Part II: Quantitative Evaluation of Choices Used in Setting Noncancer Chronic Human Health Reference Values Across Organizations

Environmental and public health organizations, including the World Health Organization (WHO) and the U.S. Environmental Protection Agency (USEPA), develop human health reference values (HHRV) that set “safe” levels of exposure to noncarcinogens. Here, we systematically analyze chronic HHRVs from four organizations: USEPA, Health Canada, RIVM (the Netherlands), and the U.S. Agency for Toxic Substances and Disease Registry. This study is an extension of our earlier work and both closely examines the choices made in setting HHRVs and presents a quantitative method for identifying the primary factors influencing HHRV agreement or disagreement.⁽¹⁾ We evaluated 171 organizational comparisons, developing a quantitative method for identifying the factors to which HHRV agreement (that is, when both organizations considering the same data set the identical HHRV values) is most sensitive. To conduct this analysis, a Bayesian belief network was built using expert judgment, including the specific science policy choices analysis made in the context of setting an HHRV. Based on a sensitivity of findings analysis, HHRV agreement is most sensitive to the point of departure value, followed by the total uncertainty factor (UF), critical study, critical effect, animal model, and point of departure approach. This analysis also considered the specific impacts of individual UFs, with the database UF and the subchronic‐to‐chronic UF being identified as primary factors impacting the total UF differences observed across organizations. The sensitivity of findings analysis results were strengthened and confirmed by frequency analyses evaluating which choices most often disagreed when the HHRV and the total UF disagreed.     

A Profitability Evaluation of America's Best Hospitals, 2000–2008

Each year U.S. News and World Report evaluates more than 5,000 U.S. hospitals, of which approximately 3% are considered the best hospitals in America, and hospital profitability has emerged as a business objective for these hospitals. This study investigates the profitability performance of the best (highest quality) hospitals in the United States. A 9‐year longitudinal investigation of profitability for the best hospitals in the United States is conducted. The results offer evidence that the primary drivers of hospital profitability are the case mix index and daily bed capacity. In terms of hospital profitability, there appears to be a tradeoff between these two factors. Finally, caution must be used when ranking U.S. News and World Report Honor Roll hospitals, in terms of profitability and performance.     

A Look at State‐Level Risk Assessment in the United States: Making Decisions in the Absence of Federal Risk Values

State environmental agencies in the United States are charged with making risk management decisions that protect public health and the environment while managing limited technical, financial, and human resources. Meanwhile, the federal risk assessment community that provides risk assessment guidance to state agencies is challenged by the rapid growth of the global chemical inventory. When chemical toxicity profiles are unavailable on the U.S. Environmental Protection Agency's Integrated Risk Information System or other federal resources, each state agency must act independently to identify and select appropriate chemical risk values for application in human health risk assessment. This practice can lead to broad interstate variation in the toxicity values selected for any one chemical. Within this context, this article describes the decision‐making process and resources used by the federal government and individual U.S. states. The risk management of trichloroethylene (TCE) in the United States is presented as a case study to demonstrate the need for a collaborative approach among U.S. states toward identification and selection of chemical risk values while awaiting federal risk values to be set. The regulatory experience with TCE is contrasted with collaborative risk science models, such as the European Union's efforts in risk assessment harmonization. Finally, we introduce State Environmental Agency Risk Collaboration for Harmonization, a free online interactive tool designed to help to create a collaborative network among state agencies to provide a vehicle for efficiently sharing information and resources, and for the advancement of harmonization in risk values used among U.S. states when federal guidance is unavailable.     

国际原油价格系统结构性突变识别与分析

选取1997年至2011年作为样本区间,以国际原油市场结构的周期性和突变特征作为研究对象,在筛选变量的基础上,以原油的价格、供应、需求、美元指数和中国原油净进口为内生变量,以库存和投机因素为外生变量,建立原油市场结构经验VARX模型,分析各变量对原油价格的影响,并以此为基础建立基于Bayes理论的原油价格系统MSBVAR模型,识别和分析原油价格系统在考察期内的结构性变化。研究结果表明,影响原油价格波动的首要因素为中国原油净进口,存在亚洲溢价现象且持续期为2个多季度,美元指数影响次之,之后是原油需求,原油供应的贡献率影响最小;原油价格的翘尾效应在不同状态下的滞后期均为1个季度,且效应显著。突发事件对原油价格系统均衡结构的冲击不可忽视,1997年至2011年国际原油市场只存在一个结构突变点,即美国金融危机是导致该次原油价格系统结构平衡被打破的唯一事件。     

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.     

