Risk Assessment of Nongenotoxic Carcinogens Based upon Cell Proliferation/Death Rates in Rodents

Increased cell proliferation increases the opportunity for transformations of normal cells to malignant cells via intermediate cells. Nongenotoxic cytotoxic carcinogens that increase cell proliferation rates to replace necrotic cells are likely to have a threshold dose for cytotoxicity below which necrosis and hence, carcinogenesis do not occur. Thus, low dose cancer risk estimates based upon nonthreshold, linear extrapolation are inappropriate for this situation. However, a threshold dose is questionable if a nongenotoxic carcinogen acts via a cell receptor. Also, a nongenotoxic carcinogen that increases the cell proliferation rate, via the cell division rate and/or cell removal rate by apoptosis, by augmenting an existing endogenous mechanism is not likely to have a threshold dose. Whether or not a threshold dose exists for nongenotoxic carcinogens, it is of interest to study the relationship between lifetime tumor incidence and the cell proliferation rate. The Moolgavkar–Venzon–Knudson biologically based stochastic two-stage clonal expansion model is used to describe a carcinogenic process. Because the variability in cell proliferation rates among animals often makes it impossible to detect changes of less than 20% in the rate, it is shown that small changes in the cell proliferation rate, that may be obscured by the background noise in rates, can produce large changes in the lifetime tumor incidence as calculated from the Moolgavkar–Venzon–Knudson model. That is, dose response curves for cell proliferation and tumor incidence do not necessarily mimic each other. This makes the use of no observed effect levels (NOELs) for cell proliferation rates often inadmissible for establishing acceptable daily intakes (ADIs) of nongenotoxic carcinogens. In those cases where low dose linearity is not likely, a potential alternative to a NOEL is a benchmark dose corresponding to a small increase in the cell proliferation rate, e. g., 1%, to which appropriate safety (uncertainty) factors can be applied to arrive at an ADI.     

Assessing Cancer Risks from Short-Term Exposures in Children

For the vast majority of chemicals that have cancer potency estimates on IRIS, the underlying database is deficient with respect to early-life exposures. This data gap has prevented derivation of cancer potency factors that are relevant to this time period, and so assessments may not fully address children's risks. This article provides a review of juvenile animal bioassay data in comparison to adult animal data for a broad array of carcinogens. This comparison indicates that short-term exposures in early life are likely to yield a greater tumor response than short-term exposures in adults, but similar tumor response when compared to long-term exposures in adults. This evidence is brought into a risk assessment context by proposing an approach that: (1) does not prorate children's exposures over the entire life span or mix them with exposures that occur at other ages; (2) applies the cancer slope factor from adult animal or human epidemiology studies to the children's exposure dose to calculate the cancer risk associated with the early-life period; and (3) adds the cancer risk for young children to that for older children/adults to yield a total lifetime cancer risk. The proposed approach allows for the unique exposure and pharmacokinetic factors associated with young children to be fully weighted in the cancer risk assessment. It is very similar to the approach currently used by U.S. EPA for vinyl chloride. The current analysis finds that the database of early life and adult cancer bioassays supports extension of this approach from vinyl chloride to other carcinogens of diverse mode of action. This approach should be enhanced by early-life data specific to the particular carcinogen under analysis whenever possible.     

旅游目的地竞争力问题的一种解释

任何旅游目的地都面临着如何提供最好的社会福利并提高居民生活质量的决策。决策的选择要涉及复杂的经济、文化、社会、政治和环境方面的问题。近年来,由于认识到旅游产业潜在的、巨大的经济回报,越来越多的省份、城市将旅游产业作为地方新的经济增长点。我们注意到,旅游目的地(特别是大尺度的目的地)需要在地方居民生活质量提高和游客旅游体验满足之间找到平衡点。如果处理得当,旅游业可以成为扩大社会目标的巨大动力。许多地方正在为达成这个目标而谋求旅游目的地竞争力的提升。遗憾的是,没有一个完整的研究框架清晰地描述旅游目的地竞争力所涉及的方方面面的问题。在本研究中,作者运用区域竞争的有关理论考察了旅游竞争力与目的地发展之间的关系,分析了影响旅游目的地核心竞争力的六个关键性因素,并构建了描述它们之间关系的模型。     

Optimal ordering time interval taking account of time value

In this paper, the optimal inventory policies for an infinite lime span taking account of time value is discussed. First, bounds for the optimal ordering time interval are derived. Second, with these bounds, a simple algorithm to compute die optimal ordering time interval is developed. Numerical examples are given to illustrate the algorithm.     

