Exposure reconstruction for reducing uncertainty in risk assessment: example using MTBE biomarkers and a simple pharmacokinetic model

Adverse health risks from environmental agents are generally related to average (long-term) exposures. Because a given individual's contact with a pollutant is highly variable and dependent on activity patterns, local sources and exposure pathways, simple ‘snapshot’ measurements of surrounding environmental media may not accurately assign the exposure level. Furthermore, susceptibility to adverse effects from contaminants is considered highly variable in the population so that even similar environmental exposure levels may result in differential health outcomes in different individuals. The use of biomarker measurements coupled to knowledge of rates of uptake, metabolism and elimination has been suggested as a remedy for reducing this type of uncertainty. To demonstrate the utility of such an approach, we invoke results from a series of controlled human exposure tests and classical first-order rate kinetic calculations to estimate how well spot measurements of methyl tertiary butyl ether and the primary metabolite, tertiary butyl alcohol, can be expected to predict different hypothetical scenarios of previous exposures. We found that blood and breath biomarker measurements give similar results and that the biological damping effect of the metabolite production gives more stable estimates of previous exposure. We also explore the value of a potential urinary biomarker, 2-hydroxyisobutyrate suggested in the literature. We find that individual biomarker measurements are a valuable tool in reconstruction of previous exposures and that a simple pharmacokinetic model can identify the time frames over which an exogenous chemical and the related chemical biomarker are useful. These techniques could be applied to broader ranges of environmental contaminants to assess cumulative exposure risks if ADME (Absorption, Distribution, Metabolization and Excretion) is understood and systemic biomarkers can be measured.     

Exposure reconstruction for reducing uncertainty in risk assessment: example using MTBE biomarkers and a simple pharmacokinetic model

Adverse health risks from environmental agents are generally related to average (long-term) exposures. Because a given individual's contact with a pollutant is highly variable and dependent on activity patterns, local sources and exposure pathways, simple 'snapshot' measurements of surrounding environmental media may not accurately assign the exposure level. Furthermore, susceptibility to adverse effects from contaminants is considered highly variable in the population so that even similar environmental exposure levels may result in differential health outcomes in different individuals. The use of biomarker measurements coupled to knowledge of rates of uptake, metabolism and elimination has been suggested as a remedy for reducing this type of uncertainty. To demonstrate the utility of such an approach, we invoke results from a series of controlled human exposure tests and classical first-order rate kinetic calculations to estimate how well spot measurements of methyl tertiary butyl ether and the primary metabolite, tertiary butyl alcohol, can be expected to predict different hypothetical scenarios of previous exposures. We found that blood and breath biomarker measurements give similar results and that the biological damping effect of the metabolite production gives more stable estimates of previous exposure. We also explore the value of a potential urinary biomarker, 2-hydroxyisobutyrate suggested in the literature. We find that individual biomarker measurements are a valuable tool in reconstruction of previous exposures and that a simple pharmacokinetic model can identify the time frames over which an exogenous chemical and the related chemical biomarker are useful. These techniques could be applied to broader ranges of environmental contaminants to assess cumulative exposure risks if ADME (Absorption, Distribution, Metabolization and Excretion) is understood and systemic biomarkers can be measured.     

Human Risk Assessment for Nonylphenol

This article presents a risk assessment for human exposure to nonylphenol (NP). We critically reviewed and assessed all relevant full-text publications based on a variety of data quality attributes. Two categories of data, environmental monitoring and biomonitoring from exposed individuals, were used to estimate human exposure to NP. Environmental monitoring data included the measurement of NP in food, water, air, and dust. From these data and estimates of human intake rates for the sources, exposures were estimated from each source and source-specific Margins of Exposure (MOEs) calculated. However, the nature of the populations studied prevented the calculation of aggregate exposure calculations from these data. Rather, the most reliable estimates of aggregate exposure to NP were those derived from biomonitoring studies in exposed individuals. Using the daily absorbed dose estimates for NP, MOEs were calculated for these populations. The MOEs were based on the use of a No-Observed-Adverse-Effect-Level (NOAEL) for sensitive toxicological endpoints of interest, that is, systemic and reproductive toxicity from continuous-feeding more than 3.5 generations (13 mg/kg/day). The MOEs were all greater than 1000 (ranging from 2863 to 8.4 × 10⁷), clearly indicating reasonable certainty of no harm for source-specific and aggregate (based on biomonitoring) exposures to NP.     