Aldrin and Dieldrin: A Reevaluation of the Cancer and Noncancer Dose‐Response Assessments

The dose‐response analyses of cancer and noncancer health effects of aldrin and dieldrin were evaluated using current methodology, including benchmark dose analysis and the current U.S. Environmental Protection Agency (U.S. EPA) guidance on body weight scaling and uncertainty factors. A literature review was performed to determine the most appropriate adverse effect endpoints. Using current methodology and information, the estimated reference dose values were 0.0001 and 0.00008 mg/kg‐day for aldrin and dieldrin, respectively. The estimated cancer slope factors for aldrin and dieldrin were 3.4 and 7.0 (mg/kg‐day)^?1, respectively (i.e., about 5‐ and 2.3‐fold lower risk than the 1987 U.S. EPA assessments). Because aldrin and dieldrin are no longer used as pesticides in the United States, they are presumed to be a low priority for additional review by the U.S. EPA. However, because they are persistent and still detected in environmental samples, quantitative risk assessments based on the best available methods are required. Recent epidemiologic studies do not demonstrate a causal association between aldrin and dieldrin and human cancer risk. The proposed reevaluations suggest that these two compounds pose a lower human health risk than currently reported by the U.S. EPA.     

Probabilistic Framework for the Estimation of the Adult and Child Toxicokinetic Intraspecies Uncertainty Factors

Human health risk assessments use point values to develop risk estimates and thus impart a deterministic character to risk, which, by definition, is a probability phenomenon. The risk estimates are calculated based on individuals and then, using uncertainty factors (UFs), are extrapolated to the population that is characterized by variability. Regulatory agencies have recommended the quantification of the impact of variability in risk assessments through the application of probabilistic methods. In the present study, a framework that deals with the quantitative analysis of uncertainty (U) and variability (V) in target tissue dose in the population was developed by applying probabilistic analysis to physiologically-based toxicokinetic models. The mechanistic parameters that determine kinetics were described with probability density functions (PDFs). Since each PDF depicts the frequency of occurrence of all expected values of each parameter in the population, the combined effects of multiple sources of U/V were accounted for in the estimated distribution of tissue dose in the population, and a unified (adult and child) intraspecies toxicokinetic uncertainty factor UFH-TK was determined. The results show that the proposed framework accounts effectively for U/V in population toxicokinetics. The ratio of the 95th percentile to the 50th percentile of the annual average concentration of the chemical at the target tissue organ (i.e., the UFH-TK) varies with age. The ratio is equivalent to a unified intraspecies toxicokinetic UF, and it is one of the UFs by which the NOAEL can be divided to obtain the RfC/RfD. The 10-fold intraspecies UF is intended to account for uncertainty and variability in toxicokinetics (3.2x) and toxicodynamics (3.2x). This article deals exclusively with toxicokinetic component of UF. The framework provides an alternative to the default methodology and is advantageous in that the evaluation of toxicokinetic variability is based on the distribution of the effective target tissue dose, rather than applied dose. It allows for the replacement of the default adult and children intraspecies UF with toxicokinetic data-derived values and provides accurate chemical-specific estimates for their magnitude. It shows that proper application of probability and toxicokinetic theories can reduce uncertainties when establishing exposure limits for specific compounds and provide better assurance that established limits are adequately protective. It contributes to the development of a probabilistic noncancer risk assessment framework and will ultimately lead to the unification of cancer and noncancer risk assessment methodologies.     

