Dermal Versus Total Uptake of Benzene from Mineral Spirits Solvent During Parts Washing

Quantitative approaches to assessing exposure to, and associated risk from, benzene in mineral spirits solvent (MSS), used widely in parts washing and degreasing operations, have focused primarily on the respiratory pathway. The dermal contribution to total benzene uptake from such operations remains uncertain because measuring in vivo experimental dermal uptake of this volatile human carcinogen is difficult. Unprotected dermal uptake involves simultaneous sustained immersion events and transient splash/wipe events, each yielding residues subject to evaporation as well as dermal uptake. A two‐process dermal exposure framework to assess dermal uptake to normal and damaged skin was applied to estimate potential daily dermal benzene dose (D_skin) to workers who used historical or current formulations of recycled MSS in manual parts washers. Measures of evaporation and absorption of MSS dermally applied to human subjects were modeled to estimate in vivo dermal uptake of benzene in MSS. Uncertainty and interindividual variability in D_skin was characterized by Monte Carlo simulation, conditioned on uncertainty and/or variability estimated for each model input. Dermal exposures are estimated to average 33% of total (inhalation + dermal) benzene parts washing dose, with approximately equal predicted portions of dermal dose due to splash/wipe and to continuous contact with MSS. The estimated median (95th percentile) dermal and total daily benzene doses from parts washing are: 0.0069 (0.024) and 0.025 (0.18) mg/day using current, and 0.027 (0.085) and 0.098 (0.69) mg/day using historical, MSS solvents, respectively.     

A Bayesian Model and Stochastic Exposure (Dose) Estimation for Relative Exposure Risk Comparison Involving Asbestos‐Containing Dropped Ceiling Panel Installation and Maintenance Tasks

Assessing exposures to hazards in order to characterize risk is at the core of occupational hygiene. Our study examined dropped ceiling systems commonly used in schools and commercial buildings and lay‐in ceiling panels that may have contained asbestos prior to the mid to late 1970s. However, most ceiling panels and tiles do not contain asbestos. Since asbestos risk relates to dose, we estimated the distribution of eight‐hour TWA concentrations and one‐year exposures (a one‐year dose equivalent) to asbestos fibers (asbestos f/cc‐years) for five groups of workers who may encounter dropped ceilings: specialists, generalists, maintenance workers, nonprofessional do‐it‐yourself (DIY) persons, and other tradespersons who are bystanders to ceiling work. Concentration data (asbestos f/cc) were obtained through two exposure assessment studies in the field and one chamber study. Bayesian and stochastic models were applied to estimate distributions of eight‐hour TWAs and annual exposures (dose). The eight‐hour TWAs for all work categories were below current and historic occupational exposure limits (OELs). Exposures to asbestos fibers from dropped ceiling work would be categorized as “highly controlled” for maintenance workers and “well controlled” for remaining work categories, according to the American Industrial Hygiene Association exposure control rating system. Annual exposures (dose) were found to be greatest for specialists, followed by maintenance workers, generalists, bystanders, and DIY. On a comparative basis, modeled dose and thus risk from dropped ceilings for all work categories were orders of magnitude lower than published exposures for other sources of banned friable asbestos‐containing building material commonly encountered in construction trades.     

Characterizing and Communicating Risk with Exposure Reconstruction and Bayesian Analysis: Historical Locomotive Maintenance/Repair Associated with Asbestos Woven Tape Pipe Lagging

