A Causal Model of Chronic Obstructive Pulmonary Disease (COPD) Risk

Research on the etiology of chronic pulmonary disease (COPD), an irreversible degenerative lung disease affecting 15% to 20% of smokers, has blossomed over the past half‐century. Profound new insights have emerged from a combination of in vitro and –omics studies on affected lung cell populations (including cytotoxic CD8⁺ T lymphocytes, regulatory CD4⁺ helper T cells, dendritic cells, alveolar macrophages and neutrophils, alveolar and bronchiolar epithelial cells, goblet cells, and fibroblasts) and extracellular matrix components (especially, elastin and collagen fibers); in vivo studies on wild‐type and genetically engineered mice and other rodents; clinical investigation of cell‐ and molecular‐level changes in asymptomatic smokers and COPD patients; genetic studies of susceptible and rapidly‐progressing phenotypes (both human and animal); biomarker studies of enzyme and protein degradation products in induced sputum, bronchiolar lavage, urine, and blood; and epidemiological and clinical investigations of the time course of disease progression. To this rich mix of data, we add a relatively simple in silico computational model that incorporates recent insights into COPD disease causation and progression. Our model explains irreversible degeneration of lung tissue as resulting from a cascade of positive feedback loops: a macrophage inflammation loop, a neutrophil inflammation loop, and an alveolar epithelial cell apoptosis loop. Unrepaired damage results in clinical symptoms. The resulting model illustrates how to simplify and make more understandable the main aspects of the very complex dynamics of COPD initiation and progression, as well as how to predict the effects on risk of interventions that affect specific biological responses.     

Air Nicotine and Saliva Cotinine as Indicators of Workplace Passive Smoking Exposure and Risk1

We model nicotine from environmental tobacco smoke (ETS) in office air and salivary cotinine in nonsmoking U.S. workers. We estimate that: an average salivary cotinine level of 0.4 ng/ml corresponds to an increased lifetime mortality risk of 1/1000 for lung cancer, and 1/100 for heart disease; >95% of ETS-exposed office workers exceed OSHA's significant risk level for heart disease mortality, and 60% exceed significant risk for lung cancer mortality; 4000 heart disease deaths and 400 lung cancer deaths occur annually among office workers from passive smoking in the workplace, at the current 28% prevalence of unrestricted smoking in the office workplace.     

Modeling the Modification of the Risk of Radon-Induced Lung Cancer by Environmental Tobacco Smoke

The presence of environmental tobacco smoke (ETS) in homes has been implicated in the causation of lung cancer. While of interest in its own right, ETS also influences the risk imposed by radon and its decay products. The interaction between radon progeny and ETS alters the exposure, intake, uptake, biokinetics, dosimetry, and radiobiology of those progeny. The present paper details model predictions of the various influences of ETS on these factors in the U.S. population and provides estimates of the resulting change in the risk from average levels of radon progeny. It is predicted that the presence of ETS produces a very small (perhaps unmeasurable) increase in the risk of radiation-induced tracheobronchial cancer in homes with initially very high particle concentrations for both active and never-smokers, but significantly lowers the risk in homes with initially lower particle concentrations for both groups when generation 4 of the lung is considered the target site. For generation 16, the presence of ETS generally increases the radon-induced risk of lung cancer, although the increase should be unmeasurable at high initial particle concentrations. The net effect of ETS on human health is suggested to be a complicated function of the initial housing conditions, the concentration of particles introduced by smoking, the target generation considered, and the smoking status of exposed populations. This situation precludes any simple statements concerning the role of ETS in governing the incidence of lung cancer in a population.     

Modeling Lung Carcinogenesis in Radon‐Exposed Miner Cohorts: Accounting for Missing Information on Smoking

Epidemiological miner cohort data used to estimate lung cancer risks related to occupational radon exposure often lack cohort‐wide information on exposure to tobacco smoke, a potential confounder and important effect modifier. We have developed a method to project data on smoking habits from a case‐control study onto an entire cohort by means of a Monte Carlo resampling technique. As a proof of principle, this method is tested on a subcohort of 35,084 former uranium miners employed at the WISMUT company (Germany), with 461 lung cancer deaths in the follow‐up period 1955–1998. After applying the proposed imputation technique, a biologically‐based carcinogenesis model is employed to analyze the cohort's lung cancer mortality data. A sensitivity analysis based on a set of 200 independent projections with subsequent model analyses yields narrow distributions of the free model parameters, indicating that parameter values are relatively stable and independent of individual projections. This technique thus offers a possibility to account for unknown smoking habits, enabling us to unravel risks related to radon, to smoking, and to the combination of both.     

