Reproductive and Developmental Risks from Ethylene Oxide: A Probabilistic Characterization of Possible Regulatory Thresholds

Ethylene oxide is a gas produced in large quantities in the United States that is used primarily as a chemical intermediate in the production of ethylene glycol, propylene glycol, non-ionic surfactants, ethanolamines, glycol ethers, and other chemicals. It has been well established that ethylene oxide can induce cancer, genetic, reproductive and developmental, and acute health effects in animals. The U.S. Environmental Protection Agency is currently developing both a cancer potency factor and a reference concentration (RfC) for ethylene oxide. This study used the rich database on the reproductive and developmental effects of ethylene oxide to develop a probabilistic characterization of possible regulatory thresholds for ethylene oxide. This analysis was based on the standard regulatory approach for noncancer risk assessment, but involved several innovative elements, such as: (1) the use of advanced statistical methods to account for correlations in developmental outcomes among littermates and allow for simultaneous control of covariates (such as litter size); (2) the application of a probabilistic approach for characterizing the uncertainty in extrapolating the animal results to humans; and (3) the use of a quantitative approach to account for the variation in heterogeneity among the human population. This article presents several classes of results, including: (1) probabilistic characterizations of ED10s for two quantal reproductive outcomes-resorption and fetal death, (2) probabilistic characterizations of one developmental outcome-the dose expected to yield a 5% reduction in fetal (or pup) weight, (3) estimates of the RfCs that would result from using these values in the standard regulatory approach for noncancer risk assessment, and (4) a probabilistic characterization of the level of ethylene oxide exposure that would be expected to yield a 1/1,000 increase in the risk of reproductive or developmental outcomes in exposed human populations.     

Risk Characterization for Nanotechnology

Nanotechnology is a broad term that encompasses materials, structures, or processes that utilize engineered nanomaterials, which can be defined as materials intentionally designed to have one or more dimensions between 1 and 100 nm. Historically, risk characterization has been viewed as the final phase of a risk assessment process that integrates hazard identification, dose‐response assessment, and exposure assessment. The novelty and diversity of materials, structures, and tools that are covered by above‐defined “nanotechnology” raise substantial methodological issues and pose significant challenges for each of these phases of risk assessment. These issues and challenges culminate in the risk characterization phase of the risk assessment process, and this article discusses several of these key issues and approaches to developing risk characterization results and their implications for risk management decision making that are specific to nanotechnology.     

Distribution and Expected Time of Residence for U.S. Households

For risk assessments, the average current residence time (time since moving into current residence) has often been used as a surrogate for the average total residence time (time between moving into and out of a residence). Since the distributions of the two quantities are not necessarily the same, neither are their averages. Housing surveys provide current residence time data; total residence times must, therefore, be inferred. By modeling the moving process, the total residence time distribution can be estimated from current residence time data. Using 1985 and 1987 U.S. housing survey data, distributions and averages for both current and total residence times were calculated for several housing categories. The average total residence time calculated for all U.S. households, 4.6 ( se = 0.6) years, is less than half the average current residence time, 10.6 ( se = 0.1) years.     

Managing Risk: A Joint U.S.-German Perspective

Ideas from a USA-FRG conference on risk management are presented. In general, the difficulties confronted by risk management authorities in the two countries are similar, from discovering important risks at an early stage to setting acceptable goals. Government regulation is overburdened and somewhat inefficient in both countries, leading to greater search for alternatives. The many differences in approach between the two countries can inform both. German risk management is done largely through negotiations among the affected parties; when this does not resolve a dispute, a specialized administrative court takes charge. In both countries nonregulatory methods of managing risk should be enhanced and given a larger role. A matrix of risk management method versus criteria proved stimulating in comparing and ranking approaches. The conceptual differences between managing discrete events (auto crashes, boiler explosions, etc.) and chronic exposures have not been appreciated. Although uncertainty and probability are involved in both, there are qualitative differences in both analysis and management. Public perceptions of risk and the role these should play have been characterized by "objectivist" and "subjectivist" positions. In the former view, risks are subject to analysis, are calculable, and the public must be educated to accept the conclusions of experts. In the latter view what people perceive is what is most important, both psychologically and politically, and the risk experts must understand public fears and desires. These are important opportunities for cross cultural studies.     