Our reconstructed historical work scenarios incorporating a vintage 1950s locomotive can assist in better understanding the historical asbestos exposures associated with past maintenance and repairs and fill a literature data gap. Air sampling data collected during the exposure scenarios and analyzed by NIOSH 7400 (PCM) and 7402 (PCME) methodologies show personal breathing zone asbestiform fiber exposures were below the current OSHA exposure limits for the eight‐hour TWA permissible exposure limit (PEL) of 0.1 f/cc (range <0.007–0.064 PCME f/cc) and the 30‐minute short‐term excursion limit (EL) of 1.0 f/cc (range <0.045–0.32 PCME f/cc) and orders of magnitude below historic OSHA PEL and ACGIH TLVs. Bayesian decision analysis (BDA) results demonstrate that the 95th percentile point estimate falls into an AIHA exposure category 3 or 4 as compared to the current PEL and category 1 when compared to the historic PEL. BDA results demonstrate that bystander exposures would be classified as category 0. Our findings were also significantly below the published calcium magnesium insulations exposure range of 2.5 to 7.5 f/cc reported for historic work activities of pipefitters, mechanics, and boilermakers. Diesel‐electric locomotive pipe systems were typically insulated with a woven tape lagging that may have been chrysotile asbestos and handled, removed, and reinstalled during repair and maintenance activities. We reconstructed historical work scenarios containing asbestos woven tape pipe lagging that have not been characterized in the published literature. The historical work scenarios were conducted by a retired railroad pipefitter with 37 years of experience working with materials and locomotives.     

Worker Exposure Standard for Phosphine Gas

The 1998 U.S. Environmental Protection Agency Office of Pesticide Programs (OPP) re-registration eligibility decision (RED) for phosphine fumigants has generated much interest in defining safe levels of exposure for workers and worker bystanders. This report summarizes the pertinent literature on phosphine toxicity, including animal inhalation studies and human epidemiology studies, and also describes a margin-of-exposure (MOE) analysis based on available worker exposure data. In addition, a safe occupational exposure limit is estimated using typical OPP assumptions, after determination of appropriate uncertainty factors, based on quality of data in the principal study and pharmacokinetic considerations. While a conservative 8-hour time-weighted average (TWA) of 0.1 ppm was calculated, the overall weight of evidence, from a risk-management perspective, supports a conclusion that an occupational TWA of 0.3 ppm provides adequate health protection. In addition, a 15-minute short-term exposure limit (STEL) of 3 ppm was estimated. Finally, in contrast to the MOE analysis described in the OPP's phosphine RED, the MOE analysis described herein does not indicate that fumigation workers are currently being exposed to unacceptable levels of phosphine. Collectively, these findings support the occupational exposure limits of 0.3 ppm (8-hour TWA) and 1 ppm (STEL) established in the updated applicator's manuals for phosphine-generating products, which recently received approval from OPP.     

Evaluation of Take‐Home Exposure and Risk Associated with the Handling of Clothing Contaminated with Chrysotile Asbestos

The potential for para‐occupational (or take‐home) exposures from contaminated clothing has been recognized for the past 60 years. To better characterize the take‐home asbestos exposure pathway, a study was performed to measure the relationship between airborne chrysotile concentrations in the workplace, the contamination of work clothing, and take‐home exposures and risks. The study included air sampling during two activities: (1) contamination of work clothing by airborne chrysotile (i.e., loading the clothing), and (2) handling and shaking out of the clothes. The clothes were contaminated at three different target airborne chrysotile concentrations (0–0.1 fibers per cubic centimeter [f/cc], 1–2 f/cc, and 2–4 f/cc; two events each for 31–43 minutes; six events total). Arithmetic mean concentrations for the three target loading levels were 0.01 f/cc, 1.65 f/cc, and 2.84 f/cc (National Institute of Occupational Health and Safety [NIOSH] 7402). Following the loading events, six matched 30‐minute clothes‐handling and shake‐out events were conducted, each including 15 minutes of active handling (15‐minute means; 0.014–0.097 f/cc) and 15 additional minutes of no handling (30‐minute means; 0.006–0.063 f/cc). Percentages of personal clothes‐handling TWAs relative to clothes‐loading TWAs were calculated for event pairs to characterize exposure potential during daily versus weekly clothes‐handling activity. Airborne concentrations for the clothes handler were 0.2–1.4% (eight‐hour TWA or daily ratio) and 0.03–0.27% (40‐hour TWA or weekly ratio) of loading TWAs. Cumulative chrysotile doses for clothes handling at airborne concentrations tested were estimated to be consistent with lifetime cumulative chrysotile doses associated with ambient air exposure (range for take‐home or ambient doses: 0.00044–0.105 f/cc year).     

