U.S. EPA Reference Dose/Reference Concentration Methodology: Update on a Review of the Process

The U.S. Environmental Protection Agency (USEPA) has been reviewing several approaches to testing and risk assessment related to implementation of the Food Quality Protection Act (FQPA) and the Amendments to the Safe Drinking Water Act (SDWA), both signed into law in 1996. Based on recommendations from a review of issues related to children's health protection under these laws, the USEPA established the RfD Technical Panel to evaluate in depth the current reference dose (RfD) and reference concentration (RfC) process in general, and in particular with respect to how well children and other potentially sensitive subpopulations are protected. The RfD Technical Panel also was asked to consider scientific issues that have become of greater concern in RfD and RfC derivation (e.g., neurotoxicity, immunotoxicity), and to raise issues that should be explored or developed further for application in the RfD/RfC process. This paper provides the current status of the activities of the RfD Technical Panel. The Technical Panel has recommended that acute, short- term, and intermediate reference values should be set for chemicals, where possible, and that these values should be incorporated into the USEPA's Integrated Risk Information System (IRIS) Database. A review of current testing procedures is underway, including the endpoints assessed, life stages covered by exposure and outcome evaluation, and information that can be derived from current protocols on various durations of exposure. Data gaps identified for risk assessment include the types of pharmacokinetic data that should be collected, especially for developmental toxicity studies, the impact of aging on toxic responses occurring after early exposure as well as concomitant with exposure in old age, and information available on latency to response. The implications of the RfD Technical Panel's recommendations for various uncertainty factors are also being explored.     

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.     

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.     

Institutional Diagnostic Reference Levels and Peak Skin Doses in selected diagnostic and therapeutic interventional radiology procedures

PurposeInstitutional (local) Diagnostic Reference Levels for Cerebral Angiography (CA), Percutaneous Transhepatic Cholangiography (PTC), Transarterial Chemoembolization (TACE) and Percutaneous Transhepatic Biliary Drainage (PTBD) are reported in this study.Materials and methodsData for air kerma-area product (P_KA), air kerma at the patient entrance reference point (K_a,r), fluoroscopy time (FT) and number of images (NI) as well as estimates of Peak Skin Dose (PSD) were collected for 142 patients. Therapeutic procedure complexity was also evaluated, in an attempt to incorporate it into the DRL analysis.ResultsLocal P_KA DRL values were 70, 34, 189 and 54 Gy.cm² for CA, PTC, TACE and PTBD respectively. The corresponding DRL values for K_a,r were 494, 194, 1186 and 400 mGy, for FT they were 9.2, 14.2, 27.5 and 22.9 min, for the NI they were 844, 32, 602 and 13 and for PSD they were 254, 256, 1598 and 540 mGy respectively. P_KA for medium complexity PTBD procedures was 2.5 times higher than for simple procedures. For TACE, the corresponding ratio was 1.6. PSD was estimated to be roughly 50% of recorded K_a,r for procedures in the head/neck region and 10% higher than recorded K_a,r for procedures in the body region. In only 5 cases the 2 Gy dose alarm threshold for skin deterministic effects was exceeded.ConclusionProcedure complexity can differentiate DRLs in Interventional Radiology procedures. PSD could be deduced with reasonable accuracy from values of K_a,r that are reported in every angiography system.     

A Preliminary Human Health Risk Assessment of Organochlorine Pesticide Residues Associated with Aquatic Organisms from the Rangsit Agricultural Area,Central Thailand

Food consumption is one of the main routes of human exposure to organochlorine pesticide residues (OCPRs). To assess the potential health risks associated with OCPRs contaminants due to freshwater organism consumption, a number of vegetables, prawn, snail, and fish were collected from Khlong 7 (canal), Rangsit agricultural area, Pathum-Thani Province, Thailand. The samples were extracted using a multiresidue extraction method and then analyzed by gas chromatography with microelectron capture detector (μ -ECD). The results show that low concentrations of OCPRs were detected in parts per billion (ppb) levels. Based on a plausible worst-case scenario, the local population could be at risk for cancer due to consumption of fish contaminated by α -, β -HCH, heptachlor, heptachlor epoxide, aldrin, dieldrin, DDD, DDE, and DDT. Likewise, individuals may be at risk from consumption of Lanchester's freshwater prawn Macrobrachium lanchesteri, freshwater snail Filopaludina mertensi, swamp morning-glory Ipomomea aquatica, neptunia Neptunia oleracea, and water lily Nymphaea lotus because these species all contained elevated concentrations of α -, β -HCH, heptachlor, heptachlor epoxide, aldrin, and dieldrin.     