Critical Radionuclide/Critical Pathway Analysis for the U.S. Department of Energy's Savannah River Site

Many different radionuclides have been released to the environment from the Savannah River Site (SRS) during the facility's operational history. However, as shown by this analysis, only a small number of the released radionuclides have been significant contributors to potential doses and risks to off-site people. This article documents the radiological critical contaminant/critical pathway analysis performed for SRS. If site missions and operations remain constant over the next 30 years, only tritium oxide releases are projected to exceed a maximally exposed individual (MEI) risk of 1.0E-06 for either the airborne or liquid pathways. The critical exposure pathways associated with site airborne releases are inhalation and vegetation consumption, whereas the critical exposure pathways associated with liquid releases are drinking water and fish consumption. For the SRS-specific, nontypical exposure pathways (i.e., recreational fishing and deer and hog hunting), cesium-137 is the critical radionuclide.     

Health Risk Characterization of Chlorpyrifos Using Epidemiological Dose‐Response Data and Probabilistic Techniques: A Case Study with Rice Farmers in Vietnam

Various methods for risk characterization have been developed using probabilistic approaches. Data on Vietnamese farmers are available for the comparison of outcomes for risk characterization using different probabilistic methods. This article addresses the health risk characterization of chlorpyrifos using epidemiological dose‐response data and probabilistic techniques obtained from a case study with rice farmers in Vietnam. Urine samples were collected from farmers and analyzed for trichloropyridinol (TCP), which was converted into absorbed daily dose of chlorpyrifos. Adverse health response doses due to chlorpyrifos exposure were collected from epidemiological studies to develop dose‐adverse health response relationships. The health risk of chlorpyrifos was quantified using hazard quotient (HQ), Monte Carlo simulation (MCS), and overall risk probability (ORP) methods. With baseline (prior to pesticide spraying) and lifetime exposure levels (over a lifetime of pesticide spraying events), the HQ ranged from 0.06 to 7.1. The MCS method indicated less than 0.05% of the population would be affected while the ORP method indicated that less than 1.5% of the population would be adversely affected. With postapplication exposure levels, the HQ ranged from 1 to 32.5. The risk calculated by the MCS method was that 29% of the population would be affected, and the risk calculated by ORP method was 33%. The MCS and ORP methods have advantages in risk characterization due to use of the full distribution of data exposure as well as dose response, whereas HQ methods only used the exposure data distribution. These evaluations indicated that single‐event spraying is likely to have adverse effects on Vietnamese rice farmers.     

Managing Safety‐Related Disruptions: Evidence from the U.S. Nuclear Power Industry

Low‐probability, high‐impact events are difficult to manage. Firms may underinvest in risk assessments for low‐probability, high‐impact events because it is not easy to link the direct and indirect benefits of doing so. Scholarly research on the effectiveness of programs aimed at reducing such events faces the same challenge. In this article, we draw on comprehensive industry‐wide data from the U.S. nuclear power industry to explore the impact of conducting probabilistic risk assessment (PRA) on preventing safety‐related disruptions. We examine this using data from over 25,000 monthly event reports across 101 U.S. nuclear reactors from 1985 to 1998. Using Poisson fixed effects models with time trends, we find that the number of safety‐related disruptions reduced between 8% and 27% per month in periods after operators submitted their PRA in response to the Nuclear Regulatory Commission's Generic Letter 88‐20, which required all operators to conduct a PRA. One possible mechanism for this is that the adoption of PRA may have increased learning rates, lowering the rate of recurring events by 42%. We find that operators that completed their PRA before Generic Letter 88‐20 continued to experience safety improvements during 1990–1995. This suggests that revisiting PRA or conducting it again can be beneficial. Our results suggest that even in a highly safety‐conscious industry as nuclear utilities, a more formal approach to quantifying risk has its benefits.     

