Journal Article•
Chromium(VI)-induced DNA Lesions and Chromium Distribution in Rat Kidney, Liver, and Lung
TL;DR: The lung and kidney may be more sensitive than liver to chromium-induced DNA damage, an observation which correlates with the reported toxicity and carcinogenicity data for chromium(VI) in both animals and humans.
Abstract: DNA lesions were detected in rat organ nuclei following an i.p. injection of sodium dichromate. Kidney, liver, and lung nuclei were examined for DNA interstrand cross-links, strand breaks, and DNA-protein cross-links using the alkaline elution technique. The time course for formation of cross-links in kidney nuclei revealed the presence of DNA interstrand and DNA-protein cross-links 1 hr after injection of sodium dichromate. By 40 hr in kidney, DNA interstrand cross-links had been repaired, but DNA-protein cross-links persisted. In liver nuclei, the time course for formation of cross-links after injection of dichromate showed a maximum in DNA-protein cross-linking at 4 hr and a maximum in DNA interstrand cross-linking at 2 hr. By 36 hr, in the liver, both types of lesions had been repaired. In lung nuclei, both DNA interstrand and DNA-protein cross-links were observed 1 hr after dichromate injection; however, by 36 hr, only DNA-protein cross-links persisted. No DNA lesions were detectable in kidney 1 hr after an i.p. injection of chromium(III) chloride. Chromium distribution in rat kidney, liver, and lung was measured and is discussed with respect to the observed DNA lesions. The lung and kidney may be more sensitive than liver to chromiuminduced DNA damage, an observation which correlates with the reported toxicity and carcinogenicity data for chromlum(VI) in both animals and humans.
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01 Sep 2012
TL;DR: This public health statement tells you about chromium and the effects of exposure to it.
Abstract: This public health statement tells you about chromium and the effects of exposure to it.The Environmental Protection Agency (EPA) identifies the most serious hazardous waste sites in the nation. These sites are then placed on the National Priorities List (NPL) and are targeted for long-term federal clean-up activities. Chromium has been found in at least 1,127 of the 1,699 current or former NPL sites. Although the total number of NPL sites evaluated for this substance is not known, the possibility exists that the number of sites at which chromium is found may increase in the future as more sites are evaluated. This information is important because these sites may be sources of exposure and exposure to this substance may be harmful.When a substance is released either from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment. Such a release does not always lead to exposure. You can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, eating, or drinking the substance, or by skin contact.If you are exposed to chromium, many factors will determine whether you will be harmed. These factors include the dose (how much), the duration (how long), the form (chromium VI as opposed to chromium III), and how you come in contact with it. You must also consider any other chemicals you are exposed to and your age, sex, diet, family traits, lifestyle, and state of health.
490 citations
TL;DR: Further information is needed regarding the potential involvement of oxygen radicals in Cr genotoxicity, the specific DNA repair pathways activated by Cr and the complex signaling mechanisms involved in the cellular response to Cr(VI).
Abstract: Certain hexavalent chromium (Cr(VI))-containing compounds are recognized occupational human lung carcinogens and may pose an environmental health risk. The carcinogenicity of Cr(VI) is targeted to particulate forms of moderate to low solubility. Soluble Cr(VI) oxyanions in the immediate cellular microenvironment traverse the cell membrane by non-specific anionic transporters. Cr(VI) is reductively metabolized within cells by agents including ascorbic acid (Asc), glutathione (GSH) and cysteine (Cys). During Cr(VI) reduction, a diverse range of genetic lesions are generated including Cr-DNA binary (mono) adducts, Cr-DNA ternary adducts, DNA protein crosslinks (DPCs), bi-functional (DNA interstrand crosslinks (ICLs)) adducts, single-strand breaks (SSBs) and oxidized bases. Some forms of Cr damage, such as ICLs, present physical barriers to DNA replication/transcription and, thus, likely promote a terminal cell fate such as apoptosis or terminal growth arrest. Other lesions, such as ternary DNA adducts, are potentially pre-mutagenic. Cr(VI) exposure elicits a classical DNA damage response within cells including activation of the p53 signaling pathway and cell cycle arrest or apoptosis. Moreover, Cr(VI) also induces the ATM-dependent DNA damage response pathway which is paradoxically required for both apoptosis and survival after Cr(VI) insult. In yeast, moderately cytotoxic concentrations of Cr(VI) result in an initial G1 arrest and delayed S phase progression, whereas less toxic levels of Cr(VI) induce G2 arrest, which requires homologous recombination for exit and survival. The past several years has witnessed many important advances in our understanding of the genetic/cellular damage produced by exposure to Cr(VI). Further information is needed regarding the potential involvement of oxygen radicals in Cr genotoxicity, the specific DNA repair pathways activated by Cr and the complex signaling mechanisms involved in the cellular response to Cr(VI). These pertinent issues must be considered in relation to the potential role that each plays in the induction of human respiratory tract cancer by particulate Cr(VI) compounds.
