Framework for the Integration of Health and Ecological Risk Assessment

The World Health Organization's International Programme on Chemical Safety (IPCS), the Organization for Economic Cooperation and Development (OECD), and the U.S. Environmental Protection Agency have developed a collaborative partnership to foster integration of assessment approaches for human health and ecological risks. This paper presents the framework developed by that group. Integration provides coherent expressions of assessment results, incorporates the interdependence of humans and the environment, uses sentinel organisms, and improves the efficiency and quality of assessments relative to independent human health and ecological risk assessments. The paper describes how integration can occur within each component of risk assessment, and communicates the benefits of integration at each point. The goal of this effort is to promote the use of this internationally accepted guidance as a basis for harmonization of risk assessment.     

The effect of essentiality on risk assessment

Metals are ubiquitous in the human environment, making exposure inevitable and requiring scientifically sound risk assessment methodology to ensure adequate health protection. Within this area, as part of its ongoing efforts to improve and harmonize internationally approaches to risk assessments, the International Program on Chemical Safety (IPCS) has initiated work to improve the risk assessment procedures for essential trace elements (ETEs). Zn, Cu, Se, Cr, and MO are ETEs for humans, with increasing evidence of an essential role for boron (B). For ETEs, there is a range of daily intake within which the organism maintains homeostasis. At intakes below this range, there is an increased risk from deficiency, and at intakes above the range toxicity may develop. Obviously, for ETEs one cannot assume zero exposure is without risk. Adequate health protection will require the cooperative effort of scientists in nutrition and toxicology to develop the limits of the accepted range for ETEs considering such unique properties of metals as bioavailability, speciation, interactions, and biokinetics. Based on previous work by other groups and the recommendations of an IPCS consultation, a scientific monograph will be completed by IPCS. It will examine present risk assessment methodology for ETEs, and develop scientific principles supporting use of a homeostatic model for the development of dietary reference values and tolerable daily intakes. The objective is to develop an internationally accepted methodology for assessing ETEs as part of the IPCS effort to harmonize approaches to risk assessment worldwide. A recent IPCS Task Group on Zn highlighted some of the scientific issues that require resolution to avoid an overlap of the recommended daily intake based on nutritional needs with that based on toxicity and will serve as a case study.     

International approach of the assessment of chemical risks

One of the primary objectives of the International Programme on Chemical Safety (IPCS) which is a cooperative venture of the International Labour Organization (ILO), the United Nations Environment Programme (UNEP) and the World Health Organization (WHO), is to carry out and disseminate evaluations of the risk to human health and the environment from exposure to chemicals. These evaluations are distributed to all Member States in order to provide a scientific and objective basis that national health or other relevant authorities may be able to use for planning, and for the development of regulatory and control measures. In view of frequent discrepancies in toxicological evaluations performed by different groups, it is recommended that a mechanism be established to assure a higher degree of uniformity and harmonization in the safety assessment of chemicals, and to develop globally acceptable standardized control measures.     

Application of Kinetic and Dynamic Data for Antihistamines to Risk Characterization in Sensitive Populations

A major goal of risk assessment is to protect the health of individuals who may be more sensitive than the general population. This study compared human phar-macokinetic and pharmacodynamic data in sensitive groups (i.e., children, the elderly, diseased states, and poor metabolizers) versus young, healthy adults for the antihistamines cetirizine, fexofenadine, loratadine, azelastine, ebastine, chlorpheniramine, and diphenhydramine. The default components (3.16 each for kinetic and dynamic aspects) of the intraspecies uncertainty factor were adjusted with compound specific data for the antihistamines. The majority (16 of 18) of the composite factors (kinetics X dynamics) for the sensitive groups were less than 10. Children had the lowest composite factors for antihistamines, ranging from 1.1 to 6.3. Application of kinetic and dynamic data for antihistamines to the Renwick/International Programme on Chemical Safety (IPCS) scheme can aid in characterizing the extent of variability in sensitive populations, thereby reducing the uncertainty associated with the risk assessment of sensitive populations.     