A Quantitative Analysis of Factors Affecting PELs and TLVs for Carcinogens

For carcinogens, this paper provides a quantitative examination of the roles of potency and weight-of-evidence (WOE) in setting permissible exposure limits (PELs) at the U.S. Occupational Safety and Health Administration (OSHA) and threshold limit values (TLVs) at the private American Conference of Governmental Industrial Hygienists (ACGIH). On normative grounds, both of these factors should influence choices about the acceptable level of exposures. Our major objective is to examine whether and in what ways these factors have been considered by these organizations. A lesser objective is to identify outliers, which might be candidates for further regulatory scrutiny. Our sample (N=48) includes chemicals for which EPA has estimated a unit risk as a measure of carcinogenic potency and for which OSHA or the ACGIH has a PEL or TLV. Different assessments of the strength of the evidence of carcinogenicity were obtained from EPA, ACGIH, and the International Agency for Research on Cancer. We found that potency alone explains 49% of the variation in PELs and 62% of the variation in TLVs. For the ACGIH, WOE plays a much smaller role than potency. TLVs set by the ACGIH since 1989 appear to be stricter than earlier TLVs. We suggest that this change represents evidence that the ACGIH had responded to criticisms leveled at it in the late 1980s for failing to adopt sufficiently protective standards. The models developed here identify 2-nitropropane, ethylene dibromide, and chromium as having OSHA PELs significantly higher than predicted on the basis of potency and WOE.     

Computer Models Used to Support Cleanup Decision-Making at Hazardous and Radioactive Waste Sites

Massive efforts are underway to clean up hazardous and radioactive waste sites located throughout the United States. To help determine cleanup priorities, computer models are being used to characterize the source, transport, fate, and effects of hazardous chemicals and radioactive materials found at these sites. Although the U.S. Environmental Protection Agency (EPA), the U.S. Department of Energy (DOE), and the U.S. Nuclear Regulatory Commission (NRC)have provided preliminary guidance to promote the use of computer models for remediation purposes, no agency has produced directed guidance on models that must be used in these efforts. As a result, model selection is currently done on an ad hoc basis. This is administratively ineffective and costly, and can also result in technically inconsistent decision-making. To identify what models are actually being used to support decision-making at hazardous and radioactive waste sites, a project jointly funded by EPA, DOE, and NRC was initiated. The purpose of this project was to: (1)identify models being used for hazardous and radioactive waste site assessment purposes; and (2)describe and classify these models. This report presents the results of this study. A mail survey was conducted to identify models in use. The survey was sent to 550 persons engaged in the cleanup of hazardous and radioactive waste sites; 87 individuals responded. They represented organizations including federal agencies, national laboratories, and contractor organizations. The respondents identified 127 computer models that were being used to help support cleanup decision-making. There were a few models that appeared to be used across a large number of sites (e.g., RESRAD). In contrast, the survey results also suggested that most sites were using models which were not reported in use elsewhere. Information is presented on the types of models being used and the characteristics of the models in use. Also shown is a list of models available, but not identified in the survey itself.     

A MODEL OF SITE‐SPECIFIC ANTECEDENTS OF ISO 14001 CERTIFICATION

ISO 14001 constitutes a major dilemma for many American firms. This new standard holds the promise of waste reduction and better process management, but the benefits and costs are very difficult to predict. This study attempts to identify and explain antecedents impacting the decision to pursue certification for some of the first plants certified in the United States. Using data from a large survey of U.S. managers and a Logit analysis, we find the factors influencing management decisions to actively pursue ISO 14001 certification to be distinctly different from those factors influencing management's decision not to pursue certification. For the latter, the decision is economically based; for the former, it is driven by other, more qualitative considerations.     

Methods and Rationale for Derivation of a Reference Dose for Methylmercury by the U.S. EPA

In 2001, the U.S. Environmental Protection Agency derived a reference dose (RfD) for methylmercury, which is a daily intake that is likely to be without appreciable risk of deleterious effects during a lifetime. This derivation used a series of benchmark dose (BMD) analyses provided by a National Research Council (NRC) panel convened to assess the health effects of methylmercury. Analyses were performed for a number of endpoints from three large longitudinal cohort studies of the neuropsychological consequences of in utero exposure to methylmercury: the Faroe Islands, Seychelles Islands, and New Zealand studies. Adverse effects were identified in the Faroe Islands and New Zealand studies, but not in the Seychelles Islands. The NRC also performed an integrative analysis of all three studies. The EPA applied a total uncertainty factor (UF) of 10 for intrahuman toxicokinetic and toxicodynamic variability and uncertainty. Dose conversion from cord blood mercury concentrations to maternal methylmercury intake was performed using a one-compartment model. Derivation of potential RfDs from a number of endpoints from the Faroe Islands study converged on 0.1 microg/kg/day, as did the integrative analysis of all three studies. EPA identified several areas for which further information or analyses is needed. Perhaps the most immediately relevant is the ratio of cord:maternal blood mercury concentration, as well as the variability around this ratio. EPA assumed in its dose conversion that the ratio was 1.0; however, available data suggest it is perhaps 1.5-2.0. Verification of a deviation from unity presumably would be translated directly into comparable reduction in the RfD. Other areas that EPA identified as significant areas requiring further attention are cardiovascular consequences of methylmercury exposure and delayed neurotoxicity during aging as a result of previous developmental or adult exposure.     