Methods and Rationale for Derivation of a Reference Dose for Methylmercury by the U.S. EPA

In 2001, the U.S. Environmental Protection Agency derived a reference dose (RfD) for methylmercury, which is a daily intake that is likely to be without appreciable risk of deleterious effects during a lifetime. This derivation used a series of benchmark dose (BMD) analyses provided by a National Research Council (NRC) panel convened to assess the health effects of methylmercury. Analyses were performed for a number of endpoints from three large longitudinal cohort studies of the neuropsychological consequences of in utero exposure to methylmercury: the Faroe Islands, Seychelles Islands, and New Zealand studies. Adverse effects were identified in the Faroe Islands and New Zealand studies, but not in the Seychelles Islands. The NRC also performed an integrative analysis of all three studies. The EPA applied a total uncertainty factor (UF) of 10 for intrahuman toxicokinetic and toxicodynamic variability and uncertainty. Dose conversion from cord blood mercury concentrations to maternal methylmercury intake was performed using a one-compartment model. Derivation of potential RfDs from a number of endpoints from the Faroe Islands study converged on 0.1 microg/kg/day, as did the integrative analysis of all three studies. EPA identified several areas for which further information or analyses is needed. Perhaps the most immediately relevant is the ratio of cord:maternal blood mercury concentration, as well as the variability around this ratio. EPA assumed in its dose conversion that the ratio was 1.0; however, available data suggest it is perhaps 1.5-2.0. Verification of a deviation from unity presumably would be translated directly into comparable reduction in the RfD. Other areas that EPA identified as significant areas requiring further attention are cardiovascular consequences of methylmercury exposure and delayed neurotoxicity during aging as a result of previous developmental or adult exposure.     

Estimates of the Health Risk Reductions Associated with Attainment of Alternative Particulate Matter Standards in Two U.S. Cities

As part of its periodic re-evaluation of particulate matter (PM) standards, the U.S. Environmental Protection Agency estimated the health risk reductions associated with attainment of alternative PM standards in two locations in the United States with relatively complete air quality data: Philadelphia and Los Angeles. PM standards at the time of the analysis were defined for particles of aerodynamic diameter less than or equal to 10 microm, denoted as PM-10. The risk analyses estimated the risk reductions that would be associated with changing from attainment of the PM-10 standards then in place to attainment of alternative standards using an indicator measuring fine particles, defined as those particles of aerodynamic diameter less than or equal to 2.5 microm and denoted as PM-2.5. Annual average PM-2.5 standards of 12.5, 15, and 20 microg/m3 were considered in various combinations with daily PM-2.5 standards of 50 and 65 microg/m3. Attainment of a standard or set of standards was simulated by a proportional rollback of "as is" daily PM concentrations to daily PM concentrations that would just meet the standard(s). The predicted reductions in the incidence of health effects varied from zero, for those alternative standards already being met, to substantial reductions of over 88% of all PM-associated incidence (e.g., in mortality associated with long-term exposures in Los Angeles, under attainment of an annual standard of 12.5 microg/m3). Sensitivity analyses and integrated uncertainty analyses assessed the multiple-source uncertainty surrounding estimates of risk reduction.     

A Delphi Method Expert Survey to Derive Standards for Flood Damage Data Collection

For the purpose of flood damage analyses reliable, comparable, comprehensive, consistent, and up-to-date data are an indispensable need. Like in many other countries a database with this kind of datasets does not exist in Germany. To establish it, standards have to be set for flood damage data collection. We approached this problem by questioning experts about their information needs for flood damage analysis. This survey is done by applying a Delphi survey approach. The aptitude of the Delphi approach to assess, structure, and standardize expert knowledge is evaluated in this article. In the survey a panel of 55 experts working in the field of flood damage analysis for insurances, engineering companies/consultancy, public water management, and universities and other scientific institutions helped to identify common information needs. The multi-step Delphi method proved to reduce the deviation of answers thereby enabling consensual results and also enhanced the quality by modifying group answers in the direction of experience based answers. There was also a high level of congruence in information needs between experts from different fields of employment that allowed the derivation of common standards.     

A Nuclear Utility's Views on the Use of Probabilistic Risk Assessment

Probabilistic risk assessment (PRA) is a relatively new tool in the nuclear industry. The Reactor Safety Study started the present trend of conducting PRAs for nuclear power plants when it was published in 1975. Now, nine years later, those in the industry currently using PRA techniques are frequently asked the same question: Why should the nuclear utility industry, with so many accepted analytical tools already available, invest the time and manpower to develop a new technique with so many uncertainties?     