Exposures from Chrysotile‐Containing Joint Compound: Evaluation of New Model Relating Respirable Dust to Fiber Concentrations

The potential for fiber exposure during historical use of chrysotile‐containing joint compounds (JCC) has been documented, but the published data are of limited use for reconstructing exposures and assessing worker risk. Consequently, fiber concentration distributions for workers sanding JCC were independently derived by applying a recently developed model based on published dust measurements from sanding modern‐day (asbestos‐free) joint compound and compared to fiber concentration distributions based on limited historical measurements. This new procedure relies on factors that account for (i) differences in emission rates between modern‐day and JCC and (ii) the number of fibers (quantified by phase contrast microscopy [PCM]) per mass of dust generated by sanding JCC, as determined in a bench‐scale chamber study using a recreated JCC, that convert respirable dust concentrations to fiber concentrations. Airborne respirable PCM‐fiber concentration medians (and 95% confidence intervals) derived for output variables using the new procedure were 0.26 (0.039, 1.7) f/cm³ and 0.078 (0.013, 0.47) f/cm³, and corresponding total fiber concentrations were 1.2 (0.17, 9.2) f/cm³ and 0.37 (0.056, 2.5) f/cm³, in enclosed and nonenclosed environments, respectively. Corresponding estimates of respirable and total PCM fiber concentrations measured historically during sanding of asbestos‐containing joint compound—adjusted for differences between peak and time‐weighted average (TWA) concentrations and documented analytical preparation and sampling artifacts—were 0.15 (0.019, 0.95) f/cm³ and 0.86 (0.11, 5.4) f/cm³, respectively. The PCM‐fiber concentration distributions estimated using the new procedure bound the distribution estimated from adjusted TWA historical fiber measurements, suggesting reasonable consistency of these estimates taking into account uncertainties addressed in this study.     

The Use of Multizone Models to Estimate an Airborne Chemical Contaminant Generation and Decay Profile: Occupational Exposures of Hairdressers to Vinyl Chloride in Hairspray During the 1960s and 1970s

Vinyl chloride (VC) was used as a propellant in a limited percentage of aerosol hairspray products in the United States from approximately 1967 to 1973. The question has arisen whether occupational exposures of hairdressers to VC-containing hairsprays in hair salons were sufficient to increase the risk for developing hepatic angiosarcoma (HAS). Transient two-zone and steady-state three-zone models were used to estimate the historical airborne concentration of VC for individual hairdressers using hairspray as well as estimated contributions from other hairdressers in the same salon. Concentrations of VC were modeled for small, medium, and large salons, as well as a representative home salon. Model inputs were determined using published literature, and variability in these inputs was also considered using Monte Carlo techniques. The 95th percentile for the daily time-weighted average exposure for small, medium, and large salons, assuming a market-share fraction of VC-containing hairspray use from the Monte Carlo analysis, was about 0.3 ppm, and for the home salon scenario was 0.1 ppm. The 95th percentile value for the cumulative lifetime exposure of the hairdressers was 2.8 ppm-years for the home salon scenario and 2.0 ppm-years for the small, medium, and large salon scenarios. If using the assumption that all hairsprays used in a salon contained VC, the 95th percentile of the theoretical lifetime cumulative dose was estimated to be 52–79 ppm-years. Estimated lifetime doses were all below the threshold dose for HAS of about 300 to 500 ppm-years reported in the published epidemiology literature.     