New Approaches in Risk Assessment for Carcinogens

Methods are needed to improve the ability of biomonitoring and epidemiological studies to identify potential carcinogenic hazards and to quantify human risk. The limitations of pharmacokinetic models can be mitigated by the direct measurement of molecular markers of biologically effective dose of carcinogen. Parallel animal and human studies are recommended as a means of validating these markers.     

A temporal investigation of the direct,interactive, and reverse relations between demand and control and affective strain

Abstract

Few studies have tested how stressors affect outcomes over time. We sought to extend the literature by means of a longitudinal study testing for direct, interactive, and causal relations between demands and control and affective strain. We extended prior work testing causal relationships for Karasek's (1979 Karasek, R.A. Jr. 1979. Job demands, job decision latitude, and mental strain: Implications for job redesign. Administrative Science Quarterly, 24: 285–307. [Crossref], [Web of Science ®] , [Google Scholar]) Job Demand-Control (JDC) model by examining both the effects of demands and control on strain and in turn the effects of strain on demand and control. We tested our hypotheses using hierarchical linear modelling with a military sample of 1539 soldiers who completed six waves of survey data at 3-month time lags. The results replicate earlier cross-sectional studies reporting effects of work characteristics on strain; however, in our study these effects did not persist past three months. The results also provide evidence for reverse causal effects such that higher strain was associated with higher subsequent work overload and lower control over a six month time period. Similar to past research, we did not find support for the interactive effects of work overload and control on strain. We discuss the implications of our findings for theory and practice (such as the optimum time for applying interventions during the management of change), especially in terms of understanding the specific time lags for different stress–strain associations and the need for additional theories to explain reverse relationships.     

基于产品生命周期的多阶段剩余收益项目决策模型

剩余收益模型（Residual Income Model,RIM）是评估公司权益价值的经典模型,特别地,奥尔森系列剩余收益模型由于可以利用历史财务与会计数据而得到广泛运用。本文在一般剩余收益模型的基础上,运用规范研究、逻辑推理等方法,基于产品生命周期理论,即项目处于产品生命周期的不同阶段时,其净资产收益率不同,在增长期的净资产收益率持续上升,衰退期的净资产收益率持续下降,而成熟期的净资产收益率则围绕行业平均水平波动,从理论上就项目投资价值的评估构建了多阶段剩余收益项目决策模型,并就所构建的多阶段剩余收益项目决策模型进行参数赋值分析。研究结果表明该新构建的决策模型具有较好的理论和运用价值,可以作为一种有效的项目投资决策模型。本文的研究一是拓展了剩余收益模型的应用,从主要用于对公司权益价值的估值拓展至对项目投资决策的评估;二是有利于寻求项目投资决策的价值最大化。     

ON THE EQUIVALENCE OF TWO VERSIONS OF THE PRESENT VALUE PROCEDURE

The central issue in equipment investment analysis is the selection of the best of two or more alternatives. A common procedure is to first assume that for each alternative there is an infinite stream of identical pieces of equipment. The present value of the associated infinite stream of revenues and costs is calculated. Then the alternative having the highest present value (where revenues are positive and costs are negative) is selected. The assumption of the infinite stream, though computationally desirable, is not very palatable to the decision maker. In this paper we show that the above procedure is equivalent to using a criterion which is definitely more appealing. The author has found this “equivalence” result to be helpful in teaching the basic concepts of the present value procedure. Also the result should be of interest to practitioners involved in equipment investment decision making.     

博弈者认知模式与合作意愿度分析

建立了无限合作博弈类型下的合作意愿度(DWC)运算模型,目的是研究博弈者不同的认知模式将会对博弈者的DWC值和收益率产生怎样的影响;突发事件和合作环境如何影响博弈者的DWC值.模拟了2人无限合作博弈的三种模式,得出主要结论:双方都是柔性思维的博弈者比双方都是刚性思维的博弈者获得的收益率较小;如果一方为柔性思维,另一方是刚性思维,则柔性思维博弈者能够获得较高的收益,而刚性思维博弈者却能获得较高的DWC值;如果博弈者都具有柔性思维功能,合作不会稳定与满意;在突发事件起决定作用的情况下,博弈双方的平均收益率和平均DWC值都要减小;博弈一方为柔性思维者,另一方为刚性思维是较好的一种合作模式.     

