Drinking water disinfection byproducts: review and approach to toxicity evaluation.
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There is widespread potential for human exposure to disinfection byproducts (DBPs) in drinking water because everyone drinks, bathes, cooks, and cleans with water. The need for clean and safe water led the U.S. Congress to pass the Safe Drinking Water Act more than 20 years ago in 1974. In 1976, chloroform, a trihalomethane (THM) and a principal DBP, was shown to be carcinogenic in rodents. This prompted the U.S. Environmental Protection Agency (U.S. EPA) in 1979 to develop a drinking water rule that would provide guidance on the levels of THMs allowed in drinking water. Further concern was raised by epidemiology studies suggesting a weak association between the consumption of chlorinated drinking water and the occurrence of bladder, colon, and rectal cancer. In 1992 the U.S. EPA initiated a negotiated rulemaking to evaluate the need for additional controls for microbial pathogens and DBPs. The goal was to develop an approach that would reduce the level of exposure from disinfectants and DBPs without undermining the control of microbial pathogens. The product of these deliberations was a proposed stage 1 DBP rule. It was agreed that additional information was necessary on how to optimize the use of disinfectants while maintaining control of pathogens before further controls to reduce exposure beyond stage 1 were warranted. In response to this need, the U.S. EPA developed a 5-year research plan to support the development of the longer term rules to control microbial pathogens and DBPs. A considerable body of toxicologic data has been developed on DBPs that occur in the drinking water, but the main emphasis has been on THMs. Given the complexity of the problem and the need for additional data to support the drinking water DBP rules, the U.S. EPA, the National Institute of Environmental Health Sciences, and the U.S. Army are working together to develop a comprehensive biologic and mechanistic DBP database. Selected DBPs will be tested using 2-year toxicity and carcinogenicity studies in standard rodent models; transgenic mouse models and small fish models; in vitro mechanistic and toxicokinetic studies; and reproductive, immunotoxicity, and developmental studies. The goal is to create a toxicity database that reflects a wide range of DBPs resulting from different disinfection practices. This paper describes the approach developed by these agencies to provide the information needed to make scientifically based regulatory decisions. (+info)
Chemistry and toxicity of flame retardants for plastics.
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An overview of commercially used flame retardants is give. The most used flame retardants are illustrated and the seven major markets, which use 96% of all flame-retarded polymers, are described. Annual flame retardant growth rate for each major market is also projected. Toxicity data are reviewed on only those compositions that are considered commercially significant today. This includes 18 compounds or families of compounds and four inherently flame-retarded polymers. Toxicological studies of flame retardants for most synthetic materials are of recent origin and only a few of the compounds have been evaluated in any great detail. Considerable toxicological problems may exist in the manufacturing of some flame retardants, their by-products, and possible decomposition products. (+info)
Predicting vehicle effects on the dermal absorption of halogenated methanes using physiologically based modeling.
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Occupational and environmental settings present opportunities for humans to come into contact with a variety of chemicals via the dermal route. The chemicals contacting the skin are likely to be diluted with a vehicle or present as a component of a mixture. In order to support risk assessment activities, we evaluated the vehicle effects on dermal penetration of two halogenated hydrocarbons, dibromomethane (DBM) and bromochloromethane (BCM). In vivo exposures to 15 combinations of of these in water, mineral oil, and corn oil vehicles were conducted, and blood was sampled for dibromomethane and bromochloromethane during the exposure at 0.5, 1, 2, 4, 8, 12, and 24 h. A physiologically based pharmacokinetic (PBPK) model was used to estimate the total amounts of dibromomethane or bromochloromethane that were absorbed during the exposure, and the dermal permeability coefficients were determined. While the permeability coefficients for dibromomethane and bromochloromethane were approximately 73- and 40-fold higher, respectively, in the water vehicle than in the corn oil, the permeability coefficient, when normalized for the skin:vehicle matrix partition coefficient, varied by less than a factor of 2. The permeability in an aqueous vehicle was then successfully used to predict the permeability coefficient for dibromomethane in a nonpolar vehicle, peanut oil. (+info)
Flame retardant exposure: polybrominated diphenyl ethers in blood from Swedish workers.
