A Compartmental Model for the Prediction of Breath Concentration and Absorbed Dose of Chloroform After Exposure While Showering

In order to predict the exhaled breath concentration of chloroform in individuals exposed to chloroform while showering, an existing physiologically based pharmacokinetic (PB-PK) model was modified to include a multicompartment, PB-PK model for the skin and a completely mixed shower exposure model. The PB-PK model of the skin included the stratum corneum as the principal resistance to absorption and a viable epidermis which is in dynamic equilibrium with the skin microcirculation. This model was calibrated with measured exhaled breath concentrations of chloroform in individuals exposed while showering with and without dermal absorption. The calibration effort indicated that the expected value of skin-blood partitioning coefficient would be 1.2 when the degree of transfer of chloroform from shower water into shower air was 61%. The stratum corneum permeability coefficient for chloroform was estimated to be within the range of 0.16-0.36 cm/hr and the expected value was 0.2 cm/hr. The estimated ratio of the dermally and inhaled absorbed doses ranged between 0.6 and 2.2 and the expected value was 0.75. These results indicate that for the purposes of risk assessment for dermal exposure to chloroform, a simple steady-state model can be used to predict the degree of dermal absorption and that a reasonable value of skin permeability coefficient for chloroform used in this model would be 0.2 cm/hr. Further research should be conducted to compare the elimination of chloroform via exhaled breath when different exposure routes are being compared. The model results from this study suggest that multiple measurements of exhaled breath concentrations after exposure may be necessary when making comparisons of breath concentrations that involve different exposure routes.     

Dermal Uptake of Organic Chemicals from a Soil Matrix

Uptake of chemicals from soil on human skin is considered. Based on a review of literature on the structure of human skin, the processes by which chemicals pass through this boundary, and experiments that reveal the rate and magnitude of this transport process; a two-layer model is presented for estimating how chemical uptake through the stratum corneum depends on chemical properties, skin properties, soil properties and exposure conditions. The model is applied to two limiting scenarios--(1) continuous deposition and removal of soil on the skin surface and (2) a one-time deposition of soil onto the skin surface. The fraction of soil-bound chemical that passes through the stratum corneum is dependent on the skin-soil layer thickness; the dimensionless Henry's law constant, Kh and the octanol-water partition coefficient, Kow of the soil-bound chemical. The nature of this dependence is discussed.     

Uptake of Chloroform by Skin During Short Exposures to Contaminated Water

Uptake of chloroform into hairless rat stratum corneum from dilute aqueous solutions was studied using tape-stripping to determine amounts deposited in the skin under various environmental exposure scenarios. The length of exposure of sedated animals to the chloroform-containing medium, the frequency and duration of tape-stripping, and the number of tape-strips per location were varied to map the stratum corneum substantivity of chloroform. Eight minutes immersion of the rat within a well-stirred solution at 36°C was found to be adequate time for the gradient to be established fully across the stratum corneum. Penetration was progressively deeper as the exposure time increased. Substantial evaporative loss of chloroform from the aqueous medium of application seem to be responsible for lower cumulative amounts taken up when the same solution was held on the rat's skin within a stainless steel template of fixed area. Of the total uptake (29 mg) from a dilute stirred solution of chloroform (0.44 mg/ml) at 36°C, about 95% was systematically absorbed after a 30 min exposure as determined by residuals (measurement of bath concentrations).     

Significance of the Dermal Route of Exposure to Risk Assessment

The skin is a route of exposure that needs to be considered when conducting a risk assessment. It is necessary to identify the potential for dermal penetration by a chemical as well as to determine the overall importance of the dermal route of exposure as compared with inhalation or oral routes of exposure. The physical state of the chemical, vapor or liquid, the concentration, neat or dilute, and the vehicle, lipid or aqueous, is also important. Dermal risk is related to the product of the amounts of penetration and toxicity. Toxicity involves local effects on the skin itself and the potential for systemic effects. Dermal penetration is described in large part by the permeability constant. When permeability constants are not known, partition coefficients can be used to estimate a chemical's potential to permeate the skin. With these concepts in mind, a tiered approach is proposed for dermal risk assessment. A key first step is the determination of a skin-to-air or skin-to-medium partition coefficient to estimate a potential for dermal absorption. Building a physiologically-based pharmacokinetic (PBPK) model is another step in the tiered approach and is useful prior to classical in vivo toxicity tests. A PBPK model can be used to determine a permeability constant for a chemical as well as to show the distribution of the chemical systemically. A detailed understanding of species differences in the structure and function of the skin and how they relate to differences in penetration rates is necessary in order to extrapolate animal data from PBPK models to the human. A study is in progress to examine anatomical differences for four species.     