Adding value to water resource management through biological assessment of rivers

Water resource management encompasses a variety of regulations and mandates relevant to water protection and restoration. Awareness of the value-added biological monitoring and assessment to water resource management is increasing worldwide, but especially in countries that have implemented proactive water law and regulatory frameworks for protection of surface waters. Biological communities provide an integrated response to pollutants and human disturbance within watersheds through their continuous exposure to the magnitude, duration, and frequency of stressors, and, thus, are important for assessing ecosystem health. The selection of proper bioindicators can provide additional benefits through their use in causal analysis of impaired waters and measurement of ecosystem recovery after restoration. A process for implementing biological indicators in a monitoring and assessment framework is outlined for managers and practitioners of water resource protection and restoration.     

Justification and optimization of radiation exposures: a new framework to aggregate arbitrary detriments and benefits

Myriad radiation effects, including benefits and detriments, complicate justifying and optimizing radiation exposures. The purpose of this study was to develop a comprehensive conceptual framework and corresponding quantitative methods to aggregate the detriments and benefits of radiation exposures to individuals, groups, and populations. In this study, concepts from the ICRP for low dose were integrated with clinical techniques focused on high dose to develop a comprehensive figure of merit (FOM) that takes into account arbitrary host- and exposure-related factors, endpoints, and time points. The study built on existing methods with three new capabilities: application to individuals, groups, and populations; extension to arbitrary numbers and types of endpoints; and inclusion of limitation, where relevant. The FOM was applied to three illustrative exposure situations: emergency response, diagnostic imaging, and cancer radiotherapy, to evaluate its utility in diverse settings. The example application to radiation protection revealed the FOM’s utility in optimizing the benefits and risks to a population while keeping individual exposures below applicable regulatory limits. Examples in diagnostic imaging and cancer radiotherapy demonstrated the FOM’s utility for guiding population- and patient-specific decisions in medical applications. The major finding of this work is that it is possible to quantitatively combine the benefits and detriments of any radiation exposure situation involving an individual or population to perform cost-effectiveness analyses using the ICRP key principles of radiation protection. This FOM fills a chronic gap in the application of radiation-protection theory, i.e., limitations of generalized frameworks to algorithmically justify and optimize radiation exposures. This new framework potentially enhances objective optimization and justification, especially in complex exposure situations.

     

生态风险评价方法述评

生态风险是由环境的自然变化或人类活动引起的生态系统组成、结构的改变而导致系统功能损失的可能性。生态风险评价是定量预测各种风险源对生态系统产生风险的或然性以及评估该风险可接受程度的方法体系,因而是生态环境风险管理与决策的定量依据。在介绍了生态风险概念的基础上,按照风险源性质的分类标准将生态风险划分为化学污染类风险源、生态事件类风险源、复合类风险源3类,并分别论述了3类生态风险对应评价方法的特点与发展的方向。另外,针对生态风险评价研究的现状,讨论了我国生态风险研究的优先领域,包括建立急性、慢性毒理数据库,构建外来生物入侵风险评价标准等,同时,建议将综合概率统计学、复杂系统理论与遥感技术等手段引入生态风险评价方法中,以进一步提高风险评价结果在生态风险管理中的有效性。     