Measuring Perceptions of Synergistic Circulatory Disease Risk Due to Smoking and the Oral Contraceptive Pill

There is evidence that the oral contraceptive pill (OCP) and smoking contribute independently to risk of circulatory disease. There is mixed evidence that the combined risk may be greater than the sum of these factors operating in isolation. Little is known about how the general population views the risks from OCP use, singly and in combination with smoking. Previous attempts at assessing whether the public views risks as operating synergistically have generally found evidence for subadditive models, where the combined risk is less than the sum of factors operating in isolation. However, concerns have been expressed over the validity of the measures of risk perception used. Therefore, this study used three distinct methods of measurement to assess the extent to which 241 undergraduate students perceive the risks of smoking and the OCP separately and combined, for circulatory disease. For all three methods, respondents read each of four vignettes describing information about a woman's risk factors (with high and low levels of both OCP and smoking), and then estimated risk of circulatory disease using one of the three risk measures. The three measures produced similar ratings. Consistent with the epidemiological evidence, information about smoking had more impact on estimates of overall risk than did information about the OCP For all three measures, responses were consistent with an additive model of risk from smoking and the OCP. This convergence of results from different methods suggests that all three methods of measurement employed, which all had a large number of response options, may be valid.     

Environmental Tobacco Smoke Revisited: The Reliability of the Data Used for Risk Assessment

Several epidemiological studies have found a weak, but consistent association between lung cancer in nonsmokers and exposure to environmental tobacco smoke (ETS). In addition, a purported link between such exposure and coronary heart disease (CHD) has been of major concern. Although it is biologically plausible that ETS has a contributory role in the induction of lung cancer in nonsmoking individuals, dose-response extrapolation-supported by the more solid database for active smokers-gives an additional risk for lung cancer risk that is more than one order of magnitude lower than that indicated by major positive epidemiological studies. The discrepancy between available epidemiological data and dosimetric estimates seems, to a major part, to reflect certain systematic biases in the former that are difficult to control by statistical analysis when dealing with risks of such low magnitudes. These include, most importantly, misclassification of smoking status, followed by inappropriate selection of controls, as well as certain confounding factors mainly related to lifestyle, and possibly also hereditary disposition. A significant part of an association between lung cancer and exposure to ETS would disappear, if, on the average, 1 patient out of 20 nonsmoking cases had failed to tell the interviewer that he had, in fact, recently stopped smoking. In the large International Agency for Research on Cancer (IARC) multicenter study even lower misclassification rates would abolish the weak, statistically nonsignificant associations that were found. In the former study an apparent significant protective effect from exposure to ETS in childhood with respect to lung cancer later in life was reported, a most surprising finding. The fact that the mutation spectrum of the p53 tumor suppressor gene in lung tumors of ETS-exposed nonsmokers generally differs from that found in tumors of active smokers lends additional support to the notion that the majority of tumors found in ETS-exposed nonsmokers have nothing to do with tobacco smoke. The one-sided preoccupation with ETS as a causative factor of lung cancer in nonsmokers may seriously hinder the elucidation of the multifactorial etiology of these tumors. Due to the high prevalence of cardiovascular disease in the population, even a modest causal association with ETS would, if valid, constitute a serious public health problem. By pooling data from 20 published studies on ETS and heart disease, some of which reported higher risks than is known to be caused by active smoking, a statistically significant association with spousal smoking is obtained. However, in most of these studies, many of the most common confounding risk factors were ignored and there appears to be insufficient evidence to support an association between exposure to ETS and CHD. Further, it seems highly improbable that exposure to a concentration of tobacco smoke at a level that is generally much less than 1% of that inhaled by a smoker could result in an excess risk for CHD that-as has been claimed-is some 30% to 50% of that found in active smokers. There are certainly valid reasons to limit exposure to ETS as well as to other air pollutants in places such as offices and homes in order to improve indoor air quality. This goal can be achieved, however, without the introduction of an extremist legislation based on a negligible risk of lung cancer as well as an unsupported and highly hypothetical risk for CHD.     