482 citations
TL;DR: This article reviews approximately 700 results reported in the literature with 32 chromium compounds assayed in 130 short-term tests, using different targets and/or genetic end-points, to provide useful information for predicting and interpreting the peculiar patterns of Cr(VI) carcinogenicity.
Abstract: This article reviews approximately 700 results reported in the literature with 32 chromium compounds assayed in 130 short-term tests, using different targets and/or genetic end-points. The large majority of the results obtained with Cr(VI) compounds were positive, as a function of Cr(VI) solubility and bioavailability to target cells. On the other hand, Cr(III) compounds, although even more reactive than Cr(VI) with purified nucleic acids, did not induce genotoxic effects in the majority of studies using intact cells. Coupled with the findings of metabolic studies, the large data-base generated in short-term test systems provides useful information for predicting and interpreting the peculiar patterns of Cr(VI) carcinogenicity.
428 citations
TL;DR: This review summarizes current information on the genotoxicity of arsenic, chromium, nickel, beryllium and cadmium compounds and their possible roles in carcinogenesis.
346 citations
322 citations
References
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Book•
01 Jan 1962
TL;DR: In this paper, the mean and dispersion probability of the mean propagation of errors was defined as a function of the normal error function rejection of data goodness of fit further developments standard deviation of the Mean POR method of least squares least squares with several unknowns correlations.
Abstract: Kinds of errors propagation of errors the mean and dispersion probability the meaning of probability permutations and combinations probability distributions the meaning of a probability distribution binomial distribution poisson distribution gauss distribution or normal error function rejection of data goodness of fit further developments standard deviation of the mean propagation of errors method of least squares least squares with several unknowns correlations. Appendices: summary of formulas evaluation of "n" for "o" for binomial distribution derivation of gauss distribution evaluation of normal error integral answers to problems.
461 citations
Journal Article•
TL;DR: There may be a relationship between cytotoxicity and interstrand cross-linking of cis- and trans-platinum(II) diamminedichloride on L1210 cells.
Abstract: The effects of cis- and trans-platinum(II) diamminedichloride on L1210 cells were investigated using the technique of DNA alkaline elution. Both agents produced reductions in alkaline elution rates which were partially or, in some cases, almost completely reversed by incubation of the cell lysates with proteinase K. The proteinase-sensitive component of this effect is taken to reflect DNA-protein cross-linking, while the proteinase-resistant component of this effect may include interstrand cross-links. The cytotoxicity of the two agents did not correlate with the extent of DNA-protein cross-linking but did appear to correlate with the extent of proteinase-resistant cross-linking; therefore, there may be a relationship between cytotoxicity and interstrand cross-linking.
426 citations
TL;DR: Present evidence indicates that the trivalent chromium compounds do not cause cancer although high concentrations in some in vitro systems have shown genetic toxicity, and proper action should be taken in all industries with regard to such exposure.
