Human Variability in Susceptibility to Toxic Chemicals— A Preliminary Analysis of Pharmacokinetic Data from Normal Volunteers

The tenfold "uncertainty" factor traditionally used to guard against human interindividual differences in susceptibility to toxicity is not based on human observations. To begin to build a basis for quantifying an important component of overall variability in susceptibility to toxicity, a data base has been constructed of individual measurements of key pharmacokinetic parameters for specific substances (mostly drugs) in groups of at least five healthy adults. 72 of the 101 data sets studied were positively skewed, indicating that the distributions are generally closer to expectations for log-normal distributions than for normal distributions. Measurements of interindividual variability in elimination half-lives, maximal blood concentrations, and AUC (area under the curve of blood concentration by time) have median values of log10 geometric standard deviations in the range of 0.11-0.145. For the median chemical, therefore, a tenfold difference in these pharmacokinetic parameters would correspond to 7-9 standard deviations in populations of normal healthy adults. For one relatively lipophilic chemical, however, interindividual variability in maximal blood concentration and AUC was 0.4--implying that a tenfold difference would correspond to only about 2.5 standard deviations for those parameters in the human population. The parameters studied to date are only components of overall susceptibility to toxic agents, and do not include contributions from variability in exposure- and response-determining parameters. The current study also implicitly excludes most human interindividual variability from age and illness. When these other sources of variability are included in an overall analysis of variability in susceptibility, it is likely that a tenfold difference will correspond to fewer standard deviations in the overall population, and correspondingly greater numbers of people at risk of toxicity.     

On Broadening Failure Rate Distributions in PRA Uncertainty Analyses

Several recent nuclear power plant probabilistic risk assessments (PRAs) have utilized broadened Reactor Safety Study (RSS) component failure rate population variability curves to compensate for such things as expert "overvaluation bias" in the estimates upon which the curves are based.
A simple two-components of variation empirical Bayes model is proposed for use in estimating the between-expert variability curve in the presence of such biases. Under certain conditions this curve is a population variability curve. Comparisons are made with the existing method.
The popular procedure appears to be generally much more conservative than the empirical Bayes method in removing such biases. In one case the broadened curve based on the popular method is more than two orders of magnitude broader than the empirical Bayes curve. In another case it is found that the maximum justifiable degree of broadening of the RSS curve is to increase α from 5% to 12%, which is significantly less than the 20% value recommended in the popular approach.     

Managing demand variability and operational effectiveness: case of lean improvement programmes and MRP planning integration

Although a lean focus is widely popular in general manufacturing environments, there are limited studies that empirically investigate how lean improvement programmes can be integrated with a material requirement planning (MRP) system. The aim of this research is to examine if the integration of lean improvement programmes with a MRP system has a positive effect on operational effectiveness when manufacturers are experiencing high levels of customer demand variability. Based on the contingency theory perspective and using data collected from the international manufacturing strategy survey (IMSS-V), a sample of 382 international manufacturing companies are first divided into two groups based on the degree of their customer demand fluctuation. Moderated hierarchical regression is then applied to each group to empirically test the research hypotheses. Statistical results suggest that operational effectiveness significantly improves when lean improvement programmes support MRP systems as manufacturers are experiencing high levels of fluctuations in demand.     

Geographical variability and network structure

In this paper, we explore the potential implications of geographical variability for the structure of social networks. Beginning with some basic simplifying assumptions, we derive a number of ways in which local network structure should be expected to vary across a region whose population is unevenly distributed. To examine the manner in which these effects would be expected to manifest given realistic population distributions, we then perform an exploratory simulation study that examines the features of large-scale interpersonal networks generated using block-level data from the 2000 U.S. Census. Using a stratified sample of micropolitan and metropolitan areas with populations ranging from approximately 1000 to 1,000,000 persons, we extrapolatively simulate network structure using spatial network models calibrated to two fairly proximate social relations. From this sample of simulated networks, we examine the effect of both within-location and between-location heterogeneity on a variety of structural properties. As we demonstrate, geographical variability produces large and distinctive features in the “social fabric” that overlies it; at the same time, however, many aggregate network properties can be fairly well-predicted from relatively simple spatial demographic variables. The impact of geographical variability is thus predicted to depend substantially on the type of network property being assessed, and on the spatial scale involved.     