Dose-Response and Risk Assessment of Airborne Hexavalent Chromium and Lung Cancer Mortality

This study evaluates the dose-response relationship for inhalation exposure to hexavalent chromium [Cr(VI)] and lung cancer mortality for workers of a chromate production facility, and provides estimates of the carcinogenic potency. The data were analyzed using relative risk and additive risk dose-response models implemented with both Poisson and Cox regression. Potential confounding by birth cohort and smoking prevalence were also assessed. Lifetime cumulative exposure and highest monthly exposure were the dose metrics evaluated. The estimated lifetime additional risk of lung cancer mortality associated with 45 years of occupational exposure to 1 microg/m3 Cr(VI) (occupational exposure unit risk) was 0.00205 (90%CI: 0.00134, 0.00291) for the relative risk model and 0.00216 (90%CI: 0.00143, 0.00302) for the additive risk model assuming a linear dose response for cumulative exposure with a five-year lag. Extrapolating these findings to a continuous (e.g., environmental) exposure scenario yielded an environmental unit risk of 0.00978 (90%CI: 0.00640, 0.0138) for the relative risk model [e.g., a cancer slope factor of 34 (mg/kg-day)-1] and 0.0125 (90%CI: 0.00833, 0.0175) for the additive risk model. The relative risk model is preferred because it is more consistent with the expected trend for lung cancer risk with age. Based on statistical tests for exposure-related trend, there was no statistically significant increased lung cancer risk below lifetime cumulative occupational exposures of 1.0 mg-yr/m3, and no excess risk for workers whose highest average monthly exposure did not exceed the current Permissible Exposure Limit (52 microg/m3). It is acknowledged that this study had limited power to detect increases at these low exposure levels. These cancer potency estimates are comparable to those developed by U.S. regulatory agencies and should be useful for assessing the potential cancer hazard associated with inhaled Cr(VI).     

Bounding Poorly Characterized Risks: A Lung Cancer Example

For diseases with more than one risk factor, the sum of probabilistic estimates of the number of cases caused by each individual factor may exceed the total number of cases observed, especially when uncertainties about exposure and dose response for some risk factors are high. In this study, we outline a method of bounding the fraction of lung cancer fatalities not due to specific well-studied causes. Such information serves as a "reality check" for estimates of the impacts of the minor risk factors, and, as such, complements the traditional risk analysis. With lung cancer as our example, we allocate portions of the observed lung cancer mortality to known causes (such as smoking, residential radon, and asbestos fibers) and describe the uncertainty surrounding those estimates. The interactions among the risk factors are also quantified, to the extent possible. We then infer an upper bound on the residual mortality due to "other" causes, using a consistency constraint on the total number of deaths, the maximum uncertainty principle, and the mathematics originally developed of imprecise probabilities.     

Environmental Tobacco Smoke: Science vs. Rhetoric

After an extensive review and analysis of the scientific evidence on the respiratory health effects of passive smoking, the U.S. Environmental Protection Agency concluded that environmental tobacco smoke causes lung cancer in adult nonsmokers and increases the risk of a variety of non-cancer respiratory disorders, especially in children. This article is a response to claims in Dr. Gio Gori's article "Policy Against Science: The Case of Environmental Tobacco Smoke," appearing in the same issue of this journal, that such conclusions are unwarranted. This response focuses only on the respiratory health effects of environmental tobacco smoke.     

An Exposure‐Response Threshold for Lung Diseases and Lung Cancer Caused by Crystalline Silica

