Evaluating the 10X Uncertainty Factor for Children and Elderly with Data-Derived Values for Neuromuscular Blocking Agents

Conventional risk assessment process utilizes a 10-fold uncertainty factor (UF) to extrapolate from the general human population to sensitive subgroups, such as children and elderly. The purpose of this investigation was to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharmacody-namic data are incorporated to characterize human sensitivity. An extensive literature search was conducted on seven neuromuscular blocking agents (mivacurium, atracurium, rocuronium, vecuronium, doxacurium, pancuronium, pipecuronium). Composite factors (kinetics × dynamics) were calculated using the highest data-derived kinetic and dynamic values. For the drugs examined, all of the composite factors for the sensitivity of children were lower than 5. In the elderly, all of the composite factors were lower than 10, and five of seven composite factors were less than 5. From this study, it was concluded that relevant compound-specific kinetic and dynamic data can reduce the uncertainties associated with sensitive subgroups.     

A Study of Safety Factors for Risk Assessment of Drugs Used for Treatment of Attention Deficiency Hyperactivity Disorder in Sensitive Populations

The aim of this study was to search the literature through the library and Internet resources from pharmaceutical companies and associations to obtain pharmacoki-netic and pharmacodynamic data for six of the most used drugs for treatment of Attention Deficiency Hyperactivity Disorder (ADHD). The drugs included meth-ylphenidate, pemoline, haloperidol, bupropion, imipramine, and desipramine. The data collected allowed the evaluation of the 10X uncertainty factor, which was related to healthy adults and sensitive populations (children, elderly and health affected). Once the extensive database review was completed, the data were used to calculate a composite factor (kinetics x dynamics) for each drug. Ten of the 12 data-derived composite factors were less than 10. Therefore, incorporation of human kinetic and dynamic data into risk assessment can help to reduce the uncertainties associated with sensitive subgroups.     

Application of Kinetic and Dynamic Data for Antihistamines to Risk Characterization in Sensitive Populations

A major goal of risk assessment is to protect the health of individuals who may be more sensitive than the general population. This study compared human phar-macokinetic and pharmacodynamic data in sensitive groups (i.e., children, the elderly, diseased states, and poor metabolizers) versus young, healthy adults for the antihistamines cetirizine, fexofenadine, loratadine, azelastine, ebastine, chlorpheniramine, and diphenhydramine. The default components (3.16 each for kinetic and dynamic aspects) of the intraspecies uncertainty factor were adjusted with compound specific data for the antihistamines. The majority (16 of 18) of the composite factors (kinetics X dynamics) for the sensitive groups were less than 10. Children had the lowest composite factors for antihistamines, ranging from 1.1 to 6.3. Application of kinetic and dynamic data for antihistamines to the Renwick/International Programme on Chemical Safety (IPCS) scheme can aid in characterizing the extent of variability in sensitive populations, thereby reducing the uncertainty associated with the risk assessment of sensitive populations.     

Pathway-Related Factors: The Potential for Human Data to Improve the Scientific Basis of Risk Assessment

The default uncertainty factors used for risk assessment are applied either to allow for different aspects of extrapolation of the dose-response curve or to allow for database deficiencies. Replacement of toxicokinetic or toxicodynamics defaults by chemical-specific data allows the calculation of a chemical-specific “data-derived factor”, which is the product of chemical-specific values and default uncertainty factors. Such chemical-specific composite values will improve the scientific basis of the risk assessment of that chemical, but the necessary chemical-specific data are rarely available. Categorical defaults related to pathways of elimination and mechanisms of toxicity could be used when the overall fate or mechanism is known, but there are no chemical-specific data sufficient to allow replacement of the default, and the development of an overall data-derived factor. The development of pathway-related categorical defaults is being undertaken using data on selected probe substrates for which adequate data are available. The concept and difficulties of this approach are illustrated using data for CYP1A2.     

Extrapolation in Risk Assessment: Improving the Quantification of Uncertainty,and Improving Information to Reduce the Uncertainty

Risk assessments inevitably extrapolate from the known to the unknown. The resulting calculation of risk involves two fundamental kinds of uncertainty: uncertainty owing to intrinsically unpredictable (random) components of the future events, and uncertainty owing to imperfect prediction formulas (parameter uncertainty and error in model structure) that are used to predict the component that we think is predictable. Both types of uncertainty weigh heavily both in health and ecological risk assessments. Our first responsibility in conducting risk assessments is to ensure that the reported risks correctly reflect our actual level of uncertainty (of both types). The statistical methods that lend themselves to correct quantification of the uncertainty are also effective for combining different sources of information. One way to reduce uncertainty is to use all the available data. To further sharpen future risk assessments, it is useful to partition the uncertainty between the random component and the component due to parameter uncertainty, so that we can quantify the expected reduction in uncertainty that can be achieved by investing in a given amount of future data. An example is developed to illustrate the potential for use of comparative data, from toxicity testing on other species or other chemicals, to improve the estimates of low-effect concentration in a particular case with sparse case-specific data.     