Potential Exposure and Cancer Risk from Formaldehyde Emissions from Installed Chinese Manufactured Laminate Flooring

Lumber Liquidators (LL) Chinese‐manufactured laminate flooring (CLF) has been installed in >400,000 U.S. homes over the last decade. To characterize potential associated formaldehyde exposures and cancer risks, chamber emissions data were collected from 399 new LL CLF, and from LL CLF installed in 899 homes in which measured aggregate indoor formaldehyde concentrations exceeded 100 μg/m³ from a total of 17,867 homes screened. Data from both sources were combined to characterize LL CLF flooring‐associated formaldehyde emissions from new boards and installed boards. New flooring had an average (±SD ) emission rate of 61.3 ± 52.1 μg/m²‐hour; >one‐year installed boards had ∼threefold lower emission rates. Estimated emission rates for the 899 homes and corresponding data from questionnaires were used as inputs to a single‐compartment, steady‐state mass‐balance model to estimate corresponding residence‐specific TWA formaldehyde concentrations and potential resident exposures. Only ∼0.7% of those homes had estimated acute formaldehyde concentrations >100 μg/m³ immediately after LL CLF installation. The TWA daily formaldehyde inhalation exposure within the 899 homes was estimated to be 17 μg/day using California Proposition 65 default methods to extrapolate cancer risk (below the regulation “no significant risk level” of 40 μg/day). Using a U.S. Environmental Protection Agency linear cancer risk model, 50th and 95th percentile values of expected lifetime cancer risk for residents of these homes were estimated to be 0.33 and 1.2 per 100,000 exposed, respectively. Based on more recent data and verified nonlinear cancer risk assessment models, LL CLF formaldehyde emissions pose virtually no cancer risk to affected consumers.     

Combining Food Frequency and Survey Data to Quantify Long-Term Dietary Exposure: A Methyl Mercury Case Study

Twenty-four-hour recall data from the Continuing Survey of Food Intake by Individuals (CSFII) are frequently used to estimate dietary exposure for risk assessment. Food frequency questionnaires are traditional instruments of epidemiological research; however, their application in dietary exposure and risk assessment has been limited. This article presents a probabilistic method of bridging the National Health and Nutrition Examination Survey (NHANES) food frequency and the CSFII data to estimate longitudinal (usual) intake, using a case study of seafood mercury exposures for two population subgroups (females 16 to 49 years and children 1 to 5 years). Two hundred forty-nine CSFII food codes were mapped into 28 NHANES fish/shellfish categories. FDA and state/local seafood mercury data were used. A uniform distribution with minimum and maximum blood-diet ratios of 0.66 to 1.07 was assumed. A probabilistic assessment was conducted to estimate distributions of individual 30-day average daily fish/shellfish intakes, methyl mercury exposure, and blood levels. The upper percentile estimates of fish and shellfish intakes based on the 30-day daily averages were lower than those based on two- and three-day daily averages. These results support previous findings that distributions of "usual" intakes based on a small number of consumption days provide overestimates in the upper percentiles. About 10% of the females (16 to 49 years) and children (1 to 5 years) may be exposed to mercury levels above the EPA's RfD. The predicted 75th and 90th percentile blood mercury levels for the females in the 16-to-49-year group were similar to those reported by NHANES. The predicted 90th percentile blood mercury levels for children in the 1-to-5-year subgroup was similar to NHANES and the 75th percentile estimates were slightly above the NHANES.     

Determination of Leukemogenic Benzene Exposure Concentrations: Refined Analyses of the Pliofilm Cohort

