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.     

Accounting for Missing Data in Noncancer Risk Assessment

Noncancer risk assessments are generally forced to rely on animal bioassay data to estimate a Tolerable Daily Intake or Reference Dose, as a proxy for the threshold of human response. In cases where animal bioassays are missing from a complete data base, the critical NOAEL (no-observed-adverse-effect level) needs to be adjusted to account for the impact of the missing bioassay(s). This paper presents two approaches for making such adjustments. One is based on regression analysis and seeks to provide a point estimate of the adjustment needed. The other relies on non-parametric analysis and is intended to provide a distributional estimate of the needed adjustment. The adjustment needed is dependent on the definition of a complete data base, the number of bioassays missing, the specific bioassays which are missing, and the method used for interspecies scaling. The results from either approach can be used in conjunction with current practices for computing the TDI or RfD, or as an element of distributional approaches for estimating the human population threshold.     

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.     

A Probabilistic Human Health Risk Assessment for Environmental Exposure to Dibutylphthalate

In the European Union, Directive 92/32/EC and EC Council Regulation (EC) 793/93 require the risk assessment of industrial chemicals. In this framework, it is agreed to characterise the level of “risk” by means of the deterministic quotient of exposure and effects parameters. Decision makers require that the uncertainty in the risk assessment be accounted for as explicitly as possible. Therefore, this paper intends to show the advantages and possibilities of a probabilistic human health risk assessment of an industrial chemical, dibutylphthalate (DBP). The risk assessment is based on non-cancer endpoints assumed to have a threshold for toxicity. This example risk assessment shows that a probabilistic risk assessment in the EU framework covering both the exposure and the effects assessment is feasible with currently available techniques. It shows the possibility of comparing the various uncertainties involved in a typical risk assessment, including the uncertainty in the exposure estimate, the uncertainty in the effect parameter, and the uncertainty in assessment factors used in the extrapolation from experimental animals to sensitive human beings. The analysis done did not confirm the reasonable worst-case character of the deterministic EU-assessment of DBP. Sensitivity analysis revealed the extrapolation procedure in the human effects assessment to be the main source of uncertainty. Since the probabilistic approach allows determination of the range of possible outcomes and their likelihood, it better informs both risk assessors and risk managers.     

Probabilistic Environmental Risk Assessment for Dibutylphthalate (DBP)

In the risk assessment methods for new and existing chemicals in the European Union (EU), environmental “risk” is characterized by the deterministic quotient of exposure and effects (PEC/PNEC). From a scientific viewpoint, the uncertainty in the risk quotient should be accounted for explicitly in the decision making, which can be done in a probabilistic risk framework. To demonstrate the feasibility and benefits of such a framework, a sample risk assessment for an existing chemical (dibutylphthalate, DBP) is presented in this paper. The example shows a probabilistic framework to be feasible with relatively little extra effort; such a framework also provides more relevant information. The deterministic risk quotients turned out to be worst cases at generally higher than the 95th percentile of the probability distributions. Sensitivity analysis proves to be a powerful tool in identifying the main sources of uncertainty and thus will be effective for efficient further testing. The distributions assigned to the assess ment factors (derivation of the PNEC) dominate the total uncertainty in the risk assessment; uncertainties in the release estimates come second. Large uncertainties are an inherent part of risk assessment that we have to deal with quantitatively. However, the most appropriate way to characterise effects and risks requires further attention. Recommendations for further study are identified.     

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.     

A Probabilistic Assessment of Household Exposures to MTBE from Drinking Water

The oxygenate methyl tertiary butyl ether (MTBE) has been added to reformulated gasoline in the U.S. to meet national ambient air quality standards. Although MTBE has provided significant health benefits in terms of reduced criteria and toxic air pollutants, detections of MTBE in some groundwater and drinking water sources have raised concerns about potential environmental contamination and human exposures. In this paper, we examine the frequency and concentration of MTBE detections in drinking water sources in California from 1995 to 1999, and provide a preliminary analysis of the distribution of household exposures to MTBE from water-related activities. Using published data on the toxicity and possible cancer hazard posed by MTBE, we estimate the likely cancer and non-cancer risks for the general population in California from past and potential future MTBE exposures. More highly exposed subgroups were also addressed. Our findings indicate that less than 2% of all sampled drinking water sources in California had detectable levels of MTBE in 1999, with average MTBE drinking water concentrations ranging from 0.09 to 4.9?ppb for this year. Both the detection rate for MTBE and average MTBE concentrations have remained relatively stable since 1995, despite increased sampling of drinking water sources in California. The probabilistic exposure analysis suggests that drinking water exposures to MTBE are unlikely to pose a significant health risk for the general population or more highly exposed individuals in California.     