Differential Sensitivity of Children and Adults to Chemical Toxicity

Children, particularly neonates, can be biologically more sensitive to the same toxicant on a body weight basis than adults. Current understanding of the rates of maturation of metabolism and evidence from case studies indicate that human infants up to 6 months of age typically lack the capacity to detoxify and eliminate substances as readily as adults. For most chemicals, the infant physiologic systems usually produce higher blood levels for longer periods. The newborn's metabolic capacity rapidly matures and, by 6 months of age, children are usually not more sensitive than adults based on their pharmacokinetic competence. Whether children are at greater risk from chemical exposures is another question. Drawing conclusions about the ability of the U.S. Environmental Protection Agency's intraspecies (UF_H) and database (UF_D) uncertainty factors to protect children on the basis of the modest data available is challenging. However, virtually all studies available suggest that a high percentage of the population, including children, is protected by using a 10-fold UF_H or by using a 3.16-fold factor each for toxicokinetic and toxicodynamic variability. Based on specific comparisons for newborns, infants, children, adults and those with severe disease, the population protected is between 60% and 100%, with the studies in larger populations that include sensitive individuals suggesting that the value is closer to 100%. UF_D is likewise protective when used with databases that are missing substantive studies.     

Harmonizing the Incorporation of Uncertainty and Variability Into Risk Assessment: An International Approach

International harmonization of risk assessment approaches affords a number of opportunities and advantages. Overall, harmonization will lead to more efficient use of resources, but also will lead to better understanding amongst scientists and regulators worldwide. It is with these goals in mind that in 1994 the International Programme on Chemical Safety (IPCS) initiated its Project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals (Harmonization Project). An ongoing activity under this project addresses uncertainty and variability in risk assessment. The goal of the overall activity is to promote harmonization of risk assessment methodologies for noncancer endpoints. However, given the common links in uncertainty and variability that apply across a range of end-point-specific activities, these links are identified wherever possible. This paper provides an overview of the IPCS Harmonization Project and reviews the activity and future plans related to uncertainty and variability.     

Risk Analysis,Uncertainty Factors,and the Susceptibilities of Children

This article examines the use of uncertainty factors (UFs) by the Agency for Toxic Substances and Disease Registry (ATSDR) when developing health guidance values known as minimal risk levels (MRLs) in environmental risk analysis as it applies to children. Improvements in the chemical-specific databases often reveal new information and thereby reduce uncertainty or alternatively raise new concerns. As a result, MRLs can and will change. Children, in particular, are not “small adults” and in some instances demonstrate greater risks of exposure to environmental toxicants and greater susceptibility for adverse health effects once exposed. Recent experience with risk analysis for three toxicants (organic mercury, dioxin, and manganese) is recounted to demonstrate how ATSDR has revised MRLs as the emerging science generates greater knowledge and awareness of children's special vulnerabilities to toxic substances in the environment.     

A Perspective on the Effectiveness of Risk Assessment by First-Line Workers and Supervisors in a Safety Management System

In 1996, the Los Alamos National Laboratory restructured its safety management system to require formal hazard analysis and risk determination for its operations and activities. This paper provides a perspective on the effectiveness of those efforts. An overview of the safety management system is provided, and some influencing factors reviewed, such as management, bureaucratic hurdles, paperwork, hazard analysis, behavioral aspects, and the role of failure. Barriers to success, potential benefits, and challenges are discussed.     

Relevance of Rhizosphere Research to the Ecological Risk Assessment of Trace Metals in Soils

The chemical, mineralogical, and microbial properties of the rhizosphere of a range of forested ecosystems were studied to identify the key processes controlling the distribution and fate of trace metals at the soil–root interface. The results of our research indicate that: (1) the rhizosphere is a soil microenvironment where properties (e.g., pH, organic matter, microbes) and processes (nutrient and water absorption, exudation) differ markedly from those of the adjacent bulk soil; (2) the rhizosphere is a corrosive medium where the weathering and neoformation of soil solid phases are enhanced; (3) the concentrations of solid-phase and water-soluble trace metals like Cd, Cu, Ni, Pb, and Zn are generally higher in the rhizosphere as shown by both macroscopic and microscopic approaches; (4) a larger fraction of water-soluble metals is complexed by dissolved organic substances in the rhizosphere; and (5) soil microorganisms play, either directly or indirectly, a distinct role on metal speciation, in particular Cu and Zn, in the rhizosphere. These results improve our capacity to estimate metal speciation and bioavailability at the soil–root interface. Furthermore, the research emphasizes the crucial physical position occupied by the rhizosphere with respect to the process of elemental uptake by plants and its key functional role in the transfer of trace metals along the food chain. We conclude that the properties and processes of the rhizosphere should be viewed as key components of assessments of the ecological risks associated with the presence of trace metals in soils.     

