Issues Related to Time Averaging of Exposure in Modeling Risks Associated with Intermittent Exposures to Lead

Typical exposures to lead often involve a mix of long-term exposures to relatively constant exposure levels (e.g., residential yard soil and indoor dust) and highly intermittent exposures at other locations (e.g., seasonal recreational visits to a park). These types of exposures can be expected to result in blood lead concentrations that vary on a temporal scale with the intermittent exposure pattern. Prediction of short-term (or seasonal) blood lead concentrations arising from highly variable intermittent exposures requires a model that can reliably simulate lead exposures and biokinetics on a temporal scale that matches that of the exposure events of interest. If exposure model averaging times (EMATs) of the model exceed the shortest exposure duration that characterizes the intermittent exposure, uncertainties will be introduced into risk estimates because the exposure concentration used as input to the model must be time averaged to account for the intermittent nature of the exposure. We have used simulation as a means of determining the potential magnitude of these uncertainties. Simulations using models having various EMATs have allowed exploration of the strengths and weaknesses of various approaches to time averaging of exposures and impact on risk estimates associated with intermittent exposures to lead in soil. The International Commission of Radiological Protection (ICRP) model of lead pharmacokinetics in humans simulates lead intakes that can vary in intensity over time spans as small as one day, allowing for the simulation of intermittent exposures to lead as a series of discrete daily exposure events. The ICRP model was used to compare the outcomes (blood lead concentration) of various time-averaging adjustments for approximating the time-averaged intake of lead associated with various intermittent exposure patterns. Results of these analyses suggest that standard approaches to time averaging (e.g., U.S. EPA) that estimate the long-term daily exposure concentration can, in some cases, result in substantial underprediction of short-term variations in blood lead concentrations when used in models that operate with EMATs exceeding the shortest exposure duration that characterizes the intermittent exposure. Alternative time-averaging approaches recommended for use in lead risk assessment more reliably predict short-term periodic (e.g., seasonal) elevations in blood lead concentration that might result from intermittent exposures. In general, risk estimates will be improved by simulation on shorter time scales that more closely approximate the actual temporal dynamics of the exposure.     

Health Risks of PCB Spills from Electrical Equipment

The Southern California Edison Company (SCE) has instituted a series of control strategies designed to minimize human exposure to polychlorinated biphenyls (PCBs) in electrical equipment used on its system. This paper describes a method of analyzing PCB risks using conservative estimates of human intake of PCBs originating from accidental spills from electrical equipment. The PCB releases from the Edison system were determined. The fate of these releases in soil, air, and water was analyzed to determine how much material reaches human receptors. The air and water pathways were determined to be the most likely candidates for the exposure and risk considerations. PCB intake via ingestion of soil at the spill site was neglected as an exposure pathway. Equipment spills without controls resulted in at the most 2 ng/day human intake of PCBs via the water exposure pathway. This was determined to be negligible in comparison with intake rates used in conjunction with the setting of food tolerance levels based on fish being the main dietary pathway of human exposure. The inhalation exposure of the hundred or so persons in the immediate vicinity of a spill was determined to equal the PCB intakes of the fish-eating subpopulation analyzed by the Food and Drug Administration for 2 ppm tolerance standard in the case of no controls or cleanup. Current cleanup procedures assure that even the persons in the immediate area are well below the intake of the subjects in the fish contamination analysis. All exposures were well below a "virtual safe dose" level estimated in the fish tolerance study.     

Importance of Uncertainty and Variability to Predicted Risks from Trophic Transfer of PCBs in Dredged Sediments

Biomagnification of organochlorine and other persistent organic contaminants by higher trophic level organisms represents one of the most significant sources of uncertainty and variability in evaluating potential risks associated with disposal of dredged materials. While it is important to distinguish between population variability (e.g., true population heterogeneity in fish weight, and lipid content) and uncertainty (e.g., measurement error), they can be operationally difficult to define separately in probabilistic estimates of human health and ecological risk. We propose a disaggregation of uncertain and variable parameters based on: (1) availability of supporting data; (2) the specific management and regulatory context (in this case, of the U.S. Army Corps of Engineers/U.S. Environmental Protection Agency tiered approach to dredged material management); and (3) professional judgment and experience in conducting probabilistic risk assessments. We describe and quantitatively evaluate several sources of uncertainty and variability in estimating risk to human health from trophic transfer of polychlorinated biphenyls (PCBs) using a case study of sediments obtained from the New York-New Jersey Harbor and being evaluated for disposal at an open water off-shore disposal site within the northeast region. The estimates of PCB concentrations in fish and dietary doses of PCBs to humans ingesting fish are expressed as distributions of values, of which the arithmetic mean or mode represents a particular fractile. The distribution of risk values is obtained using a food chain biomagnification model developed by Gobas by specifying distributions for input parameters disaggregated to represent either uncertainty or variability. Only those sources of uncertainty that could be quantified were included in the analysis. Results for several different two-dimensional Latin Hypercube analyses are provided to evaluate the influence of the uncertain versus variable disaggregation of model parameters. The analysis suggests that variability in human exposure parameters is greater than the uncertainty bounds on any particular fractile, given the described assumptions.     