The Use of Kinetic and Dynamic Data in Risk Assessment of Drugs

The risk assessment process for non-carcinogens must incorporate all available scientific information, including toxicokinetic and toxicodynamic data. The framework for exposure limit setting proposed by Renwick and the International Programme on Chemical Safety (IPCS) subdivides traditional 10X uncertainty factors (UFs) into separate partial-log default values based on kinetic and dynamic considerations and allows for incorporation of compound-specific data when available. In this investigation, an extensive literature search was conducted on nine pharmaceuticals in order to incorporate information on kinetics and dynamics to allow extrapolation across species and among susceptible humans. The drugs are diazepam, oxazepam, midazolam, buspirone, fluoxetine, venlafaxine, amlodipine, felodipine, and nifedipine. The composite factors were calculated using the highest ratio or the average ratio for appropriate parameters and default subfactor. For the drugs examined, most of the subfactors for kinetics and dynamics were less than the proposed values by Renwick and IPCS, and the composite factors were far less than 100. From this study, it was concluded that relevant compound-specific kinetic and dynamic data can reduce uncertainties associated with interspecies differences and interindividual variability.     

Inter- and Intra-Species Extrapolation in Risk Assessment of Different Classes of Pesticides

Risk assessors routinely use the reference dose (RfD) approach for non-cancer risk assessment. In this approach, No-Observed-Adverse-Effect-Level (NOAEL) is divided by the product of uncertainty factors (UFs) and, occasionally, an additional modifying factor (MF), each usually employed by default as factors of 10. In the present investigation, kinetic and dynamic data have been used in order to reduce uncertainties when establishing exposure guidelines for examples of chemicals representing four classes of pesticides (warfarin, lindane, carbaryl and parathion). An intensive search of databases was conducted for these pesticides, and toxicokinetic and toxicodynamic parameters in inter- and intra-species were evaluated. The kinetic and dynamic subfactors were less than the proposed values of Renwick and the International Programme on Chemical Safety (IPCS). The composite factors for all the examined pesticides were less than 100. The present study indicated that in setting exposure levels it is important to incorporate kinetic and dynamic data, as they become available, rather than rely on default uncertainty factors, which are imprecise in many cases.     

Évaluation de la réponse au traitement des lymphomes : rôle de la TEP-FDG

Positron emission tomography (PET) with FDG has a prominent role in the staging of lymphoma, including Hodgkin's lymphoma and aggressive non Hodgkin's lymphoma. Its value in the assessment of end therapy response is also well established, especially with residual masses on CT scan to differentiate between fibrosis (scar) and active tissue. International experts with the International Harmonization Project of lymphoma have proposed a set of interpretation criteria. Finally, FDG-PET looks very promising in the early response assessment; it has shown to be predictive of chemosensitivity and of therapy response. Interpretation criteria have been improved and proposed. FDG-PET usefulness is being evaluated in national and international research protocols where therapeutic strategies are based on FDG-PET results.     

Life Cycle Greenhouse Gas Emissions of Electricity Generated from Conventionally Produced Natural Gas

This research provides a systematic review and harmonization of the life cycle assessment (LCA) literature of electricity generated from conventionally produced natural gas. We focus on estimates of greenhouse gases (GHGs) emitted in the life cycle of electricity generation from natural gas‐fired combustion turbine (NGCT) and combined‐cycle (NGCC) systems. The smaller set of LCAs of liquefied natural gas power systems and natural gas plants with carbon capture and storage were also collected, but analyzed to a lesser extent. A meta‐analytical process we term “harmonization” was employed to align several system boundaries and technical performance parameters to better allow for cross‐study comparisons, with the aim of clarifying central tendency and reducing variability in estimates of life cycle GHG emissions. Of over 250 references identified, 42 passed screens for technological relevance and study quality, providing a total of 69 estimates for NGCT and NGCC. Harmonization increased the median estimates in each category as a result of several factors not typically considered in the previous research, including the regular clearing of liquids from a well, and consolidated the interquartile range for NGCC to 420 to 480 grams of carbon dioxide equivalent per kilowatt‐hour (g CO₂‐eq/kWh) and for NGCT to 570 to 750 g CO₂‐eq/kWh, with medians of 450 and 670 CO₂‐eq/kWh, respectively. Harmonization of thermal efficiency had the largest effect in reducing variability; methane leakage rate is likely similarly influential, but was unharmonized in this assessment as a result of the significant current uncertainties in its estimation, an area that is justifiably receiving significant research attention.     