On Intergenerational Equity and Its Clash with Intragenerational Equity and on the Need for Policies to Guide the Regulation of Disposal of Wastes and Other Activities Posing Very Long-Term Risks

This article begins with some history of the derivation of 40 CFR Part 191, the U.S. Environmental Protection Agency (EPA) standard that governs the geologic disposal of spent nuclear fuel and high-level and transuranic radioactive wastes. This is followed by criticisms of the standard that were made by a Sub-Committee of the EPA Science Advisory Board, by the staff of the U.S. Nuclear Regulatory Commission, and by a panel of the National Academies of Science and Engineering. The large disparity in the EPA approaches to regulation of disposal of radioactive wastes and disposal of hazardous, long-lived, nonradioactive chemical waste is illustrated. An examination of the intertwined matters of intergenerational equity and the discounting of future health effects follows, together with a discussion of the conflict between intergenerational equity and intragenerational equity. Finally, issues related to assumptions in the regulations concerning the future state of society and the biosphere are treated, as is the absence of any national philosophy or guiding policy for how to deal with societal activities that pose very long-term risks.     

Combining Occurrence and Toxicity Information to Identify Priorities for Drinking-Water Mixture Research

Characterizing all possible chemical mixtures in drinking water is a potentially overwhelming project, and the task of assessing each mixture's net toxicity even more daunting. We propose that analyzing occurrence information on mixtures in drinking water may help to narrow the priorities and inform the approaches taken by researchers in mixture toxicology. To illustrate the utility of environmental data for refining the mixtures problem, we use a recent compilation of national ground-water-quality data to examine proposed U.S. Environmental Protection Agency (EPA) and Agency for Toxic Substances and Disease Registry (ATSDR) models of noncancer mixture toxicity. We use data on the occurrence of binary and ternary mixtures of arsenic, cadmium, and manganese to parameterize an additive model and compute hazard index scores for each drinking-water source in the data set. We also use partially parameterized interaction models to perform a bounding analysis estimating the interaction potential of several binary and ternary mixtures for which the toxicological literature is limited. From these results, we estimate a relative value of additional toxicological information for each mixture. For example, we find that according to the U.S. EPA's interaction model, the levels of arsenic and cadmium found in U.S. drinking water are unlikely to have synergistic cardiovascular effects, but the same mixture's potential for synergistic neurological effects merits further study. Similar analysis could in future be used to prioritize toxicological studies based on their potential to reduce scientific and regulatory uncertainty. Environmental data may also provide a means to explore the implications of alternative risk models for the toxicity and interaction of complex mixtures.     

The Role of the Community in the Implementation of the EPA's Rule on Risk Management Programs for Chemical Accidental Release Prevention

Regulations under the 1990 Clean Air Act Amendments (CAAA) include requirements for preventing accidental chemical releases. Section 112(r) of the CAAA, the Accidental Release Provisions, requires the U.S. Environmental Protection Agency (EPA) to develop and implement regulations for preventing accidental releases to the air of regulated substances and to minimize the consequences of releases that do occur. The regulations require regulated facilities to have in place the structural elements of a sound process safety program, and to practice, document, and communicate the elements of their program. The rule requires also that registered facilities calculate and make available worst case accidental chemical release information. The rule does not set a level of risk that a facility must achieve after it takes the required compliance steps, the level of risk a community must accept, the limit of consequences the community might suffer from a worst case chemical release, nor the specific actions a community must take in its response plan. These are issues that local communities and local officials must decide. Because the regulation involves the community in many unsettled risk issues the Wharton School initiated a project within the City Philadelphia to evaluate the proposition that productive dialogue on the implementation of the Rule and resolution of unsettled risk issues can take place in advance of a crisis occasioned by a major accidental release. This paper describes the steps taken by Wharton to bring together various stakeholders in the community to explore the implementation of the rule and the reaction of those stakeholders to be involved in such a process. It outlines some principal choices communities will have to make in order to implement 112(r) and explains some of the dilemmas associated with these choices. It describes the stakeholder-based implementation effort being undertaken in Philadelphia in the hope that others may benefit from what has been learned there.     

