The hazard evaluation system and information service: a physician's resource in toxicology and occupational medicine.
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Hazard evaluation is an emerging science. The Hazard Evaluation System and Information Service (HESIS), part of California's program in preventive occupational health, is a resource for clinicians who wish to stay abreast of the relationship between toxicology and occupational health. For example, advances in assays for cancer or reproductive effects in test animals enable us to identify with greater confidence significant cancer or reproductive hazards among the increasing variety of workplace exposures. Occupational experiences with dibromochloropropane (DBCP), Kepone, bis(chloromethyl) ether, benzidine and vinyl chloride demonstrate the shortcomings of relying on human data. The latency period of cancer, limited sensitivity of epidemiologic studies and severity of effects require us to use animal test data to evaluate the potential cancer and reproductive risks of workplace substances. HESIS gives appropriate weight to experimental data in hazard evaluations of chemicals such as ethylene oxide, ethylene dibromide, polychlorinated biphenyls and the glycol ethers. A similar approach is apparent in the California Department of Health Services' recently released Carcinogen Identification Policy. (+info)
Mortality experience of 161 employees exposed to ethylene dibromide in two production units.
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Animal studies have indicated the carcinogenic potential of ethylene dibromide (EDB). Examination of the mortality experience of employees exposed to EDB in two production units operated from 1942 to 1969 and from the mid-1920s to 1976, respectively, showed that in the first unit two deaths from malignant neoplasms were observed against 3.6 expected (based on US white male mortality), and in the second unit, where there was potential exposure to various organic bromide products, five deaths from malignant neoplasms (2.2 expected) were observed. Findings of this investigation neither rule out nor establish EDB to be a human carcinogen. Far fewer malignant neoplasms, however, have been observed than might have been expected from a direct extrapolation of data obtained from experiments on animals. (+info)
Carcinogenicity of dietary dimethylnitrosomorpholine, N-methyl-N'-nitro-N-nitrosoguanidine, and dibromoethane in rainbow trout.
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Eighteen-mo feeding trials of rainbow trout were used to test the carcinogenicity of 5 chemicals in this species. A single exposure level was used for each substance. The doses and chemicals tested were 1,556 ppm 2,6-dimethylnitrosomorpholine (DMNM), 500 ppm N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 2,000 ppm 1,2-dibromoethane (DBE), 2,000 ppm 1,1-dichloroethylene (DCE), and 200 ppm cyclophosphamide (CP). Liver and/or glandular stomach neoplasms were produced by DMNM (liver and stomach), MNNG (stomach), and DBE (chiefly, stomach tumors). In addition, DMNM produced a low incidence of swimbladder papillomas and caused testicular atrophy in 50% of treated males. DCE and CP produced no neoplasms at the exposure levels used. No evidence of other chronic toxicity was seen for any of the 5 compounds. (+info)
Changes in total nitrogen, lipoproteins and amino acids in epididymal and ejaculated spermatozoa of bulls treated orally with ethylene dibromide.
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Protein changes in epididymal and ejaculated spermatozoa were studied in bulls treated orally on alternate days with a total of 10 doses (each of 4 mg/kg body weight) of ethylene dibromide. No significant changes were found in the total nitrogen, amino acid or lipoprotein contents of the spermatozoa collected either from the epididymis 1 day after the last dose, or from ejaculates 9-13 days after the end of the treatment. Significant changes were found in the percentage composition of amino acids of the sperm proteins and lipoproteins but the changes differed in the caput, cauda and ejaculated spermatozoa. (+info)
Potential hazards of fumigant residues.
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A spectrum of fumigants (primarily ethylene dibromide, 1,2-dibromo-3-chloropropane, ethylene oxide, symdibromotetetrachloroethane, 1,3-dichloropropene, dichlorovos, carbon tetrachloride, methyl bromide) as well as their degradation products in foodstuffs and soil have been examined mainly in regard to the potential mutagenicity of their residues. (+info)
Dexamethasone inhibits induction of liver tumor necrosis factor-alpha mRNA and liver growth induced by lead nitrate and ethylene dibromide.