International programme on chemical safety (IPCS) environmental health criteria on boron human health risk assessment

The International Program on Chemical Safety (IPCS), a collaborative program of the United Nations Environment Program, the International Labour Organization (ILO), and the World Health Organization (WHO), includes the Environmental Health Criteria (EHC) Program inaugurated in 1973 by WHO. These EHC are integrated evaluations of the human health and environmental risks from exposure to specific chemicals carried out by a group of international scientists. Boron (B) was evaluated at an IPCS Task Group (TG) convened in November 1996. All TGs are convened under WHO rules and procedures. These procedures relate the overall process used to prepare an EHC including transparency of the process, conflict of interest, the roles of Members and Observers, and the conduct of the TG. The scope and purpose of an EHC, for an element such as B, and its possible role in national and international chemical safety programs will be discussed. In the early 1990s, countries asked that IPCS request TGs to prepare, where data permit, health-based guidance values (GVs) (both total daily intake and to recommend health-based guidelines for various environmental media). This final evaluation in an EHC reflects the collective consensus view of the TG Members. To foster the use of consistent methodology by TGs, IPCS prepared in 1994 an EHC on the methodology for the preparation of GVs for human exposure limits (EHC 170). In developing their final evaluation, TGs have been asked to consider using this methodology. This was done by the TG on B, and a total daily intake for humans of 0.4 mg/kg body wt was derived from animal studies of reproductive and developmental effects in rodents and pharmacokinetic data from both animals and humans. The application of the methodology described in EHC 170 regarding choice of critical effect and uncertainty factors will be discussed.     

WHO health risk assessment process for static fields

The World Health Organization (WHO) has a commitment to helping Member States achieve safe, sustainable and health-enhancing human environments, protected from biological, chemical and physical agents. The latter includes advising on the health impact of electromagnetic fields (EMFs) and radiation.

The results of the WHO/ICNIRP/NRPB workshop on static magnetic fields, published in this volume, provide a valuable and much needed contribution to the health risk assessment of exposure to static electric and magnetic fields, which is currently being coordinated by the WHO's International EMF Project. This WHO health risk assessment will be published as an environmental health criteria (EHC) monograph in early 2005.

This paper briefly gives an overview of the process of developing the WHO static fields EHC monograph, the criteria applied to studies that could contribute to the EHC, along with the ‘weight-of-evidence’ approach to health risk assessment. In addition, there is an increasing awareness of the need to account for uncertainty in the science database. This is traditionally addressed by further research, and the EMF project addresses these needs through the development of a ‘research agenda’. However, research programmes may take several years to complete, and the long latency associated with diseases such as cancer in people may also preclude a rapid outcome in some studies. The issue of current uncertainty is being addressed by the WHO EMF project through the development of a ‘precautionary framework’ in which precautionary measures will be applied to policy recommendations.     

The Use of Probabilistic Risk Assessment in Establishing Drinking Water Quality Objectives

There has been a trend in recent years toward the use of probabilistic methods for the analysis of uncertainty and variability in risk assessment. By developing a plausible distribution of risk, it is possible to obtain a more complete characterization of risk than is provided by either best estimates or upper limits. We describe in this paper a general framework for evaluating uncertainty and variability in risk estimation and outline how this framework can be used in the establishment of drinking water quality objectives. In addition to characterizing uncertainty and variability in risk, this framework also facilitates the identification of specific factors that contribute most to uncertainty and variability. The application of these probabilistic risk assessment methods is illustrated using tetrachloroethylene and trihalomethanes as examples.     

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.     

Challenges for Risk Assessors

At the early part of the 21st century, occupational safety and health risk assessors face a variety of challenges. In addition to technical issues, the challenges for risk assessors include: assessment of risks of mixtures/and synergistic effects; incorporation of biological information into risk assessments; development of different ways of presenting risk information to better inform policy makers and the public; better expressions of uncertainty and assumptions; and harmonization of assessments across agencies and countries. All of these challenges will occur against a background of unfolding understanding of human and other genomes. Risk assessors will be motivated and pressured to use genomic and related technologies, but ethical, social, and technical issues need to be addressed before widespread use.     

