Determinants of whether or not mixtures of disinfection by-products are similar.
ABSTRACT Reactive chemicals have been used to disinfect drinking waters for over a century. In the 1970s, it was first observed that the reaction of these chemicals with the natural organic matter (NOM) in source waters results in the production of variable, complex mixtures of disinfection by-products (DBP). Because limited toxicological and epidemiological data are available to assess potential human health risks from complex DBP mixture exposures, methods are needed to determine when health effects data on a specific DBP mixture may be used as a surrogate for evaluating another environmental DBP mixture of interest. Before risk assessors attempt such efforts, a set of criteria needs to be in place to determine whether two or more DBP mixtures are similar in composition and toxicological potential. This study broadly characterizes the chemical and toxicological measures that may be used to evaluate similarities among DBP mixtures. Variables are discussed that affect qualitative and quantitative shifts in the types of DBP that are formed, including disinfectants used, their reactions with NOM and with bromide/iodide, pH, temperature, time, and changes in the water distribution system. The known toxicological activities of DBP mixtures and important single DBPs are also presented in light of their potential for producing similar toxicity. While DBP exposures are associated with a number of health effects, this study focuses on (1) mutagenic activity of DBP mixtures, (2) DBP cancer epidemiology, and (3) toxicology studies to evaluate similarity among DBP mixtures. Data suggest that further chemical characterization of DBP mixtures and more systematic study of DBP toxicology will improve the quality and usefulness of similarity criteria.
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ABSTRACT: Human parasitic pathogens of the genus Leishmania are the causative agents of cutaneous, mucocutaneous, and visceral leishmaniasis. Currently, there are millions of people infected with these diseases and over 50,000 deaths occur annually. Recently, it was shown that the flavin-dependent enzyme UDP-galactopyranose mutase (UGM) is a virulence factor in Leishmania major. UGM catalyzes the conversion of UDP-galactopyranose to UDP-galactofuranose. The product, UDP-galactofuranose, is the only source of galactofuranose which is present on the cell surface of this parasite and has been implicated to be important for host-parasite interactions. The recombinant form of this enzyme was obtained in a soluble and active form. The enzyme was shown to be active only in the reduced state. A k(cat) value of 5 ± 0.2s(-1) and a K(M) value of 87 ± 11 μM were determined with UDP-galactofuranose as the substrate. Different from the dimeric bacterial and tetrameric fungal UGMs, this parasitic enzyme functions as a monomer.Biochemical and Biophysical Research Communications 03/2011; 407(3):552-6. · 2.28 Impact Factor
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ABSTRACT: When assessing risks posed by environmental chemical mixtures, whole mixture approaches are preferred to component approaches. When toxicological data on whole mixtures as they occur in the environment are not available, Environmental Protection Agency guidance states that toxicity data from a mixture considered "sufficiently similar" to the environmental mixture can serve as a surrogate. We propose a novel method to examine whether mixtures are sufficiently similar, when exposure data and mixture toxicity study data from at least one representative mixture are available. We define sufficient similarity using equivalence testing methodology comparing the distance between benchmark dose estimates for mixtures in both data-rich and data-poor cases. We construct a "similar mixtures risk indicator"(SMRI) (analogous to the hazard index) on sufficiently similar mixtures linking exposure data with mixtures toxicology data. The methods are illustrated using pyrethroid mixtures occurrence data collected in child care centers (CCC) and dose-response data examining acute neurobehavioral effects of pyrethroid mixtures in rats. Our method shows that the mixtures from 90% of the CCCs were sufficiently similar to the dose-response study mixture. Using exposure estimates for a hypothetical child, the 95th percentile of the (weighted) SMRI for these sufficiently similar mixtures was 0.20 (i.e., where SMRI <1, less concern; >1, more concern).Risk Analysis 02/2013; · 2.28 Impact Factor
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ABSTRACT: Lifetime exposure to trihalomethanes (THM) has been associated with increased risk of bladder cancer. We explored methods of analyzing bladder cancer risk associated with 4 THM (chloroform, bromodichloromethane, dibromochloromethane, and bromoform) as surrogates for disinfection by-product (DBP) mixtures in a case-control study in Spain (1998-2001). Lifetime average concentrations of THM in the households of 686 incident bladder cancer cases and 750 matched hospital-based controls were calculated. Several exposure metrics were modeled through conditional logistic regression, including the following analyses: total THM (μg/L), cytotoxicity-weighted sum of total THM (pmol/L), 4 THM in separate models, 4 THM in 1 model, chloroform and the sum of brominated THM in 1 model, and a principal-components analysis. THM composition, concentrations, and correlations varied between areas. The model for total THM was stable and showed increasing dose-response trends. Models for separate THM provided unstable estimates and inconsistent dose-response relationships. Risk estimation for specific THM is hampered by the varying composition of the mixture, correlation between species, and imprecision of historical estimates. Total THM (μg/L) provided a proxy measure of DBPs that yielded the strongest dose-response relationship with bladder cancer risk. A variety of metrics and statistical approaches should be used to evaluate this association in other settings.American journal of epidemiology 05/2013; · 5.59 Impact Factor