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We have recently demonstrated that a single injection of the mitogen lead nitrate to rats induced a rapid increase of tumor necrosis factor-alpha (TNF-alpha) mRNA in the liver and suggested that this cytokine may be involved in triggering hepatocyte proliferation in this model of direct hyperplasia. In this study, we examined whether a similar induction of liver TNF-alpha mRNA could be observed preceding the onset of hepatocyte proliferation induced by ethylene dibromide, another hepatocyte mitogen. In addition, we used dexamethasone, a well known inhibitor of TNF-alpha production, to determine whether its administration could suppress hepatocyte proliferation induced by lead nitrate and ethylene dibromide. A single intragastric administration of ethylene dibromide (100 mg/kg) to male Wistar rats enhanced liver TNF-alpha mRNA after 4 and 7 hours, which then returned to control levels by 24 hours. TNF-alpha mRNA was detectable only in a nonparenchymal cell fraction of the liver. Pretreatment of rats with a single dose of dexamethasone (2 mg/kg) 60 minutes before lead nitrate (100 mumol/kg) or ethylene dibromide completely abolished the increased levels of liver TNF-alpha mRNA induced by these agents. Inhibition by dexamethasone of TNF-alpha mRNA was associated with an inhibition of liver cell proliferation induced by these mitogens, as measured by [3H]thymidine incorporation into hepatic DNA, mitotic index, and DNA content. These results further support the hypothesis that TNF-alpha may be involved in triggering hepatocyte proliferation induced by primary mitogens. (+info)
Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes.
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Dihalomethanes can produce liver tumors in mice but not in rats, and concern exists about the risk of these compounds to humans. Glutathione (GSH) conjugation of dihalomethanes has been considered to be a critical event in the bioactivation process, and risk assessment is based upon this premise; however, there is little experimental support for this view or information about the basis of genotoxicity. A plasmid vector containing rat GSH S-transferase 5-5 was transfected into the Salmonella typhimurium tester strain TA1535, which then produced active enzyme. The transfected bacteria produced base-pair revertants in the presence of ethylene dihalides or dihalomethanes, in the order CH2Br2 > CH2BrCl > CH2Cl2. However, revertants were not seen when cells were exposed to GSH, CH2Br2, and an amount of purified GSH S-transferase 5-5 (20-fold excess in amount of that expressed within the cells). HCHO, which is an end product of the reaction of GSH with dihalomethanes, also did not produce mutations. S-(1-Acetoxymethyl)GSH was prepared as an analog of the putative S-(1-halomethyl)GSH reactive intermediates. This analog did not produce revertants, consistent with the view that activation of dihalomethanes must occur within the bacteria to cause genetic damage, presenting a model to be considered in studies with mammalian cells. S-(1-Acetoxymethyl)GSH reacted with 2'-deoxyguanosine to yield a major adduct, identified as S-[1-(N2-deoxyguanosinyl)methyl]GSH. Demonstration of the activation of dihalomethanes by this mammalian GSH S-transferase theta class enzyme should be of use in evaluating the risk of these chemicals, particularly in light of reports of the polymorphic expression of a similar activity in humans. (+info)
Human glutathione S-transferase T1-1 enhances mutagenicity of 1,2-dibromoethane, dibromomethane and 1,2,3,4-diepoxybutane in Salmonella typhimurium.
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The rat theta class glutathione S-transferase (GST) 5-5 has been shown to affect the mutagenicity of halogenated alkanes and epoxides. In Salmonella typhimurium TA1535 expressing the rat GST5-5 the number of revertants was increased compared to the control strain by CH2Br2, ethylene dibromide (EDB) and 1,2,3,4-diepoxybutane (BDE); in contrast, mutagenicity of 1,2-epoxy-3-(4'-nitro-phenoxy)propane (EPNP) was reduced. S.typhimurium TA1535 cells were transformed with an expression plasmid carrying the cDNA of the human theta ortholog GST1-1 either in sense or antisense orientation, the latter being the control. These transformed bacteria were utilized for mutagenicity assays. Mutagenicity of EDB, BDE, CH2Br2, epibromohydrin and 1,3-dichloroacetone was higher in the S.typhimurium TA1535 expressing GSTT1-1 than in the control strain. The expression of active enzyme did not affect the mutagenicity of 1,2-epoxy-3-butene or propylene oxide. GSTT1-1 expression reduced the mutagenicity of EPNP. Glutathione S-transferase 5-5 and GSTT1-1 modulate genotoxicity of several industrially important chemicals in the same way. Polymorphism of the GSTT1 locus in humans may therefore cause differences in cancer susceptibility between the two phenotypes. (+info)