Evaluation of Environmental Risk Assessment Parameters Due to Hillslope Developments in Penang Island,Malaysia

Slope failure and soil erosion due to increased development activity in hilly areas can be catastrophic and affect the environment and humans’ well-being. This article investigates the parameters that contribute to environmental risk. Nine contributing parameters were identified. Rating the risk was proposed based on the prediction of occurrences of environmental issues and were categorized from very high (5) to very low (1) with high, medium, and low in between. The assessments were reviewed and evaluated based on rating for the chosen parameters. Maps quantifying risks were developed identifying areas of environmental risk. The overall result shows that development areas PD3 of Tanjung Bungah, and PD3, PD8, and PD9 of Paya Terubong have high rating of environmental risk. No development area is classified as very high risk or very low risk. The rating can be used to develop zones of potential high risk, and from this zoning guideline the viability can be measured for any proposed development.     

Recommended Practice Regarding Selection of Sensitivity Analysis Methods Applied to Microbial Food Safety Process Risk Models

A guideline is presented for selection of sensitivity analysis methods applied to microbial food safety process risk (MFSPR) models. The guideline provides useful boundaries and principles for selecting sensitivity analysis methods for MSFPR models. Although the guideline is predicated on a specific branch of risk assessment models related to food-borne diseases, the principles and recommendations provided are typically generally applicable to other types of risk models. Applicable situations include: prioritizing potential critical control points; identifying key sources of variability and uncertainty; and refinement, verification, and validation of a model. Based on the objective of the analysis, characteristics of the model under study, amount of detail expected from sensitivity analysis, and characteristics of the sensitivity analysis method, recommendations for selection of sensitivity analysis methods are provided. A decision framework for method selection is introduced. The decision framework can substantially facilitate the process of selecting a sensitivity analysis method.     

Landscape Ecotoxicology and Assessment of Risk at Multiple Scales

Traditional approaches to ecotoxicology and ecological risk assessment frequently have ignored the complexities arising due to the spatial heterogeneity of natural systems. In recent years, however, ecologists have become increasingly aware of the influence of spatial organization on ecological processes. Landscape ecology provides a conceptual and theoretical framework for the analysis of spatial patterns, the characterization of spatial aspects of ecosystem function, and the understanding of landscape dynamics. Incorporating the insights of landscape ecology into ecotoxicology will enhance our ability to understand and ultimately predict the effects of toxic substances in ecological systems. Ecological risk assessments need to explicitly consider multiple spatial scales, accounting for heterogeneity within contaminated areas and for the larger landscape context. A simple simulation model is presented to illustrate the effects of spatial heterogeneity by linking an individual-based toxicokinetic model with a spatially distributed metapopulation model. Dispersal of organisms between contaminated and uncontaminated patches creates a situation where risk analysis must consider a spatial extent broader than the toxicant-contaminated area. In general, the addition of a toxicant to a source patch (i.e., a net exporter of individuals) will have a greater impact than the same toxicant addition to a sink patch (i.e., a net importer of individuals).     

Subdivision of Uncertainty Factors to Allow for Toxicokinetics and Toxicodynamics

Tenfold uncertainty factors have been used in risk assessment for about 40 years to allow for species differences and inter-individual variability. Each factor has to allow for toxicokinetic and toxicodynamic differences. Subdividing the 10-fold factors into kinetic and dynamic defaults, which when multiplied give a product of 10, offers a number of advantages. A major advantage is that chemical-specific data can be introduced to replace one or more of the default subfactors, hence contributing to a chemical-related overall factor. Subdivision of the 10-fold factors also facilitates analysis of the appropriateness of the overall 10-fold defaults, and the development of a more refined approach to the use of uncertainty factors.     

Ethical Issues in the Use of Data from Testing of Human Subjects to Support Risk Assessment

The public understands and supports the ethical use of human subjects in medical research, recognizing the unique role for this type of study in the development of new drugs and therapeutic strategies for treatment of disease. The use of data from human subjects can also be of value in understanding the circumstances under which individuals exposed to chemicals in the food supply, in the workplace, or in the environment might experience toxicity, i.e., in support of risk assessment. However, questions have been raised as to whether this latter type of research is ethical, or can be performed in an ethical manner. Under what circumstances is it acceptable to intentionally expose human subjects to potentially toxic agents? This is an extremely important issue for the risk assessment community to address, because it affects in a fundamental way the types of information that will be available to conduct human health risk assessments. Four papers in this issue offer viewpoints on the value of human data, the circumstances under which human subjects might be exposed to toxic chemicals for research purposes, the ethical problems associated with this research, and the role of human vs. animal data in the development of toxicity values for human health risk assessment     