Policy Incentives for Dangerous (But Necessary) Operations

In industries where firms perform dangerous (but necessary) operations, liability costs—due to potential harm to third parties—can be significant. Firms may therefore find it optimal to exit the market, and this may lead to an inefficiently low number of incumbents. A social planner can discourage exit by offering appropriately designed subsidies. Ex ante subsidies defray the costs associated with making operations safer (e.g., funds to subsidize the purchase of safety equipment). Ex post subsidies mitigate the financial damages caused by an accident (e.g., funds to defray the cost of cleaning up a toxic spill). We consider a model where (i) firms have private information about their ability to improve reliability and (ii) reliability investments are unobservable. We demonstrate that when the social value of reliability outweighs the benefit of increased competition, it is optimal to offer ex ante subsidies alone (i.e., to subsidize the cost of making operations safer). Conversely, when the benefits of competition outweigh the benefits of reliability, a combination of ex ante and ex post subsidies is optimal (i.e., not only to subsidize safer operations, but also to share the costs of a potential accident).     

Predicting the Probability that a Chemical Causes Steatosis Using Adverse Outcome Pathway Bayesian Networks (AOPBNs)

Adverse outcome pathway Bayesian networks (AOPBNs) are a promising avenue for developing predictive toxicology and risk assessment tools based on adverse outcome pathways (AOPs). Here, we describe a process for developing AOPBNs. AOPBNs use causal networks and Bayesian statistics to integrate evidence across key events. In this article, we use our AOPBN to predict the occurrence of steatosis under different chemical exposures. Since it is an expert-driven model, we use external data (i.e., data not used for modeling) from the literature to validate predictions of the AOPBN model. The AOPBN accurately predicts steatosis for the chemicals from our external data. In addition, we demonstrate how end users can utilize the model to simulate the confidence (based on posterior probability) associated with predicting steatosis. We demonstrate how the network topology impacts predictions across the AOPBN, and how the AOPBN helps us identify the most informative key events that should be monitored for predicting steatosis. We close with a discussion of how the model can be used to predict potential effects of mixtures and how to model susceptible populations (e.g., where a mutation or stressor may change the conditional probability tables in the AOPBN). Using this approach for developing expert AOPBNs will facilitate the prediction of chemical toxicity, facilitate the identification of assay batteries, and greatly improve chemical hazard screening strategies.     

Derivation of a Target Level of Lead in Soil at Residential Sites Corresponding to a De Minimis Contribution to Blood Lead Concentration1

Inability to define either a clear toxicologic threshold or a stochastic all-or-nothing (cancer-type) response model for the noncarcinogenic effects of lead (Pb) in young children has posed difficulties for derivation of risk-based target levels of Pb in residential soil. Approaches based on empirical relationships between Pb levels in blood (PbB) and Pb in soil suffer from inability to specify the numerous variables which mediate between these two quantities. Approaches based on achieving a toxicologically de minimis target PbB level (e.g., 10 μg/dl) are subject to large uncertainty in estimating the distribution of existing PbB levels in a specific exposed population and in estimating the relative contribution from nonsoil sources of Pb. The multisource contribution to the distribution of PbB makes this approach unsuited for determination of a target Pb level in a single medium. An alternative approach is presented based on achieving a de minimis contribution to PbB (ΔPbB) from soil. Contributions to Pb exposure from outdoor soil and indoor soil-derived dust (ISDD) are modeled and appropriate values are suggested for input parameters. This analysis predicts that chronic exposure of young children to 200 μg Pb/g (ppm) in residential soil will result in a ΔPbB of 2 μg Pb/dl blood. This concentration of Pb in soil may provide an appropriate target level for residential soil when other significant sources of Pb exposure are present. In other cases, this approach can be used to predict a soil concentration of Pb corresponding to an appropriate non-de minimisΔPbB.     