语言顺应论的运用维度:翻译过程探析

Verschueren的语言顺应论提出语言的产生和理解是变异性、商讨性和顺应性语用因素相互作用的结果。文章用该理论重新审视翻译过程及其本质,认为翻译实质上是变异、商讨、顺应并据此作出选择的过程,语言顺应论下的翻译过程是基于这三个语言特性相互协作共同持续于话语产生、理解与转换的动态阐释过程。     

How social ties transcend class boundaries? Network variability as tool for exploring occupational homophily

The research on social network analysis established the existence of class homophily, the tendency that personal networks are homogeneous in the class sense, as one of the governing patterns. This is explained via two main mechanisms: choice homophily and induced homophily. But the literature focused less on the question how can class boundaries be transgressed and what are the channels of class heterophily. This paper explores class heterophily on Croatian data acquired through position generator, which measures social capital (resources captured in social relations) by exploring the range of different occupational positions which are accessible to an individual (extensity index). Network variability is thereby taken as proxy for class composition of personal networks. The paper concludes that that political participation and sociability enable cross-class ties, since this offers an opportunity to meet and befriend people from all walks of life; and that people on the middle of the social hierarchy have the most diverse social networks. The hypotheses that social mobility can represent a vehicle for class heterophily; and that class heterophily is more pronounced in smaller settlements, where society networks show more overlap between social circles; were confirmed only partially, and require further investigation. These findings concern class boundaries related to the notion of choice homophily. As for induced homophily, the paper concludes that here too the boundaries are not watertight, as cultural omnivores have a wider range of class contacts.     

中介语可变性在文体方面的研究

第二语言习得中,可变性引起了很大争议。目前的国内外对中介语可变性的研究大都体现集中在文化、心理方面,本文主要从中介语可变性在文体中方面入手,探讨中介语可变性在文体方面变化的体现方式以及影响因素,并提出它对日常交际和对外语教学的启示。     

Science and Decisions: Advancing Risk Assessment

At the request of the U.S. Environmental Protection Agency (EPA), the National Research Council (NRC) recently completed a major report, Science and Decisions: Advancing Risk Assessment, that is intended to strengthen the scientific basis, credibility, and effectiveness of risk assessment practices and subsequent risk management decisions. The report describes the challenges faced by risk assessment and the need to consider improvements in both the technical analyses of risk assessments (i.e., the development and use of scientific information to improve risk characterization) and the utility of risk assessments (i.e., making assessments more relevant and useful for risk management decisions). The report tackles a number of topics relating to improvements in the process, including the design and framing of risk assessments, uncertainty and variability characterization, selection and use of defaults, unification of cancer and noncancer dose‐response assessment, cumulative risk assessment, and the need to increase EPA's capacity to address these improvements. This article describes and summarizes the NRC report, with an eye toward its implications for risk assessment practices at EPA.     

Human Interindividual Variability in Susceptibility to Airborne Particles

Part of the explanation for the persistent epidemiological findings of associations between mortality and morbidity with relatively modest ambient exposures to airborne particles may be that some people are much more susceptible to particle-induced responses than others. This study assembled a database of quantitative observations of interindividual variability in pharmacokinetic and pharmacodynamic parameters likely to affect particle response. The pharmacodynamic responses studied included data drawn from epidemiologic studies of doses of methacholine, flour dust, and other agents that induce acute changes in lung function. In general, the amount of interindividual variability in several of these pharmacodynamic response parameters was greater than the variability in pharmacokinetic (breathing rate, deposition, and clearance) parameters. Quantitatively the results indicated that human interindividual variability of breathing rates and major pharmacokinetic parameters-total deposition and tracheobronchial clearance-were in the region of Log(GSD) = 0.1 to 0.2 (corresponding to geometric standard deviations of 10(.1)-10(.2) or 1.26-1.58). Deposition to the deep lung (alveolar region) appeared to be somewhat more variable: Log(GSD) of about 0.3 (GSD of about 2). Among pharmacodynamic parameters, changes in FEV1 in response to ozone and metabisulfite (an agent that is said to act primarily on neural receptors in the lung) were in the region of Log(GSD) of 0.2 to 0.4. However, similar responses to methacholine, an agent that acts on smooth muscle, seemed to have still more variability (0.4 to somewhat over 1.0, depending on the type of population studied). Similarly high values were suggested for particulate allergens. Central estimates of this kind of variability, and the close correspondence of the data to lognormal distributions, indicate that 99.9th percentile individuals are likely to respond at doses that are 150 to 450-fold less than would be needed in median individuals. It seems plausible that acute responses with this amount of variability could form part of the mechanistic basis for epidemiological observations of enhanced mortality in relation to ambient exposures to fine particles.