Estimating Dermal Uptake of Nonionic Organic Chemicals from Water and Soil: I. Unified Fugacity-Based Models for Risk Assessments

Contamination of water and soil that might eventually contact human skin makes it imperative to include the dermal uptake route in efforts to assess potential environmental health risks. Direct measurements of dermal uptake from either water or soil are only available for a small number of the thousands of chemicals likely to be found in the environment. We propose here a mass-transfer model for estimating skin permeability and dermal uptake for organic chemicals that contaminate soil and water. Statistical relationships between measured permeabilities and chemical properties reveal that permeability varies primarily with the octanol-water partition coefficient (Kow) and secondarily with the molecular weight. From these results, we derive a fugacity-based model for skin permeability that addresses the inherent permeability of the skin, the interaction of the skin with the environmental medium on skin (water or soil), and retains a relatively simple algebraic form. Model predictions are compared to measured human skin permeabilities for some 50 compounds in water and four compounds in soil. The model is adjusted to account for dermal uptake during both short-term (10-20 min) and long-term (several hour) exposures. This model is recommended for compounds with molecular weight less than or equal to 280 g.     

Short-Term Dermal Absorption and Penetration of Chemicals from Aqueous Solutions: Theory and Experiment

Dermal penetration of organic chemical-contaminated water from showering and bathing scenarios is a concern of regulatory agencies that have been tasked with determining safe exposure levels. During household showering and bathing, nearly the entire surface area of the body is exposed for short periods of time (5-15 minutes). The primary means of predicting body burden during brief exposures is to estimate total chemical penetrated from the steady-state penetration rate using a skin permeability coefficient. A variety of approaches has been recommended to estimate "body burden." The purpose of this investigation was to collect experimental data from short-term exposures to an organic chemical (dibromomethane [DBM]) in aqueous solution so that methods for estimating body burden could be compared. Rat skins were exposed in vitro to saturated aqueous solutions of DBM for 20 minutes and the amount of chemical in the receptor solution and the skin was analyzed. The total DBM mass in the receptor solution and the skin was taken to represent an in vivo body burden. These results were compared with the estimates of penetration from steady-state calculations, square root of time calculations, and a biologically based mathematical model. Results indicated that the amount of chemical in the skin and its fate during short exposures is important. The square root of time approach predicted total amount of chemical absorbed and penetrated better than did the steady-state approach. The biologically based mathematical model accurately predicted total body burden and could be used to distinguish between the amount of chemical in the skin and the amount of chemical that penetrated through the skin, which would be useful for understanding local toxicity.     

Systemic Uptake and Clearance of Chloroform by Hairless Rats Following Dermal Exposure. I. Brief Exposure to Aqueous Solutions

The systemic uptake of chloroform from dilute aqueous solutions into live hairless rats under conditions simulating dermal environmental exposure was studied. Whole blood was sampled during a 30-min immersion of an animal within water containing a known concentration of chloroform and then for 5.5 h following its removal from the bath. The amount of chloroform systemically absorbed was determined by comparing the AUCs of the blood concentration vs. time plots from dermal exposure to that obtained after IV infusion (for a period of 30 min) of an aqueous solution containing a known amount of chloroform (positive control). Although dermal data implied two-compartment disposition characteristics, IV infusion data fit best to a three-compartment disposition. Linear pharmacokinetics was observed both by IV administration and percutaneous absorption at the dose levels studied. Chloroform was detected in the rat blood as early as 4 min following exposure. Our findings suggest that about 10.2 mg of chloroform was systemically absorbed after dermal exposure of a rat to an aqueous solution of 0.44 mg/ml. This amount is substantially higher than the predictions of mathematical risk-models put forth by some investigators. However, when expressed as the "effective" permeability coefficient ( K _p^eff), close agreement was noticed between our value and those estimated by others using physiologically based pharmacokinetic (PBPK) models. Also, in terms of K _p^eff, reasonable agreement existed between our and another investigator's past estimates of uptake based on depletion of bath level of chloroform and the actual uptake measured in our current experiments. The estimated onset of systemic entry seen here is entirely consistent with our estimate of how long it takes to establish the diffusion gradient across the stratum comeum based on tape stripping.     

高技术企业联盟知识扩散研究基于小世界网络的视角

知识通过网络可以加快扩散.作者基于NW小世界网络视角,构建高技术企业联盟知识扩散模型,揭示联盟的知识扩散特性,并运用MATLAB软件进行模拟仿真.研究发现,减小网络的特征路径长度、增大网络的集聚系数和提高成员间的知识交流频率是促进高技术企业联盟知识扩散、提高创新效率、加快知识创新的有效途径.     