Biologic data on benzene metabolite doses, cytotoxicity, and genotoxicity often show that these effects do not vary directly with cumulative benzene exposure (i.e., concentration times time, or c × t ). To examine the effect of an alternate exposure metric, we analyzed cell-type specific leukemia mortality in Pliofilm workers. The work history of each Pliofilm worker was used to define each worker's maximally exposed job/department combination over time and the associated long-term average concentration associated with the maximally exposed job (LTA-MEJ). Using this measure, in conjunction with four job exposure estimates, we calculated SMRs for groups of workers with increasing LTA-MEJs. The analyses suggest that a critical concentration of benzene exposure must be reached in order for the risk of leukemia or, more specifically, AMML to be expressed. The minimum concentration is between 20 and 60 ppm depending on the exposure estimate and endpoint (all leukemias or AMMLs only). We believe these analyses are a useful adjunct to previous analyses of the Pliofilm data. They suggests that (a) AMML risk is shown only above a critical concentration of benzene exposure, measured as a long-term average and experienced for years, (b) the critical concentration is between 50 and 60 ppm when using a median exposure estimate derived from three previous exposure assessments, and is between 20 and 25 ppm using the lowest exposure estimates, and (c) risks for total leukemia are driven by risks for AMML, suggesting that AMML is the cell type related to benzene exposure.     

Methods for Assessing Uncertainty in Fundamental Assumptions and Associated Models for Cancer Risk Assessment

The distributional approach for uncertainty analysis in cancer risk assessment is reviewed and extended. The method considers a combination of bioassay study results, targeted experiments, and expert judgment regarding biological mechanisms to predict a probability distribution for uncertain cancer risks. Probabilities are assigned to alternative model components, including the determination of human carcinogenicity, mode of action, the dosimetry measure for exposure, the mathematical form of the dose‐response relationship, the experimental data set(s) used to fit the relationship, and the formula used for interspecies extrapolation. Alternative software platforms for implementing the method are considered, including Bayesian belief networks (BBNs) that facilitate assignment of prior probabilities, specification of relationships among model components, and identification of all output nodes on the probability tree. The method is demonstrated using the application of Evans, Sielken, and co‐workers for predicting cancer risk from formaldehyde inhalation exposure. Uncertainty distributions are derived for maximum likelihood estimate (MLE) and 95th percentile upper confidence limit (UCL) unit cancer risk estimates, and the effects of resolving selected model uncertainties on these distributions are demonstrated, considering both perfect and partial information for these model components. A method for synthesizing the results of multiple mechanistic studies is introduced, considering the assessed sensitivities and selectivities of the studies for their targeted effects. A highly simplified example is presented illustrating assessment of genotoxicity based on studies of DNA damage response caused by naphthalene and its metabolites. The approach can provide a formal mechanism for synthesizing multiple sources of information using a transparent and replicable weight‐of‐evidence procedure.     

On the Effect of Probability Distributions of Input Variables in Public Health Risk Assessment

A central part of probabilistic public health risk assessment is the selection of probability distributions for the uncertain input variables. In this paper, we apply the first-order reliability method (FORM)^(1–3) as a probabilistic tool to assess the effect of probability distributions of the input random variables on the probability that risk exceeds a threshold level (termed the probability of failure) and on the relevant probabilistic sensitivities. The analysis was applied to a case study given by Thompson et al. ⁽⁴⁾ on cancer risk caused by the ingestion of benzene contaminated soil. Normal, lognormal, and uniform distributions were used in the analysis. The results show that the selection of a probability distribution function for the uncertain variables in this case study had a moderate impact on the probability that values would fall above a given threshold risk when the threshold risk is at the 50th percentile of the original distribution given by Thompson et al. ⁽⁴⁾ The impact was much greater when the threshold risk level was at the 95th percentile. The impact on uncertainty sensitivity, however, showed a reversed trend, where the impact was more appreciable for the 50th percentile of the original distribution of risk given by Thompson et al. ⁴ than for the 95th percentile. Nevertheless, the choice of distribution shape did not alter the order of probabilistic sensitivity of the basic uncertain variables.     

