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.     

Derivation of Risk Management Criteria for Chemicals of Unknown Toxic Potency at Contaminated Sites

Environmental investigations of former industrial sites often detect the presence of chemicals for which no soil criteria exist and for which regulatory agencies have not derived estimates of toxic potency. This poses a considerable problem for making informed risk management decisions involving sites where such chemicals are present. As a result, a methodology has been developed for making risk-based decisions for chemicals of unknown toxic potency in soil at contaminated sites. The method is based on principles and procedures used by the US Food and Drug Administration (USFDA), the US Environmental Protection Agency (USEPA) and the Canadian Council of Ministers of the Environment (CCME). After analyzing the data on hundreds of carcinogenic and non-carcinogenic substances, the USFDA and other leading researchers have concluded that, if no toxicological data is available on a chemical, exposures less than 1.5?µg/person/day (i.e., 0.02?µg/kg body weight/day) are unlikely to result in appreciable health risks even if the substance was later found to be a carcinogen. To develop maximum soil concentrations that will be protective of human health (i.e., Risk Management Criteria or RMC), the above exposure limit of 0.02?µg/kg body weight/day has been assumed to be protective of risks from exposure to chemicals lacking toxicological data. Using a stochastic risk assessment model for estimating exposures to chemicals from contaminated sites, our analyses indicate that a soil concentration of 2?µg/g would be protective of human health for land uses that include residential, commercial, and industrial development provided no major indirect pathways exist at the site. If indirect pathways exists (e.g., vapor infiltration of soil gases, uptake of chemicals into garden produce, etc.), alternate RMC could be developed, that include such indirect pathways, using the methodology provided in this paper. Used by experienced risk assessors, the approach is a scientifically defensible screening method that will preclude many chemicals from unnecessary evaluation, while allowing risk assessors to focus efforts on chemicals of greater concern and make informed risk management decisions.     

A Critical Review of the Traditional Methodology of Cost-Benefit Analysis and a Proposed Alternative

“Risk management” is essential to the decision-making process that prescribes regulations for protecting human health. As a comprehensive decision-making approach, risk management encompasses risk assessment, risk perception, economic factors, and their respective uncertainties. Cost-benefit analysis (CBA) has long been the preferred methodology for evaluating the economic factors associated with such regulations. Within this context, CBA confirms whether or not the “benefit” of a given regulatory option is greater than its “cost.” This article proposes an alternative CBA methodology whose guiding concept is the “optimization” of outcomes for the stakeholders in regulations that aim to protect human health. This article further proposes evaluation criteria for CBA and critiques the traditional and alternative variants against this standard, ultimately to demonstrate the superiority of the latter.     

Current and future needs for developmental toxicity testing

A review is presented of the use of developmental toxicity testing in the United States and international regulatory assessment of human health risks associated with exposures to pharmaceuticals (human and veterinary), chemicals (agricultural, industrial, and environmental), food additives, cosmetics, and consumer products. Developmental toxicology data are used for prioritization and screening of pharmaceuticals and chemicals, for evaluating and labeling of pharmaceuticals, and for characterizing hazards and risk of exposures to industrial and environmental chemicals. The in vivo study designs utilized in hazard characterization and dose-response assessment for developmental outcomes have not changed substantially over the past 30 years and have served the process well. Now there are opportunities to incorporate new technologies and approaches to testing into the existing assessment paradigm, or to apply innovative approaches to various aspects of risk assessment. Developmental toxicology testing can be enhanced by the refinement or replacement of traditional in vivo protocols, including through the use of in vitro assays, studies conducted in alternative nonmammalian species, the application of new technologies, and the use of in silico models. Potential benefits to the current regulatory process include the ability to screen large numbers of chemicals quickly, with the commitment of fewer resources than traditional toxicology studies, and to refine the risk assessment process through an enhanced understanding of the mechanisms of developmental toxicity and their relevance to potential human risk. As the testing paradigm evolves, the ability to use developmental toxicology data to meet diverse critical regulatory needs must be retained.     

