Methods for Assessing Uncertainty in Fundamental Assumptions and Associated Models for Cancer Risk Assessment

The distributional approach for uncertainty analysis in cancer risk assessment is reviewed and extended. The method considers a combination of bioassay study results, targeted experiments, and expert judgment regarding biological mechanisms to predict a probability distribution for uncertain cancer risks. Probabilities are assigned to alternative model components, including the determination of human carcinogenicity, mode of action, the dosimetry measure for exposure, the mathematical form of the dose‐response relationship, the experimental data set(s) used to fit the relationship, and the formula used for interspecies extrapolation. Alternative software platforms for implementing the method are considered, including Bayesian belief networks (BBNs) that facilitate assignment of prior probabilities, specification of relationships among model components, and identification of all output nodes on the probability tree. The method is demonstrated using the application of Evans, Sielken, and co‐workers for predicting cancer risk from formaldehyde inhalation exposure. Uncertainty distributions are derived for maximum likelihood estimate (MLE) and 95th percentile upper confidence limit (UCL) unit cancer risk estimates, and the effects of resolving selected model uncertainties on these distributions are demonstrated, considering both perfect and partial information for these model components. A method for synthesizing the results of multiple mechanistic studies is introduced, considering the assessed sensitivities and selectivities of the studies for their targeted effects. A highly simplified example is presented illustrating assessment of genotoxicity based on studies of DNA damage response caused by naphthalene and its metabolites. The approach can provide a formal mechanism for synthesizing multiple sources of information using a transparent and replicable weight‐of‐evidence procedure.     

Bayesian Estimation of Pharmacokinetic and Pharmacodynamic Parameters in a Mode-of-Action-Based Cancer Risk Assessment for Chloroform

Chloroform is a carcinogen in rodents and its carcinogenicity is secondary to events associated with cytotoxicity and regenerative cell proliferation. In this study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that links the processes of chloroform metabolism, reparable cell damage, cell death, and regenerative cellular proliferation was developed to support a new cancer dose-response assessment for chloroform. Model parameters were estimated using Markov Chain Monte Carlo (MCMC) analysis in a two-step approach: (1) metabolism parameters for male and female mice and rats were estimated against available closed chamber gas uptake data; and (2) PD parameters for each of the four rodent groups were estimated from hepatic and renal labeling index data following inhalation exposures. Subsequently, the resulting rodent PD parameters together with literature values for human age-dependent physiological and metabolism parameters were used to scale up the rodent model to a human model. The human model was used to predict exposure conditions under which chloroform-mediated cytolethality is expected to occur in liver and kidney of adults and children. Using the human model, inhalation Reference Concentrations (RfCs) and oral Reference Doses (RfDs) were derived using an uncertainty factor of 10. Based on liver and kidney dose metrics, the respective RfCs were 0.9 and 0.09 ppm; and the respective RfDs were 0.4 and 3 mg/kg/day.     

Potential Health Effects of Light-Duty Diesel Exhaust

The purpose of this paper is to review briefly the evidence for potential human health effects that may result from increased dieselization of the nation's light-duty vehicle fleet. An effort is made to put the potential effects into perspective, both with regard to projected excess cancer deaths, should diesel exhaust be carcinogenic to humans, and in relation to past use of vehicles using leaded gasoline. Certain related research needs are highlighted. Available data concerning the relationship between diesel emissions, ambient air quality, and human health are summarized. On the basis of exposure estimates and relative potency factors, the authors conclude that the best estimate of the number of excess annual U.S. lung cancer deaths as a result of lifetime exposure to light-duty diesel particulate under 1990 conditions is between 80 and 1500. Available data suggest that the carcinogenic hazard of exhaust from vehicles burning leaded gasoline may be an order of magnitude greater, on a per mile basis, than that of diesel engines. The hazard of emissions from diesel are, in turn, probably an order of magnitude greater than that of gasoline engines with catalytic converters burning unleaded gasoline. Important research needs identified by the authors include determining whether diesel exhaust is in fact a human carcinogen, studying the effect of atmospheric chemical transformation of organics in diesel exhaust on the toxicity of the exhaust, making a better determination of the relative carcinogenicity of diesel and gasoline exhausts, and determining whether exposure to diesel exhaust contributes to the development or exacerbation of chronic lung disease or of respiratory illness, especially in the very young and the aged.     