Modeled Estimates of Soil and Dust Ingestion Rates for Children

Daily soil/dust ingestion rates typically used in exposure and risk assessments are based on tracer element studies, which have a number of limitations and do not separate contributions from soil and dust. This article presents an alternate approach of modeling soil and dust ingestion via hand and object mouthing of children, using EPA's SHEDS model. Results for children 3 to <6 years old show that mean and 95th percentile total ingestion of soil and dust values are 68 and 224 mg/day, respectively; mean from soil ingestion, hand‐to‐mouth dust ingestion, and object‐to‐mouth dust ingestion are 41 mg/day, 20 mg/day, and 7 mg/day, respectively. In general, hand‐to‐mouth soil ingestion was the most important pathway, followed by hand‐to‐mouth dust ingestion, then object‐to‐mouth dust ingestion. The variability results are most sensitive to inputs on surface loadings, soil‐skin adherence, hand mouthing frequency, and hand washing frequency. The predicted total soil and dust ingestion fits a lognormal distribution with geometric mean = 35.7 and geometric standard deviation = 3.3. There are two uncertainty distributions, one below the 20th percentile and the other above. Modeled uncertainties ranged within a factor of 3–30. Mean modeled estimates for soil and dust ingestion are consistent with past information but lower than the central values recommended in the 2008 EPA Child‐Specific Exposure Factors Handbook. This new modeling approach, which predicts soil and dust ingestion by pathway, source type, population group, geographic location, and other factors, offers a better characterization of exposures relevant to health risk assessments as compared to using a single value.     

Distribution of Exposure Concentrations and Doses for Constituents of Environmental Tobacco Smoke

The ultimate goal of the research reported in this series of three articles is to derive distributions of doses of selected environmental tobacco smoke (ETS)-related chemicals for nonsmoking workers. This analysis uses data from the 16-City Study collected with personal monitors over the course of one workday in workplaces where smoking occurred. In this article, we describe distributions of ETS chemical concentrations and the characteristics of those distributions (e.g., whether the distribution was log normal for a given constituent) for the workplace exposure. Next, we present population parameters relevant for estimating dose distributions and the methods used for estimating those dose distributions. Finally, we derive distributions of doses of selected ETS-related constituents obtained in the workplace for people in smoking work environments. Estimating dose distributions provided information beyond the usual point estimate of dose and showed that the preponderance of individuals exposed to ETS in the workplace were exposed at the low end of the dose distribution curve. The results of this analysis include estimations of hourly maxima and time-weighted average (TWA) doses of nicotine from workplace exposures to ETS (extrapolated from 1 day to 1 week) and doses derived from modeled lung burdens of ultraviolet-absorbing particulate matter (UVPM) and solanesol resulting from workplace exposures to ETS (extrapolated from 1 day to 1 year).     

Influenza Infection Risk and Predominate Exposure Route: Uncertainty Analysis

An effective nonpharmaceutical intervention for influenza interrupts an exposure route that contributes significantly to infection risk. Herein, we use uncertainty analysis (point‐interval method) and Monte Carlo simulation to explore the magnitude of infection risk and predominant route of exposure. We utilized a previously published mathematical model of a susceptible person attending a bed‐ridden infectious person. Infection risk is sensitive to the magnitude of virus emission and contact rates. The contribution of droplet spray exposure to infection risk increases with cough frequency, and decreases with virus concentration in cough particles. We consider two infectivity scenarios: greater infectivity of virus deposited in the upper respiratory tract than virus inhaled in respirable aerosols, based on human studies; and equal infectivity in the two locations, based on studies in guinea pigs. Given that virus have equal probability of infection throughout the respiratory tract, the mean overall infection risk is 9.8 × 10^?2 (95th percentile 0.78). However, when virus in the upper respiratory tract is less infectious than inhaled virus, the overall infection risk is several orders of magnitude lower. In this event, inhalation is a significant exposure route. Contact transmission is important in both infectivity scenarios. The presence of virus in only respirable particles increases the mean overall infection risk by 1–3 orders of magnitude, with inhalation contributing ≥ 99% of the infection risk. The analysis indicates that reduction of uncertainties in the concentration of virus in expiratory particles of different sizes, expiratory event frequency, and infectivity at different sites in the respiratory tract will clarify the predominate exposure routes for influenza.     