Treatments of Uncertainty and Variability in Ecological Risk Assessment of Single-Species Populations

The selection of the most appropriate model for an ecological risk assessment depends on the application, the data and resources available, the knowledge base of the assessor, the relevant endpoints, and the extent to which the model deals with uncertainty. Since ecological systems are highly variable and our knowledge of model input parameters is uncertain, it is important that models include treatments of uncertainty and variability, and that results are reported in this light. In this paper we discuss treatments of variation and uncertainty in a variety of population models. In ecological risk assessments, the risk relates to the probability of an adverse event in the context of environmental variation. Uncertainty relates to ignorance about parameter values, e.g., measurement error and systematic error. An assessment of the full distribution of risks, under variability and parameter uncertainty, will give the most comprehensive and flexible endpoint. In this paper we present the rationale behind probabilistic risk assessment, identify the sources of uncertainty relevant for risk assessment and provide an overview of a range of population models. While all of the models reviewed have some utility in ecology, some have more comprehensive treatments of uncertainty than others. We identify the models that allow probabilistic assessments and sensitivity analyses, and we offer recommendations for further developments that aim towards more comprehensive and reliable ecological risk assessments for populations.     

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.     

Analysis and Portrayal of Uncertainty in a Food-Web Exposure Model

The results of quantitative risk assessments are key factors in a risk manager's decision of the necessity to implement actions to reduce risk. The extent of the uncertainty in the assessment will play a large part in the degree of confidence a risk manager has in the reported significance and probability of a given risk. The two main sources of uncertainty in such risk assessments are variability and incertitude. In this paper we use two methods, a second-order two-dimensional Monte Carlo analysis and probability bounds analysis, to investigate the impact of both types of uncertainty on the results of a food-web exposure model. We demonstrate how the full extent of uncertainty in a risk estimate can be fully portrayed in a way that is useful to risk managers. We show that probability bounds analysis is a useful tool for identifying the parameters that contribute the most to uncertainty in a risk estimate and how it can be used to complement established practices in risk assessment. We conclude by promoting the use of probability analysis in conjunction with Monte Carlo analyses as a method for checking how plausible Monte Carlo results are in the full context of uncertainty.     

Importance of dose‐response model form in probabilistic risk assessment: A case study of health effects from methylmercury in fish

We compared the effect of uncertainty in dose‐response model form on health risk estimates to the effect of uncertainty and variability in exposure. We used three different dose‐response models to characterize neurological effects in children exposed in utero to methylmercury, and applied these models to calculate risks to a native population exposed to potentially contaminated fish from a reservoir in British Columbia. Uncertainty in model form was explicitly incorporated into the risk estimates. The selection of dose‐response model strongly influenced both mean risk estimates and distributions of risk, and had a much greater impact than altering exposure distributions. We conclude that incorporating uncertainty in dose‐response model form is at least as important as accounting for variability and uncertainty in exposure parameters in probabilistic risk assessment.     

Developing Univariate Distributions from Data for Risk Analysis

The importance of fitting distributions to data for risk analysis continues to grow as regulatory agencies, like the Environmental Protection Agency (EPA), continue to shift from deterministic to probabilistic risk assessment techniques. The use of Monte Carlo simulation as a tool for propagating variability and uncertainty in risk requires specification of the risk model's inputs in the form of distributions or tables of data. Several software tools exist to support risk assessors in their efforts to develop distributions. However, users must keep in mind that these tools do not replace clear thought about judgments that must be made in characterizing the information from data. This overview introduces risk assessors to the statistical concepts and physical reasons that support important judgments about appropriate types of parametric distributions and goodness-of-fit. In the context of using data to improve risk assessment and ultimately risk management, this paper discusses issues related to the nature of the data (representativeness, quantity, and quality, correlation with space and time, and distinguishing between variability and uncertainty for a set of data), and matching data and distributions appropriately. All data analysis (whether “Frequentist” or “Bayesian” or oblivious to the distinction) requires the use of subjective judgment. The paper offers an iterative process for developing distributions using data to characterize variability and uncertainty for inputs to risk models that provides incentives for collecting better information when the value of information exceeds its cost. Risk analysts need to focus attention on characterizing the information appropriately for purposes of the risk assessment (and risk management questions at hand), not on characterization for its own sake.