Whether crystalline silica (CS) exposure increases risk of lung cancer in humans without silicosis, and, if so, whether the exposure‐response relation has a threshold, have been much debated. Epidemiological evidence is ambiguous and conflicting. Experimental data show that high levels of CS cause lung cancer in rats, although not in other species, including mice, guinea pigs, or hamsters; but the relevance of such animal data to humans has been uncertain. This article applies recent insights into the toxicology of lung diseases caused by poorly soluble particles (PSPs), and by CS in particular, to model the exposure‐response relation between CS and risk of lung pathologies such as chronic inflammation, silicosis, fibrosis, and lung cancer. An inflammatory mode of action is described, having substantial empirical support, in which exposure increases alveolar macrophages and neutrophils in the alveolar epithelium, leading to increased reactive oxygen species (ROS) and nitrogen species (RNS), pro‐inflammatory mediators such as TNF‐alpha, and eventual damage to lung tissue and epithelial hyperplasia, resulting in fibrosis and increased lung cancer risk among silicotics. This mode of action involves several positive feedback loops. Exposures that increase the gain factors around such loops can create a disease state with elevated levels of ROS, TNF‐alpha, TGF‐beta, alveolar macrophages, and neutrophils. This mechanism implies a “tipping point” threshold for the exposure‐response relation. Applying this new model to epidemiological data, we conclude that current permissible exposure levels, on the order of 0.1 mg/m³, are probably below the threshold for triggering lung diseases in humans.     

Development of the PEARLS model (Particulate Exposure from Ambient to Regional Lung by Subgroup) and use of Monte Carlo simulation to predict internal exposure to 2.5 in Toronto.

Air pollution is a current and growing concern for Canadians, and there is evidence that ambient levels that meet current exposure standards may be associated with mortality and morbidity in Toronto, Canada. Evaluating exposure is an important step in understanding the relationship between particulate matter (PM) exposure and health outcomes. This report describes the PEARLS model (Particulate Exposure from Ambient to Regional Lung by Subgroup), which predicts exposure distributions for 11 age-gender population subgroups in Toronto to PM2.5 (PM with a median aerodynamic diameter of 2.5 microm or less) using Monte Carlo simulation techniques. The model uses physiological and activity pattern characteristics of each subgroup to determine region-specific lung exposure to PM2.5, which is defined as the mass of PM2.5 deposited per unit time to each of five lung regions (two extrathoracic, bronchial, bronchiolar, and alveolar). The modeling results predict that children, toddlers, and infants have the broadest distributions of exposure, and the greatest chance of experiencing extreme exposures in the alveolar region of the lung. Importance analysis indicates that the most influential model variables are air exchange rate into indoor environments, time spent outdoors, and time spent at high activity levels. Additionally, a "critical point" was defined and introduced to the PEARLS to investigate the effects of possible threshold-pathogenic phenomena on subgroup exposure patterns. The analysis indicates that the subgroups initially predicted to be most highly exposed were likely to have the highest proportion of their population exposed above the critical point. Substantial exposures above the critical point were predicted in all subgroups for ambient concentrations of PM2.5 commonly observed in Toronto after continuous exposure of 24 hours or more.     

一类基于SPE的物流配送量优化模型

在对物流配送过程进行分析时,将完全垄断企业物流配送量优化问题看作一个带“有向边”的网络,从而利用交通网络优化中的用户均衡原则,将物流配送量的优化问题转化为需求函数未知时的空间价格均衡问题。在给出与空间价格均衡问题等价的隐式变分不等式后,利用求解变分不等式的预测-校正方法的思想,对所得的模型进行动态化求解,通过对物流配送量与商品价格的数值观察结果对物流配送量进行动态调整,在经过较少次数的迭代后可以得到最优解。最后给出了数值试验的结果。     

基于心智模型的恐怖主义袭击扩展式演化博弈分析

政府反恐措施与恐怖分子袭击手段存在着相互观察、适应性演化的过程。本文首先构建了政府作为先行动者、恐怖分子作为后行动者的斯塔克伯格博弈模型,进一步建立了恐怖袭击问题的扩展式演化博弈模型。由于扩展式演化博弈的均衡分析需要考虑代际内和代际间不同层次的信念学习,造成了演化分析的复杂性。本文将"心智模型"概念引入到演化博弈,采取了心智模型演化解的分析方法,得出了简化后的演化均衡解。最后,结合新疆墨玉县6.28暴恐事件进行算例分析,比较怀特流形演化解和心智模型演化解的差异。心智模型演化解的结果表明,根据恐怖分子群体中选择袭击比例是否高于临界值,政府策略收敛到防御或者不防御。该求解方法通过将普遍接受的社会规范引入到演化过程分析,不仅简化了怀特流形的分析过程,而且均衡解展示了更为丰富的、更为切合实际管理问题的演化特征。     