The Concept of Data Utility in Health Risk Assessment: A Multi-Disciplinary Perspective

Human and ecological health risk assessments and the decisions that stem from them require the acquisition and analysis of data. In agencies that are responsible for health risk decision-making, data (and/or opinions/judgments) are obtained from sources such as scientific literature, analytical and process measurements, expert elicitation, inspection findings, and public and private research institutions. Although the particulars of conducting health risk assessments of given disciplines may be dramatically different, a common concern is the subjective nature of judging data utility. Often risk assessors are limited to available data that may not be completely appropriate to address the question being asked. Data utility refers to the ability of available data to support a risk-based decision for a particular risk assessment. This article familiarizes the audience with the concept of data utility and is intended to raise the awareness of data collectors (e.g., researchers), risk assessors, and risk managers to data utility issues in health risk assessments so data collection and use will be improved. In order to emphasize the cross-cutting nature of data utility, the discussion has not been organized into a classical partitioning of risk assessment concerns as being either human health- or ecological health-oriented, as per the U.S. Environmental Protection Agency's Superfund Program.     

Applying USEPA Risk Assessment Guidance in the 90s

Over the past decade, risk assessment has become increasingly relied upon for helping to make environmental management decisions. This trend has been accompanied by research and refinements in basic risk assessment methodologies to improve our ability to understand and evaluate the human health risks associated with chemical exposures.Despite this progress, significant uncertainties continue to be associated with the risk assessment process. These uncertainties typically derive from gaps in available data regarding chemical toxicity, and from difficulties in reliably estimating the magnitude of chemical exposures. Given these limitations, risk assessment is generally most valuable in evaluating relative risk; for example, when comparing alternatives to achieving a specified goal, setting priorities for protecting human health, or establishing procedures for properly allocating resources. Risk assessment can also be useful for developing regulatory benchmarks such as permit limits for air or water. In many cases, however, the limitations of the risk assessment process make it difficult (if not impossible) to reliably estimate an absolute level of risk, especially for a specific individual in an exposed population. In such cases, risk assessment can be seriously misapplied, and its results misinterpreted.This paper discusses some of the challenges that have been faced by the field of risk assessment during the 1990s. Current trends in risk assessment, and its use by regulatory agencies in making risk management decisions, are also described.     

Risk Assessment and Safety Evaluation Using Probabilistic Fault Tree Analysis

Risk assessment is an essential prelude to the development of accident prevention strategies in any chemical or petrochemical industry. Many techniques and methodologies such as HAZOP, failure mode effect analysis, fault tree analysis, preliminary hazard analysis, quantitative risk assessment and probabilistic safety analysis are available to conduct qualitative, quantitative, and probabilistic risk assessment. However, these methodologies are limited by: extensive data requirements, the length of study, results are not directly interpretable for decision making, simulation is often difficult, and they are applicable only at the operation or late design stage. Khan et al. (2001a) recently proposed a detailed methodology for risk assessment and safety evaluation. This methodology is simple, yet it is effective in safety and design-related decision making, and it has been applied successfully to many case studies. It is named SCAP, where S stands for safety, C and A stand for credible accident respectively, and P stands for probabilistic fault tree analysis. This paper recapitulates the SCAP methodology and demonstrates its application to a petrochemical plant.     

Practical Issues in the Use of Probabilistic Risk Assessment

Probabilistic risk assessment (PRA) represents an important step in the evolution of risk assessment methodology to assist decision-making at hazardous waste sites. Despite considerable progress in the development of PRA techniques, regulatory acceptance of PRA has been limited, in part because a number of practical issues in its use must yet be resolved. A recent workshop on PRA identified several areas to be addressed, including the need for: (1) better demonstration of the value of PRA in risk management; (2) PRA training and education opportunities; (3) the development of technical criteria for acceptability of a PRA; (4) policy decisions on acceptable risk distributions; (5) ways to deal with risk communication issues; and (6) a variety of technical issues, including ways to include estimates of variability and uncertainty associated with toxicity values. Solutions to many of these issues will require better dialog between risk assessors and risk managers than has existed in the past.     