A Health Risk Benchmark for the Neurologic Effects of Styrene: Comparison with NOAEL/LOAEL Approach

Benchmark dose (BMD) analysis was used to estimate an inhalation benchmark concentration for styrene neurotoxicity. Quantal data on neuropsychologic test results from styrene-exposed workers [Mutti et al. (1984). American Journal of Industrial Medicine, 5, 275-286] were used to quantify neurotoxicity, defined as the percent of tested workers who responded abnormally to > or = 1, > or = 2, or > or = 3 out of a battery of eight tests. Exposure was based on previously published results on mean urinary mandelic- and phenylglyoxylic acid levels in the workers, converted to air styrene levels (15, 44, 74, or 115 ppm). Nonstyrene-exposed workers from the same region served as a control group. Maximum-likelihood estimates (MLEs) and BMDs at 5 and 10% response levels of the exposed population were obtained from log-normal analysis of the quantal data. The highest MLE was 9 ppm (BMD = 4 ppm) styrene and represents abnormal responses to > or = 3 tests by 10% of the exposed population. The most health-protective MLE was 2 ppm styrene (BMD = 0.3 ppm) and represents abnormal responses to > or = 1 test by 5% of the exposed population. A no observed adverse effect level/lowest observed adverse effect level (NOAEL/LOAEL) analysis of the same quantal data showed workers in all styrene exposure groups responded abnormally to > or = 1, > or = 2, or > or = 3 tests, compared to controls, and the LOAEL was 15 ppm. A comparison of the BMD and NOAEL/LOAEL analyses suggests that at air styrene levels below the LOAEL, a segment of the worker population may be adversely affected. The benchmark approach will be useful for styrene noncancer risk assessment purposes by providing a more accurate estimate of potential risk that should, in turn, help to reduce the uncertainty that is a common problem in setting exposure levels.     

Threshold Evaluation of Emergency Risk Communication for Health Risks Related to Hazardous Ambient Temperature

Emergency risk communication (ERC) programs that activate when the ambient temperature is expected to cross certain extreme thresholds are widely used to manage relevant public health risks. In practice, however, the effectiveness of these thresholds has rarely been examined. The goal of this study is to test if the activation criteria based on extreme temperature thresholds, both cold and heat, capture elevated health risks for all‐cause and cause‐specific mortality and morbidity in the Minneapolis‐St. Paul Metropolitan Area. A distributed lag nonlinear model (DLNM) combined with a quasi‐Poisson generalized linear model is used to derive the exposure–response functions between daily maximum heat index and mortality (1998–2014) and morbidity (emergency department visits; 2007–2014). Specific causes considered include cardiovascular, respiratory, renal diseases, and diabetes. Six extreme temperature thresholds, corresponding to 1st–3rd and 97th–99th percentiles of local exposure history, are examined. All six extreme temperature thresholds capture significantly increased relative risks for all‐cause mortality and morbidity. However, the cause‐specific analyses reveal heterogeneity. Extreme cold thresholds capture increased mortality and morbidity risks for cardiovascular and respiratory diseases and extreme heat thresholds for renal disease. Percentile‐based extreme temperature thresholds are appropriate for initiating ERC targeting the general population. Tailoring ERC by specific causes may protect some but not all individuals with health conditions exacerbated by hazardous ambient temperature exposure.     

Physiologically-Based Pharmacokinetic Modeling of Benzene in Humans: A Bayesian Approach