The Use of PBPK Models to Inform Human Health Risk Assessment: Case Study on Perchlorate and Radioiodide Human Lifestage Models

Physiologically‐based pharmacokinetic (PBPK) models are often submitted to or selected by agencies, such as the U.S. Environmental Protection Agency (U.S. EPA) and Agency for Toxic Substances and Disease Registry, for consideration for application in human health risk assessment (HHRA). Recently, U.S. EPA evaluated the human PBPK models for perchlorate and radioiodide for their ability to estimate the relative sensitivity of perchlorate inhibition on thyroidal radioiodide uptake for various population groups and lifestages. The most well‐defined mode of action of the environmental contaminant, perchlorate, is competitive inhibition of thyroidal iodide uptake by the sodium‐iodide symporter (NIS). In this analysis, a six‐step framework for PBPK model evaluation was followed, and with a few modifications, the models were determined to be suitable for use in HHRA to evaluate relative sensitivity among human lifestages. Relative sensitivity to perchlorate was determined by comparing the PBPK model predicted percent inhibition of thyroidal radioactive iodide uptake (RAIU) by perchlorate for different lifestages. A limited sensitivity analysis indicated that model parameters describing urinary excretion of perchlorate and iodide were particularly important in prediction of RAIU inhibition; therefore, a range of biologically plausible values available in the peer‐reviewed literature was evaluated. Using the updated PBPK models, the greatest sensitivity to RAIU inhibition was predicted to be the near‐term fetus (gestation week 40) compared to the average adult and other lifestages; however, when exposure factors were taken into account, newborns were found to be populations that need further evaluation and consideration in a risk assessment for perchlorate.     

Incorporating Risk Assessment and Benefit-Cost Analysis in Environmental Management1

Using data from interviews with a key set of individuals at the U.S. Environmental Protection Agency, this study examines intraagency views about the incorporation of risk assessment and benefit-cost analysis in environment management.     

Optimal and dysfunctional turnover: toward an organizational level model

Dysfunctional turnover is defined here as the level that produces a divergence between the organization's optimal balance of costs associated with turnover and the costs associated with retaining employees. Under this approach, the optimal level of aggregate turnover for most organizations will be (1) greater than zero and (2) variable across organizations, contingent on particular factors influencing retention costs and quit propensities. The model presented posits that individual, organizational, and environmental attributes influence individual quit propensities of employees and, hence, expected turnover rates for the organization.     

Purchasers and the impact of managed care on physicians

In much the same way that demands by managed care organizations are shaping the way physicians practice, health care purchasers impact how managed care organizations operate. Corporations purchase managed health care through their employee benefits programs, and understanding the language, objectives, and limitations of these purchasers is essential to grasping the forces influencing managed care organizations and the modern practice of medicine. The emergence of value-based purchasing as a strategic corporate approach to health benefits programs will dictate the forces on physicians, hospitals, and managed care organizations for years to come. These forces have already led to price reductions, health plan accreditation, employee-directed report cards, outcomes management, and organized systems of care, and they will determine the broad outlines of the emerging U.S. health care system.     

Evaluation of the Uncertainty in an Oral Reference Dose for Methylmercury Due to Interindividual Variability in Pharmacokinetics

An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 g/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 g/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 g/kg/day and an MRL of 0.3 g/kg/day.     

A Risk Assessment for Selected Lead-Induced Health Effects: An Example of a General Methodology

The research described here is part of a larger risk assessment project to aid the U.S. Environmental Protection Agency (EPA) in its review of the primary National Ambient Air Quality Standard for lead. The methodology can be applied to many situations in which a policy decision about a toxic substance is required in the face of incomplete data. Numerical results are presented for three potentially adverse lead-induced effects of interest to EPA: elevated erythrocyte protoporphyrin (EP), hemoglobin (Hb) decrement, and intelligence quotient (IQ) decrement.