Improving Cancer Dose–Response Characterization by Using Physiologically Based Pharmacokinetic Modeling: An Analysis of Pooled Data for Acrylonitrile-Induced Brain Tumors to Assess Cancer Potency in the Rat

Historically, U.S. regulators have derived cancer slope factors by using applied dose and tumor response data from a single key bioassay or by averaging the cancer slope factors of several key bioassays. Recent changes in U.S. Environmental Protection Agency (EPA) guidelines for cancer risk assessment have acknowledged the value of better use of mechanistic data and better dose–response characterization. However, agency guidelines may benefit from additional considerations presented in this paper. An exploratory study was conducted by using rat brain tumor data for acrylonitrile (AN) to investigate the use of physiologically based pharmacokinetic (PBPK) modeling along with pooling of dose–response data across routes of exposure as a means for improving carcinogen risk assessment methods. In this study, two contrasting assessments were conducted for AN-induced brain tumors in the rat on the basis of (1) the EPA's approach, the dose–response relationship was characterized by using administered dose/concentration for each of the key studies assessed individually; and (2) an analysis of the pooled data, the dose–response relationship was characterized by using PBPK-derived internal dose measures for a combined database of ten bioassays. The cancer potencies predicted for AN by the contrasting assessments are remarkably different (i.e., risk-specific doses differ by as much as two to four orders of magnitude), with the pooled data assessments yielding lower values. This result suggests that current carcinogen risk assessment practices overestimate AN cancer potency. This methodology should be equally applicable to other data-rich chemicals in identifying (1) a useful dose measure, (2) an appropriate dose–response model, (3) an acceptable point of departure, and (4) an appropriate method of extrapolation from the range of observation to the range of prediction when a chemical's mode of action remains uncertain.     

International investment motivations of U.S. wineries

This study used personal and telephone interviews of wine industry executives and observers to examine the foreign direct investment motivations of U.S. wineries. Underlying most winery motivations was the recognition that U.S. wineries sense increasing pressure to offer a competitive range of wines that meet the price/quality needs of consumers and retailers in important markets and market segments. Wineries’ marketing plans are often constrained by their ability to obtain adequate grape and juice supplies that meet important price and quality criteria, especially when domestic grape production drops. The importance of product portfolios and the industry’s resource dependence have placed tremendous pressures on U.S. wineries to coordinate winegrape and juice acquisitions, especially as retailers consolidate their supply chains. Some U.S. wineries have invested abroad in response to these pressures while others have not. Interview results suggest that foreign investments by U.S. wineries were primarily motivated by the need for greater access to stable or adequate winegrape/juice supplies, the need for more control over the winegrape costs within given quality levels, and the desire to expand wine portfolios.     

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.     

The Role of Behavioral Responses in the Total Economic Consequences of Terrorist Attacks on U.S. Air Travel Targets

U.S. airports and airliners are prime terrorist targets. Not only do the facilities and equipment represent high‐value assets, but the fear and dread that is spread by such attacks can have tremendous effects on the U.S. economy. This article presents the methodology, data, and estimates of the macroeconomic impacts stemming from behavioral responses to a simulated terrorist attack on a U.S. airport and on a domestic airliner. The analysis is based on risk‐perception surveys of these two scenarios. The responses relate to reduced demand for airline travel, shifts to other modes, spending on nontravel items, and savings of potential travel expenditures by U.S. resident passengers considering flying domestic routes. We translate these responses to individual spending categories and feed these direct impact results into a computable general equilibrium (CGE) model of the U.S. economy to ascertain the indirect and total impacts on both the airline industry and the economy as a whole. Overall, the estimated impacts on GDP of both types of attacks exceed $10B. We find that the behavioral economic impacts are almost an order of magnitude higher than the ordinary business interruption impacts for the airliner attack and nearly two orders of magnitude higher for the airport attack. The results are robust to sensitivity tests on the travel behavior of U.S. residents in response to terrorism.     