Microbiota and Dose Response: Evolving Paradigm of Health Triangle

SRA Dose‐Response and Microbial Risk Analysis Specialty Groups jointly sponsored symposia that addressed the intersections between the “microbiome revolution” and dose response. Invited speakers presented on innovations and advances in gut and nasal microbiota (normal microbial communities) in the first decade after the Human Microbiome Project began. The microbiota and their metabolites are now known to influence health and disease directly and indirectly, through modulation of innate and adaptive immune systems and barrier function. Disruption of healthy microbiota is often associated with changes in abundance and diversity of core microbial species (dysbiosis), caused by stressors including antibiotics, chemotherapy, and disease. Nucleic‐acid‐based metagenomic methods demonstrated that the dysbiotic host microbiota no longer provide normal colonization resistance to pathogens, a critical component of innate immunity of the superorganism. Diverse pathogens, probiotics, and prebiotics were considered in human and animal models (in vivo and in vitro ). Discussion included approaches for design of future microbial dose–response studies to account for the presence of the indigenous microbiota that provide normal colonization resistance , and the absence of the protective microbiota in dysbiosis. As NextGen risk analysis methodology advances with the “microbiome revolution,” a proposed new framework, the Health Triangle, may replace the old paradigm based on the Disease Triangle (focused on host, pathogen, and environment) and germophobia. Collaborative experimental designs are needed for testing hypotheses about causality in dose–response relationships for pathogens present in our environments that clearly compete in complex ecosystems with thousands of bacterial species dominating the healthy superorganism.     

Car Occupant Life Expectancy: Car Mass and Seat Belt Effects

Average human life expectancies for the U.S. resident population are calculated using tabulated population and survival rate data. These life expectancies are recalculated assuming elimination of various types of motor vehicle fatalities using Fatal Accident Reporting System (FARS) data. The differences between the original and recalculated values provide estimates of life expectancy reductions due to the motor vehicle fatalities. These estimates are combined with prior work relating the likelihood of an occupant fatality to car mass, so that reductions in life expectancy are determined as a function of car mass. The estimates of life expectancy reductions are also used to determine the effect of seat belt use on life expectancy. The estimates, which are based on data for 1978, assume that survival rates remain unchanged. Estimates of the changes in life expectancy associated with switching from a large (1800 kg) car to a small (900 kg) car, and switching from not using to using a seat belt are presented as functions of the age at which an individual makes the switch.     

Unveiling Variability and Uncertainty for Better Science and Decisions on Cancer Risks from Environmental Chemicals

The National Research Council 2009 “Silver Book” panel report included a recommendation that the U.S. Environmental Protection Agency (EPA) should increase all of its chemical carcinogen (CC) potency estimates by ～7‐fold to adjust for a purported median‐vs.‐mean bias that I recently argued does not exist (Bogen KT. “Does EPA underestimate cancer risks by ignoring susceptibility differences?,” Risk Analysis, 2014; 34(10):1780–1784). In this issue of the journal, my argument is critiqued for having flaws concerning: (1) intent, bias, and conservatism of EPA estimates of CC potency; (2) bias in potency estimates derived from epidemiology; and (3) human‐animal CC‐potency correlation. However, my argument remains valid, for the following reasons. (1) EPA's default approach to estimating CC risks has correctly focused on bounding average (not median) individual risk under a genotoxic mode‐of‐action (MOA) assumption, although pragmatically the approach leaves both inter‐individual variability in CC–susceptibility, and widely varying CC‐specific magnitudes of fundamental MOA uncertainty, unquantified. (2) CC risk estimates based on large epidemiology studies are not systematically biased downward due to limited sampling from broad, lognormal susceptibility distributions. (3) A good, quantitative correlation is exhibited between upper‐bounds on CC‐specific potency estimated from human vs. animal studies (n = 24, r = 0.88, p = 2 × 10^?8). It is concluded that protective upper‐bound estimates of individual CC risk that account for heterogeneity in susceptibility, as well as risk comparisons informed by best predictions of average‐individual and population risk that address CC‐specific MOA uncertainty, should each be used as separate, complimentary tools to improve regulatory decisions concerning low‐level, environmental CC exposures.     