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Polybrominated diphenyl ethers (PBDEs) are used as additives in polymers and textiles to prohibit the development of fires. Because of the production and use of PBDEs, their lipophilic characteristics, and persistence, these compounds have become ubiquitous environmental contaminants. The aim of the present study was to determine potential exposures of PBDEs to clerks working full-time at computer screens and personnel at an electronics-dismantling plant, with hospital cleaners as a control group. Five PBDE congeners--2,2',4,4'-tetraBDE; 2,2',4,4',5,5'-hexaBDE; 2,2',4,4',5, 6'-hexaBDE; 2,2',3,4,4',5',6-heptaBDE; and decaBDE--were quantified in blood serum from all three categories of workers. Subjects working at the dismantling plant showed significantly higher levels of all PBDE congeners in their serum as compared to the control group. Decabromodiphenyl ether is present in concentrations of 5 pmol/g lipid weight (lw) in the personnel dismantling electronics; these concentrations are comparable to the concentrations of 2,2',4, 4'-tetraBDE. The latter compound was the dominating PBDE congener in the clerks and cleaners. The major compound in personnel at the dismantling plant was 2,2',3,4,4',5',6-heptaBDE. Concentrations of this PBDE congener are almost twice as high as for 2,2',4, 4'-tetraBDE in these workers and seventy times the level of this heptaBDE in cleaners. The total median PBDE concentrations in the serum from workers at the electronics-dismantling plant, clerks, and cleaners were 37, 7.3, and 5.4 pmol/g lw, respectively. The results show that decabromodiphenyl ether is bioavailable and that occupational exposure to PBDEs occurs at the electronics-dismantling plant. (+info)
An isotopic approach for understanding the CH(3)Br budget of the atmosphere.
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The atmospheric budget of methyl bromide (CH(3)Br), an ozone-depleting gas, is highly uncertain, because it has complex sources and sinks. Although oceans, biomass burning, and industrial production are identified as the major sources, the fraction of CH(3)Br that is contributed by each source is not well known. A mass-balance approach that exploits differences in the carbon isotopic signature (delta(13)C) of CH(3)Br sources and sinks may provide a means of reducing uncertainties in the atmospheric budget. This approach depends on the distinctiveness of industrially produced methyl bromide. Our delta(13)C measurements of industrial CH(3)Br from the three largest manufacturers worldwide yield a weighted average of -54.4 per thousand relative to the Peedee Belemnite standard. This result suggests that industrial CH(3)Br is isotopically distinct and that the carbon isotopic composition of atmospheric CH(3)Br may indicate what fraction of atmospheric CH(3)Br is anthropogenic. (+info)
Examination of low-incidence brain tumor responses in F344 rats following chemical exposures in National Toxicology Program carcinogenicity studies.
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Neoplasms in the brain are uncommon in control Fischer 344 (F344) rats; they occur at a rate of less than 1% in 2-yr toxicity/carcinogenicity studies. Furthermore, only 10 of nearly 500 studies conducted by the National Toxicology Program (NTP) showed any evidence of chemically related neoplastic effects in the brain. Generally, the brain tumor responses were considered equivocal, because the characteristics of potential neurocarcinogenic agents (such as statistically significant increased incidences, decreased latency and/or survival, and demonstration of dose-response relationships) were not observed. A thorough examination, including comparisons with a well-established historical database, is often critical in evaluating rare brain tumors. Chemicals that gave equivocal evidence of brain tumor responses were generally associated with carcinogenicity at other sites, and many chemicals were mutagenic when incubated with metabolic activating enzymes. Other factors that were supportive of the theory that marginal increases in brain tumor incidence were related to chemical exposure were that (a) some of the tumors were malignant, (b) no brain neoplasms were observed in concurrent controls from some studies, and/or (c) brain tumors were also seen following exposure to structurally related chemicals. In 2-yr studies in F344 rats (studies conducted by the NTP), equivocal evidence of carcinogenicity was observed for the following 9 chemicals: isoprene, bromoethane, chloroethane, 3,3'-dimethylbenzidine dihydrochloride, 3,3'-dimethoxybenzidine dihydrochloride, furosemide, C.I. direct blue 15, diphenhydramine hydrochloride, and 1-H-benzotriazole. Glycidol was the only chemical evaluated by the NTP with which there was clear evidence of brain tumor induction in F344 rats. Clarification of the potential neurocarcinogenic risks of chemicals that produce equivocal evidence of a brain tumor response in conventional 2-yr rodent studies may be aided by the use of transgenic mouse models that exhibit genetic alterations that reflect those present in human brain tumors as well as by the use of in utero exposures. (+info)
Oxidation of methyl halides by the facultative methylotroph strain IMB-1.
