Mechanistic aspects of cyanogenesis from active-site mutant Ser80Ala of hydroxynitrile lyase from Manihot esculenta in complex with acetone cyanohydrin.
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The structure and function of hydroxynitrile lyase from Manihot esculenta (MeHNL) have been analyzed by X-ray crystallography and site-directed mutagenesis. The crystal structure of the MeHNL-S80A mutant enzyme has been refined to an R-factor of 18.0% against diffraction data to 2.1-A resolution. The three-dimensional structure of the MeHNL-S80A-acetone cyanohydrin complex was determined at 2.2-A resolution and refined to an R-factor of 18.7%. Thr11 and Cys81 involved in substrate binding have been substituted by Ala in site-directed mutagenesis. The kinetic measurements of these mutant enzymes are presented. Combined with structural data, the results support a mechanism for cyanogenesis in which His236 as a general base abstracts a proton from Ser80, thereby allowing proton transfer from the hydroxyl group of acetone cyanohydrin to Ser80. The His236 imidazolium cation then facilitates the leaving of the nitrile group by proton donating. (+info)
Sharing toxicological information on industrial chemicals.
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A clear and comprehensive appreciation of the toxicological hazards of a substance is an essential prerequisite to establishing appropriate, balanced and effective risk management measures in the workplace. For many substances, there are currently numerous problems and issues surrounding: the adequacy of the toxicological information base; its interpretation; the transfer of key messages to, and their understanding by, those who need to take action; and the roles and practices of the various standard-setting bodies operating in this area and the interaction between them. This paper briefly touches on these issues, on a range of activities and initiatives directed at improving the current situation, and on the implications for all those involved, particularly the world occupational hygiene community. (+info)
Parental occupational exposures to chemicals and incidence of neuroblastoma in offspring.
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To evaluate the effects of parental occupational chemical exposures on incidence of neuroblastoma in offspring, the authors conducted a multicenter case-control study, using detailed exposure information that allowed examination of specific chemicals. Cases were 538 children aged 19 years who were newly diagnosed with confirmed neuroblastoma in 1992-1994 and were registered at any of 139 participating hospitals in the United States and Canada. One age-matched control for each of 504 cases was selected through random digit dialing. Self-reported exposures were reviewed by an industrial hygienist, and improbable exposures were reclassified. Effect estimates were calculated using unconditional logistic regression, adjusting for child's age and maternal demographic factors. Maternal exposures to most chemicals were not associated with neuroblastoma. Paternal exposures to hydrocarbons such as diesel fuel (odds ratio (OR) = 1.5; 95% confidence interval (CI): 0.8, 2.6), lacquer thinner (OR = 3.5; 95% CI: 1.6, 7.8), and turpentine (OR = 10.4; 95% CI: 2.4, 44.8) were associated with an increased incidence of neuroblastoma, as were exposures to wood dust (OR = 1.5; 95% CI: 0.8, 2.8) and solders (OR = 2.6; 95% CI: 0.9, 7.1). The detailed exposure information available in this study has provided additional clues about the role of parental occupation as a risk factor for neuroblastoma. (+info)
Biologically motivated quantitative models and the mixture toxicity problem.
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The article highlighted in this issue is "A PBPK Modeling-Based Approach to Account for Interactions in the Health Risk Assessment of Chemical Mixtures" by Sami Haddad, Martin Beliveau, Robert Tardif, and Kannan Krishnan (pp. 125-131). (+info)
Analyzing exposure of school children to accidental releases of hazardous substances.
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Concerns regarding consequences of hazardous chemical accidents and children's environmental health have increased substantially in recent years. The objectives of this paper are to: (a) demonstrate a methodology for identifying areas potentially exposed to accidental releases of hazardous substances in a large metropolitan region (Hillsborough County, Florida); (b) examine the number and type of schools and school children at risk; and (c) explore the relationship between potential exposure levels and school enrollment patterns in the region. Methods based on the integration of environmental modeling and geographic information systems (GIS) technology are used to achieve these goals. The results indicate that almost 80% of schools and enrolled students in the study area is potentially exposed to worst-case accidents. Compared to elementary school children, a higher proportion of middle school children and a lower proportion of high school students are exposed to multiple releases of hazardous chemicals. A significant and negative association is observed between exposure levels and school enrollment size, which suggests fewer children in regions of highest exposure. (+info)
Trangenic fish as models in environmental toxicology.
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Historically, fish have played significant roles in assessing potential risks associated with exposure to chemical contamination in aquatic environments. Considering the contributions of transgenic rodent models to biomedicine, it is reasoned that the development of transgenic fish could enhance the role of fish in environmental toxicology. Application of transgenic fish in environmental studies remains at an early stage, but recent introduction of new models and methods demonstrates progress. Rapid advances are most evident in the area of in vivo mutagenesis using fish carrying transgenes that serve as recoverable mutational targets. These models highlight many advantages afforded by fish as models and illustrate important issues that apply broadly to transgenic fish in environmental toxicology. Development of fish models carrying identical transgenes to those found in rodents is beneficial and has revealed that numerous aspects of in vivo mutagenesis are similar between the two classes of vertebrates. Researchers have revealed that fish exhibit frequencies of spontaneous mutations similar to rodents and respond to mutagen exposure consistent with known mutagenic mechanisms. Results have demonstrated the feasibility of in vivo mutation analyses using transgenic fish and have illustrated their potential value as a comparative animal model. Challenges to development and application of transgenic fish relate to the needs for improved efficiencies in transgenic technology and in aspects of fish husbandry and use. By taking advantage of the valuable and unique attributes of fish as test organisms, it is anticipated that transgenic fish will make significant contributions to studies of environmentally induced diseases. (+info)
Increasing worker and community awareness of toxic hazards in the workplace.(39/726)