Issues in Exposure and Dose Assessment for Epidemiology and Risk Assessment

Epidemiologic studies have been effective in identifying human environmental and occupational hazards. However, most epidemiologic data has been difficult to use in quantitative risk assessments because of the vague specification of exposure and dose. Toxicologic animal studies have used applied doses (quantities administered, or exposures with fixed duration) and well characterized end points to determine effects. However, direct use of animal data in human risk assessment has been limited by uncertainties in the extrapolation. The applied dose paradigm of toxicology is not suited for cross species extrapolation, nor for use in epidemiology as a dose metric because of the complexity of human exposures. Physiologically based pharmacokinetic (PBPK) modeling can estimate the time course of tissue concentrations in humans, given an exposure-time profile, and it has been used for extrapolating findings from animals to humans. It is proposed that human PBPK modeling can be used in appropriately designed epidemiologic studies to estimate tissue concentrations. Secondly, tissue time courses can be used to form dose metrics based on the type and time course of adverse effects. These dose metrics will strengthen the determination of epidemiologic dose-response relationships by reducing misclassification. Findings from this approach can be readily integrated into quantitative risk assessment.     

Improving Risk Assessment: Toxicological Research Needs

A workshop convened to define research needs in toxicology identified several deficiencies in data and methods currently applied in risk assessment. The workshop panel noted that improving the link between chemical exposure and toxicological response requires a better understanding of the biological basis for inter-and intra-human variability and susceptibility. This understanding will not be complete unless all life stages are taken into consideration. Because animal studies serve as a foundation for toxicological assessment, proper accounting for cross-species extrapolation is essential. To achieve this, adjustments for dose-rate effects must be improved, which will aid in extrapolating toxicological responses to low doses and from short-term exposures. Success depends on greater use of validated biologically based dose-response models that include pharmacokinetic and pharmacodynamic data. Research in these areas will help define uncertainty factors and reduce reliance on underlying default assumptions. Throughout the workshop the panel recognized that biomedical science and toxicology in particular is on the verge of a revolution because of advances in genomics and proteomics. Data from these high-output technologies are anticipated to greatly improve risk assessment by enabling scientists to better define and model the elements of the relationship between exposure to biological hazards and health risks in populations with differing susceptibilities.     

What Can Be Done to Ensure the Usefulness of Epidemiologic Data for Risk Assessment Purposes?

Epidemiologic studies can play a central role in risk assessments. They are used in all risk assessment phases: hazard identification, dose-response, and exposure assessment. Epidemiologic studies have often been the first to show that a particular environmental exposure is a hazard to health. They have numerous advantages with respect to other sources of data which are used in risk assessments, the most important being that they do not require the assumption that they are generalizable to humans. For this reason, fewer and lower uncertainty factors may be appropriate in risk characterization based on epidemiologic studies. Unfortunately, epidemiologic studies have numerous problems, the most important being that the exposures are often not precisely measured. This article presents in detail the advantages of and problems with epidemiologic studies. It discusses two approaches to ensure their usefulness, biomarkers and an ordinance which requires baseline and subsequent surveillance of possible exposures and health effects from newly sited potentially polluting facilities. Biomarkers are biochemical measures of exposure, susceptibility factors, or preclinical pathological changes. Biomarkers are a way of dealing with the problems of poor measures, differential susceptibility and lack of early measures of disease occurrence that inherent in many environmental epidemiologic studies. The advantages of biomarkers is they can provide objective information on exposure days, months or even years later and evidence of pathology perhaps years earlier. The ordinance makes possible the use of a powerful epidemiologic study design, the prospective cohort study, where confounder(s) are best measured, and exposures, pathological changes, and health effects can be detected as soon as possible.     

The Use of Epidemiology in Environmental Risk Assessment

Epidemiology provides estimates of the concentration–response relation for environmental and occupational toxicants in the species of interest, in or close to the dose range of interest. As such, when available, they provide the primary source for risk assessments. Further information can be acquired by using modern biostatistical techniques to assess the shape of the dose response relation, examine effect modification, and assure control for confounding. These approaches are particularly effective if they are done in the context of a meta-analysis or hierarchical model. This is illustrated with examples from the air pollution literature.     