Separating NE from some nonuniform nondeterministic complexity classes

We investigate the question whether NE can be separated from the reduction closures of tally sets, sparse sets and NP. We show that (1) \(\mathrm{NE}\not\subseteq R^{\mathrm{NP}}_{n^{o(1)}-T}(\mathrm{TALLY})\); (2) \(\mathrm{NE}\not\subseteq R^{SN}_{m}(\mathrm{SPARSE})\); (3) \(\mathrm{NEXP}\not\subseteq \mathrm{P}^{\mathrm{NP}}_{n^{k}-T}/n^{k}\) for all k≥1; and (4) \(\mathrm{NE}\not\subseteq \mathrm{P}_{btt}(\mathrm{NP}\oplus\mathrm{SPARSE})\). Result (3) extends a previous result by Mocas to nonuniform reductions. We also investigate how different an NE-hard set is from an NP-set. We show that for any NP subset A of a many-one-hard set H for NE, there exists another NP subset A′ of H such that A′? A and A′?A is not of sub-exponential density.     

Radon as a Tracer of Lung Changes Induced by Smoking

After smoking, exposure to radon and its progeny is the second leading cause of lung cancer. The probability of inducing lung carcinomas by inhaled radon progeny depends on the deposited radiation dose, and is significantly affected by physiological and morphometric changes induced by smoking. Due to irritation of the airways, the inhalation of cigarette smoke leads to the hyperproduction of mucus. Two concurrent processes occur: on one hand, increased production of mucus protects the target cells against radiation damage; on the other hand, in the case of long-term smokers, a chronic lung obstruction develops, causing an increase in the radiation dose to the lungs. Depending on the duration and intensity of smoking, these processes contribute to the final radiation dose with different weights. The primary objective of this study was to investigate to what extent these smoke-induced changes can modify the resulting absorbed dose of inhaled radon progeny relative to healthy nonsmokers. Since the bronchial dose depends on the degree of lung tissue damage, we have used this dose as a tool for detecting the effects of smoking on the lung epithelium. In other words, the biological effect of radon served as a tracer of changes induced by smoking.     

Could Removing Arsenic from Tobacco Smoke Significantly Reduce Smoker Risks of Lung Cancer?

If a specific biological mechanism could be determined by which a carcinogen increases lung cancer risk, how might this knowledge be used to improve risk assessment? To explore this issue, we assume (perhaps incorrectly) that arsenic in cigarette smoke increases lung cancer risk by hypermethylating the promoter region of gene p16INK4a, leading to a more rapid entry of altered (initiated) cells into a clonal expansion phase. The potential impact on lung cancer of removing arsenic is then quantified using a three‐stage version of a multistage clonal expansion (MSCE) model. This refines the usual two‐stage clonal expansion (TSCE) model of carcinogenesis by resolving its intermediate or “initiated” cell compartment into two subcompartments, representing experimentally observed “patch” and “field” cells. This refinement allows p16 methylation effects to be represented as speeding transitions of cells from the patch state to the clonally expanding field state. Given these assumptions, removing arsenic might greatly reduce the number of nonsmall cell lung cancer cells (NSCLCs) produced in smokers, by up to two‐thirds, depending on the fraction (between 0 and 1) of the smoking‐induced increase in the patch‐to‐field transition rate prevented if arsenic were removed. At present, this fraction is unknown (and could be as low as zero), but the possibility that it could be high (close to 1) cannot be ruled out without further data.     

成本控制、棘轮效应与最优激励契约

国企总部(委托人)授权生产单元(代理人)进行的成本控制通常在不对称信息下实施,不对称信息导致激励方案的使用。随着时间的推移,委托人将代理人成本控制绩效提供的信息考虑进去修订方案,促使后者以低努力来避免未来更严格的方案,棘轮效应出现。本文探讨无跨期承诺合理假设下的这一现象,研究发现,为最大化效用,实现分离均衡的激励方案更为理想。最优值处,分离均衡状态下,信息租金和努力程度得到较好的权衡,而准分离均衡或混同均衡,棘轮效应产生了比静态模型中更强的激励。委托人需要支付高额租金诱使代理人揭示其真实类型,但国企实施的"限薪令"可能会阻止这一行为,从而无法实现分离均衡。     