Harmonization: Developing Consistent Guidelines for Applying Mode of Action and Dosimetry Information to Cancer and Noncancer Risk Assessment

The 1983 book, Risk Assessment in the Federal Government: Managing the Process, recommended developing consistent inference guidelines for cancer risk assessment. Over the last 15 years, extensive guidance have been provided for hazard assessment for cancer and other endpoints. However, as noted in several recent reports, much less progress has occurred in developing consistent guidelines for quantitative dose response assessment methodologies. This paper proposes an approach for dose response assessment guided by consideration of mode of action (pharmacodynamics) and tissue dosimetry (pharmacokinetics). As articulated here, this systematic process involves eight steps in which available information is integrated, leading first to quantitative analyses of dose response behaviors in the test species followed by quantitative analyses of relevant human exposures. The process should be equally appropriate for both cancer and noncancer endpoints. The eight steps describe the necessary procedures for incorporating mechanistic data and provide multiple options based upon the mode of action by which the chemical causes the toxicity. Given the range of issues involved in developing such a procedure, we have simply sketched the process, focusing on major approaches for using toxicological data and on major options; many details remain to be filled in. However, consistent with the revised carcinogen risk assessment guidance (USEPA, 1996c), we propose a process that would ultimately utilize biologically based or chemical specific pharmacokinetic and pharmacodynamic models as the backbone of these analyses. In the nearer term, these approaches will be combined with analysis of data using more empirical models including options intended for use in the absence of detailed information. A major emphasis in developing any harmonized process is distinguishing policy decisions from those decisions that are affected by the quality and quantity of toxicological data. Identification of data limitations also identifies areas where further study should reduce uncertainty in the final risk evaluations. A flexible dose response assessment procedure is needed to insure that sound toxicological study results are appropriately used to influence risk management decision-making and to encourage the conduct of toxicological studies oriented toward application for dose response assessments.     

Assessment of Regional Human Health Risks from Lead Contamination in Yunnan Province,Southwestern China

Identification and management the ''critical risk areas'' where hotspot lead exposures are a potential risk to human health, become a major focus of public health efforts in China. But the knowledge of health risk assessment of lead pollution at regional and national scales is still limited in China. In this paper, under the guidance of ''sources-pathways-receptors'' framework, regional human health risk assessment model for lead contamination was developed to calculate the population health risk in Yunnan province. And the cluster and AHP (analytic hierarchy process) analysis was taken to classify and calculate regional health risk and the decomposition of the regional health risk in the greatest health risk region, respectively. The results showed that Yunnan province can be divided into three areas. The highest health risk levels, located in northeastern Yunnan, including Kunming, Qujing, Zhaotong region. In those regions, lead is present at high levels in air, food, water and soil, and high population density which pose a high potential population risk to the public. The current study also reveals that most regional health risk was derived from the child receptors (age above 3 years) 4.3 times than the child receptors (age under 3years), and ingestion of lead-contaminated rice was found to be the most significant contributor to the health risk (accounting for more than 49 % health risk of total). This study can provide a framework for regional risk assessment in China and highlighted some indicators and uncertainties.     

The impact of new technologies on human population studies

Human population studies involve clinical or epidemiological observations that associate environmental exposures with health endpoints and disease. Clearly, these are the most sought after data to support assessments of human health risk from environmental exposures. However, the foundations of many health risk assessments rest on experimental studies in rodents performed at high doses that elicit adverse outcomes, such as organ toxicity or tumors. Using the results of human studies and animal data, risk assessors define the levels of environmental exposures that may lead to disease in a portion of the population. These decisions on potential health risks are frequently based on the use of default assumptions that reflect limitations in our scientific knowledge. An important immediate goal of toxicogenomics, including proteomics and metabonomics, is to offer the possibility of making decisions affecting public health and public based on detailed toxicity, mechanistic, and exposure data in which many of the uncertainties have been eliminated. Ultimately, these global technologies will dramatically impact the practice of public health and risk assessment as applied to environmental health protection. The impact is already being felt in the practice of toxicology where animal experimentation using highly controlled dose-time parameters is possible. It is also being seen in human population studies where understanding human genetic variation and genomic reactions to specific environmental exposures is enhancing our ability to uncover the causes of variations in human response to environmental exposures. These new disciplines hold the promise of reducing the costs and time lines associated with animal and human studies designed to assess both the toxicity of environmental pollutants and efficacy of therapeutic drugs. However, as with any new science, experience must be gained before the promise can be fulfilled. Given the numbers and diversity of drugs, chemicals and environmental agents; the various species in which they are studied and the time and dose factors that are critical to the induction of beneficial and adverse effects, it is only through the development of a profound knowledge base that toxicology and environmental health can rapidly advance. The National Institute of Environmental Health Sciences (NIEHS), National Center for Toxicogenomics and its university-based Toxicogenomics Research Consortium (TRC), and resource contracts, are engaged in the development, application and standardization of the science upon which to the build such a knowledge base on Chemical Effects in Biological Systems (CEBS). In addition, the NIEHS Environmental Genome Project (EGP) is working to systematically identify and characterize common sequence polymorphisms in many genes with suspected roles in determining chemical sensitivity. The rationale of the EGP is that certain genes have a greater than average influence over human susceptibility to environmental agents. If we identify and characterize the polymorphism in those genes, we will increase our understanding of human disease susceptibility. This knowledge can be used to protect susceptible individuals from disease and to reduce adverse exposure and environmentally induced disease.     