Explaining performing R&D through alliances: Implications for the business model of Italian dedicated biotech firms

In recent years management scholars and practitioners have been interested in Research and Development (R&D) partnering, especially in high-tech industries. While the motivations of research partnership formation have been widely explored in literature, little attempt has been undertaken to examine the effects of research partnerships on R&D productivity and the implications for business models of the new ventures. In this paper we try to shed some light on the business models of the young ventures involved in R&D partnerships and their effect on R&D productivity. Our hypotheses are that experience in previous alliances, repeated partnerships and tight relationships have positive effects on R&D productivity while rigid governance structures and public R&D subsidies have negative effects on such productivity. We discuss how these aspects affect the business models of biotech firms. We test our hypotheses on a sample of 55 Italian DBFs (Dedicated Biotech Firms). Results support our hypotheses. Managerial implications and further issues for future research are discussed.     

A Pharmacokinetic Study of Occupational and Environmental Benzene Exposure with Regard to Gender

Using physiologically-based pharmacokinetic (PBPK) modeling, occupational, personal, and environmental benzene exposure scenarios are simulated for adult men and women. This research identifies differences in internal exposure due to physiological and biochemical gender differences. Physiological and chemical-specific model parameters were obtained from other studies reported in the literature and medical texts for the subjects of interest. Women were found to have a higher blood/air partition coefficient and maximum velocity of metabolism for benzene than men (the two most sensitive parameters affecting gender-specific differences). Additionally, women generally have a higher body fat percentage than men. These factors influence the internal exposure incurred by the subjects and should be considered when conducting a risk assessment. Results demonstrated that physicochemical gender differences result in women metabolizing 23–26% more benzene than men when subject to the same exposure scenario even though benzene blood concentration levels are generally higher in men. These results suggest that women may be at significantly higher risk for certain effects of benzene exposure. Thus, exposure standards based on data from male subjects may not be protective for the female population.     

Chronic Health Risks from Aggregate Exposures to Ionizing Radiation and Chemicals: Scientific Basis for an Assessment Framework

Very little quantitative analysis is currently available on the cumulative effects of exposure to multiple hazardous agents that have either similar or different mechanisms of action. Over the past several years, efforts have been made to develop the methodologies for risk assessment of chemical mixtures, but mixed exposures to two or more dissimilar agents such as radiation and one or more chemical agents have not yet been addressed in any substantive way. This article reviews the current understanding of the health risks arising from mixed exposures to ionizing radiation and specific chemicals. Specifically discussed is how mixed radiation/chemical exposures, when evaluated in aggregation, were linked to chronic health endpoints such as cancer and intermediate health outcomes such as chromosomal aberrations. Also considered is the extent to which the current practices are consistent with the scientific understanding of the health risks associated with mixed-agent exposures. From this the discussion moves to the research needs for assessing the cumulative health risks from aggregate exposures to ionizing radiation and chemicals. The evaluation indicates that essentially no guidance has been provided for conducting risk assessment for two agents with different mechanisms of action (i.e., energy deposition from ionizing radiation versus DNA interactions with chemicals) but similar biological endpoints (i.e., chromosomal aberrations, mutations, and cancer). The literature review also reveals the problems caused by the absence of both the basic science and an appropriate evaluation framework for the combined effects of mixed-agent exposures. This makes it difficult to determine whether there is truly no interaction or somehow the interaction is masked by the scale of effect observation or inappropriate dose-response assumptions.     

Can information technology enable profitable diversification? An empirical examination

Investments in information technology (IT) are now a major part of corporate investment, and the management of IT is essential to performance. In general, IT is expected to have performance effects when it is judiciously used to complement existing corporate capabilities. In this research, we examine how IT can complement diversification strategy. Using hypotheses and measures suggested by information processing theory and the theory of corporate strategy, testable hypotheses are derived to examine how IT can complement diversification. Results suggest that spending on computer technology significantly complements a strategy of unrelated diversification. Implications for theory and practice are discussed.     

The Value of Organizational Ambivalence for Small and Medium Size Enterprises in an Uncertain World

Prior literature suggests two competing mechanisms for how organizations respond to environmental forces – absorption and reduction – but there is no consensus on which mechanism is more effective. We solve this puzzle by analysing one underlying dimension of these two mechanisms – organizational ambivalence – in a small and medium size enterprise context. Specifically, we believe that because of the difference in consuming resources, organizational ambivalence can be divided into latent and active, which exhibit different uses in dealing with environmental forces and improving firm performance. We conducted two studies in four countries to test our hypotheses. These two studies yield unanimous support for our hypotheses regarding the impact of organizational ambivalence on organizational performance and mixed support for our hypotheses concerning environmental impacts on organizational ambivalence.     