Improving Risk Assessment Calculations for Traditional Foods Through Collaborative Research with First Nations Communities

As industrial development is increasing near northern Canadian communities, human health risk assessments (HHRA) are conducted to assess the predicted magnitude of impacts of chemical emissions on human health. One exposure pathway assessed for First Nations communities is the consumption of traditional plants, such as muskeg tea (Labrador tea) (Ledum/Rhododendron groenlandicum) and mint (Mentha arvensis). These plants are used to make tea and are not typically consumed in their raw form. Traditional practices were used to harvest muskeg tea leaves and mint leaves by two First Nations communities in northern Alberta, Canada. Under the direction of community elders, community youth collected and dried plants to make tea. Soil, plant, and tea decoction samples were analyzed for inorganic elements using inductively coupled plasma‐mass spectrometry. Concentrations of inorganic elements in the tea decoctions were orders of magnitude lower than in the vegetation (e.g., manganese 0.107 mg/L in tea, 753 mg/kg in leaves). For barium, the practice of assessing ingestion of raw vegetation would have resulted in a hazard quotient (HQ) greater than the benchmark of 0.2. Using measured tea concentrations it was determined that exposure would result in risk estimates orders of magnitude below the HQ benchmark of 0.2 (HQ = 0.0049 and 0.017 for muskeg and mint tea, respectively). An HHRA calculating exposure to tea vegetation through direct ingestion of the leaves may overestimate risk. The results emphasize that food preparation methods must be considered when conducting an HHRA. This study illustrates how collaboration between Western scientists and First Nations communities can add greater clarity to risk assessments.     

The Spread of a PCB Spill on a Soil Surface

Determining the fate of an oil spill on soil is often the first step in analyzing the risks of human exposure to hazardous viscous liquids such as PCBs. The special surface properties of rigidity and porosity are not among the boundary conditions in previous analyses of spills on water. The present work solves the expressions of mass and momentum conservation using a perturbation approach. Using the example of an Aroclor 1254 spill to illustrate the approach, we find that the radius at the halt of spreading is roughly proportional to spill volume for large spills. Spreading halts when the infiltration equals the spill volume. The radial distribution of infiltration decreases gradually from its central maximum, but falls suddenly to zero approaching the outer edge. Sample results are plotted for Aroclor 1254 spills from 4 to 21 liters in volume.     

Dermal Uptake of Organic Chemicals from a Soil Matrix

Uptake of chemicals from soil on human skin is considered. Based on a review of literature on the structure of human skin, the processes by which chemicals pass through this boundary, and experiments that reveal the rate and magnitude of this transport process; a two-layer model is presented for estimating how chemical uptake through the stratum corneum depends on chemical properties, skin properties, soil properties and exposure conditions. The model is applied to two limiting scenarios--(1) continuous deposition and removal of soil on the skin surface and (2) a one-time deposition of soil onto the skin surface. The fraction of soil-bound chemical that passes through the stratum corneum is dependent on the skin-soil layer thickness; the dimensionless Henry's law constant, Kh and the octanol-water partition coefficient, Kow of the soil-bound chemical. The nature of this dependence is discussed.     

A Sales Forecast Model for Short‐Life‐Cycle Products: New Releases at Blockbuster

We develop, in this article, a sales model for movie and game products at Blockbuster. The model assumes that there are three sales components: the first is from consumers who have already committed to purchasing (or renting) a product (e.g., based on promotion of, or exposure to, the product prior to its launch); the second comes from consumers who are potential buyers of the product; and the third comes from either a networking effect on closely tied (as in a social group) potential buyers from previous buyers (in the case of movie rental and all retail products) or re‐rents (in the case of game rental). In addition, we explicitly formulate into our model dynamic interactions between these sales components, both within and across sales periods. This important feature is motivated by realism, and it significantly contributes to the accuracy of our model. The model is thoroughly tested against sales data for rental and retail products from Blockbuster. Our empirical results show that the model offers excellent fit to actual sales activity. We also demonstrate that the model is capable of delivering reasonable sales forecasts based solely on environmental data (e.g., theatrical sales, studio, genre, MPAA ratings, etc.) and actual first‐period sales. Accurate sales forecasts can lead to significant cost savings. In particular, it can improve the retail operations at Blockbuster by determining appropriate order quantities of products, which is critical in effective inventory management (i.e., it can reduce the extent of over‐stocking and under‐stocking). While our model is developed specifically for product sales at Blockbuster, we believe that with context‐dependent modifications, our modeling approach could also provide a reasonable basis for the study of sales for other short‐Life‐Cycle products.     

