Predictive Bayesian Microbial Dose-Response Assessment Based on Suggested Self-Organization in Primary Illness Response: Cryptosporidium parvum

The probability of illness caused by very low doses of pathogens cannot generally be tested due to the numbers of subjects that would be needed, though such assessments of illness dose response are needed to evaluate drinking water standards. A predictive Bayesian dose-response assessment method was proposed previously to assess the unconditional probability of illness from available information and avoid the inconsistencies of confidence-based approaches. However, the method uses knowledge of the conditional dose-response form, and this form is not well established for the illness endpoint. A conditional parametric dose-response function for gastroenteric illness is proposed here based on simple numerical models of self-organized host-pathogen systems and probabilistic arguments. In the models, illnesses terminate when the host evolves by processes of natural selection to a self-organized critical value of wellness. A generalized beta-Poisson illness dose-response form emerges for the population as a whole. Use of this form is demonstrated in a predictive Bayesian dose-response assessment for cryptosporidiosis. Results suggest that a maximum allowable dose of 5.0 x 10(-7) oocysts/exposure (e.g., 2.5 x 10(-7) oocysts/L water) would correspond with the original goals of the U.S. Environmental Protection Agency Surface Water Treatment Rule, considering only primary illnesses resulting from Poisson-distributed pathogen counts. This estimate should be revised to account for non-Poisson distributions of Cryptosporidium parvum in drinking water and total response, considering secondary illness propagation in the population.     

农村剩余劳动力档案管理信息系统初探

实现农村劳动力的有效转移 ,需要宏观政策的引导 ,更需要微观措施的落实。本文提出建立档案式管理的诚信打工用工管理服务机制 ,既是微观管理措施的设计 ,也是宏观方针策略的探讨 ,寻求宏观政策与微观措施的有机结合 ,充分发挥宏观与微观的整合功能 ,促进农村剩余劳动力的有效转移     

Bootstrap Estimation of Benchmark Doses and Confidence Limits with Clustered Quantal Data

The benchmark dose (BMD) is an exposure level that would induce a small risk increase (BMR level) above the background. The BMD approach to deriving a reference dose for risk assessment of noncancer effects is advantageous in that the estimate of BMD is not restricted to experimental doses and utilizes most available dose-response information. To quantify statistical uncertainty of a BMD estimate, we often calculate and report its lower confidence limit (i.e., BMDL), and may even consider it as a more conservative alternative to BMD itself. Computation of BMDL may involve normal confidence limits to BMD in conjunction with the delta method. Therefore, factors, such as small sample size and nonlinearity in model parameters, can affect the performance of the delta method BMDL, and alternative methods are useful. In this article, we propose a bootstrap method to estimate BMDL utilizing a scheme that consists of a resampling of residuals after model fitting and a one-step formula for parameter estimation. We illustrate the method with clustered binary data from developmental toxicity experiments. Our analysis shows that with moderately elevated dose-response data, the distribution of BMD estimator tends to be left-skewed and bootstrap BMDL s are smaller than the delta method BMDL s on average, hence quantifying risk more conservatively. Statistically, the bootstrap BMDL quantifies the uncertainty of the true BMD more honestly than the delta method BMDL as its coverage probability is closer to the nominal level than that of delta method BMDL. We find that BMD and BMDL estimates are generally insensitive to model choices provided that the models fit the data comparably well near the region of BMD. Our analysis also suggests that, in the presence of a significant and moderately strong dose-response relationship, the developmental toxicity experiments under the standard protocol support dose-response assessment at 5% BMR for BMD and 95% confidence level for BMDL.     

Modeling for Risk Assessment of Neurotoxic Effects

The regulation of noncancer toxicants, including neurotoxicants, has usually been based upon a reference dose (allowable daily intake). A reference dose is obtained by dividing a no-observed-effect level by uncertainty (safety) factors to account for intraspecies and interspecies sensitivities to a chemical. It is assumed that the risk at the reference dose is negligible, but no attempt generally is made to estimate the risk at the reference dose. A procedure is outlined that provides estimates of risk as a function of dose. The first step is to establish a mathematical relationship between a biological effect and the dose of a chemical. Knowledge of biological mechanisms and/or pharmacokinetics can assist in the choice of plausible mathematical models. The mathematical model provides estimates of average responses as a function of dose. Secondly, estimates of risk require selection of a distribution of individual responses about the average response given by the mathematical model. In the case of a normal or lognormal distribution, only an estimate of the standard deviation is needed. The third step is to define an adverse level for a response so that the probability (risk) of exceeding that level can be estimated as a function of dose. Because a firm response level often cannot be established at which adverse biological effects occur, it may be necessary to at least establish an abnormal response level that only a small proportion of individuals would exceed in an unexposed group. That is, if a normal range of responses can be established, then the probability (risk) of abnormal responses can be estimated. In order to illustrate this process, measures of the neurotransmitter serotonin and its metabolite 5-hydroxyindoleacetic acid in specific areas of the brain of rats and monkeys are analyzed after exposure to the neurotoxicant methylene-dioxymethamphetamine. These risk estimates are compared with risk estimates from the quantal approach in which animals are classified as either abnormal or not depending upon abnormal serotonin levels.     