Analysis of Inland Crude Oil Spill Threats,Vulnerabilities, and Emergency Response in the Midwest United States

Although coastal oil spills tend to be highly publicized, crude oil spills in the United States affect inland areas relatively often. Spills to inland areas often affect sensitive environments and can have greater impacts to health and welfare than spills to coastal areas. For these reasons, the authors investigated inland crude oil spill threats, vulnerabilities, and emergency response in the midwestern U.S. states of Illinois, Indiana, Michigan, Minnesota, Ohio, and Wisconsin. These states work with the Region 5 Offices of the U.S. Environmental Protection Agency. Region 5's geospatial data in the Inland Sensitivity Atlas were turned into metrics indicating inland crude oil spill threats and vulnerabilities among the Region's sub‐watersheds. These threats and vulnerabilities were weighted using data from the National Response Center and the Department of Energy's Environmental Restoration Priority System. The locations of the Region's emergency responders were geocoded in GIS. The GIS calculated the emergency response times to the Region's sub‐watersheds. The resulting scatter plots are connected to the sub‐watersheds in the map so stakeholders can (1) see the outlying sub‐watersheds of concern and (2) better understand how reducing threats and better response time can reduce the risk of inland crude oil spills.     

A Stochastic Assessment of the Public Health Risks of the Use of Macrolide Antibiotics in Food Animals

Campylobacteriosis is an important food-borne illness with more than a million U.S. cases annually. Antibiotic treatment is usually not required. However, erythromycin, a macrolide antibiotic, is recommended for the treatment of severe cases. Therefore, it is considered a critically important antibiotic and given special attention as to the risk that food animal use will lead to resistant infections and compromised human treatment. To assess this risk, we used a retrospective approach; estimating the number of campylobacteriosis cases caused by specific meat consumption utilizing the preventable fraction. We then determined the number of cases with macrolide resistance Campylobacter spp. based on a linear model relating the resistance fraction to on-farm macrolide use. In this article, we considered the uncertainties in the parameter estimates, utilized a more elaborate model of resistance development and separated C. coli and C. jejuni . There are no published data for the probability of compromised treatment outcome due to macrolide resistance. Therefore, our estimates of compromised treatment outcome were based on data for fluoroquinolone-resistant infections. The conservative results show the human health risks are extremely low. For example, the predicted risk of suboptimal human treatment of infection with C. coli from swine is only 1 in 82 million; with a 95% chance it could be as high as 1 in 49 million. Risks from C. jejuni in poultry or beef are even less. Reduced antibiotic use can adversely impact animal health. These low human risks should be weighed against the alternative risks.     

The derived demand for imported cheese in Hong Kong

The objective of this paper was to provide the U.S. dairy industry with empirical estimates of Hong Kong’s derived demand for imported cheese differentiated by source country of production. These estimates were used to simulate the effects of European Union (EU) subsidy reductions on the U.S. share of Hong Kong cheese imports. Simulation results suggested that Oceania was the primary beneficiary from EU subsidy reductions. Hong Kong cheese imports from the U.S. were expected to increase by 12% if subsidy reductions continue at the same pace as the 1994 GATT agreement and 21% if reductions were twice the pace.     

Assessing the Benefits and Costs of Homeland Security Research: A Risk-Informed Methodology with Applications for the U.S. Coast Guard

This article describes a methodology for risk-informed benefit–cost analyses of homeland security research products. The methodology is field-tested with 10 research products developed for the U.S. Coast Guard. Risk-informed benefit–cost analysis is a tool for risk management that integrates elements of risk analysis, decision analysis, and benefit–cost analysis. The cost analysis methodology includes a full-cost accounting of research projects, starting with initial fundamental research costs and extending to the costs of implementation of the research products and, where applicable, training, maintenance, and upgrade costs. The benefits analysis methodology is driven by changes in costs and risks leading to five alternative models: cost savings at the same level of security, increased security at the same cost, signal detection improvements, risk reduction by deterrence, and value of information. The U.S. Coast Guard staff selected 10 research projects to test and generalize the methodology. Examples include tools to improve the detection of explosives, reduce the costs of harbor patrols, and provide better predictions of hurricane wind speeds and floods. Benefits models and estimates varied by research project and many input parameters of the benefit estimates were highly uncertain, so risk analysis for sensitivity testing and simulation was important. Aggregating across the 10 research products, we found an overall median net present value of about $385 million, with a range from $54 million (5th percentile) to $877 million (95th percentile). Lessons learned are provided for future applications.     