Dose-Response and Risk Assessment of Airborne Hexavalent Chromium and Lung Cancer Mortality

This study evaluates the dose-response relationship for inhalation exposure to hexavalent chromium [Cr(VI)] and lung cancer mortality for workers of a chromate production facility, and provides estimates of the carcinogenic potency. The data were analyzed using relative risk and additive risk dose-response models implemented with both Poisson and Cox regression. Potential confounding by birth cohort and smoking prevalence were also assessed. Lifetime cumulative exposure and highest monthly exposure were the dose metrics evaluated. The estimated lifetime additional risk of lung cancer mortality associated with 45 years of occupational exposure to 1 microg/m3 Cr(VI) (occupational exposure unit risk) was 0.00205 (90%CI: 0.00134, 0.00291) for the relative risk model and 0.00216 (90%CI: 0.00143, 0.00302) for the additive risk model assuming a linear dose response for cumulative exposure with a five-year lag. Extrapolating these findings to a continuous (e.g., environmental) exposure scenario yielded an environmental unit risk of 0.00978 (90%CI: 0.00640, 0.0138) for the relative risk model [e.g., a cancer slope factor of 34 (mg/kg-day)-1] and 0.0125 (90%CI: 0.00833, 0.0175) for the additive risk model. The relative risk model is preferred because it is more consistent with the expected trend for lung cancer risk with age. Based on statistical tests for exposure-related trend, there was no statistically significant increased lung cancer risk below lifetime cumulative occupational exposures of 1.0 mg-yr/m3, and no excess risk for workers whose highest average monthly exposure did not exceed the current Permissible Exposure Limit (52 microg/m3). It is acknowledged that this study had limited power to detect increases at these low exposure levels. These cancer potency estimates are comparable to those developed by U.S. regulatory agencies and should be useful for assessing the potential cancer hazard associated with inhaled Cr(VI).     

DAMS: A Model to Assess Domino Effects by Using Agent‐Based Modeling and Simulation

Historical data analysis shows that escalation accidents, so‐called domino effects, have an important role in disastrous accidents in the chemical and process industries. In this study, an agent‐based modeling and simulation approach is proposed to study the propagation of domino effects in the chemical and process industries. Different from the analytical or Monte Carlo simulation approaches, which normally study the domino effect at probabilistic network levels, the agent‐based modeling technique explains the domino effects from a bottom‐up perspective. In this approach, the installations involved in a domino effect are modeled as agents whereas the interactions among the installations (e.g., by means of heat radiation) are modeled via the basic rules of the agents. Application of the developed model to several case studies demonstrates the ability of the model not only in modeling higher‐level domino effects and synergistic effects but also in accounting for temporal dependencies. The model can readily be applied to large‐scale complicated cases.     

Steady-State Solutions to PBPK Models and Their Applications to Risk Assessment I: Route-to-Route Extrapolation of Volatile Chemicals

Although analysis of in vivo pharmacokinetic data necessitates use of time-dependent physiologically-based pharmacokinetic (PBPK) models, risk assessment applications are often driven primarily by steady-state and/or integrated (e.g., AUC) dosimetry. To that end, we present an analysis of steady-state solutions to a PBPK model for a generic volatile chemical metabolized in the liver. We derive an equivalent model that is much simpler and contains many fewer parameters than the full PBPK model. The state of the system can be specified by two state variables-the rate of metabolism and the rate of clearance by exhalation. For a given oral dose rate or inhalation exposure concentration, the system state only depends on the blood-air partition coefficient, metabolic constants, and the rates of blood flow to the liver and of alveolar ventilation. At exposures where metabolism is close to linear, only the effective first-order metabolic rate is needed. Furthermore, in this case, the relationship between cumulative exposure and average internal dose (e.g., AUCs) remains the same for time-varying exposures. We apply our analysis to oral-inhalation route extrapolation, showing that for any dose metric, route equivalence only depends on the parameters that determine the system state. Even if the appropriate dose metric is unknown, bounds can be placed on the route-to-route equivalence with very limited data. We illustrate this analysis by showing that it reproduces exactly the PBPK-model-based route-to-route extrapolation in EPA's 2000 risk assessment for vinyl chloride. Overall, we find that in many cases, steady-state solutions exactly reproduce or closely approximate the solutions using the full PBPK model, while being substantially more transparent. Subsequent work will examine the utility of steady-state solutions for analyzing cross-species extrapolation and intraspecies variability.     