Summary of the Workshop on Issues in Risk Assessment: Quantitative Methods for Developmental Toxicology

This report summarizes the proceedings of a conference on quantitative methods for assessing the risks of developmental toxicants. The conference was planned by a subcommittee of the National Research Council's Committee on Risk Assessment Methodology ⁴ in conjunction with staff from several federal agencies, including the U.S. Environmental Protection Agency, U.S. Food and Drug Administration, U.S. Consumer Products Safety Commission, and Health and Welfare Canada. Issues discussed at the workshop included computerized techniques for hazard identification, use of human and animal data for defining risks in a clinical setting, relationships between end points in developmental toxicity testing, reference dose calculations for developmental toxicology, analysis of quantitative dose-response data, mechanisms of developmental toxicity, physiologically based pharmacokinetic models, and structure-activity relationships. Although a formal consensus was not sought, many participants favored the evolution of quantitative techniques for developmental toxicology risk assessment, including the replacement of lowest observed adverse effect levels (LOAELs) and no observed adverse effect levels (NOAELs) with the benchmark dose methodology.     

Generalized Leverage and its Applications

The generalized leverage of an estimator is defined in regression models as a measure of the importance of individual observations. We derive a simple but powerful result, developing an explicit expression for leverage in a general M -estimation problem, of which the maximum likelihood problems are special cases. A variety of applications are considered, most notably to the exponential family non-linear models. The relationship between leverage and local influence is also discussed. Numerical examples are given to illustrate our results     

Sequential Hypothesis Tests for Identifying the Minimum Dose with a Threshold Effect

We propose a procedure to identify a lowest dose having greater effect than a threshold dose under the assumption of monotonicity of dose mean response in dose response test. So, we use statistics based on contrasts among sample means and apply a group sequential procedure to our procedure to identify effectively the dose. If we can identify the dose at an early step in the sequential test, since we can terminate the procedure with a few observations, the procedure is useful from an economical point of view. In a simulation studies, we compare the superiority among these procedures based on three contrasts.     

国际组织与成员国法律责任多重归属问题研究

国际组织和成员国的法律责任归属问题一直以来都是国际法争论的话题。政府间国际组织作为一类国际法主体,应独立承担法律责任。但在实践中,成员国在执行国际组织决议的过程中往往滥用国际组织法律人格,其行为不仅是国际组织法律人格的体现,还代表了自己的意志,造成法律责任归属不明。以此种争议情形为研究对象,结合1999年的使用武力合法性案,2007年欧洲人权法院的拜拉米案和萨拉马提(Behrami/Saramati)案、阿尔吉达(Al-Jedda)案以及2014年海牙法院关于斯雷布雷尼察(Srebrenica)诉荷兰案的相关判决,借鉴国外学者近几年的相关研究,认为应当坚持国际组织和成员国法律责任的多重归属。围绕责任多重归属原则的确立过程,通过对2011年《国际组织责任条款草案》相关条文的分析,明确了行为归属与责任归属的关系:只有确定行为归属之后,才能确定责任归属;为了最终确定责任的多重归属,提出以有效控制为标准认定行为归属,并明确这种有效控制是对具体行为的事实控制。     

A pool-adjacent-violators-algorithm approach to detect infinite parameter estimates in one-regressor dose–response models with asymptotes

Binary response models are often applied in dose–response settings where the number of dose levels is limited. Commonly, one can find cases where the maximum likelihood estimation process for these models produces infinite values for at least one of the parameters, often corresponding to the ‘separated data’ issue. Algorithms for detecting such data have been proposed, but are usually incorporated directly into in the parameter estimation. Additionally, they do not consider the use of asymptotes in the model formulation. In order to study this phenomenon in greater detail, we define the class of specifiably degenerate functions where this can occur (including the popular logistic and Weibull models) that allows for asymptotes in the dose–response specification. We demonstrate for this class that the well-known pool-adjacent-violators algorithm can efficiently pre-screen for non-estimable data. A simulation study demonstrates the frequency with which this problem can occur for various response models and conditions.     

Model Uncertainty and Bayesian Model Averaged Benchmark Dose Estimation for Continuous Data

The benchmark dose (BMD) approach has gained acceptance as a valuable risk assessment tool, but risk assessors still face significant challenges associated with selecting an appropriate BMD/BMDL estimate from the results of a set of acceptable dose‐response models. Current approaches do not explicitly address model uncertainty, and there is an existing need to more fully inform health risk assessors in this regard. In this study, a Bayesian model averaging (BMA) BMD estimation method taking model uncertainty into account is proposed as an alternative to current BMD estimation approaches for continuous data. Using the “hybrid” method proposed by Crump, two strategies of BMA, including both “maximum likelihood estimation based” and “Markov Chain Monte Carlo based” methods, are first applied as a demonstration to calculate model averaged BMD estimates from real continuous dose‐response data. The outcomes from the example data sets examined suggest that the BMA BMD estimates have higher reliability than the estimates from the individual models with highest posterior weight in terms of higher BMDL and smaller 90th percentile intervals. In addition, a simulation study is performed to evaluate the accuracy of the BMA BMD estimator. The results from the simulation study recommend that the BMA BMD estimates have smaller bias than the BMDs selected using other criteria. To further validate the BMA method, some technical issues, including the selection of models and the use of bootstrap methods for BMDL derivation, need further investigation over a more extensive, representative set of dose‐response data.