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  • 1
    Electronic Resource
    Electronic Resource
    A Biologically-Based Dose—Response Model for Developmental Toxicology (1996)
    Oxford, UK : Blackwell Publishing Ltd
    Risk analysis 16 (1996), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: The methods currently used to evaluate the risk of developmental defects in humans from exposure to potential toxic agents do not reflect biological processes in extrapolating estimated risks to low doses and from test species to humans. We develop a mathematical model to describe aspects of the dynamic process of organogenesis, based on branching process models of cell kinetics. The biological information that can be incorporated into the model includes timing and rates of dynamic cell processes such as differentiation, migration, growth, and replication. The dose-response models produced can explain patterns of malformation rates as a function of both dose and time of exposure, resulting in improvements in risk assessment and understanding of the underlying mechanistic processes. To illustrate the use of the model, we apply it to the prediction of the effects of methylmercury on brain development in rats.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1539-6924.1996.tb01092.x
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Who Holds the Stakes? A Case Study of Stakeholder Identification at Two Nuclear Weapons Production Sites (1996)
    Oxford, UK : Blackwell Publishing Ltd
    Risk analysis 16 (1996), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Traditional risk assessments, including those involving the United States Department of Energy (USDOE), are often criticized for producing useless or noncredible management responses because they did not meaningfully involve the public. The first step to involve the public is to identify appropriate active participants (stakeholders). This study was done to understand the processes used to identify stakeholders to serve on advisory boards established at the two largest remediation sites in the United States: the Hanford Nuclear Reservation in Washington state and the Savannah River Site in South Carolina. The Hanford stakeholder identification process produced an interest-based board whereas the Savannah River Site strategy produced population-based representation. The basic goals of the stakeholder advisory groups were similar. However, different processes were used to identify the participants for the groups in part because of distinctly different social and cultural conditions in the areas affected by the operations of the two facilities, and in part because of the different level of trust of the USDOE and their contractors at Hanford compared with Savannah River. The discussion analyzes their different needs and potential for successful citizen participation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1539-6924.1996.tb01454.x
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Risk Estimation and Value-of-Information Analysis for Three Proposed Genetic Screening Programs for Chronic Beryllium Disease Prevention (2000)
    Boston, USA and Oxford, UK : Blackwell Publishers Inc.
    Risk analysis 20 (2000), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Genetic differences (polymorphisms) among members of a population are thought to influence susceptibility to various environmental exposures. In practice, however, this information is rarely incorporated into quantitative risk assessment and risk management. We describe an analytic framework for predicting the risk reduction and value-of-information (VOI) resulting from specific risk management applications of genetic biomarkers, and we apply the framework to the example of occupational chronic beryllium disease (CBD), an immune-mediated pulmonary granulomatous disease. One described Human Leukocyte Antigen gene variant, HLA-DPβ1*0201, contains a substitution of glutamate for lysine at position 69 that appears to have high sensitivity (∼94%) but low specificity (∼70%) with respect to CBD among individuals occupationally exposed to respirable beryllium. The expected postintervention CBD prevalence rates for using the genetic variant (1) as a required job placement screen, (2) as a medical screen for semiannual in place of annual lymphocyte proliferation testing, or (3) as a voluntary job placement screen are 0.08%, 0.8%, and 0.6%, respectively, in a hypothetical cohort with 1% baseline CBD prevalence. VOI analysis is used to examine the reduction in total social cost, calculated as the net value of disease reduction and financial expenditures, expected for proposed CBD intervention programs based on the genetic susceptibility test. For the example cohort, the expected net VOI per beryllium worker for genetically based testing and intervention is $13,000, $1,800, and $5,100, respectively, based on a health valuation of $1.45 million per CBD case avoided. VOI results for alternative CBD valuations are also presented. Despite large parameter uncertainty, probabilistic analysis predicts generally positive utility for each of the three evaluated programs when avoidance of a CBD case is valued at $1 million or higher. Although the utility of a proposed risk management program may be evaluated solely in terms of risk reduction and financial costs, decisions about genetic testing and program implementation must also consider serious social, legal, and ethical factors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/0272-4332.00009
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Use of Quality-Adjusted Life Year Weights with Dose-Response Models for Public Health Decisions: A Case Study of the Risks and Benefits of Fish Consumption (2000)
    Boston, USA and Oxford, UK : Blackwell Publishers Inc.