Chemical Health Effects Assessment Methodology for Airborne Contaminants

Chemical Health Effects Assessment Methodology (CHEM) is a new procedure for assessing hazardous properties of airborne toxic contaminants. CHEM evaluates substances for four major health effect categories: carcinogenicity, mutagenicity, reproductive/developmental toxicity, and toxic effects other than the first three. Three elements are considered in the assessment: weight of evidence, potency, and severity of effect. This approach produces a profile of toxic properties of chemicals which preserves their unique multidimensional character and highlights data gaps.     

Opportunism in Distribution Networks: The Role of Network Embeddedness and Dependence

Prior research documents the value of network relationships to firm behavior but is relatively silent on how networks influence opportunism in distribution channels. Focusing on a common type of distribution networks in which multiple distributors serve a single, dominant supplier, this study moves beyond a dyadic view to examine how a focal distributor's relational and structural embeddedness in such a distribution network influences its opportunism toward the dominant supplier. In particular, we postulate that a distributor's relational embeddedness in the network curbs its opportunism, whereas its network centrality, as a form of structural embeddedness in the network, promotes its opportunism. Moreover, we propose that relational embeddedness magnifies the role of a focal distributor's dependence on the supplier in suppressing the distributor's opportunism, whereas network centrality buffers such a role. We first empirically test these hypotheses using data collected from car dealers in China; the results provide support for the hypotheses. We then develop an analytical model to validate and further explain the underlying mechanisms of the network effects. Our analytical results not only validate the empirical results but also provide guidance for managers on controlling opportunism in distribution networks.     

An Empirical Investigation of Information Search Strategies with Implications for Decision Support System Design

Understanding how people search through and combine information before making decisions is an important concern in the study of decision making and in the design of decision support systems (DSS). The purpose of this study is to examine DSS search strategies in relation to the body of empirical research on information load. Prior research is examined in relation to basic empirically-testable hypotheses and compared to the results of this study as a way of validating the procedures used here. The transfer of information load empirical research to a DSS scenario is confirmed statistically. Then, results of an analysis of information search patterns under DSS conditions are described. Finally, implications for DSS design are discussed in terms of possible search support mechanisms for specific search strategies.     

Engaging leader – Engaged employees? A cross-lagged study on employee engagement

The goal of this study is to provide a cross-lagged examination of the relationships between engaging leadership, job resources and employee work engagement. We propose a mediation model and we postulate that engaging leadership can increase perceptions of three specific job resources (i.e. autonomy, support from colleagues and opportunities for learning and development) which theoretically correspond to the three facets of engaging leadership (i.e., inspiring, connecting and strengthening, respectively). Subsequently, in keeping with the extant body of Job Demands-Resources (JD-R) research, we link job resources to employee work engagement. Our hypotheses were tested on data collected at two time-points – T1 (N = 759) and T2 (N = 273) –from employees working for a hotel chain in the Netherlands. In line with our expectations, engaging leadership showed a significant cross-lagged relationship with autonomy and support from colleagues, but did not predict learning opportunities and work engagement across time. While we formulated specific hypotheses, we also tested reversed causation relationships. We found no direct effect from engaging leadership on employee work engagement, however, the reversed effect was significant; employee perceptions of engaging leadership were shaped by their own engagement experiences. Importantly, engaged employees at T1 reported more job resources at T2. By providing a cross-lagged examination of our model, we showed that engaging leaders as well as employees’ positive affective state of being engaged, are essential to shaping a resourceful work context. A comprehensive view on the triggers and outcomes of work engagement and engaging leadership is needed, as the traditional unidirectional cause-effect rationale fails to explain how these concepts relate to one another and to employee experiences of job resources.     

Estimation of Acute Toxicity by Fitting a Dose-Time-Response Surface

In acute toxicity testing, organisms are continuously exposed to progressively increasing concentrations of a chemical and deaths of test organisms are recorded at several selected times. The results of the test are traditionally summarized by a dose-response curve, and the time course of effect is usually ignored for lack of a suitable model. A model which integrates the combined effects of dose and exposure duration on response is derived from the biological mechanisms of aquatic toxicity, and a statistically efficient approach for estimating acute toxicity by fitting the proposed model is developed in this paper. The proposed procedure has been computerized as software and a typical data set is used to illustrate the theory and procedure. The new statistical technique is also tested by a data base of a variety of chemical and fish species.     