The benefits and costs of U.S. employer COVID-19 vaccine mandates

In 2021, the Biden Administration issued mandates requiring COVID-19 vaccinations for U.S. federal employees and contractors and for some healthcare and private sector workers. These mandates have been challenged in court; some have been halted or delayed. However, their costs and benefits have not been rigorously appraised. This study helps fill that gap. We estimate the direct costs and health-related benefits that would have accrued if these vaccination requirements had been implemented as intended. Compared with the January 2022 vaccination rates, we find that the mandates could have led to 15 million additional vaccinated individuals, increasing the overall proportion of the fully vaccinated U.S. population from 64% to 68%. The associated net benefits depend on the subsequent evolution of the pandemic—information unavailable ex ante to analysts or policymakers. In scenarios involving the emergence of a novel, more transmissible variant, against which vaccination and previous infection offer moderate protection, the estimated net benefits are potentially large. They reach almost $20,000 per additional vaccinated individual, with more than 20,000 total deaths averted over the 6-month period assessed. In scenarios involving a fading pandemic, existing vaccination-acquired or infection-acquired immunity provides sufficient protection, and the mandates’ benefits are unlikely to exceed their costs. Thus, mandates may be most useful when the consequences of inaction are catastrophic. However, we do not compare the effects of mandates with alternative policies for increasing vaccination rates or for promoting other protective measures, which may receive stronger public support and be less likely to be overturned by litigation.     

Risk Assessment for Aflatoxin: II. Implications of Human Epidemiology Data

A review of epidemiology literature revealed that only studies conducted in Africa and Asia included data adequate to permit quantitative assessment of the dose-response relationship between aflatoxin exposure levels and liver cancer rates. Although these studies were judged adequate, their direct use to predict risks in U.S. populations may be questioned since hepatitis B virus (HBV) infections are far more common in the studied areas than in the U.S. Recent research indicates that, if aflatoxin contributes to the development of liver cancer, it almost always does so in the presence of HBV infection. The African/Asian data do not permit us to estimate the potency of aflatoxin in the absence of HBV. Recognizing this, these data can only be used to establish upper limits for the predicted excess lifetime risk for liver cancer in the U.S. When used in conjunction with aflatoxin exposure estimates for the Southeast U.S., these data predict a liver cancer rate, due to aflatoxin alone, far above that actually observed due to all causes; this provides an indication of the conservatism of this approach. Data from the Southeast U.S. may be used to estimate an excess lifetime risk for liver cancer of 2.17 x 10(-6) x (aflatoxin intake, ng/kg/day).     

Host-country Headquarters of U.S. Firms in China: An Empirical Study

Recent studies show that large multinational enterprises (MNEs) adopt an organizational unit, called host-country headquarters (HCHQ), in key foreign countries (Ma and Delios, 2010; Ma, Delios and Lau, 2013). In this study, we examine the factors that are associated with the establishment of an HCHQ by US firms in China. We hypothesize that an HCHQ is associated with both firm-specific factors and host country-specific factors. We find that an HCHQ is associated with the firm's scope diversification and degree of internationalization, and the strategic importance of foreign host country and subsidiary diversification in that host country. The findings are based on archival data of U.S. Fortune 500 firms. The findings add to the understanding of an important organizational structure of large U.S. firms in China, and possibly to MNE structures more widely in key foreign countries.     

Emotional labour,collectivism and strain: a comparison of Turkish and U.S. service employees

ABSTRACT

Global growth in service employment highlights the need to understand how cross-cultural differences impact emotional labour processes for service employees. The current study investigates these differences by examining the impact of national and individual level collectivistic values on emotional labour strategies and employee strain (emotional strain, turnover intentions, job satisfaction, and organisational commitment). Cross-sectional data was collected from U.S. (n?=?191) and Turkish (n?=?249) customer service employees. Results indicate that collectivism impacts the process model of emotional labour via direct and interaction effects. Collectivism was associated with higher emotional labour engagement and lower employee strains. Surface acting was uncorrelated with Turkish employees’ strain, though moderated regression analyses revealed interaction effects associated with national and individual level collectivism. These results suggest that collectivistic values may serve as a buffer against harmful effects associated with surface acting. This study is the first to directly compare emotional labour processes in U.S. and Turkish service employees and expand the process model of emotional labour to include collectivism. The theoretical implications of this expanded model are discussed, along with future research directions and practical applications of these findings.     