    Risk analysis 20 (2000), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Risks associated with toxicants in food are often controlled by exposure reduction. When exposure recommendations are developed for foods with both harmful and beneficial qualities, however, they must balance the associated risks and benefits to maximize public health. Although quantitative methods are commonly used to evaluate health risks, such methods have not been generally applied to evaluating the health benefits associated with environmental exposures. A quantitative method for risk-benefit analysis is presented that allows for consideration of diverse health endpoints that differ in their impact (i.e., duration and severity) using dose-response modeling weighted by quality-adjusted life years saved. To demonstrate the usefulness of this method, the risks and benefits of fish consumption are evaluated using a single health risk and health benefit endpoint. Benefits are defined as the decrease in myocardial infarction mortality resulting from fish consumption, and risks are defined as the increase in neurodevelopmental delay (i.e., talking) resulting from prenatal methylmercury exposure. Fish consumption rates are based on information from Washington State. Using the proposed framework, the net health impact of eating fish is estimated in either a whole population or a population consisting of women of childbearing age and their children. It is demonstrated that across a range of fish methylmercury concentrations (0–1 ppm) and intake levels (0–25 g/day), individuals would have to weight the neurodevelopmental effects 6 times more (in the whole population) or 250 times less (among women of child-bearing age and their children) than the myocardial infarction benefits in order to be ambivalent about whether or not to consume fish. These methods can be generalized to evaluate the merits of other public health and risk management programs that involve trade-offs between risks and benefits.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/0272-4332.204050
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    Paper (German National Licenses)
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  • 5
    Electronic Resource
    Electronic Resource
    A Model for Optimization of Biomarker Testing Frequency to Minimize Disease and Cost: Example of Beryllium Sensitization Testing (2003)
    350 Main Street , Malden , MA 02148 , USA , and 9600 Garsington Road , Oxford OX4 2DQ , UK . : Blackwell Publishing, Inc.
    Risk analysis 23 (2003), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: A common problem with medical surveillance programs using biomarkers is determining the optimal frequency of testing to minimize adverse health effects and cost. In the case of beryllium-exposed workers, frequency of testing for beryllium sensitization may be especially important. Recent studies indicate a lack of dose response for beryllium sensitization, but do support a dose response for the development of chronic beryllium disease (CBD). Though unproven, this implies that early identification of sensitization and immediate removal from exposure may reduce development of CBD. A model is proposed to project the optimal frequency of sensitization testing using the current beryllium lymphocyte proliferation test (BeLPT) to minimize disease-related costs, assuming that a positive BeLPT will precede CBD. Conversion rates for cumulative exposure to disease development were adapted from the literature and used with testing costs and cost of disease estimates in the model. The model was run assuming several test frequency regimes. Results support the use of periodic testing in line with the annual schedule proposed in the Final Chronic Beryllium Disease Prevention Program Rule (1999) following initial testing within three months of first beryllium exposure. The financial and health benefits of reducing the time from exposure to detection of early disease was also explored with the model and demonstrated as a highly desirable characteristic for an alternative test or improved BeLPT. Limitations of the approach are discussed as well as options for adapting this biomarker optimization methodology to consider biomarkers of other exposure-associated diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.0272-4332.2003.00396.x
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    Paper (German National Licenses)
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  • 6
    Electronic Resource
    Electronic Resource
    Effects of Uncertainties on Exposure Estimates to Methylmercury: A Monte Carlo Analysis of Exposure Biomarkers versus Dietary Recall Estimation (2001)
    Boston, USA and Oxford, UK : Blackwell Publishers Inc.