Making Causal Claims about Environmentally Induced Adverse Effects

Causal inferences are a vital and intrinsic part of assessing the risk of adverse effects on human populations and ecological resources from biological, chemical, physical, and psychosocial stressors. While it is well known that a statistical association does not necessarily imply a causal association, the central role of causal theory in health and ecological risk assessment is often overlooked. In this article, we present a succinct account of causal theory in the health sciences, emphasize the importance of differentiating between formal and informal approaches to causal inference, describe the weight-of-evidence process that is currently the predominant means of inferring causality in the context of science-based regulatory decisions, and discuss the effects of causal theory on the current and future practice of risk assessment. Our aim is to highlight the significance of decisions about causation and causal inference, and to suggest that explicit, well-considered choices will serve to strengthen the scientific underpinnings of regulatory decision-making.     

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.     

The potential role of life cycle assessment in regulation of chemicals in the European union

Scope and Background  This paper presents the preliminary results from an ongoing feasibility study, investigating potential application of elements from the life cycle assessment (LCA) framework in European chemicals’ policy. Many policy areas affect manufacturing, marketing and use of chemicals. This article focuses on the general chemical legislation, especially issues related to regulatory risk assessment and subsequent decisions on risk reduction measures. Method  Current and upcoming chemical regulation has been reviewed and empirical knowledge has been gained from an ongoing case study and from dialogues with various stakeholders. Results and Discussion  LCAs are comparative and more holistic in view as compared to chemical risk assessments for regulatory purposes¹. LCAs may therefore potentially improve the basis for decisions between alternatives in cases where a risk assessment calls for risk reduction. In this process, LCA results might feed into a socio-economic analysis having similar objectives, but some methodological aspects related to system boundaries need to be sorted out. Life cycle impact assessment (LCIA) of toxic effects has traditionally been inspired by the more regulatory-orientated risk assessment approaches. However, the increasing need for regulatory priority setting and comparative/ cumulative assessments might in the future convey LCIA principles into the regulatory framework. The same underlying databases on inherent properties of chemicals are already applied in both types of assessment. Similarly, data on the use and exposure of chemicals are needed within both risk assessments and LCA, and the methodologies might therefore benefit from a joint ‘inventory’ database. Outlook  The final outcome of the feasibility study will be an implementation plan suggesting incorporation of core findings in future chemical regulation and related policy areas.     

The Contribution of Systematic Review and Meta-Analysis Methods to Human Health Risk Assessment: Neurobehavioral Effects of Manganese

Current methods of human health risk assessment may lack transparency in respect of identification, review, and synthesis of potentially relevant human and animal evidence. The nature, degree, and source of uncertainties are often unclear. This article aims to demonstrate the contribution that systematic review and meta-analysis methods can make to providing more structured, transparent, and systematic risk assessments. We focus on disparities between five risk assessments for neurobehavioral effects of manganese, and then illustrate advantages of a systematic approach. Fifty-five human epidemiological studies and 37 animal experiments were identified. Where appropriate, meta-analysis methods demonstrated consistent adverse effects associated with manganese exposure across species. In particular, there was reduced activity in subjects exposed to manganese, although exposed rats tended to be more active than controls. Limitations of exposure measurement and reporting restricted use of more quantitative methods of evidence synthesis. From a methodological viewpoint, we conclude that systematic review and meta-analysis methods can contribute to a more systematic and transparent human health risk assessment making more efficient use of available evidence, compared to current methods of risk assessment. More complex methods could encompass further differences between relevant studies and so further improve the risk assessment process.     

Initial Risk-Based Screening of Potential Brownfield Development Sites

Brownfield redevelopment is sustainable only when it is a transparent process protective of public health. The objective of the brownfield health risk screening matrix is to provide a scientifically based, transparent process to evaluate human health risks on proposed redevelopment sites as well as a framework that can be critically evaluated by both environmentalists and the community in general. Public discussion and understanding of current health risk assessment, as well as the risks specific to each brownfield redevelopment site, are essential for an effective brownfield redevelopment program.