Steady-State Solutions to PBPK Models and Their Applications to Risk Assessment I: Route-to-Route Extrapolation of Volatile Chemicals

Although analysis of in vivo pharmacokinetic data necessitates use of time-dependent physiologically-based pharmacokinetic (PBPK) models, risk assessment applications are often driven primarily by steady-state and/or integrated (e.g., AUC) dosimetry. To that end, we present an analysis of steady-state solutions to a PBPK model for a generic volatile chemical metabolized in the liver. We derive an equivalent model that is much simpler and contains many fewer parameters than the full PBPK model. The state of the system can be specified by two state variables-the rate of metabolism and the rate of clearance by exhalation. For a given oral dose rate or inhalation exposure concentration, the system state only depends on the blood-air partition coefficient, metabolic constants, and the rates of blood flow to the liver and of alveolar ventilation. At exposures where metabolism is close to linear, only the effective first-order metabolic rate is needed. Furthermore, in this case, the relationship between cumulative exposure and average internal dose (e.g., AUCs) remains the same for time-varying exposures. We apply our analysis to oral-inhalation route extrapolation, showing that for any dose metric, route equivalence only depends on the parameters that determine the system state. Even if the appropriate dose metric is unknown, bounds can be placed on the route-to-route equivalence with very limited data. We illustrate this analysis by showing that it reproduces exactly the PBPK-model-based route-to-route extrapolation in EPA's 2000 risk assessment for vinyl chloride. Overall, we find that in many cases, steady-state solutions exactly reproduce or closely approximate the solutions using the full PBPK model, while being substantially more transparent. Subsequent work will examine the utility of steady-state solutions for analyzing cross-species extrapolation and intraspecies variability.     

Extending the Stochastic Two-Stage Model of Carcinogenesis to Include Self-Regulation of the Nonmalignant Cell Population

One of the challenges of introducing greater biological realism into stochastic models of cancer induction is to find a way to represent the homeostatic control of the normal cell population over its own size without complicating the analysis too much to obtain useful results. Current two-stage models of carcinogenesis typically ignore homeostatic control. Instead, a deterministic growth path is specified for the population of "normal" cells, while the population of "initiated" cells is assumed to grow randomly according to a birth-death process with random immigrations from the normal population. This paper introduces a simple model of homeostatically controlled cell division for mature tissues, in which the size of the nonmalignant population remains essentially constant over time. Growth of the nonmalignant cell population (normal and initiated cells) is restricted by allowing cells to divide only to fill the "openings" left by cells that die or differentiate, thus maintaining the constant size of the nonmalignant cell population. The fundamental technical insight from this model is that random walks, rather than birth-and-death processes, are the appropriate stochastic processes for describing the kinetics of the initiated cell population. Qualitative and analytic results are presented, drawn from the mathematical theories of random walks and diffusion processes, that describe the probability of spontaneous extinction and the size distribution of surviving initiated populations when the death/differentiation rates of normal and initiated cells are known. The constraint that the nonmalignant population size must remain approximately constant leads to much simpler analytic formulas and approximations, flowing directly from random walk theory, than in previous birth-death models.(ABSTRACT TRUNCATED AT 250 WORDS)     

聚类系数无显著性差异下的灰色综合聚类方法研究

在灰色聚类评估分析中,当灰色聚类系数无显著性差异时,按照已有的灰色聚类方法无法对聚类对象进行准确的聚类,而在实际研究中经常会遇到聚类系数无显著性差异这类问题。因此本文提出了一种新的灰色综合聚类方法。具体步骤是:首先计算各聚类对象的聚类系数,并对其进行归一化处理;再根据对象中每一灰类的灰色聚类系数在聚类过程中的作用,计算聚类对象的综合聚类系数;最后根据综合聚类系数对聚类对象进行聚类,确定聚类对象应属的灰类。并且证明了当聚类对象的聚类系数差异大于1-2/S时,一般灰色聚类方法与灰色综合聚类方法所得聚类结果完全相同。最后,以江苏省第二产业内部主导产业选择为例进行了实证分析。     