A lifestage approach to assessing children's exposure

Understanding and characterizing risks to children has been the focus of considerable research efforts at the U.S. Environmental Protection Agency (EPA). Potential health risks resulting from environmental exposures before conception and during pre‐ and postnatal development are often difficult to recognize and assess because of a potential time lag between the relevant periods of exposure during development and associated outcomes that may be expressed at later lifestages. Recognizing this challenge, a lifestage approach for assessing exposure and risk is presented in the recent EPA report titled A Framework for Assessing Health Risks of Environmental Exposures to Children (U.S. EPA, 2006 ). This EPA report emphasizes the need to account for the potential exposures to environmental agents during all stages of development, and consideration of the relevant adverse health outcomes that may occur as a result of such exposures. It identifies lifestage‐specific issues associated with exposure characterization for regulatory risk assessment, summarizes the lifestage‐specific approach to exposure characterization presented in the Framework, and discusses emerging research needs for exposure characterization in the larger public‐health context. This lifestage approach for characterizing children's exposures to environmental contaminants ensures a more complete evaluation of the potential for vulnerability and exposure of sensitive populations throughout the life cycle. Birth Defects Res (Part B) 2008. © 2008 Wiley‐Liss, Inc.     

污染场地土壤生态风险评估研究进展

随着我国快速城市化以及产业结构的调整,遗留下了大量的污染场地,发展和实施污染场地土壤生态风险评估是进行大规模污染场地修复行动的必要条件。本文围绕污染场地土壤生态风险评估的科学原理、框架构建及技术方法等方面的关键问题: 1)评估框架的场地实际针对性;2)概念模型的不确定性;3)土壤复合污染毒性机制;4)评估终点筛选;5)评估方法和框架构建等展开讨论,指出土壤复合污染的制毒机制,即污染物生物有效性和联合效应是污染场地土壤生态风险评估的关键科学问题。耦合美国环保局四步法和欧盟层级法的“证据-权重法”评估框架适用于野外复杂环境条件下的土壤污染生态风险评估。建议今后重点开展以下5个方面的工作: 1)污染场地土壤生态风险评估技术框架与风险管控技术框架之间的联合;2)概念模型研究;3)基于过程的场地土壤污染物反应运移模型研究;4)场地土壤复合污染生态毒理学机制研究;5)生态系统高水平生态风险评估终点研究。旨在为形成我国本土污染场地土壤生态风险评估技术指南提供理论基础和构架。     

Proposed pathophysiologic framework to explain some excess cardiovascular death associated with ambient air particle pollution: Insights for public health translation

The paper proposes a pathophysiologic framework to explain the well-established epidemiological association between exposure to ambient air particle pollution and premature cardiovascular mortality, and offers insights into public health solutions that extend beyond regulatory environmental protections to actions that can be taken by individuals, public health officials, healthcare professionals, city and regional planners, local and state governmental officials and all those who possess the capacity to improve cardiovascular health within the population. The foundation of the framework rests on the contribution of traditional cardiovascular risk factors acting alone and in concert with long-term exposures to air pollutants to create a conditional susceptibility for clinical vascular events, such as myocardial ischemia and infarction; stroke and lethal ventricular arrhythmias. The conceptual framework focuses on the fact that short-term exposures to ambient air particulate matter (PM) are associated with vascular thrombosis (acute coronary syndrome, stroke, deep venous thrombosis, and pulmonary embolism) and electrical dysfunction (ventricular arrhythmia); and that individuals having prevalent heart disease are at greatest risk. Moreover, exposure is concomitant with changes in autonomic nervous system balance, systemic inflammation, and prothrombotic/anti-thrombotic and profibrinolytic-antifibrinolytic balance. Thus, a comprehensive solution to the problem of premature mortality triggered by air pollutant exposure will require compliance with regulations to control ambient air particle pollution levels, minimize exposures to air pollutants, as well as a concerted effort to decrease the number of people at-risk for serious clinical cardiovascular events triggered by air pollutant exposure by improving the overall state of cardiovascular health in the population. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu.     