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Washed cell suspensions of the facultative methylotroph strain IMB-1 grown on methyl bromide (MeBr) were able to consume methyl chloride (MeCl) and methyl iodide (MeI) as well as MeBr. Consumption of >100 microM MeBr by cells grown on glucose, acetate, or monomethylamine required induction. Induction was inhibited by chloramphenicol. However, cells had a constitutive ability to consume low concentrations (<20 nM) of MeBr. Glucose-grown cells were able to readily oxidize [(14)C]formaldehyde to (14)CO(2) but had only a small capacity for oxidation of [(14)C]methanol. Preincubation of cells with MeBr did not affect either activity, but MeBr-induced cells had a greater capacity for [(14)C]MeBr oxidation than did cells without preincubation. Consumption of MeBr was inhibited by MeI, and MeCl consumption was inhibited by MeBr. No inhibition of MeBr consumption occurred with methyl fluoride, propyl iodide, dibromomethane, dichloromethane, or difluoromethane, and in addition cells did not oxidize any of these compounds. Cells displayed Michaelis-Menten kinetics for the various methyl halides, with apparent K(s) values of 190, 280, and 6,100 nM for MeBr, MeI, and MeCl, respectively. These results suggest the presence of a single oxidation enzyme system specific for methyl halides (other than methyl fluoride) which runs through formaldehyde to CO(2). The ease of induction of methyl halide oxidation in strain IMB-1 should facilitate its mass culture for the purpose of reducing MeBr emissions to the atmosphere from fumigated soils. (+info)
Human O(6)-alkylguanine-DNA alkyltransferase: protection against alkylating agents and sensitization to dibromoalkanes.
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O(6)-alkylguanine-DNA alkyltransferase (AGT) is a suicide protein that corrects DNA damage by alkylating agents and may also serve to activate environmental carcinogens. We expressed human wild-type and two active mutant AGTs in bacteria that lack endogenous AGT and are also defective in nucleotide excision repair, to examine the ability of the AGTs to protect Escherichia coli from DNA damage by different types of alkylating agents and, oppositely, to sensitize cells to the genotoxic effects of dibromoalkanes (DBAs). Control bacteria carrying the cloning vector alone were extremely sensitive to mutagenesis by low, noncytotoxic doses of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Expression of human wild-type AGT prevented most of this enlarged susceptibility to MNNG mutagenesis. Oppositely, cell killing required much higher MNNG concentrations and prevention by wild-type AGT was much less effective. Mutants V139F and V139F/P140R/L142M protected bacteria against MNNG-induced cytotoxicity more effectively than the wild-type AGT, but protection against the less stringent mutagenesis assay was variable. Subtle differences between wild-type AGT and the two mutant variants were further revealed by assaying protection against mutagenesis by more complex alkylating agents, such as N-ethyl-N-nitrosourea and 1-(2-chloro- ethyl)-3-cyclohexyl-1-nitrosourea. Unlike wild-type and V139F, the triple mutant variant, V139F/P140R/L142M was unaffected by the AGT inhibitor, O(6)-benzylguanine. Wild-type AGT and V139F potentiated the genotoxic effects of DBAs; however, the triple mutant virtually failed to sensitize the bacteria to these agents. These experiments provide evidence that in addition to the active site cysteine at position 145, the proline at position 140 might be important in defining the capacity by which AGTs modulate genotoxicity by environmentally relevant DBAs. The ability of AGTs to activate dibromoalkanes suggests that this DNA repair enzyme could be altered, and if expressed in tumors might be lethal by enhancing the activation of specific chemotherapeutic prodrugs. (+info)