Expert Scientific Judgment and Cancer Risk Assessment: A Pilot Study of Pharmacokinetic Data

When high-dose tumor data are extrapolated to low doses, it is typically assumed that the dose of a carcinogen delivered to target cells is proportional to the dose administered to test animals, even at exposure levels below the experimental range. Since pharmacokinetic data are becoming available that in some cases question the validity of this assumption, risk assessors must decide whether to maintain the standard assumption. A pilot study of formaldehyde is reported that was undertaken to demonstrate how expert scientific judgment can help guide a controversial risk assessment where pharmacokinetic data are considered inconclusive. Eight experts on pharmacokinetic data were selected by a formal procedure, and each was interviewed personally using a structured interview protocol. The results suggest that expert scientific opinion is polarized in this case, a situation that risk assessors can respond to with a range of risk characterizations considered biologically plausible by the experts. Convergence of expert opinion is likely in this case of several specific research strategies ar executed in a competent fashion. Elicitation of expert scientific judgment is a promising vehicle for evaluating the quality of pharmacokinetic data, expressing uncertainty in risk assessment, and fashioning a research agenda that offers possible forging of scientific consensus.     

A Structured Expert Judgment Study for a Model of Campylobacter Transmission During Broiler-Chicken Processing

A structured expert judgment study was organized to obtain input data for a microbial risk-assessment model describing the transmission of campylobacter during broiler-chicken processing in the Netherlands. More specially, the expert study was aimed at quantifying the uncertainty on input parameters of this model and focused on the contamination of broiler-chicken carcasses with campylobacter during processing. Following the protocol for structured expert judgment studies, expert assessments were elicited individually through subjective probability distribution functions. The classical model was used to aggregate the individual experts' distributions in order to obtain a single combined distribution per variable. Three different weighting schemes were applied, including equal weighting and performance-based weighting with and without optimalization of the combined distributions. The individual experts' weights were based on their performance on the seed variables. Results of the various weighting schemes are presented in terms of performance, robustness, and combined distributions of the seed variables and some of the query variables. All three weighting schemes had adequate performance, with the optimized combined distributions significantly outperforming both the equal weight and the nonoptimized combined distributions. Hence, this weighting scheme, having adequate robustness, was chosen for further processing of the results.     

On the risk of mortality to primates exposed to anthrax spores.

Current events have heightened the importance of understanding the risks from inhalation exposure to small numbers of spores of Bacillus anthracis. Previously reported data sets have not been fully assessed using current understanding of microbial dose response. This article presents an assessment of the reported primate dose-response data. At low doses, the risk to large populations of low doses of inhaled spores (e.g., < 100) is not insignificant.     

Risk Analysis for U.S. Offshore Wind Farms: The Need for an Integrated Approach

Wind power is becoming an increasingly important part of the global energy portfolio, and there is growing interest in developing offshore wind farms in the United States to better utilize this resource. Wind farms have certain environmental benefits, notably near‐zero emissions of greenhouse gases, particulates, and other contaminants of concern. However, there are significant challenges ahead in achieving large‐scale integration of wind power in the United States, particularly offshore wind. Environmental impacts from wind farms are a concern, and these are subject to a number of on‐going studies focused on risks to the environment. However, once a wind farm is built, the farm itself will face a number of risks from a variety of hazards, and managing these risks is critical to the ultimate achievement of long‐term reductions in pollutant emissions from clean energy sources such as wind. No integrated framework currently exists for assessing risks to offshore wind farms in the United States, which poses a challenge for wind farm risk management. In this “Perspective”, we provide an overview of the risks faced by an offshore wind farm, argue that an integrated framework is needed, and give a preliminary starting point for such a framework to illustrate what it might look like. This is not a final framework; substantial work remains. Our intention here is to highlight the research need in this area in the hope of spurring additional research about the risks to wind farms to complement the substantial amount of on‐going research on the risks from wind farms.     

Dose-Response Models for Inhalation of Bacillus anthracis Spores: Interspecies Comparisons