CSP Deposition to the Alveolar Region of the Lung: Implications of Cigarette Design

Ventilated cigarettes were designed to reduce the levels of smoke under machine testing conditions; however, smokers alter their smoking pattern to compensate for the reduction in yields. A relative shift in incidence of lung cancer from the more central lung airways to the alveolar region has also been associated with ventilated cigarette use. Validated mathematical models indicate that particle deposition patterns in the lung depend on particle size and inhalation behavior, including inhalation volume, flow rate, and breath-hold time. This article finds that most mathematical models underpredict total cigarette smoke particulate (CSP) deposition in the lung, likely because they do not account for coagulation, hygroscopicity, and cloud dynamics, which may increase the effective particle diameter of CSP reaching the lung tissue. The models that include these processes indicate that puff volume would be unlikely to affect particle deposition in the lung, but puff time, inhalation depth, breath-hold time, and exhalation time may affect total deposition. Most compensation appears to occur through a combination of increased puff volume and puff flow, with possible increases in inhalation depth and breath-hold time. The complex interaction between the extent of cigarette ventilation, which can affect puffing/inhalation behavior, CSP concentration, and CSP size with CSP dose to the alveolar versus more central lung airways is described. Deposition efficiency in the alveoli could plausibly be increased through compensation, but it is still unclear whether compensation could sufficiently alter patterns of CSP deposition in the lung to elicit a shift in lung cancer sites.     

An Enforceable Indoor Air Quality Standard for Environmental Tobacco Smoke in the Workplace1

Environmental tobacco smoke (ETS)has recently been determined by U.S. environmental and occupational health authorities to be a human carcinogen. We develop a model which permits using atmospheric nicotine measurements to estimate nonsmokers’ETS lung cancer risks in individual workplaces for the first time. We estimate that during the 1980s, the U.S. nonsmoking adult population's median nicotine lung exposure (homes and workplaces combined)was 143 micrograms (μg)of nicotine daily, and that most-exposed adult nonsmokers inhaled 1430 μg/day. These exposure estimates are validated by pharmacokinetic modeling which yields the corresponding steady-state dose of the nicotine metabolite, cotinine. For U.S. adult nonsmokers of working age, we estimate median cotinine values of about 1.0 nanogram per milliliter (ng/ml)in plasma, and 6.2 ng/ml in urine; for most-exposed nonsmokers, we estimate cotinine concentrations of about 10 ng/ml in plasma and 62 ng/ml in urine. These values are consistent to within 15% of the cotinine values observed in contemporaneous clinical epidemiological studies. Corresponding median risk from ETS exposure in U.S. nonsmokers during the 1980s is estimated at about two lung cancer deaths (LCDs)per 1000 at risk, and for most-exposed nonsmokers, about two LCDs per 100. Risks abroad appear similar. Modeling of the lung cancer mortality risk from passive smoking suggests that de minimis [i.e., “acceptable” (10^-6)], risk occurs at an 8-hr time-weighted-average exposure concentration of 7.5 nanograms of ETS nicotine per cubic meter of workplace air for a working lifetime of 40 years. This model is based upon a linear exposure-response relationship validated by physical, clinical, and epidemiological data. From available data, it appears that workplaces without effective smoking policies considerably exceed this de minimis risk standard. For a substantial fraction of the 59 million nonsmoking workers in the U.S., current workplace exposure to ETS also appears to pose risks exceeding the de manifestos risk level above which carcinogens are strictly regulated by the federal government.     

POWER INSIDE THE FIRM AND THE MARKET: A GENERAL EQUILIBRIUM APPROACH

Recent years have witnessed an enormous amount of reorganization of the corporate sector in the United States and Europe. This article examines the role of market competition in this trend of corporate reorganization. We find that, at intermediate levels of competition, the CEO of the corporation decides to have less power inside the firm and to delegate control to lower levels of the firms' hierarchy. Workers' empowerment and the move to a flatter organizational structure emerge as an equilibrium when competition is not too tough and not too weak. The model predicts merger waves or waves of outsourcing when countries become more integrated in the global economy as the corporate sector reorganizes in response to an increase in international competition. (JEL: F12, D23, L22, L1)