产业生命周期不同阶段的最优集体创新网络结构

本文采用仿真方法从创新效率的角度对产业生命周期不同阶段下的最优集体创新网络结构进行了研究。研究发现,在产业生命周期的导入期,以较高的平均聚集系数为特征的规则网络具有最高的集体创新效率;在产业生命周期的成长期,以较高的小世界系数为特征的小世界网络具有最高的集体创新效率;当产业生命周期进入成熟期以后,以较短的最短路径长度为特征的随机网络具有最高的集体创新效率。本文通过对上述结果的进一步分析得出,上述结果是由以下三个层次的原因造成的。第一,产业生命周期的不同阶段具有不同的产业知识特征和技术机会。第二,产业知识特征会影响产业内部的知识流动和企业实现知识重组的能力,而技术机会的多少会影响企业搜寻并发现创新机会的能力。第三,较高的网络平均聚集系数有利于促进知识流动,而较短的平均最短路径长度有利于企业搜寻并发现创新机会。最后,本文提出了以上结论对创新政策制定者的一些重要启示。     

A Distributed Parameter Physiologically-Based Pharmacokinetic Model for Dermal and Inhalation Exposure to Volatile Organic Compounds

Estimates of dermal dose from exposures to toxic chemicals are typically derived using models that assume instantaneous establishment of steady-state dermal mass flux. However, dermal absorption theory indicates that this assumption is invalid for short-term exposures to volatile organic chemicals (VOCs). A generalized distributed parameter physiologically-based pharmacokinetic model (DP-PBPK), which describes unsteady state dermal mass flux via a partial differential equation (Fickian diffusion), has been developed for inhalation and dermal absorption of VOCs. In the present study, the DP-PBPK model has been parameterized for chloroform, and compared with two simpler PBPK models of chloroform. The latter are lumped parameter models, employing ordinary differential equations, that do not account for the dermal absorption time lag associated with the accumulation of permeant chemical in tissue represented by permeability coefficients. All three models were evaluated by comparing simulated post-exposure exhaled breath concentration profiles with measured concentrations following environmental chloroform exposures. The DP-PBPK model predicted a time-lag in the exhaled breath concentration profile, consistent with the experimental data. The DP-PBPK model also predicted significant volatilization of chloroform, for a simulated dermal exposure scenario. The end-exposure dermal dose predicted by the DP-PBPK model is similar to that predicted by the EPA recommended method for short-term exposures, and is significantly greater than the end-exposure dose predicted by the lumped parameter models. However, the net dermal dose predicted by the DP-PBPK model is substantially less than that predicted by the EPA method, due to the post-exposure volatilization predicted by the DP-PBPK model. Moreover, the net dermal dose of chloroform predicted by all three models was nearly the same, even though the lumped parameter models did not predict substantial volatilization.     

Changes in Product Attributes and Costs as Drivers of New Product Diffusion and Substitution

Diffusion theory has typically focused on how communication, internal or external to a social system, leads to adoptions and diffusion of an innovation. We develop a diffusion and substitution model based on a somewhat different perspective. In some cases, progressive improvements in product attributes and/or continual cost reduction seem to be a key driver of the diffusion process. For example, after introduction of the 5.25‐inch disk drive, its capacity continually increased, and accordingly, so did customer willingness‐to‐pay. Our model is based on a linear reservation price framework, in which a product is described by its depth (defined as the difference between a product̂s maximum reservation price and its production cost), and its breadth (related to the slope of its reservation price curve), indicating how broadly it appeals across various customer segments. Because of changes in product depths and breadths over time, customers who previously preferred the old product may later prefer the new product, thus creating the diffusion process. While the Bass model describes diffusion as a function of the coefficients of innovation and imitation, in our model, it is described by the coefficients of depth and breadth (the rates of change in relative depth and breadth), along with an S‐coefficient that we associate with the technology S‐curve. We fit our model to data from the disk‐drive and the microprocessor industries.     

储量不确定对可耗竭资源优化开采的影响研究

回采率是储量不确定的重要参数之一。利用回采率提高的概率、调整次数及调整幅度描述回采率不确定,给出回采率的调整方法,进而确定了有效可采储量,然后利用最优控制理论建立了可耗竭资源最优开采模型,确定了资源最优开采路径、影子价格和耗竭时间。结果表明:提高回采率,能增加企业资源供给量,延长采区的服务年限;回采率提高的越多,需要调整的次数也越多,回采率提高的概率较高时,相应调整次数可以减少些;在理论上验证了当前提高回采率政策的有效性。     

Dermal Uptake of 18 Dilute Aqueous Chemicals: In Vivo Disappearance‐Method Measures Greatly Exceed In Vitro‐Based Predictions