The concept of translocational regulation

Biological processes are regulated to provide cells with exquisite adaptability to changing environmental conditions and cellular demands. The mechanisms regulating secretory and membrane protein translocation into the endoplasmic reticulum (ER) are unknown. A conceptual framework for translocational regulation is proposed based on our current mechanistic understanding of ER protein translocation and general principles of regulatory control.     

An informative Bayesian structural equation model to assess source-specific health effects of air pollution

A primary objective of current air pollution research is the assessment of health effects related to specific sources of air particles or particulate matter (PM). Quantifying source-specific risk is a challenge because most PM health studies do not directly observe the contributions of the pollution sources themselves. Instead, given knowledge of the chemical characteristics of known sources, investigators infer pollution source contributions via a source apportionment or multivariate receptor analysis applied to a large number of observed elemental concentrations. Although source apportionment methods are well established for exposure assessment, little work has been done to evaluate the appropriateness of characterizing unobservable sources thus in health effects analyses. In this article, we propose a structural equation framework to assess source-specific health effects using speciated elemental data. This approach corresponds to fitting a receptor model and the health outcome model jointly, such that inferences on the health effects account for the fact that uncertainty is associated with the source contributions. Since the structural equation model (SEM) typically involves a large number of parameters, for small-sample settings, we propose a fully Bayesian estimation approach that leverages historical exposure data from previous related exposure studies. We compare via simulation the performance of our approach in estimating source-specific health effects to that of 2 existing approaches, a tracer approach and a 2-stage approach. Simulation results suggest that the proposed informative Bayesian SEM is effective in eliminating the bias incurred by the 2 existing approaches, even when the number of exposures is limited. We employ the proposed methods in the analysis of a concentrator study investigating the association between ST-segment, a cardiovascular outcome, and major sources of Boston PM and discuss the implications of our findings with respect to the design of future PM concentrator studies.     

In situ contaminants and environmental assessment — An ecological summary

This paper outlines the origins of the concept of environmental impact assessment and attempts to explain why the scientific basis has not developed as well as the procedural aspects. It raises the question of the role of ecological science in environmental impact assessment and discusses the compatability of the objectives of the ecologist with those of the decision makers. A conceptual framework for the consideration of the problems of in situ contaminants is presented within the context of environmental assessment. Recent developments regarding the support of assessment research are discussed and future priorities are suggested.     

A Weight-of-Evidence Framework for Assessing Sediment (Or Other) Contamination: Improving Certainty in the Decision-Making Process

A basic framework is presented for the ecological weight-of-evidence (WOE) process for sediment assessment that clearly defines its essential elements and will improve the certainty of conclusions about whether or not impairment exists due to sediment contamination, and, if so, which stressors and biological species (or ecological responses) are of greatest concern. The essential “Certainty Elements” are addressed in a transparent best professional judgment (BPJ) process with multiple lines-of-evidence (LOE) ultimately quantitatively integrated (but not necessarily combined into a single value). The WOE Certainty Elements include: (1) Development of a conceptual model (showing linkages of critical receptors and ecosystem quality characteristics); (2) Explanation of linkages between measurement endpoint responses (direct and indirect with associated spatial/temporal dynamics) and conceptual model components; (3) Identification of possible natural and anthropogenic stressors with associated exposure dynamics; (4) Evaluation of appropriate and quantitatively based reference (background) comparison methods; (5) Consideration of advantages and limitations of quantification methods used to integrate LOE; (6) Consideration of advantages and limitations of each LOE used; (7) Evaluation of causality criteria used for each LOE during output verification and how they were implemented; and (8) Combining the LOE into a WOE matrix for interpretation, showing causality linkages in the conceptual model. The framework identifies several statistical approaches for integrating within LOE, the suitability of which depends on physical characteristics of the system and the scale/nature of impairment. The quantification approaches include: (1) Gradient (regression methods); (2) Paired reference/test (before/after control impact and ANOVA methods); (3) Multiple reference (ANOVA and multivariate methods); and 4) Gradient with reference (regression, ANOVA and multivariate methods). This WOE framework can be used for any environmental assessment and is most effective when incorporated into the initial and final study design stages (e.g., the Problem Formulation and Risk Characterization stages of a risk assessment) with reassessment throughout the project and decision-making process, rather than in a retrospective data analysis approach where key certainty elements cannot be adequately addressed.     