Trinque problem: covering complete graphs by plane degree-bounded hypergraphs

Let \(K_n\) be a complete graph drawn on the plane with every vertex incident to the infinite face. For any integers i and d, we define the (i, d)-Trinque Number of \(K_n\), denoted by \({\mathcal {T}}^d_{i}(K_n)\), as the smallest integer k such that there is an edge-covering of \(K_n\) by k “plane” hypergraphs of degree at most d and size of edge bounded by i. We compute this number for graphs (that is \(i=2\)) and gives some bounds for general hypergraphs.     

Lactational Transfer of Tetrachloroethylene in Rats

Tetrachloroethylene (PCE) is a commonly used organic solvent and a suspected human carcinogen, reportedly transferred to human breast milk following inhalation exposure. Transfer of PCE to milk may represent a threat to the nursing infant. A physiologically based pharmacokinetic (PBPK) model was developed to quantitatively assess the transfer of inhaled PCE into breast milk and the consequent exposure of the nursing infant. The model was validated in lactating rats. Lactating Sprague-Dawley female rats were exposed via inhalation to PCE at concentrations ranging from 20-1000 ppm, and then returned to their nursing, 10- to 11-day-old pups. Tetrachloroethylene concentrations in the air, blood, milk, and tissue were determined by gas chromatography and compared to model predictions. The model described the distribution of inhaled PCE in maternal blood and milk, as well as the nursed pup's gastrointestinal tract, blood, and tissue. Several computer simulations of PCE distribution kinetics in exhaled air, blood, and milk of exposed human subjects were run and compared with limited human data available from the literature. It is concluded that the PBPK model successfully described the concentration of PCE in both lactating rats and humans. Although predictions vs. observations were good, the model slightly underpredicted the peak whole pup PCE concentration and underpredicted systemic clearance of PCE from the pup.     

Perceived physical work capacity, stress, sleep disturbance and occupational accidents among firefighters working during a strike

Fire-fighting and rescue work are arranged in such a way that various kinds of accidents and catastrophes can be handled. In an understaffed situation, such as a strike, this goal may not be met. The objective of this study was to investigate factors associated with perceived physical work capacity, stress, sleep disturbance, and occupational accidents among firefighters who remained at work during an extended strike. A cross-sectional questionnaire study was carried out among 543 firefighters (83% of the target group) in 71 fire brigades in Finland. After the strike had lasted for 9 to 11 weeks, most of the firefighters perceived their physical work capacity to be rather good or very good. Stress increased along with a decreasing number of personnel in a crew (OR= 2.3, CI= 1.0-5.3, for less than 75% of a normal crew vs. normal crew) and with decreasing number of personnel in a shift (OR= 2.4, CI= 1.1-5.4, for less than 25% of normal shift vs. normal shift). Sleep disturbance was reported to occur as soon as the total working time exceeded 50 h/week. Working more than 70 h/week increased the risk of occupational accidents almost 4-fold compared with working no more than 50 h/week. These results suggest that exceptional situations, such as a strike, are a challenge to human capacity. With time, increased stress and sleep disturbance may lead to serious consequences.     

Quantifying Potential Health Impacts of Cadmium in Cigarettes on Smoker Risk of Lung Cancer: A Portfolio-of-Mechanisms Approach

This article introduces an approach to estimating the uncertain potential effects on lung cancer risk of removing a particular constituent, cadmium (Cd), from cigarette smoke, given the useful but incomplete scientific information available about its modes of action. The approach considers normal cell proliferation; DNA repair inhibition in normal cells affected by initiating events; proliferation, promotion, and progression of initiated cells; and death or sparing of initiated and malignant cells as they are further transformed to become fully tumorigenic. Rather than estimating unmeasured model parameters by curve fitting to epidemiological or animal experimental tumor data, we attempt rough estimates of parameters based on their biological interpretations and comparison to corresponding genetic polymorphism data. The resulting parameter estimates are admittedly uncertain and approximate, but they suggest a portfolio approach to estimating impacts of removing Cd that gives usefully robust conclusions. This approach views Cd as creating a portfolio of uncertain health impacts that can be expressed as biologically independent relative risk factors having clear mechanistic interpretations. Because Cd can act through many distinct biological mechanisms, it appears likely (subjective probability greater than 40%) that removing Cd from cigarette smoke would reduce smoker risks of lung cancer by at least 10%, although it is possible (consistent with what is known) that the true effect could be much larger or smaller. Conservative estimates and assumptions made in this calculation suggest that the true impact could be greater for some smokers. This conclusion appears to be robust to many scientific uncertainties about Cd and smoking effects.     