ENVIRONMENTAL RISK ASSESSMENT: TASKS AND OBLIGATIONS

Synthesizing, characterizing, and communicating the risk science information used in environmental decision-making depends in the first instance on the nature and quality of the technical analysis. At the same time, other important features of the risk analysis, features that require special attention to provide context for the analysis as a whole, are frequently overlooked in practice or in presentation. Now, as the field expands to meet new challenges and to include new participants, all practitioners — government, academics, industry, and interest groups — must give renewed emphasis to certain hall marks of sound risk assessment: identifying incomplete information and its influence on the risk assessment process, articulating alternative assumptions and the scientific or policy reasons for choices made among alternatives, describing process considerations and limitations as well as numerical results, and fully informing decision makers, the press, and the interested public. The resulting greater clarity and transparency in the scientific analyses that under lie environmental decision making can enhance credibility and public confidence in the scientific foundation for those decisions.     

Organophosphate Pesticide Residues in Drinking Water from Artesian Wells and Health Risk Assessment of Agricultural Communities,Thailand

Organophosphate pesticide (OPPs) concentrations in artesian wells located in Thai agricultural and non-agricultural communities were studied during both wet and dry seasons. A total of 100 water samples were collected and subjects were asked to complete a survey. Gas chromatography flame photometric detector was used for OPP analysis. The average OPP concentration in the agricultural communities (0.085 and 0.418 μg/l in dry and wet season) was higher than in the non-agricultural communities (0.004 μg/l in both seasons). Ingestion of OPPs in contaminated water in the agricultural communities were estimated to be 0.187 and 0.919 μg/day during the dry and wet seasons, respectively, and 0.008 μg/day during both seasons in the non-agricultural communities. Agricultural communities were exposed to pesticide residues under the oral chronic reference dose. This study suggests that people in agricultural communities may be exposed to significantly greater levels of pesticides than non-agricultural populations during the dry and wet seasons (p < .001, .001).     

Exposure of aboriginals in British Columbia to methylmercury in freshwater fish: A comparison to reference doses and estimated thresholds

We have analyzed the methylmercury exposures of native women consuming fish from a reservoir and two lakes in British Columbia. Probability density functions representing methylmercury dose were generated using reasonable distributions for exposure parameters. Sensitivity analyses were performed to assess the impact of alternative parameter values on the exposure estimates. The effect of ignoring variability and uncertainty in exposure was also assessed. Calculated mean daily doses of methylmercury for the target populations were compared to the estimated average dose for the general population. We also determined the percentages of the native women populations with exposures exceeding current guidance values as well as published thresholds for neurological effects. The analysis demonstrates the importance of better characterizing the low dose effects of methylmercury, as the predicted doses fall in the range of recommended maximum daily doses but well below the higher estimates of the effect threshold.     

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.     

Immunosensors for Pesticide Analysis: Antibody Production and Sensor Development

ABSTRACT:?

Immunosensors, a type of affinity biosensor, are based on the binding interactions between an immobilized biomolecule (antibody/antigen) on the electronic transducer surface with the analyte of interest (antigen/antibody), resulting in a detectable signal. The sensor system takes advantage of the high selectivity provided by the molecular recognition characteristic of an antibody, which binds reversibly with a specific antigen.

This review article presents the current status of immunosensors, highlighting their potential benefits and limitations for pesticide analysis. The basic criteria for generating specific antibodies against low-molecular-mass pesticides, which are usually nonimmunogenic in nature, are briefly discussed. The article also describes the fundamentals of important transducer technologies and their use in immunosensor development.     

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.     

Pesticide Risk Perceptions,Knowledge, and Attitudes of Operators,Workers, and Residents: A Review of the Literature

The literature on the risk perceptions, knowledge levels, and attitudes of operators, workers, and residents in relation to non-dietary exposure to agricultural pesticides is reviewed. No literature was identified in relation to bystander exposure. Research has primarily been conducted on participants in developing countries and migrant workers in the United States. For operators and workers, illiteracy, poverty, and a perception that exposure to pesticides is an inevitable part of their work results in limited adoption of safety precautions while using and storing pesticides. As a result, risk communication activities aimed at operator and workers need to take account of the wider socioeconomic and cultural conditions in which workers and operators are working and living. There is less research focused on residents’ and bystanders’ perceptions, attitudes, and behaviors. The lack of European data in general, and residents’ and bystanders’ data in particular, represents a knowledge gap that is pertinent to emerging EU legislation requiring residents’ and bystanders’ inclusion in pesticide risk assessment. This review provides a comprehensive overview that can assist policy-makers, and risk communicators in the development of targeted training and awareness-raising material for operators, workers, bystanders, and residents. Areas for future research are suggested.     