History and perspectives of bioanalytical methods for chemical warfare agent detection

This paper provides a short historical overview of the development of bioanalytical methods for chemical warfare (CW) agents and their biological markers of exposure, with a more detailed overview of methods for organophosphorus nerve agents. Bioanalytical methods for unchanged CW agents are used primarily for toxicokinetic/toxicodynamic studies. An important aspect of nerve agent toxicokinetics is the different biological activity and detoxification pathways for enantiomers. CW agents have a relatively short lifetime in the human body, and are hydrolysed, metabolised, or adducted to nucleophilic sites on macromolecules such as proteins and DNA. These provide biological markers of exposure. In the past two decades, metabolites, protein adducts of nerve agents, vesicants and phosgene, and DNA adducts of sulfur and nitrogen mustards, have been identified and characterized. Sensitive analytical methods have been developed for their detection, based mainly on mass spectrometry combined with gas or liquid chromatography. Biological markers for sarin, VX and sulfur mustard have been validated in cases of accidental and deliberate human exposures. The concern for terrorist use of CW agents has stimulated the development of higher throughput analytical methods in support of homeland security.     

The Use of Epidemiology in Risk Assessment: Challenges and Opportunities

The assessment of risk from environmental and occupational exposures incorporates and synthesizes data from a variety of scientific disciplines including toxicology and epidemiology. Epidemiological data have offered valuable contributions to the identification of human health hazards, estimation of human exposures, quantification of the exposure–response relation, and characterization of risks to specific target populations including sensitive populations. As with any scientific discipline, there are some uncertainties inherent in these data; however, the best human health risk assessments utilize all available information, characterizing strengths and limitations as appropriate. Human health risk assessors evaluating environmental and occupational exposures have raised concerns about the validity of using epidemiological data for risk assessment due to actual or perceived study limitations. This article highlights three concerns commonly raised during the development of human health risk assessments of environmental and occupational exposures: (a) error in the measurement of exposure, (b) potential confounding, and (c) the interpretation of non-linear or non-monotonic exposure–response data. These issues are often the content of scientific disagreement and debate among the human health risk assessment community, and we explore how these concerns may be contextualized, addressed, and often ameliorated.     

Biomarkers as Predictors in Health and Ecological Risk Assessment

Biomarkers are measurable biological parameters that change in response to xenobiotic exposure and other environmental or physiological stressors, and can be indices of toxicant exposure or effects. If the biomarkers are sufficiently specific and well characterized, they can have great utility in the risk assessment process by providing an indication of the degree of exposure of humans or animals in natural populations to a specific xenobiotic or class of xenobiotics. Most biomarkers are effective as indices of exposure, but adequate information is rarely available on the appropriate dose-response curves to have well-described biomarkers of effect that can be widely applicable to additional populations. Specific examples of acetylcholinest-erase inhibition following exposure to organophosphorus insecticides are cited from experiments in both mammals (rats) and fish. These experiments have indicated that the degree of inhibition can be readily influenced by endogenous (e.g., age) and exogenous (e.g., chemical exposures) factors, and that the degree of inhibition is not readily correlated with toxicological effects. Caution is urged, therefore, in an attempt to utilize biomarkers in the risk assessment process until more complete documentation is available on the specificity, sensitivity, and time course of changes, and on the impact of multiple exposures or the time of exposures.     

The use of environmental media evaluation guides for screening environmental contamination

In conducting health assessments at hazardous‐waste sites, ATSDR staff must identify environmental chemical contaminants that pose a potential public health hazard. To assist health assessors in this effort, ATSDR has developed environmental media evaluation guides (EMEGs). EMEGs have been developed for water, soil, and air. The EMEG values are expressed as a range to account for the range in exposures in different segments of the population. The use of EMEGs provides health assessors with a consistent strategy for selecting environmental contaminants to be further evaluated in the health assessment process.     