Human and Nature‐Caused Hazards: The Affect Heuristic Causes Biased Decisions

People are more concerned about the negative consequences of human hazards compared with natural hazards. Results of four experiments show that the same negative outcome (e.g., number of birds killed by an oil spill) was more negatively evaluated when caused by humans than when caused by nature. Results further show that when identical risk information was provided, participants evaluated nuclear power more negatively compared with solar power. The affect associated with the hazard per se influenced the interpretation of the new information. Furthermore, the affect experienced in the situation fully mediated the evaluation of the negative outcomes of a hazard. People's reliance on the affect heuristic is a challenge for acceptance of cost‐benefit analyses because equally negative outcomes are differently evaluated depending on the cause. Symbolically significant information and the affect evoked by this information may result in biased and riskier decisions.     

Ecological Risk Assessment Case Study: Impacts to Aquatic Receptors at a Former Metals Mining Superfund Site

An ecological risk assessment (ERA) was conducted as part of the Baseline Risk Assessment of the Remedial Investigation (RI) for the Baxter Springs/Treece subsites, Cherokee County, Kansas Superfund site, a former metals mining site. Chemicals of potential concern were heavy metals associated with mine wastes and with base metal ore deposits that were characteristic of this area. An EPA-approved method was used to developed site-specific ambient water quality criteria. Ecological impacts were assessed using three complimentary approaches. First, potential chronic impacts were assessed by applying the toxicity quotient approach (i.e., a comparison of the measured concentration of site-related metals in surface water with calculated site-specific health-based criteria). Secondly, semi-quantitative comparative ecology data were used to provide a direct measure of impacts to key species. Finally, data on other factors (e.g., acclimation and tolerance evolution) that may affect the bioavailability and toxicity of site-related metals were also considered. Information from these three sources were used to obtain a realistic picture of actual and potential population- and community-level effects associated with exposure to mining-related metals.     

Use of Quality-Adjusted Life Year Weights with Dose-Response Models for Public Health Decisions: A Case Study of the Risks and Benefits of Fish Consumption

Risks associated with toxicants in food are often controlled by exposure reduction. When exposure recommendations are developed for foods with both harmful and beneficial qualities, however, they must balance the associated risks and benefits to maximize public health. Although quantitative methods are commonly used to evaluate health risks, such methods have not been generally applied to evaluating the health benefits associated with environmental exposures. A quantitative method for risk-benefit analysis is presented that allows for consideration of diverse health endpoints that differ in their impact (i.e., duration and severity) using dose-response modeling weighted by quality-adjusted life years saved. To demonstrate the usefulness of this method, the risks and benefits of fish consumption are evaluated using a single health risk and health benefit endpoint. Benefits are defined as the decrease in myocardial infarction mortality resulting from fish consumption, and risks are defined as the increase in neurodevelopmental delay (i.e., talking) resulting from prenatal methylmercury exposure. Fish consumption rates are based on information from Washington State. Using the proposed framework, the net health impact of eating fish is estimated in either a whole population or a population consisting of women of childbearing age and their children. It is demonstrated that across a range of fish methylmercury concentrations (0-1 ppm) and intake levels (0-25 g/day), individuals would have to weight the neurodevelopmental effects 6 times more (in the whole population) or 250 times less (among women of child-bearing age and their children) than the myocardial infarction benefits in order to be ambivalent about whether or not to consume fish. These methods can be generalized to evaluate the merits of other public health and risk management programs that involve trade-offs between risks and benefits.     

Setting Risk‐Informed Environmental Standards for Bacillus Anthracis Spores

In many cases, human health risk from biological agents is associated with aerosol exposures. Because air concentrations decline rapidly after a release, it may be necessary to use concentrations found in other environmental media to infer future or past aerosol exposures. This article presents an approach for linking environmental concentrations of Bacillus. anthracis (B. anthracis) spores on walls, floors, ventilation system filters, and in human nasal passages with human health risk from exposure to B. anthracis spores. This approach is then used to calculate example values of risk‐informed concentration standards for both retrospective risk mitigation (e.g., prophylactic antibiotics) and prospective risk mitigation (e.g., environmental clean up and reoccupancy). A large number of assumptions are required to calculate these values, and the resulting values have large uncertainties associated with them. The values calculated here suggest that documenting compliance with risks in the range of 10^?4 to 10^?6 would be challenging for small diameter (respirable) spore particles. For less stringent risk targets and for releases of larger diameter particles (which are less respirable and hence less hazardous), environmental sampling would be more promising.