The Brownfields Redevelopment Program was started by the EPA in 1995 and seeks to use already contaminated sites rather than contaminate even more greenfields. Two of the biggest difficulties are making redevelopment profitable and protecting human health. Traditional human health risk assessment evaluates single chemical exposures and identifies the level below which no adverse effect will occur to the most sensitive subgroups of the population. For cancer–causing chemicals the risk must be lower than 1:1,000,000. When brownfield redevelopment sites are associated with high cost, extensive time and unmanageable uncertainty, additional greenfield sites will become contaminated and the contamination on current brownfield sites will remain un-remediated.

The citizens' advisory group addressing brownfields in a southern New York county has developed a risk matrix to evaluate the uncertainty of the available data, the toxicity of the known or suspected contaminants and the likely exposure routes for each brownfield site in the county. The matrix categorizes sites as high, medium or low risk according to exposure groups. The risk matrix complements the triad approach currently being developed by EPA to identify and manage project decision uncertainties, addresses uncertainty as well as toxicity and has the potential to reduce the cost of traditional health risk assessment at brownfield redevelopment sites.     

Approaches to Ecological Risk Characterization and Management: Selecting the Right Tools for the Job

Chemical-specific hazard quotient (HQ) risk characterization in ecological risk assessment (ERA) can be a value-added tool for risk management decision-making at chemical release sites, when applied appropriately. However, there is little consensus regarding how HQ results can be used for risk management decision-making at the population, community, and ecosystem levels. Furthermore, stakeholders are reluctant to consider alternatives to HQ results for risk management decisions. Chemical-specific HQs risk characterization should be viewed as only one of several approaches (i.e., tools) for addressing ecological issues; and in many situations, other quantitative and qualitative approaches will likely result in superior risk management decisions. The purpose of this paper is to address fundamental issues and limitations associated with chemical-specific HQ risk characterization in ERA, to identify when it may be appropriate, to explore alternatives that are currently available, and to identify areas that could be developed for the future. Several alternatives (i.e., compensatory restoration, performance-based ecological monitoring, ecological significance criteria, net environmental benefit analysis), including their limitations, that can supplement, augment, or substitute for HQs in ERA are presented. In addition, areas of research (i.e., wildlife habitat assessment/landscape ecology/population biology, and field validated risk-based screening levels) that could yield new tools are discussed.     

Comparison of Contaminated Site Human Health Risk Assessment Approaches in Canada: Application of Provincial Methods to a Hypothetical Site

Human health risk assessment, whether at the screening level or more complex phase, is not an exact science. A wide variety of advice and direction is offered by international, national, and provincial/state environmental agencies regarding the conduct of risk assessment, and different risk assessors access and rely on the available regulatory advice and direction differently. This may result in wide variability in the estimates of chemical exposure and risk. A comparison of human health risk assessment approaches practiced at the provincial level in Canada was undertaken, wherein each jurisdiction's approach was applied to a hypothetical contaminated site. Approaches were found to vary both in terms of methodological considerations, and in matters of policy. The exercise yielded results in terms of estimated exposures and predicted hazard quotients/indexes and incremental lifetime cancer risks that were in some cases quite consistent (varying by a factor of less than 1.5 times), and in other cases remarkably different (varying by orders of magnitude). This article reviews the various approaches/frameworks applied and discusses the results of the hypothetical risk assessments, in terms of both the observed variation and the source of this variability.     

Risk Assessment in Navy Deployment Toxicology

The risk assessment process is a critical function for deployment toxicology research. It is essential to the decision making process related to establishing risk reduction procedures and for formulating appropriate exposure levels to protect naval personnel from potentially hazardous chemicals in the military that could result in a reduction in readiness operations. These decisions must be based on quality data from well-planned laboratory animal studies that guide the judgements, which result in effective risk characterization and risk management. The process of risk assessment in deployment toxicology essentially uses the same principles as civilian risk assessment, but adds activities essential to the military mission, including intended and unintended exposure to chemicals and chemical mixtures. Risk assessment and Navy deployment toxicology data are integrated into a systematic and well-planned approach to the organization of scientific information. The purpose of this paper is to outline the analytical framework used to develop strategies to protect the health of deployed Navy forces.     