Influence of systems biology response and environmental exposure level on between-subject variability in breath and blood biomarkers

To explain the underlying causes of apparently stochastic disease, current research is focusing on systems biology approaches wherein individual genetic makeup and specific ‘gene–environment’ interactions are considered. This is an extraordinarily complex task because both the environmental exposure profiles and the specific genetic susceptibilities presumably have large variance components. In this article, the focus is on the initial steps along the path to disease outcome namely environmental uptake, biologically available dose, and preclinical effect. The general approach is to articulate a conceptual model and identify biomarker measurements that could populate the model with hard data. Between-subject variance components from different exposure studies are used to estimate the source and magnitude of the variability of biomarker measurements. The intent is to determine the relative effects of different biological media (breath or blood), environmental compounds and their metabolites, different concentration levels, and levels of environmental exposure control. Examples are drawn from three distinct exposure biomarker studies performed by the US Environmental Protection Agency that studied aliphatic and aromatic hydrocarbons, trichloroethylene and methyl tertiary butyl ether. All results are based on empirical biomarker measurements of breath and blood from human subjects; biological specimens were collected under appropriate Institutional Review Board protocols with informed consent of the subjects. The ultimate goal of this work is to develop a framework for eventually assessing the total susceptibility ranges along the toxicological pathway from exposure to effect. The investigation showed that exposures are a greater contributor to biomarker variance than are internal biological parameters.     

The 3MRA Risk Assessment Framework—A Flexible Approach for Performing Multimedia,Multipathway, and Multireceptor Risk Assessments Under Uncertainty

A flexible framework for conducting nationwide multimedia, multipathway and multireceptor risk assessments (3MRA) under uncertainty was developed to estimate protective chemical concentration limits in a source area. The framework consists of two components: risk assessment and uncertainty analysis. The risk component utilizes linked source, fate/transport, exposure and risk assessment models to estimate the risk exposures for the receptors of concern. Both human and ecological receptors are included in the risk assessment framework. The flexibility of the framework is based on its ability to address problems varying in spatial scales from site-specific to regional and even national levels; and its ability to accommodate varying types of source, fate/transport, exposure and risk assessment models. The uncertainty component of the 3MRA framework is based on a two-stage Monte Carlo methodology. It allows the calculation of uncertainty in risk estimates, and the incorporation of the effects of uncertainty on the determination of regulatory concentration limits as a function of variability and uncertainty in input data, as well as potential errors in fate and transport and risk and exposure models. The framework can be adapted to handle a wide range of multimedia risk assessment problems. Two examples are presented to illustrate its use, and to demonstrate how regulatory decisions can be structured to incorporate the uncertainty in risk estimates.     

A Risk Assessment Approach for Policy Evaluation: New Jersey Case Studies

Monitoring environmental policy progress often focuses on contaminant concentrations while policy goals address health. To bridge this gap, we developed policy evaluation case studies applying risk assessment methods to explore population health risks of chemical exposures before and after policy implementation. Beginning in the 1970s the New Jersey Department of Environmental Protection provided some of the United States' first data on contaminants including trichloroethylene in drinking water and polychlorinated biphenyls (PCBs) in fish. These data provide a unique opportunity to evaluate environmental policies. The 1979 PCB manufacturing ban succeeded in reducing exposure and risk, but the persistence of these compounds in local fish requires continued state and local consumption advisories. The positive impact of drinking water standards for trichloroethylene was reflected in declining detection in public water supplies from the late 1970s to 2005, although maximum concentrations in a small percentage of supplies remain above standards. Our case studies show success and progress, and the need for multiple policies in combination when conditions warrant. Tracking specific policies and contaminants using risk assessment methods can be a valuable tool for policy evaluation and can foster population-based environmental health research. Pollution prevention policies are warranted for chemicals that persist in the environment.