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.     

Ecological Risk Assessment of Radiological Exposure to Depleted Uranium in Soils at a Weapons Testing Facility

The potential for unacceptable risks to biota from radiological exposure to depleted uranium (DU) in soils was evaluated at two sites where DU weapons testing had been conducted in the past. A screening risk assessment was conducted to determine if measured concentrations of DU-associated radionuclides in site soils exceed radionuclide levels considered protective of biota. While concentrations of individual radionuclides did not exceed acceptable levels, total radionuclide concentrations could result in potentially unacceptable doses to exposed biota. Thus, a receptor-specific assessment was conducted to estimate external and internal radiological doses to vegetation and wildlife known or expected to occur at the sites. Wildlife evaluated included herbivores, omnivores, and top-level predators. Internal dose estimates to wildlife considered exposure via fugitive dust inhalation and soil and food ingestion; root uptake was the primary exposure route evaluated for vegetation. Total doses were compared with acceptable dose levels of 1.0 and 0.1 rad/day for vegetation and wildlife, respectively, with potentially unacceptable risks indicated for doses exceeding these levels. All estimated doses were below or approximated acceptable levels, typically by an order of magnitude or more. These results indicate that current levels of DU in soils do not pose unacceptable radiological risks to biota at the sites evaluated.     

Human Health Risk Assessment: Required Reading

Over the past 30 years, risk assessment has developed into a scientific discipline. It is critical that the next generation of risk assessors understand the history of our field, and recognize the numerous successes and failures that have taken place. This short Perspective identifies and describes specific books, monographs, and reports that are required reading for any nascent risk assessor.     

Challenges and Research Needs for Risk Assessment of Pesticides for Registration in Africa

Risk assessment is necessary for registration and risk management of new pesticides. The aim of this article is to discuss challenges that risk assessors in Africa face when conducting risk assessment of pesticides. Risk assessment requires toxicity assessment, environmental fate studies, and the use of models for occupational, dietary, residential, and environmental exposure assessments. Toxicity studies are very costly with the result that toxicity data used to register pesticides in Africa are often sourced from northern hemisphere countries. Assessors also often use exposure modeling results from the northern hemisphere. This is not an ideal approach as occupational exposure is influenced by agricultural practices, climatic conditions, and other factors. Furthermore, residential exposure models require time-location-activity information, exposure factors, and toxicokinetic rate constants for particular pesticides. Dietary exposure assessment needs accurate and comprehensive local food consumption data. Authorities in African countries should therefore generate the required data, despite these being very costly and tedious. Authorities should also provide guidance on the type of models and standard scenarios for estimating predicted environmental concentrations in various environmental compartments. It is recommended that higher educational institutions in Africa should incorporate risk assessment in general and pesticide toxicity and exposure models in particular in their curricula.     

Use of Toxicological Data in Estimating Reference Values for Risk Assessment

A number of programs within the U.S. Environmental Protection Agency (USEPA) currently set less-than-lifetime exposure limits in addition to the chronic reference dose (RfD) and reference concentration (RfC). A review of procedures within the USEPA for setting reference values suggests that less-thanlifetime reference values should be more routinely developed and captured in the USEPA's online IRIS database where chronic RfDs and RfCs, as well as cancer slope factors, are currently available. A review of standard testing study protocols was conducted to determine what data were available for setting acute, short-term, and longer-term reference values, as well as chronic values. This review was done from the point of view of endpoints assessed for specific organ systems (both structural and functional), life stages covered by exposure and outcome, durations of exposure covered and the outcomes evaluated for each, and evaluation of latency to response and/or reversibility of effects. This review revealed a number of data gaps and research needs, including the need for an acute and/or short-term testing protocol that can be used to set acute and shortterm reference values, a strategy for when to conduct more extensive testing based on initial screening data or other information (e.g., chemical class, pharmacokinetics, mode of action), additonal standard testing guidlines protocols to allow more complete assessment of certain organ systems and life stages, development of pharmacokinetic data for different life stages, toxicity related to aging, and latency to response, particularly long-term latency as a result of developmental exposures. The implications of this review are discussed relative to characterizing hazard data for setting reference values, and the potential effects on uncertainty factors and low-dose extrapolation.     