Abstract: The carcinogenicity of chromium compounds is reviewed with specific attention to the gaps in knowledge for risk estimation and research needs. The most important problems at present are whether trivalent chromium compounds cause cancer, and whether there is a difference in cancer causing effects between the soluble and the slightly soluble hexavalent compounds in the practical exposure situation. Dose estimates for risk estimation based on epidemiological investigations are also lacking. Present evidence indicates that the trivalent chromium compounds do not cause cancer although high concentrations in some in vitro systems have shown genetic toxicity. Hexavalent chromium compounds cause cancer in humans, in experimental animals and exert genetic toxicity in bacteria and in mammalian cells in vitro. Epidemiological evidence and animal experiments indicate that the slightly soluble hexavalent salts are the most potent carcinogens, but proper identification and characterization of exposure patterns in epidemiological work are lacking. Workers also tend to have mixed exposures. Soluble and slightly soluble salts are equally potent genotoxic agents in vitro. Further work for establishing dose estimates for risk evaluation in epidemiological work is important. In vitro systems should be applied for further identification of the mechanism of the carcinogenic effects, and animal experiments are urgent for comparison of the carcinogenic potency of the different hexavalent salts. Hexavalent chromium salts must be regarded as established carcinogens, and proper action should be taken in all industries with regard to such exposure. At present the carcinogenic risk to the general population caused by chromium compounds seems to be negligible, chromium in cigarettes, however, is an uncertainty in this respect. The amount of chromium and the type of chromium compounds inhaled from cigarettes is not known.
238 citations
Journal Article•
TL;DR: The possibility of discriminating these two classes of cross-links in L1210 cells treated with haloethylnitrosoureas or nitrogen mustard was explored with the alkaline elution technique, based on sensitivity to proteinase K; the proteinase-sensitiveCross-links appear to be DNA-protein cross- links, and the protein enzyme-resistant class may include interstrand cross- Links.
Abstract: Bifunctional alkylating agents are known to produce cross-links between DNA and protein and between paired DNA strands. The possibility of discriminating these two classes of cross-links in L1210 cells treated with haloethylnitrosoureas or nitrogen mustard was explored with the alkaline elution technique. Two classes of cross-links were demonstrated, based on sensitivity to proteinase K; the proteinase-sensitive cross-links appear to be DNA-protein cross-links, and the proteinase-resistant class may include interstrand cross-links. Proteinase-sensitive cross-links form more rapidly than do proteinase-resistant cross-links in cells treated with chloroethylnitrosoureas, perhaps because these agents can chloroethylate protein sulfhydryl or amino groups followed by rapid reaction of these chloroethylated groups with DNA. Although both types of cross-links produced by nitrogen mustard disappeared or were repaired after 24 hr, the removal of cross-links produced by chloroethylnitrosoureas either did not occur or was incomplete in 24 hr. In addition to cross-links, cells treated with haloethylnitrosoureas exhibited DNA strand breaks; a method is suggested for estimating the apparent frequencies of strand breaks and cross-links in the DNA.
172 citations
TL;DR: Normal (IMR-90) and simian virus 40-transformed human embryo cells were treated with antitumor nitrosoureas, and the effects on cell viability and cell DNA were compared, suggesting a possible difference in DNA repair between the cell lines.
Abstract: Normal (IMR-90) and simian virus 40-transformed (VA-13) human embryo cells were treated with antitumor nitrosoureas, and the effects on cell viability and cell DNA were compared. All six nitrosoureas tested were more toxic to VA-13 cells than to IMR-90 cells as measured by decrease in cell proliferation or in colony formation. The nitrosoureas capable of generating alkylisocyanates produced a smaller difference between the cell types than did derivatives lacking this capacity. DNA damage was measured by alkaline elution in cells treated with four chloroethylnitrosoureas. Whereas VA-13 cells exhibited dose-dependent interstrand crosslinking, little or none was detected in IMR-90 cells. The IMR-90 cells, however, exhibited at least as much DNA-protein crosslinking as did VA-13 cells. The results can be interpreted in terms of a possible difference in DNA repair between the cell lines.
161 citations