Considerations Regarding the Use of Reference Area and Baseline Information in Ecological Risk Assessments

There has been debate in the recent literature as to whether a reference assessment should be included in ecological risk assessments (ERAs) of contaminated sites, and if so, how such an evaluation can be incorporated in a way that aids in decision making. It is our view that an assessment of reference conditions can be useful in the ERA process, for both prospective and retrospective ERAs, given adequate resources and acknowledgement and understanding of the limitations and uncertainties associated with this information. Suggestions and considerations for incorporating reference area information into an ecological risk assessment are discussed.     

Extrapolation for Exposure Duration in Oral Toxicity: A Quantitative Analysis of Historical Toxicity Data

For human risk assessment, experimental data often have to be extrapolated for exposure duration, which is generally done by means of default values. The purpose of the present study was twofold. First, to derive a statistical distribution for differences in exposure duration that can be used in a probabilistic concept for combining assessment factors in risk characterization. Second, to obtain insight in the magnitude of the change in No-Observed-Adverse-Effect-Level (NOAEL) with exposure duration, which will lead to more science-based assessment factors for exposure duration. A large historical database, including 198 substances, was consulted. Ratios were calculated for pairs of NOAELs for systemic toxicity from oral toxicity studies with the same species (rats or mice, various strains) and different exposure duration categories. The Geometric Mean (GM), Geometric Standard Deviation (GSD), and the 90th and 95th percentile values were determined. The traditionally applied default factors for subacute to semichronic (10), for semichronic to chronic (10), and for subacute to chronic exposure (100) corresponded with the 93, 87, and 99-percentiles of the respective distributions. Options are presented for a set of default values and probabilistic distributions for assessment factors for exposure duration based on data from the consulted historical database.     

Improving the Use of Toxicity Reference Values in Wildlife Food Chain Modeling and Ecological Risk Assessment

Ecological risk assessments often include mechanistic food chain models based on toxicity reference values (TRVs) and a hazard quotient approach. TRVs intended for screening purposes or as part of a larger weight-of-evidence (WOE) assessment are readily available. However, our experience suggests that food chain models using screening-level TRVs often form the primary basis for risk management at smaller industrial sites being redeveloped for residential or urban parkland uses. Iterative improvement of a food chain model or the incorporation of multiple lines of evidence for these sites are often impractical from a cost-benefit perspective when compared to remedial alternatives. We recommend risk assessors examine the assumptions and factors in the TRV derivation process, and where appropriate, modify the TRVs to improve their ecological relevance. Five areas where uncertainty likely contributes to excessively conservative hazard quotients are identified for consideration.     

Comparison Between Radiological and Chemical Health Risks Assessments: The Nord-Cotentin Study

In 1997, the French Ministries of the Environment and Health commissioned a detailed radioecological analysis of the Nord-Cotentin region in response to public concern about radiological risks associated with local nuclear facilities. This work was entrusted to the Groupe Radioécologie Nord-Cotentin (GRNC), a working group of experts from various origins (industrial facilities operators, public institutions, monitoring agencies, public interest and citizens groups, foreign experts). An epidemiology investigation in 1995 had reported an excess of two radiation-induced leukemia cases in an area near a nuclear reprocessing plant, a finding that attracted great interest in France, and which stimulated the need for further investigation. After the publication of its report in 1999, the GRNC was again commissioned to perform, inter alia, a corresponding assessment on the chemical releases of the local nuclear facilities. This second stage is now achieved and has revealed important similarities as well as some important differences between radiological and chemical risk assessments when applied to the specific case of the Nord-Cotentin nuclear facilities. Due to the considerable amount of work and results of the GRNC, the purpose for this article is to briefly describe the main developments of the risk assessment methodology followed by the GRNC in both cases, to detail some of the main results and to identify and explain, at each step, the similarities and the differences. The whole technical documents that support these works are available on the Internet at ?http://www.irsn.fr/nord-cotentin/?.