Approaches for Integrated Risk Assessment

Recognizing the need to enhance the effectiveness and efficiency of risk assessments globally, the World Health Organization's International Programme on Chemical Safety, the U.S. Environmental Protection Agency, the European Commission, and the Organization for Economic Cooperation and Development developed a collaborative partnership to foster integration of assessment approaches used to evaluate human health and ecological risks. The objectives of this effort included: improving understanding of the benefits of integration, identifying obstacles to the integration process, and engaging key agencies, organizations, and scientific societies to promote integration. A framework with supporting documentation was developed to describe an approach for integration. Four case studies were constructed to illustrate how integrated risk assessments might be conducted for chemical and nonchemical stressors. The concepts and approaches developed in the project were evaluated in an international workshop. The goal of this effort was international acceptance of guidance for integrated risk assessment.     

Machinery Risk Assessment for Risk Reduction

New avenues are reviewed and discussed for preventing industrial machine-related injury by means of realistic risk evaluation and reduction processes at the design and application stages of machinery development and use. U.S. guidelines and European standards on machinery risk assessment procedures are described. Applications of risk assessment for machine-related injury risk management and teaching machine-risk control are discussed.     

Improving Risk Assessment: Research Opportunities in Dose Response Modeling to Improve Risk Assessment

Substantial improvements in dose response modeling for risk assessment may result from recent and continuing advances in biological research, biochemical techniques, biostatistical/mathematical methods and computational power. This report provides a ranked set of recommendations for proposed research to advance the state of the art in dose response modeling. The report is the result of a meeting of invited workgroup participants charged with identifying five areas of research in dose response modeling that could be incorporated in a national agenda to improve risk assessment methods. Leading topics of emphasis are interindividual variability, injury risk assessment modeling, and procedures to incorporate distributional methods and mechanistic considerations into now-standard methods of deriving a reference dose (RfD), reference concentration (RfC), minimum risk level (MRL) or similar dose-response parameter estimates.     

Validity of Epidemiological Data in Risk Assessment Applications

Data from epidemiological studies might be seen as superior to data from animal bioassays for risk assessment purposes. Because humans are the population of interest, use of epidemiological data avoids interspecies extrapolation. However, one must not assume that an epidemiological study is necessarily valid at face value. We describe issues of validity that arise in the conduct and interpretation of epidemiological research and that affect the utility of epidemiological data in risk assessment. These issues include choice of study design, size and representativeness of the study sample, measurement of exposures and outcomes, control of confounding and specification of statistical model for analysis of data, all of which affect the accuracy and validity of study results.     

The Fox River Risk Assessment Teaching Tool

In 1999 and 2000, two environmental consulting companies independently prepared risk assessments of the Lower Fox River waste site in Wisconsin. Because the two assessments produced somewhat different risk characterizations, the Association for Environmental Health & Sciences was asked by the site's Potentially Responsible Party to form a peer review panel to critique and compare the two assessments. The panel found interesting differences between the two risk assessments and recommended that their observations, together with the two risk assessments, be made available as a Teaching Tool for persons interested in conducting human and ecological risk assessments. An accompanying CD contains these and other materials useful for teaching purposes.     

Framework for Human Health Risk Assessment

The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the USEPA. The U.S. Government has the right to retain a nonexclusive royalty-free license in and to any copyright covering this article. The U.S. Environmental Protection Agency has recognized the need to develop a framework for human health risk assessment that puts a perspective on the approaches in practice throughout the Agency. In response, the USEPA's Risk Assessment Forum has begun the process of developing a framework for human health risk assessment. This paper provides some additional background to the previous review of the framework efforts and notes the Agency's extramural efforts to begin the process of integrating and harmonizing risk assessment approaches for all human health endpoints.     