血管内皮生长因子和抗肿瘤血管新生药物研究进展

肿瘤的生长与迁移离不开新血管的形成,这使得抗血管新生成为肿瘤治疗的重要途径之一。血管内皮生长因子（VEGF）是针对内皮细胞作用最强、特异性最高的血管新生促进因子,因而VEGF是抗肿瘤治疗的重要靶点。我们简要介绍了VEGF的一些生物学特点及肿瘤血管新生,着重介绍了一些抗血管新生药物的最新研究成果及其临床应用。     

Stochastic and Subjective Uncertainty in the Assessment of Radiation Exposure at the Waste Isolation Pilot Plant

The Waste Isolation Pilot Plant (WIPP) is under development by the U.S. Department of Energy as a geologic (i.e., deep underground) disposal facility for transuranic waste. An analysis is presented of possible radiation exposures associated with inadvertent drilling intrusions through the WIPP using future drilling rates obtained in accordance with requirements specified by the U.S. Environmental Protection Agency (EPA) in 40 CFR 194, Subpart B. The analysis attempts to maintain a separation between stochastic (i.e., aleatory) and subjective (i.e., epistemic) uncertainty as implied in the EPA regulations 40 CFR 191, Subpart B, and 40 CFR 194. The results of the analysis are presented as distributions of complementary cumulative distribution functions (CCDFs) for radiation exposure to oil field workers, where the individual CCDFs arise from stochastic uncertainty (i.e., many possible patterns of drill ing intrusions are possible over the 10,000?yr period specified in 40 CFR 191, Subpart B) and the distributions of CCDFs arise from subjective uncertainty (i.e., many inputs to the analysis have fixed, but poorly known, values). The projected radiation exposures during the 10,000?yr period following decommissioning of the WIPP in the year 2033 were found to be small (typically less than 0.001 person-Sv), with the dominant exposure pathway being the incidental ingestion of contaminated dirt by drilling crew members.     

用BIAcore系统研究西妥昔单克隆抗体与表皮生长因子受体的结合

目的：应用基于表面等离子体共振技术的BIAcore3000系统研究国产西妥昔单克隆抗体（cetuximab）C225与可溶性重组人表皮生长因子受体（EGFR）的结合能力,并与国外已上市的西妥昔单抗Erbitux相比较。方法：在CM5传感器芯片上设置2个通道,一个氨基偶联重组人EGFR作为检测通道,另一个不固定EGFR作为空白参比通道;以HBS溶液作为工作液,流速为10μL／min;活化与封闭芯片;再以10μL／min的流速分别以梯度浓度进样C225和Erbitux,每个浓度级别检测2次;获得结合动态图谱,拟合处理后用软件模块进行参数计算。结果：C225与可溶性重组人EGFR的结合动力学常数K^为4．00×10^8L／mol,KD为2．50×10^-9mol／L;而Erbitux与可溶性重组人EGFR的结合动力学常数KA为4．25×10^8L／mol,KD为2．35×10^-9mol／L。结论：在与可溶性重组人EGFR的结合能力上,C225与Erbitux有相似的结合动力学特性。     

The contribution of Ca2+ and phospholipids to the activation of human blood-coagulation Factor X by activated Factor IX.

The role of the cofactors Ca2+ and phospholipid in the activation of human Factor X by Factor IXa was investigated. By use of a sensitive spectrophotometric Factor Xa assay, it was demonstrated that human Factor IXa can activate Factor X in the absence of cofactors. The presence of Ca2+ as the only cofactor resulted in a 7-fold stimulation of the Factor Xa formation. Kinetic analysis of the Ca2+-stimulated reaction showed that the apparent Km of Factor X was 4.6 microM, whereas the apparent Vmax. for Factor Xa formation was 0.0088 mol of Xa/min per mol of IXa. The presence of phospholipid as the only cofactor had no effect on the rate of Factor Xa formation. However, a several-hundred-fold stimulation was observed when Ca2+ and phospholipid were present in combination. The activation of Factor X in the presence of Ca2+ and phospholipid was found to be kinetically heterogeneous, involving both phospholipid-bound and free reactants. Quantitative data concerning the phospholipid binding of Factors IXa and X were used to study the relation between the rate of Factor Xa formation and the binding of enzyme and substrate to the phospholipid membrane. The results support the hypothesis that phospholipid-bound Factor X is the substrate in the phospholipid-stimulated reaction; however, phospholipid-bound and free Factor IXa seem to be equally efficient in catalysing the activation of phospholipid-bound Factor X.