Japan were examined in a study of the carcinogenicity of chromates. None of the results showed statistically significant differences that would suggest an excess risk for malignant neoplasms, particularly lung cancer, among workers engaged in the manufacture of chromate pigment in Japan. However, several other studies of workers exposed to chromium compounds have suggested an increased incidence of respiratory cancers. Lead and zinc chromates were among the chromium compounds implicated. A study was done in a pigment plant in Newark, New Jersey, USA, which utilized both of these compounds. Observed deaths from each cause were compared with expected deaths. A statistically significant relative risk of 1.6 for lung cancer was found. An increased incidence of lung cancer was also evident. A small cohort of Norwegian male workers were studied from a company which produced zinc chromate paint. They found 3 cases of bronchial carcinoma (in workers aged 41, 51, and 59) where only 0.079 was expected for the total period of observation. The three cases had six to nine years of exposure to zinc chromate dust levels of approximately 0.5 to 1.5 mg Cr/cu m. Two of the three carcinomas were found in smokers. There was also one case of nasal cancer in a man with a total of 3 months of exposure. In a study of zinc chromate spray painters and electroplaters at two large aircraft maintenance facilities, the relative excess for respiratory cancer among spray painters (21 observed vs 11.4 expected) was statistically significant. The ability of chronic exposure to zinc chromate to induce numerical chromosome instability was tested in human lung fibroblasts. The study found no increase in aneuploidy after a 24 hr exposure to zinc chromate, but with more chronic exposures, zinc chromate induced concentration- and time-dependent increases in aneuploidy in the form of hypodiploidy, hyperdiploidy, and tetraploidy. Zinc chromate also induced centrosome amplification in a concentration- and time-dependent manner in both interphase and mitotic cells after chronic exposure, producing cells with centriolar defects. Furthermore, chronic exposure to zinc chromate induced concentration- and time-dependent increases in spindle assembly checkpoint bypass with increases in centromere spreading, premature centromere division, and premature anaphase. All together, these data indicate that zinc chromate can induce chromosome instability after prolonged exposures. In human brochial cells zinc chromate was more clastogenic than all other chromium compounds. ANIMAL STUDIES: Six intratracheal injections of zinc chromate were given at 6 week intervals to 62 mice, which were observed until their death. No pulmonary carcinomas were found; pulmonary adenomas occurred in 31/62 exposed, in 7/18 untreated control and in 0/2 zinc carbonate-treated control animals. Pulmonary adenomas occurred in 1 of 21 guinea pigs that were given 6 intratracheal instillations of zinc chromate, no pulmonary adenomas occurred in controls. Chromium containing materials were examined for carcinogenic activity in a two-year study using an intrabronchial pellet implantation system whereby pellets loaded with test material were surgically implanted into the lower left bronchus of rats. Zinc chromate resulted in bronchial carcinomas in 5/100 rats tested. A further zinc chromate group produced bronchial carcinomas in 3/100, which was not statistically significant. Zinc chromate induced forward mutations to 8-azaguanine resistance in Chinese hamster V79/4 cells. Deaths in cattle believed to have had access to zinc chromate paste have been recorded in New Zealand. A daily dose of 30-40 mg/kg body weight produced severe chronic poisoning in young calves within one month. The acute lethal dose for adult cattle is about 20 times this amount. The outstanding clinical feature of the condition produced was profuse scouring, leading in chronic cases to severe dehydration and a low terminal blood pressure. Changes in the alimentary tract were the most marked post mortem finding. In acute poisoning, there was severe congestion and inflammation throughout the intestines and sloughing of the gastric mucous membranes. In chronic poisoning, congestion and inflammation were present only in the stomach (the rumen and abomasum in particular) showing severe ulceration and near perforation.
Anaemia results from the excessive absorption of zinc suppressing copper and iron absorption, most likely through competitive binding of intestinal mucosal cells. Unbalanced levels of copper and zinc binding to Cu,Zn-superoxide dismutase has been linked to amyotrophic lateral sclerosis (ALS). Stomach acid dissolves metallic zinc to give corrosive zinc chloride, which can cause damage to the stomach lining. Metal fume fever is thought to be an immune response to inhaled zinc. 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, L48, L49, A49)
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌性证据
A1; 已确认的人类致癌物。/铬酸锌，以Cr表示/
A1; Confirmed human carcinogen. /Zinc chromates, as Cr/
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/
... Chromates(VI) are absorbed /from the gastrointestinal tract/ at a rate of 3-6% in rats. ... Zinc chromate(VI) was absorbed quickly in rats exposed to known atmospheric concentrations (6.3-10.7 mg/cu m, equivalent to 1.3-2.2 mg/cu m chromium) in an inhalation chamber: a 5 fold increase in the blood chromium level was observed after 100 minutes of inhalation exposure, and this level increased at a similar rate during the next 150 minutes. Elimination from blood was slow: the blood chromium level fell by less than 50% during the first 3 days after exposure; and after 18 and 37 days, respectively, 20% and 9% of the initial concentration remained. Excretion occurred mainly via the urine.
Two groups of rats were exposed in the same zinc chromate dust cloud, 1 in open wire cages & the other in fiber glass tubes. The chromium excretion during the following 2.5 days was 8.4 times higher in feces & 5.5 times higher in urine in the animals exposed in cages compared with those exposed in tubes.
(51)Cr-labelled sodium, zinc and lead chromates were studied. Sodium chromate and the less soluble zinc chromate were absorbed by the blood, resulting in increased urinary excretion of chromium. ... The less water soluble the chromate, the higher was its elimination via the feces. Absorbed chromium was retained in the spleen and bone marrow in all three cases, and also in the liver and kidneys in the case of sodium chromate. Chromium levels in blood and urine are not indicative of inhalation exposure to insoluble chromates.
The relative significance of dust ingestion during and after short-term inhalation exposure to a zinc chromate aerosol has been studied. Two groups of rats were exposed in the same dust cloud, one in open wire cages and the other in fiber glass tubes. The chromium excretion during the following 2 1/2 days was 8.4 times higher in feces and 5.5 times higher in urine in the animals exposed in cages, compared with those exposed in tubes.
Studies on absorption and excretion of chromium in the rat exposed to known atmospheric concentrations of zinc chromate in an inhalation chamber and the influence of diurnal variations in physical activity have been carried out. Chromium analyses were performed on samples of blood, urine and feces using a method for determining chromium in small samples of biological material based on flameless atomic absorption spectrometry. Zinc chromate is absorbed quickly during exposure and excreted mainly via urine. An accumulation of chromium in blood was observed, followed by a slow elimination. It is suggested that chromium from zinc chromate enters the blood in the hexavalent state.