Potential Distribution and Risk Assessment of an Invasive Plant Species: A Case Study of Hymenachne amplexicaulis in Australia

Given the limited resources available for weed management, a strategic approach is required to give the “best bang for your buck.” The current study incorporates: (1) a model ensemble approach to identify areas of uncertainty and commonality regarding a species invasive potential, (2) current distribution of the invaded species, and (3) connectivity of systems to identify target regions and focus efforts for more effective management. Uncertainty in the prediction of suitable habitat for H. amplexicaulis (study species) in Australia was addressed in an ensemble-forecasting approach to compare distributional scenarios from four models (CLIMATCH; CLIMEX; boosted regression trees [BRT]; maximum entropy [Maxent]). Models were built using subsets of occurrence and environmental data. Catchment risk was determined through incorporating habitat suitability, the current abundance and distribution of H. amplexicaulis, and catchment connectivity. Our results indicate geographic differences between predictions of different approaches. Despite these differences a number of catchments in northern, central, and southern Australia were identified as high risk of invasion or further spread by all models suggesting they should be given priority for the management of H. amplexicaulis. The study also highlighted the utility of ensemble approaches in indentifying areas of uncertainty and commonality regarding the species’ invasive potential.     

An Assessment of Integrated Risk Assessment

In order to promote international understanding and acceptance of the integrated risk assessment process, the World Health Organization/International Programme on Chemical Safety (WHO/IPCS), in collaboration with the U.S. Environmental Protection Agency and the Organization for Economic Cooperation and Development, initiated a number of activities related to integrated risk assessment. In this project, the WHO/IPCS defines integrated risk assessment as a science-based approach that combines the processes of risk estimation for humans, biota, and natural resources in one assessment. This article explores the strengths and weaknesses of integration as identified up to this date and the degree of acceptance of this concept by the global risk assessment/risk management community. It discusses both opportunities and impediments for further development and implementation.

The major emerging opportunities for an integrated approach stem from the increasing societal and political pressure to move away from vertebrate testing leading to a demand for scientific integrated approaches to in vitro and in vivo testing, as well as to computer simulations, in so-called Intelligent Testing Strategies. In addition, by weighing the evidence from conventional mammalian toxicology, ecotoxicology, human epidemiology, and eco-epidemiology, risk assessors could better characterize mechanisms of action and the forms of the relationships of exposures to responses. It is concluded that further demonstrations of scientific, economic and regulatory benefits of an integrated approach are needed. As risk assessment is becoming more mechanistic and molecular this may create an integrated approach based on common mechanisms and a common systems-biology approach.     

Noncancer Risk Assessment: A Probabilistic Alternative to Current Practice

Based on imperfect data and theory, agencies such as the United States Environmental Protection Agency (USEPA) currently derive “reference doses” (RfDs) to guide risk managers charged with ensuring that human exposures to chemicals are below population thresholds. The RfD for a chemical is typically reported as a single number, even though it is widely acknowledged that there are significant uncertainties inherent in the derivation of this number.

In this article, the authors propose a probabilistic alternative to the EPA's method that expresses the human population threshold as a probability distribution of values (rather than a single RfD value), taking into account the major sources of scientific uncertainty in such estimates. The approach is illustrated using much of the same data that USEPA uses to justify their current RfD procedure.

Like the EPA's approach, our approach recognizes the four key extrapolations that are necessary to define the human population threshold based on animal data: animal to human, human heterogeneity, LOAEL to NOAEL, and subchronic to chronic. Rather than using available data to define point estimates of “uncertainty factors” for these extrapolations, the proposed approach uses available data to define a probability distribution of adjustment factors. These initial characterizations of uncertainty can then be refined when more robust or specific data become available for a particular chemical or class of chemicals.

Quantitative characterization of uncertainty in noncancer risk assessment will be useful to risk managers who face complex trade-offs between control costs and protection of public health. The new approach can help decision-makers understand how much extra control cost must be expended to achieve a specified increase in confidence that the human population threshold is not being exceeded.     

An NGO Perspective on Risk Assessment and Scientific Research

Concerns over risk assessment have been raised by Non-Government Organizations (NGO) and the environmental community for decades. In considering proposals for research in this area, it is important for both scientists and policymakers to consider the following points: (1) risk assessment as a method of policymaking is increasingly inaccessible to meaningful public participation, (2) the lack of fundamental toxicological data constrains the application of risk assessment methods more than any other factor, and (3) the importance of individual susceptibility in risk assessments must be tempered by the lack of control over individual exposures.