Because experiments with Bacillus anthracis are costly and dangerous, the scientific, public health, and engineering communities are served by thorough collation and analysis of experiments reported in the open literature. This study identifies available dose-response data from the open literature for inhalation exposure to B. anthracis and, via dose-response modeling, characterizes the response of nonhuman animal models to challenges. Two studies involving four data sets amenable to dose-response modeling were found in the literature: two data sets of response of guinea pigs to intranasal dosing with the Vollum and ATCC-6605 strains, one set of responses of rhesus monkeys to aerosol exposure to the Vollum strain, and one data set of guinea pig response to aerosol exposure to the Vollum strain. None of the data sets exhibited overdispersion and all but one were best fit by an exponential dose-response model. The beta-Poisson dose-response model provided the best fit to the remaining data set. As indicated in prior studies, the response to aerosol challenges is a strong function of aerosol diameter. For guinea pigs, the LD₅₀ increases with aerosol size for aerosols at and above 4.5 μm. For both rhesus monkeys and guinea pigs there is about a 15-fold increase in LD₅₀ when aerosol size is increased from 1 μm to 12 μm. Future experimental research and dose-response modeling should be performed to quantify differences in responses of subpopulations to B. anthracis and to generate data allowing development of interspecies correction factors.     

A Discussion of Findings and Their Possible Implications from a Workshop on Bioterrorism Threat Assessment and Risk Management

In November 2001, the Monterey Institute of International Studies convened a workshop on bioterrorism threat assessment and risk management. Risk assessment practitioners from various disciplines, but without specialized knowledge of terrorism, were brought together with security and intelligence threat analysts to stimulate an exchange that could be useful to both communities. This article, prepared by a subset of the participants, comments on the workshop's findings and their implications and makes three recommendations, two short term (use of threat assessment methodologies and vulnerability analysis) and one long term (application of quantitative risk assessment and modeling), regarding the practical application of risk assessment methods to bioterrorism issues.     

The U.S. Nuclear Regulatory Commission Safety Goal Policy: A Critical Review

The most recent U.S. Nuclear Regulatory Commission (NRC) statement of safety goal policy is a significant advance over previous versions. However, some areas of the policy are still in need of refinement, and the resolution of several key questions was deferred pending further review. To clarify some of these issues, this paper presents a critical review of the NRC safety goal policy to date.     

Multi-Stage Model Estimates of Lung Cancer Risk from Exposure to Diesel Exhaust, Based on a U.S. Railroad Worker Cohort

A California Environmental Protection Agency (Cal/EPA) report concluded that a reasonable and likely explanation for the increased lung cancer rates in numerous epidemiological studies is a causal association between diesel exhaust exposure and lung cancer. A version of the present analysis, based on a retrospective study of a U.S. railroad worker cohort, provided the Cal/EPA report with some of its estimates of lung cancer risk associated with diesel exhaust. The individual data for that cohort study furnish information on age, employment, and mortality for 56,000 workers over 22 years. Related studies provide information on exposure concentrations. Other analyses of the original cohort data reported finding no relation between measures of diesel exhaust and lung cancer mortality, while a Health Effects Institute report found the data unsuitable for quantitative risk assessment. None of those three works used multistage models, which this article uses in finding a likely quantitative, positive relations between lung cancer and diesel exhaust. A seven-stage model that has the last or next-to-last stage sensitive to diesel exhaust provides best estimates of increase in annual mortality rate due to each unit of concentration, for bracketing assumptions on exposure. Using relative increases of risk and multiplying by the background lung cancer mortality rates for California, the 95% upper confidence limit of the 70-year unit risks for lung cancer is estimated to be in the range 2.1 x 10(-4) (microg/m3)(-1) to 5.5 x 10(-4) (microg/m3)(-1). These risks constitute the low end of those in the Cal/EPA report and are below those reported by previous investigators whose estimates were positive using human data.     

A Risk Analysis Framework for Cyber Security and Critical Infrastructure Protection of the U.S. Electric Power Grid

The purpose of this article is to introduce a risk analysis framework to enhance the cyber security of and to protect the critical infrastructure of the electric power grid of the United States. Building on the fundamental questions of risk assessment and management, this framework aims to advance the current risk analysis discussions pertaining to the electric power grid. Most of the previous risk-related studies on the electric power grid focus mainly on the recovery of the network from hurricanes and other natural disasters. In contrast, a disproportionately small number of studies explicitly investigate the vulnerability of the electric power grid to cyber-attack scenarios, and how they could be prevented or mitigated. Such a limited approach leaves the United States vulnerable to foreign and domestic threats (both state-sponsored and “lone wolf”) to infiltrate a network that lacks a comprehensive security environment or coordinated government response. By conducting a review of the literature and presenting a risk-based framework, this article underscores the need for a coordinated U.S. cyber security effort toward formulating strategies and responses conducive to protecting the nation against attacks on the electric power grid.