Axes of Extrapolation in Risk Assessment

Extrapolation in risk assessment involves the use of data and information to estimate or predict something that has not been measured or observed. Reasons for extrapolation include that the number of combinations of environmental stressors and possible receptors is too large to characterize risks comprehensively, that direct characterization is sometimes impossible, and that the power to characterize risk in a particular situation can be enhanced by using information obtained in other similar situations. Three types of extrapolation are common in risk assessments: biological (including between taxa and across levels of biological organization), temporal, and spatial. They can be thought of conceptually as the axes of a 3-dimensional graph defining the state space of biological, temporal, and spatial scales within which extrapolations are made. Each of these types of extrapolation can introduce uncertainties into risk assessments. Such uncertainties may be reduced through synergistic research facilitated by the sharing of methods, models, and data used by human health and ecological scientists     

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.     

Using Human Data to Develop Risk Values

One of the criticisms of industry-sponsored human subject testing of toxicants is based on the perception that it is often motivated by an attempt to raise the acceptable exposure limit for the chemical. When Reference Doses (RfDs) or Reference Concentrations (RfCs) are based upon no-effect levels from human rather than animal data, an animal-to-human uncertainty factor (usually 10) is not required, which could conceivably result in a higher safe exposure limit. There has been little in the way of study of the effect of using human vs. animal data on the development of RfDs and RfCs to lend empirical support to this argument. We have recently completed an analysis comparing RfDs and RfCs derived from human data with toxicity values for the same chemicals based on animal data. The results, published in detail elsewhere, are summarized here. We found that the use of human data did not always result in higher RfDs or RfCs. In 36% of the comparisons, human-based RfDs or RfCs were lower than the corresponding animal-based toxicity values, and were more than 3-fold lower in 23% of the comparisons. In 10 out of 43 possible comparisons (23%), insufficient experimental animal data are readily available or data are inappropriate to estimate either RfDs or RfCs. Although there are practical limitations in conducting this type of analysis, it nonetheless suggests that the use of human data does not routinely lead to higher toxicity values. Given the inherent ability of human data to reduce uncertainty regarding risks from human exposures, its use in conjunction with data gathered from experimental animals is a public health protective policy that should be encouraged.     

Probabilistic Risk Assessment and Risk Mapping of Sediment Metals in Sydney Harbour Embayments

Sediment metal concentrations in embayments of Sydney Harbour, acquired from the literature and from samples collected for this study, were used to generate contaminant probability density distributions using AQUARISK. The sediment metal concentrations often exceeded Australia's interim sediment quality guidelines. Similarly, estuarine spiked sediment toxicity test literature provided adverse biotic effects concentration data to generate species sensitivity distributions using AQUARISK. Although the harbor is subject to other inorganic and organic contamination, we have used sediment metals to demonstrate an approach for ecological risk mapping and environmental management prioritization. Sufficient spiked sediment toxicity test data were found for only three metals—Cd, Cu, and Zn—and some tests were likely to overestimate toxicity. The estimates of the hazardous concentration to 5% of species (the 50th percentile of the 95% species protection level) were 5, 12, and 40 mg/kg DW of total sediment metal for Cd, Cu, and Zn, respectively. These values were generally low when compared with the interim sediment quality guidelines due to the overestimation of toxic effects in the literature data. The parameters for the species sensitivity distributions have been combined with the measured sediment metal concentrations in Homebush Bay to generate risk maps of the estimated species impact for each metal as well as for all three metals collectively assuming proportional additivity. This has demonstrated the utility of comparing contaminants on a consistent scale—ecological risk.     

A Probabilistic Analysis of Regional Mercury Impacts on Wildlife

We investigate the uncertainties associated with modeling the potential health effects on piscivorous animals of mercury released to the atmosphere. The multimedia modeling system combines an atmospheric fate and transport model, an aquatic cycling model, and a terrestrial food web model. First, the modeling system is used to calculate point values of the animals' hazard quotients (i.e., measures of toxic dose). Next, we use a simplified version of the modeling system to conduct a probabilistic analysis for the Great Lakes region that takes into account input uncertainty, variability, and uncertainty and variability combined. The use of two different software packages for the combined uncertainty/variability analysis led to similar results except for high values (>90th percentile) where some differences were evident. A sensitivity study was performed on the combined uncertainty and variability analysis. Regional variability caused more than 70% of the variance in the results, with the fish bioaccumulation factor accounting for the majority of the variability. The major sources of uncertainty were the speciation of the mercury emissions, the lake pH, and the sediment burial rate.