Benzene is myelotoxic and leukemogenic in humans exposed at high doses (>1 ppm, more definitely above 10 ppm) for extended periods. However, leukemia risks at lower exposures are uncertain. Benzene occurs widely in the work environment and also indoor air, but mostly below 1 ppm, so assessing the leukemia risks at these low concentrations is important. Here, we describe a human physiologically-based pharmacokinetic (PBPK) model that quantifies tissue doses of benzene and its key metabolites, benzene oxide, phenol, and hydroquinone after inhalation and oral exposures. The model was integrated into a statistical framework that acknowledges sources of variation due to inherent intra- and interindividual variation, measurement error, and other data collection issues. A primary contribution of this work is the estimation of population distributions of key PBPK model parameters. We hypothesized that observed interindividual variability in the dosimetry of benzene and its metabolites resulted primarily from known or estimated variability in key metabolic parameters and that a statistical PBPK model that explicitly included variability in only those metabolic parameters would sufficiently describe the observed variability. We then identified parameter distributions for the PBPK model to characterize observed variability through the use of Markov chain Monte Carlo analysis applied to two data sets. The identified parameter distributions described most of the observed variability, but variability in physiological parameters such as organ weights may also be helpful to faithfully predict the observed human-population variability in benzene dosimetry.     

A Probabilistic Arsenic Exposure Assessment for Children Who Contact Chromated Copper Arsenate (CCA)-Treated Playsets and Decks, Part 2: Sensitivity and Uncertainty Analyses

A probabilistic model (SHEDS-Wood) was developed to examine children's exposure and dose to chromated copper arsenate (CCA)-treated wood, as described in Part 1 of this two-part article. This Part 2 article discusses sensitivity and uncertainty analyses conducted to assess the key model inputs and areas of needed research for children's exposure to CCA-treated playsets and decks. The following types of analyses were conducted: (1) sensitivity analyses using a percentile scaling approach and multiple stepwise regression; and (2) uncertainty analyses using the bootstrap and two-stage Monte Carlo techniques. The five most important variables, based on both sensitivity and uncertainty analyses, were: wood surface residue-to-skin transfer efficiency; wood surface residue levels; fraction of hand surface area mouthed per mouthing event; average fraction of nonresidential outdoor time a child plays on/around CCA-treated public playsets; and frequency of hand washing. In general, there was a factor of 8 for the 5th and 95th percentiles and a factor of 4 for the 50th percentile in the uncertainty of predicted population dose estimates due to parameter uncertainty. Data were available for most of the key model inputs identified with sensitivity and uncertainty analyses; however, there were few or no data for some key inputs. To evaluate and improve the accuracy of model results, future measurement studies should obtain longitudinal time-activity diary information on children, spatial and temporal measurements of residue and soil concentrations on or near CCA-treated playsets and decks, and key exposure factors. Future studies should also address other sources of uncertainty in addition to parameter uncertainty, such as scenario and model uncertainty.     

TCDD Exposure-Response Analysis and Risk Assessment

We examined the relation between cancer mortality and time-dependent cumulative exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) estimated from a concentration- and age-dependent kinetic model of elimination, and we estimated incremental cancer risks at age 75. Data from the National Institute for Occupational Safety and Health study of 3,538 workers with occupational exposure to TCDD were analyzed using standardized mortality ratios and Cox regression procedures. Analyses adjusted for potential confounding by age, year of birth, and race and considered exposure lag periods of 0, 10, or 15 years. Other potential confounders including smoking and other occupational exposures were evaluated indirectly. To explore the influence of extreme values of cumulative TCDD ppt-years, we restricted the analysis to observations with exposure below the 95th percentile or used logarithmic (ln) transformed exposure values. We applied penalized smoothing splines to examine variation in the exposure-response relation across the exposure range. TCDD was not statistically significantly associated with cancer mortality using the full data set, regardless of the lag period. When we restricted the analysis to observations with exposure below the 95th percentile, TCDD was associated positively with cancer mortality, particularly when a 15-year lag was applied (untransformed exposure data: regression coefficient , standard error (s.e.) = 1.4 x 10(-6), p < 0.05; ln-transformed exposure data: , s.e. = 2.9 x 10(-2), p < 0.05). The estimated incremental lifetime risk of mortality at age 75 from all cancers was about 6 to more than 10 times lower than previous estimates derived from this cohort using exposure models that did not consider the age and concentration dependence of TCDD elimination.