Probabilistic Analysis of Human Health Risks Associated with Background Concentrations of Inorganic Arsenic: Use of a Margin of Exposure Approach

Substantial evidence exists from epidemiological and mechanistic studies supporting a sublinear or threshold dose–response relationship for the carcinogenicity of ingested arsenic; nonetheless, current regulatory agency evaluations have quantified arsenic risks using default, generic risk assessment procedures that assume a linear, no-threshold dose–response relationship. The resulting slope factors predict risks from U.S. background arsenic exposures that exceed certain regulatory levels of concern, an outcome that presents challenges for risk communication and risk management decisions. To better reflect the available scientific evidence, this article presents the results of a Margin of Exposure (MOE) analysis to characterize risks associated with typical and high-end background exposures of the U.S. population to arsenic from food, water, and soil. MOE values were calculated by comparing a no-observable-adverse-effect-level (NOAEL) derived from the epidemiological literature with exposure estimates generated using a probabilistic (Monte Carlo) model. The plausibility and conservative nature of the exposure and risk estimates evaluated in this analysis are supported by sensitivity and uncertainty analyses and by comparing predicted urinary arsenic concentrations with empirical data. Using the more scientifically supported MOE approach, the analysis presented in this article indicates that typical and high-end background exposures to inorganic arsenic in U.S. populations do not present elevated risks of carcinogenicity.     

Uncertainty in Multi-Pathway Risk Assessment for Combustion Facilities

Multi-pathway risk assessments (MPRAs) of contaminant emissions to the atmosphere consider both direct exposures, via ambient air, and indirect exposures, via deposition to land and water. MPRAs embody numerous interconnected models and parameters. Concatenation of many multiplicative and incompletely defined assumptions and inputs can result in risk estimates with considerable uncertainties, which are difficult to quantify and elucidate. Here, three MPRA case-studies approach uncertainties in ways that better inform context-specific judgments of risk. In the first case, default values predicted implausibly large impacts; substitution of site-specific data within conservative methods resulted in reasonable and intuitive worst-case estimates. In the second, a simpler, clearly worst-case water quality model sufficed to demonstrate acceptable risks. In the third case, exposures were intentionally and transparently overestimated. Choices made within particular MPRAs depend on availability of data as suitable replacements for default assumptions, regulatory requirements, and thoughtful consideration of the concerns of interested stakeholders. Explicit consideration of the biases inherent in each risk assessment lends greater credibility to the assessment results, and can form the bases for evidence-based decision-making.     

Using Ecological Risk Assessment Principles in a Source Water Protection Assessment

It has become increasingly common to apply ecological risk assessment (ERA) principles to watershed and regional scale environmental management. This article describes the application of watershed ERA principles to the development of a source water protection assessment and a strategic watershed management plan. The primary focus was on the protection of drinking water quality, a concern typically addressed by human health risk assessors. The approach emphasizes adaptations to the problem formulation phase of ERA (defining assessment endpoints, developing conceptual models and an analysis plan) suitable for watershed management planning in a multi-objective, multi-stressor context. Physical, chemical, and biological attributes were selected for primary drinking water quality assessment endpoints, and coupled with additional assessment endpoints relevant to other environmental and social management objectives. Conceptual models helped the planning team to better understand and communicate the multiple natural and human stressors in the watershed and the causal pathways by which they affected drinking water. The article provides an example of the types of adaptations that can make ERA principles suitable for watershed management related to human health goals, and illustrates the efficiency of integrating health and ecological assessments.     

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。     

Uncertainty-based dynamic multimedia human health risk assessment for polycyclic aromatic hydrocarbons (PAHs) in a land oil exploitation area

With the increasing development of the petrochemical industry and the growing demand for oil, polycyclic aromatic hydrocarbons (PAHs) pollutions in the environment, especially in petroleum exploitation areas, are caused by the discharge of waste from the petroleum extraction process into an environmental system. This study aims to develop a new health risk assessment approach based on interval dynamic multimedia fugacity (IDMF) model and uncertainty analysis that could analyze the human exposure risk level for PAH contamination. The developed IDM health risk assessment (IDMHRA) approach is applied to assess previous, current, and future risks at a case study site in Daqing, Heilongjiang, China, from 1985 to 2020 for model validation. The human health risk assessment results show that 11 PAHs (NAP, ANT, FLA, PYR, BaA, CHR, BbF, BkF, BaP, IPY, and DBA) in the study site require further remediation efforts in terms of their unacceptable non-carcinogenic and carcinogenic risk. The results of risk source analysis reveal that soil media is the main risk pathway as compared with other exposure pathways. It can be seen that remediation process for soil contamination in the study site is urgently demanded. The assessment results demonstrate that the developed IDMHRA approach provides an effective tool for decision-makers and environmental managers to make remediation decisions in contaminated sites.