    Risk analysis 21 (2001), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: This article presents a general model for estimating population heterogeneity and “lack of knowledge” uncertainty in methylmercury (MeHg) exposure assessments using two-dimensional Monte Carlo analysis. Using data from fish-consuming populations in Bangladesh, Brazil, Sweden, and the United Kingdom, predictive model estimates of dietary MeHg exposures were compared against those derived from biomarkers (i.e., [Hg]hair and [Hg]blood). By disaggregating parameter uncertainty into components (i.e., population heterogeneity, measurement error, recall error, and sampling error) estimates were obtained of the contribution of each component to the overall uncertainty. Steady-state diet:hair and diet:blood MeHg exposure ratios were estimated for each population and were used to develop distributions useful for conducting biomarker-based probabilistic assessments of MeHg exposure. The 5th and 95th percentile modeled MeHg exposure estimates around mean population exposure from each of the four study populations are presented to demonstrate lack of knowledge uncertainty about a best estimate for a true mean. Results from a U.K. study population showed that a predictive dietary model resulted in a 74% lower lack of knowledge uncertainty around a central mean estimate relative to a hair biomarker model, and also in a 31% lower lack of knowledge uncertainty around central mean estimate relative to a blood biomarker model. Similar results were obtained for the Brazil and Bangladesh populations. Such analyses, used here to evaluate alternative models of dietary MeHg exposure, can be used to refine exposure instruments, improve information used in site management and remediation decision making, and identify sources of uncertainty in risk estimates.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/0272-4332.215157
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    Paper (German National Licenses)
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  • 7
    Electronic Resource
    Electronic Resource
    Comments on “An Approach for Modeling Noncancer Dose Responses with an Emphasis on Uncertainty” and “A Probabilistic Framework for the Reference Dose (Probabilistic RfD)” (1998)
    Oxford, UK : Blackwell Publishing Ltd
    Risk analysis 18 (1998), S. 0 
    Details
    ISSN: 1539-6924
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1539-6924.1998.tb01107.x
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    Paper (German National Licenses)
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  • 8
    Electronic Resource
    Electronic Resource
    Comments on “An Approach for Modeling Noncancer Dose Responses with an Emphasis on Uncertainty” and “A Probabilistic Framework for the Reference Dose (Probabilistic RfD)” (1998)
    Springer
    Risk analysis 18 (1998), S. 663-664 
    Details
    ISSN: 1539-6924
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/B:RIAN.0000006251.60930.03
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    Paper (German National Licenses)
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  • 9
    Electronic Resource
    Electronic Resource
    Expression of developmentally relevant proteins by rodent embryo CNS cells in vivo and in vitro: Proto-oncogene pp60c-src and high molecular weight neurofilament protein (1992)
    Springer
    Cell biology and toxicology 8 (1992), S. 113-128 
    Details
    ISSN: 1573-6822
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The expression of proteins that play a role in neuronal differentiation was examined in central nervous system (CNS) micromass embryo cell cultures and compared to expression at comparable developmental stages in vivo. The protein product of the src proto-oncogene (pp60c-src) has been postulated to have a specific role in development because, although it is expressed in many tissues, marked increases in amount and activity of pp60c-src occur in neurons at the time of differentiation. Another protein of interest, high molecular weight neurofilament (NF) protein, is found in differentiated neurons. In the present study, changes over time in the expression of these two proteins in vitro and in vivo were examined. In the micromass cell cultures, primary cells from day 12 rat embryo CNS are plated at high density and differentiate into neurons during five days in culture. Tissues from embryos grown in vivo were assessed at 12 and 17 days post-coitum. Proteins were quantified by PAGE separation of equal amounts of total protein followed by transfer to membranes, immunoblotting, and densitometric scanning of blots. Increases in the amount of both proteins with neuronal differentiation was shown. Protein kinase activity of immunoprecipitated pp60c-src also increased in cell cultures and in embryos. Similarity in patterns of expression between in vitro and in vivo tissue samples provides further evidence that the cultures closely simulate in vivo differentiation and are a useful system for examining expression of developmental genes in vitro.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00260562
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