VCCEP Pilot: Progress on Evaluating Children''s Risks and Data Needs

The Voluntary Children's Chemical Evaluation Program (VCCEP) is designed to provide information to the public on children's potential health risks associated with chemical exposures. The key question of the VCCEP is whether the potential hazards, exposures, and risks to children have been adequately characterized, and, if not, what additional data are necessary. To answer this question, manufacturers or importers of 23 chemicals were asked by the U. S. Environmental Protection Agency (U.S. EPA) to sponsor their chemicals in the first tier of a pilot program. These chemicals were selected for evaluation because they have been found as contaminants in human tissue or fluids (adipose tissue, blood, breath, breast milk, or urine); food and water children may eat and drink; or air children may breathe (including residential or school air). Under the VCCEP framework, sponsoring companies agree to prepare Tier 1 hazard, exposure, and risk assessments on the individual chemicals, and identify the need for additional data. These assessment documents are submitted to the U.S. EPA and subsequently undergo review by experts in an independent peer consultation meeting that is open to the public. Following this peer consultation process, the U.S. EPA reviews each submission and makes a data-needs determination, which may include requesting further data collection or generation by the sponsor. Sponsoring companies then decide whether to volunteer for the next tier and collect or generate the requested data. The purpose of this article is to describe the VCCEP process and to review and present the key findings from the first set of chemicals that have been fully or partially evaluated under the pilot program (vinylidene chloride, decabromodiphenyl ether, pentabromodiphenyl ether, octabromodiphenyl ether, acetone, methyl ethyl ketone, decane, undecane, and dodecane). Specifically, we provide a brief summary of the sponsors' submissions, the peer consultation panels' discussions, and the U.S. EPA's data-needs decisions. Although we do not attempt to conduct independent analyses of the underlying data, we do identify a number of common themes that have emerged during implementation of the pilot program and discuss several key issues that could become important in the future. The information presented here should be useful for various parties interested in the progress of the VCCEP and the results of the initial (Tier 1) children's assessments.     

How does homeland security affect U.S. firms' international competitiveness?

This paper frames the issue of homeland security and its relationship to the international competitiveness of U.S. firms in general. This is largely a conceptual statement, identifying the areas of national security (homeland security) that are key to business, and exploring the management concerns of business to the new threats and opportunities that have arisen.We establish the point that homeland security is a purposeful, conscious, and rational response to terrorist events that is an emergent and evolving systems phenomenon. This systems approach is an especially useful way to look at the implications of homeland security in its relation to business. We then look specifically at the kinds of costs and risks that are generated for U.S. international business (exports, imports, incoming and outgoing investments) as a result of this phenomenon. Management strategies for dealing with these costs and risks are explored for U.S. firms.Our conclusion is to demonstrate the scope of analysis that is needed to understand and to managerially cope with the homeland security problem. We show the value of using theory from various disciplines for analyzing a multi-dimensional problem like this. And finally we are able to recommend some policy dimensions for both companies and the U.S. Government toward mitigating the negative impacts of the homeland security problem.     

次贷危机前后国际原油市场与中美股票市场间的协动性研究

本文运用基于动态条件相关的多元GARCH(DCC-MVGARCH)模型,对美国次信贷危机发生前后国际原油市场和中、美股票市场间的协动性变化进行了研究。实证结果表明在次信贷危机发生后,国际原油市场与中、美股票市场间的协动性有了明显的增强,不同市场间的波动具有明显的传导作用。国际原油市场与美国股市的协动性相对于中国股市波动性更强,说明冲击在国际原油市场与美国股市间的传导更强烈,其协动性对冲击的反应更敏感。另外,运用偏最小二乘方法(PLS)对影响国际原油市场和中、美股票市场的诸多因素在次信贷危机爆发前后对协动性解释能力的变化进行了分析,结果发现次信贷危机对这些因素的解释能力有明显的影响。     

Economic impact of a ban on the use of over the counter antibiotics in U.S. swine rations

The U.S. pork industry routinely adds antibiotics to rations of weaned pigs both to prevent illness before symptoms emerge and to increase growth rates. The European Union (EU) is in the process of restricting feed use of antibiotics, and the U.S. is currently reviewing the practice. The strategic issue facing U.S. pork producers is whether another food safety dispute with the EU is worthwhile. This paper evaluates the economic impact of such a ban in the U.S. The analysis uses a set of technical assumptions derived from the experience of a similar ban in Sweden and finds such a ban would increase production costs per head between $5.24 and $6.05; net profit would decline $0.79 per head. On the consumer side, the effects of a ban would raise the retail price of pork by 5 cents per pound.     