Average rates of total dermal uptake (K_up) from short‐term (e.g., bathing) contact with dilute aqueous organic chemicals (DAOCs) are typically estimated from steady‐state in vitro diffusion‐cell measures of chemical permeability (K_p) through skin into receptor solution. Widely used (“PCR‐vitro”) methods estimate K_up by applying diffusion theory to increase K_p predictions made by a physico‐chemical regression (PCR) model that was fit to a large set of K_p measures. Here, K_up predictions for 18 DAOCs made by three PCR‐vitro models (EPA, NIOSH, and MH) were compared to previous in vivo measures obtained by methods unlikely to underestimate K_up. A new PCR model fit to all 18 measures is accurate to within approximately threefold (r = 0.91, p < 10^?5), but the PCR‐vitro predictions (r > 0.63) all tend to underestimate the K_up measures by mean factors (UF, and p value for testing UF = 1) of 10 (EPA, p < 10^?6), 11 (NIOSH, p < 10^?8), and 6.2 (MH, p = 0.018). For all three PCR‐vitro models, log(UF) correlates negatively with molecular weight (r² = 0.31 to 0.84, p = 0.017 to < 10^?6) but not with log(vapor pressure) as an additional predictor (p > 0.05), so vapor pressure appears not to explain the significant in vivo/PCR‐vitro discrepancy. Until this discrepancy is explained, careful in vivo measures of K_up should be obtained for more chemicals, the expanded in vivo database should be compared to in vitro‐based predictions, and in vivo data should be considered in assessing aqueous dermal exposure and its uncertainty.     

跨组织知识整合下的创新网络结构分析

针对跨组织合作形成的创新网络,构建了跨组织知识整合下的创新网络模型,仿真分析得出,组织间互补程度及知识整合效率对跨组织知识整合下的创新网络结构有一定的影响,具体表现为:组织间互补程度及知识整合效率很高时,创新网络具有较短的平均路径长度与较低的集聚系数,此时网络具有随机网络特征;组织间互补程度及知识整合效率很低时,创新网络具有较长的平均路径长度与较高的集聚系数,此时网络具有规则网络的特征;组织间互补程度及知识整合效率大小适度时,创新网络具有相对较短的平均路径长度与较高的集聚系数,因此创新网络具有"小世界"网络的特征。     

Uncertainties in Pharmacokinetic Modeling for Perchloroethylene: II. Comparison of Model Predictions with Data for a Variety of Different Parameters

In this paper we compare expectations derived from 10 different human physiologically based pharmacokinetic models for perchloroethylene with data on absorption via inhalation, and concentrations in alveolar air and venous blood. Our most interesting finding is that essentially all of the models show a time pattern of departures of predictions of air and blood levels relative to experimental data that might be corrected by more sophisticated model structures incorporating either (a) heterogeneity of the fat compartment (with respect to either perfusion or partition coefficients or both) or (b) intertissue diffusion of perchloroethylene between the fat and muscle/VRG groups. Similar types of corrections have recently been proposed to reduce analogous anomalies in the fits of pharmacokinetic models to the data for several volatile anesthetics.^(17-20) A second finding is that models incorporating resting values for alveolar ventilation in the region of 5.4 L/min seemed to be most compatible with the most reliable set of perchloroethylene uptake data.     

基于SIR传染病模型的技术扩散模型的研究

科技进步推动经济和社会发展是技术扩散来实现的,所以研究技术扩散现象具有十分重要的理论和现实意义.于技术扩散过程类似于传染病的蔓延过程,因此本文利用经典的传染病模型(SIR模型)建立了单一技术在单一企业群中扩散的SIR技术扩散模型、单一技术在多个企业群中扩散的SIR技术扩散模型和多种竞争技术在单一企业群中扩散的SIR技术扩散模型,并通过对三种模型的分析,研究了技术扩散现象的一般规律.     

Estimation of Metabolic Rate Constants in PBPK‐Models from Liver Slice Experiments: What Are the Experimental Needs?

A mechanistic model is presented describing the clearance of a compound in a precision-cut liver slice that is incubated in a culture medium. The problem of estimating metabolic rate constants in PBPK models from liver slice experiments is discussed using identifiability analysis. From the identifiability problem analysis, it appears that in addition to the clearance, the compound's free fraction in the slice and the diffusion rate of the exchange of the compound between culture medium and liver slice should be identified. In addition, knowledge of the culture medium volume, the slice volume, the compound's free fraction, and octanol-water-based partition between medium and slice is presupposed. The formal solution for identification is discussed from the perspective of experimental practice. A formally necessary condition for identification is the sampling of parent compound in liver slice or culture medium. However, due to experimental limitations and errors, sampling the parent compound in the slice together with additional sampling of metabolite pooled from the medium and the slice is required for identification in practice. Moreover, it appears that identification results are unreliable when the value of the intrinsic clearance exceeds the value of the diffusion coefficient, a condition to be verified a posteriori.