Universal-deterministic and probabilistic hypotheses in operations management research: a discussion paper

Abstract

Based on Karl Popper’s approach to science, this conceptual article aims at promoting a discussion on important issues debated in the OM literature. Our focus is on the different types of hypotheses used in OM investigations and the implications of this for the formulation and testing of theory with an emphasis on case study research. Given that Popper’s methodology calls for an adequate testing of scientific propositions (universal-deterministic or probabilistic), we illustrate how case study research can be used to conduct a severe test of a scientific theory. It is also explained how case studies can be utilized to propose universal-deterministic hypotheses that should then be tested. Our investigation further discusses why it is important to clearly acknowledge the differences between the two types of hypotheses. Otherwise, inadequate research designs, deficient policy advice, and other similar problems, can arise. Topics for future research and discussion are also offered.     

Determination of Leukemogenic Benzene Exposure Concentrations: Refined Analyses of the Pliofilm Cohort

Biologic data on benzene metabolite doses, cytotoxicity, and genotoxicity often show that these effects do not vary directly with cumulative benzene exposure (i.e., concentration times time, or c × t ). To examine the effect of an alternate exposure metric, we analyzed cell-type specific leukemia mortality in Pliofilm workers. The work history of each Pliofilm worker was used to define each worker's maximally exposed job/department combination over time and the associated long-term average concentration associated with the maximally exposed job (LTA-MEJ). Using this measure, in conjunction with four job exposure estimates, we calculated SMRs for groups of workers with increasing LTA-MEJs. The analyses suggest that a critical concentration of benzene exposure must be reached in order for the risk of leukemia or, more specifically, AMML to be expressed. The minimum concentration is between 20 and 60 ppm depending on the exposure estimate and endpoint (all leukemias or AMMLs only). We believe these analyses are a useful adjunct to previous analyses of the Pliofilm data. They suggests that (a) AMML risk is shown only above a critical concentration of benzene exposure, measured as a long-term average and experienced for years, (b) the critical concentration is between 50 and 60 ppm when using a median exposure estimate derived from three previous exposure assessments, and is between 20 and 25 ppm using the lowest exposure estimates, and (c) risks for total leukemia are driven by risks for AMML, suggesting that AMML is the cell type related to benzene exposure.     

Combined Effects of Contaminant Desorption and Toxicity on Risk from PAH Contaminated Sediments

A strong inverse correlation was observed between the polycyclic aromatic hydrocarbon (PAH) mass fraction desorbed, a surrogate measure of bioavailability, and relative carcinogenicity, as quantified by potency equivalency factors (PEFs), for two study sediments from the New York/New Jersey Harbor estuary. Because compounds with the highest toxicity, such as dibenz(a,h)anthracene and benzo(a)pyrene (BAP), also tended to be the least rapidly and least extensively desorbed, the U.S. Environmental Protection Agency (EPA) default guidance may dramatically overestimate risk from exposure to PAH-contaminated soils or sediments. A "relative risk index" (RRI) was developed to account for the combined effects of compound-specific bioavailability and toxic potency in estimating excess cancer risk. Using this approach, estimated excess cancer risk may be diminished by as much as a factor of 159 times versus default EPA guidance. Also, the hierarchy of estimated risk between study sediments and among treatment fractions of study sediments differed using the two approaches, implying that the default approach may inaccurately determine site clean-up priorities. The percentage contribution of each potentially carcinogenic priority PAH to total excess cancer risk was computed under various scenarios. In each case, the contribution of BAP to total excess cancer risk was remarkably invariable, for example, ranging from 48% to 52% in one sediment, and 44% to 54% in the other, over four different exposure durations. These results suggest that BAP may be an excellent indexing compound for gauging relative exposure risk across sediments. Other important contributors to total excess cancer risk were benz(a)anthracene and dibenz(a,h)anthracene. Together, these three compounds comprised nearly 90% of total excess cancer risk from all PAHs in every scenario. This integrated RRI approach may enable regulators to more accurately gauge relative risks and make more informed sediment management decisions.     