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.     

Reconfiguration of dominating sets

We explore a reconfiguration version of the dominating set problem, where a dominating set in a graph G is a set S of vertices such that each vertex is either in S or has a neighbour in S. In a reconfiguration problem, the goal is to determine whether there exists a sequence of feasible solutions connecting given feasible solutions s and t such that each pair of consecutive solutions is adjacent according to a specified adjacency relation. Two dominating sets are adjacent if one can be formed from the other by the addition or deletion of a single vertex. For various values of k, we consider properties of \(D_k(G)\), the graph consisting of a node for each dominating set of size at most k and edges specified by the adjacency relation. Addressing an open question posed by Haas and Seyffarth, we demonstrate that \(D_{\varGamma (G)+1}(G)\) is not necessarily connected, for \(\varGamma (G)\) the maximum cardinality of a minimal dominating set in G. The result holds even when graphs are constrained to be planar, of bounded tree-width, or b-partite for \(b \ge 3\). Moreover, we construct an infinite family of graphs such that \(D_{\gamma (G)+1}(G)\) has exponential diameter, for \(\gamma (G)\) the minimum size of a dominating set. On the positive side, we show that \(D_{n-\mu }(G)\) is connected and of linear diameter for any graph G on n vertices with a matching of size at least \(\mu +1\).     

Total completion time minimization in online hierarchical scheduling of unit-size jobs

This paper investigates an online hierarchical scheduling problem on m parallel identical machines. Our goal is to minimize the total completion time of all jobs. Each job has a unit processing time and a hierarchy. The job with a lower hierarchy can only be processed on the first machine and the job with a higher hierarchy can be processed on any one of m machines. We first show that the lower bound of this problem is at least \(1+\min \{\frac{1}{m}, \max \{\frac{2}{\lceil x\rceil +\frac{x}{\lceil x\rceil }+3}, \frac{2}{\lfloor x\rfloor +\frac{x}{\lfloor x\rfloor }+3}\}\), where \(x=\sqrt{2m+4}\). We then present a greedy algorithm with tight competitive ratio of \(1+\frac{2(m-1)}{m(\sqrt{4m-3}+1)}\). The competitive ratio is obtained in a way of analyzing the structure of the instance in the worst case, which is different from the most common method of competitive analysis. In particular, when \(m=2\), we propose an optimal online algorithm with competitive ratio of \(16\) \(/\) \(13\), which complements the previous result which provided an asymptotically optimal algorithm with competitive ratio of 1.1573 for the case where the number of jobs n is infinite, i.e., \(n\rightarrow \infty \).     

Comparison of the Cancer Risk of Methylene Chloride Predicted from Animal Bioassay Data with the Epidemiologic Evidence

Methylene chloride has been shown to be a lung and liver carcinogen in the mouse; yet, the current epidemiologic data show no adverse health effects associated with chronic exposure to this compound. Hearne et al. have compared the results of a large mortality study on occupational exposure to methylene chloride to the human risk predictions based on the rodent bioassay to point out the inconsistency between the animal toxicologic and human epidemiologic data. The maximum number of lung and liver cancers predicted due to methylene chloride exposure based on the rodent bioassay data was 24 compared to 14 deaths from these cancers actually observed in the Hearne et al. epidemiology study. We assess the minimum risk detectable by the human study in order to calculate the upperbound potency of methylene chloride and compare it to the potency derived from the bioassay data. Results from the epidemiology study imply an upperbound potency of 1.5 x 10(-2) per ppm, compared to 1.4 x 10(-2) per ppm calculated using the most conservative analysis of the animal data. We conclude that the negative epidemiology study of Hearne et al. is not sufficiently powerful to show that the risk is inconsistent with the human risk estimated by modeling the rodent bioassay data. Specifically, the doses to which the workers were exposed, the population studied, and the latency period were not adequate to determine that the risks are outside the bounds of the risk estimates predicted by low-dose modeling of the animal data.