Performance Impacts of Strategy,Information Technology Applications,and Business Process Outsourcing in U.S. Manufacturing Plants

This paper develops a conceptual model to study the role of outsourcing strategies and plant‐level information technology (IT) application infrastructure in the outsourcing of production and support business processes, as well as their subsequent impact on overall plant performance. We validate this model empirically using cross‐sectional survey data from U.S. manufacturing plants. We find that some IT applications are more effective at enabling the outsourcing of business processes than others. For example, the implementation of enterprise management systems is associated with the outsourcing of both production and support processes, whereas operations management systems are not associated with the outsourcing of plant processes. Plants with a low‐cost outsourcing strategy are more likely to outsource support processes than plants with a competency‐focused outsourcing strategy. However, both cost‐ and competency‐based strategies have a positive and similar impact on the outsourcing of production processes. In terms of implications for plant performance, our findings indicate that the outsourcing of production and support processes is associated with higher gross margins. Although plant IT infrastructure is positively associated with favorable on‐time delivery rates, there is no positive association between the incidence of plant outsourcing and on‐time delivery rates. These results have implications for crafting plant‐level outsourcing strategies and for investments in IT systems to facilitate the outsourcing of business processes for enhanced plant performance.     

Improving cancer dose-response characterization by using physiologically based pharmacokinetic modeling: an analysis of pooled data for acrylonitrile-induced brain tumors to assess cancer potency in the rat.

Historically, U.S. regulators have derived cancer slope factors by using applied dose and tumor response data from a single key bioassay or by averaging the cancer slope factors of several key bioassays. Recent changes in U.S. Environmental Protection Agency (EPA) guidelines for cancer risk assessment have acknowledged the value of better use of mechanistic data and better dose-response characterization. However, agency guidelines may benefit from additional considerations presented in this paper. An exploratory study was conducted by using rat brain tumor data for acrylonitrile (AN) to investigate the use of physiologically based pharmacokinetic (PBPK) modeling along with pooling of dose-response data across routes of exposure as a means for improving carcinogen risk assessment methods. In this study, two contrasting assessments were conducted for AN-induced brain tumors in the rat on the basis of (1) the EPA's approach, the dose-response relationship was characterized by using administered dose/concentration for each of the key studies assessed individually; and (2) an analysis of the pooled data, the dose-response relationship was characterized by using PBPK-derived internal dose measures for a combined database of ten bioassays. The cancer potencies predicted for AN by the contrasting assessments are remarkably different (i.e., risk-specific doses differ by as much as two to four orders of magnitude), with the pooled data assessments yielding lower values. This result suggests that current carcinogen risk assessment practices overestimate AN cancer potency. This methodology should be equally applicable to other data-rich chemicals in identifying (1) a useful dose measure, (2) an appropriate dose-response model, (3) an acceptable point of departure, and (4) an appropriate method of extrapolation from the range of observation to the range of prediction when a chemical's mode of action remains uncertain.     

Organizing the Global Value Chain

We develop a property‐rights model of the firm in which production entails a continuum of uniquely sequenced stages. In each stage, a final‐good producer contracts with a distinct supplier for the procurement of a customized stage‐specific component. Our model yields a sharp characterization for the optimal allocation of ownership rights along the value chain. We show that the incentive to integrate suppliers varies systematically with the relative position (upstream versus downstream) at which the supplier enters the production line. Furthermore, the nature of the relationship between integration and “downstreamness” depends crucially on the elasticity of demand faced by the final‐good producer. Our model readily accommodates various sources of asymmetry across final‐good producers and across suppliers within a production line, and we show how it can be taken to the data with international trade statistics. Combining data from the U.S. Census Bureau's Related Party Trade database and estimates of U.S. import demand elasticities from Broda and Weinstein (2006), we find empirical evidence broadly supportive of our key predictions. In the process, we develop two novel measures of the average position of an industry in the value chain, which we construct using U.S. Input–Output Tables.     

Business Cycle Accounting

We propose a simple method to help researchers develop quantitative models of economic fluctuations. The method rests on the insight that many models are equivalent to a prototype growth model with time‐varying wedges that resemble productivity, labor and investment taxes, and government consumption. Wedges that correspond to these variables—efficiency, labor, investment, and government consumption wedges—are measured and then fed back into the model so as to assess the fraction of various fluctuations they account for. Applying this method to U.S. data for the Great Depression and the 1982 recession reveals that the efficiency and labor wedges together account for essentially all of the fluctuations; the investment wedge plays a decidedly tertiary role, and the government consumption wedge plays none. Analyses of the entire postwar period and alternative model specifications support these results. Models with frictions manifested primarily as investment wedges are thus not promising for the study of U.S. business cycles.