A Calibrated Human PBPK Model for Benzene Inhalation with Urinary Bladder and Bone Marrow Compartments

A physiologically‐based pharmacokinetic (PBPK) model of benzene inhalation based on a recent mouse model was adapted to include bone marrow (target organ) and urinary bladder compartments. Empirical data on human liver microsomal protein levels and linked CYP2E1 activities were incorporated into the model, and metabolite‐specific conversion rate parameters were estimated by fitting to human biomonitoring data and adjusting for background levels of urinary metabolites. Human studies of benzene levels in blood and breath, and phenol levels in urine were used to validate the rate of human conversion of benzene to benzene oxide, and urinary benzene metabolites from Chinese benzene worker populations provided model validation for rates of human conversion of benzene to muconic acid (MA) and phenylmercapturic acid (PMA), phenol (PH), catechol (CA), hydroquinone (HQ), and benzenetriol (BT). The calibrated human model reveals that while liver microsomal protein and CYP2E1 activities are lower on average in humans compared to mice, the mouse also shows far lower rates of benzene conversion to MA and PMA, and far higher conversion of benzene to BO/PH, and of BO/PH to CA, HQ, and BT. The model also differed substantially from existing human PBPK models with respect to several metabolic rate parameters of importance to interpreting benzene metabolism and health risks in human populations associated with bone marrow doses. The model provides a new methodological paradigm focused on integrating linked human liver metabolism data and calibration using biomonitoring data, thus allowing for model uncertainty analysis and more rigorous validation.     

The Role of Cancer Risk in the Regulation of Industrial Pollution

The extent of carcinogen regulation under existing U.S. environmental statutes is assessed by developing measures of the scope and stringency of regulation. While concern about cancer risk has played an important political role in obtaining support for pollution control programs, it has not provided the predominant rationale for most regulatory actions taken to date. Less than 20% of all standards established to limit concentrations of chemicals in various media address carcinogens. Restrictions on chemical use are more frequently based on concerns about noncancer human health or ecological effects. Of the chemicals in commercial use which have been identified as potential human carcinogens on the basis of rodent bioassays, only a small proportion are regulated. There is an inverse relationship between the scope of regulatory coverage and the stringency of regulatory requirements: the largest percentages of identified carcinogens are affected by the least stringent requirements, such as information disclosure. Standards based on de minimis cancer risk levels have been established for only 10% of identified carcinogens and are restricted to one medium: water. Complete bans on use have affected very few chemicals. The general role that carcinogenicity now plays in the regulatory process is not dramatically different from that of other adverse human health effects: if a substance is identified as a hazard, it may eventually be subject to economically achievable and technically feasible restrictions.     

Effects of key enabling technologies for seru production on sustainable performance

Demand uncertainty, economic globalization, and environmental deterioration force factories to innovate their manufacturing systems for achieving sustainable performance. Seru production, which is the latest manufacturing mode developed in Japan, attracts broad attention from both academia and practitioners. The overwhelming majority of existing works on seru production focus on economic performance unilaterally, while neglecting the environmental and social performance. This paper investigates the effects of key enabling technologies for seru production on sustainable performance. Firstly, four key enabling technologies for seru production are identified through systematic review, and an evaluation indicator system of sustainable performance in the context of seru production is developed. Then, the hypotheses about the effects of the identified key enabling technologies for seru production on sustainable performance are proposed on the basis of previous research achievements, theoretical analysis, and practical observations. Finally, the hypotheses are tested through structural equation modeling. Except for two hypotheses which are not supported and one which is indirectly supported, all other hypotheses are verified. The research results show that the four key enabling technologies for seru production have different effects on the three dimensions of sustainable performance. The achievements of this work are of significance to improve the comprehensive understanding of seru production, as well as to develop practical methods to implement sustainable operations.     

Integration mechanisms and R&D project performance

Information processing theory suggests the need for different types of integration mechanisms in R&D project management depending on levels of uncertainty and equivocality. This paper examines the use of these mechanisms and their links to project performance in a sample of 121 R&D projects in a large research laboratory. Overall, it is found that formal leadership, planning and process specification, and to a lesser extent information technology use are related to project performance while the positive effects of horizontal structures are apparently balanced out by their costs. The integration mechanisms studied act on performance partly through their effect on horizontal communications. Modest support was found for the contingency hypotheses derived from information processing theory. It appears that managers adjusted their use of horizontal structures, planning and process specification, and informal leadership to project uncertainty but not to project equivocality. The positive effects of horizontal communications on performance were found to be greatest under high project equivocality as would be predicted by information processing arguments. Moreover, with the exception of formal leadership, the use of integration mechanisms did not enhance performance in contexts of low uncertainty and low equivocality.