Multistage Modeling of Lung Cancer Mortality Among Arsenic-Exposed Copper-Smelter Workers

Multistage modeling incorporating a time-dependent exposure pattern is applied to lung cancer mortality data obtained from a cohort of 2802 arsenic-exposed copper-smelter workers who worked 1 or more years during the period 1940-1964 at a copper smelter at Tacoma, Washington. The workers were followed for death through 1976. There were 100 deaths due to lung cancer during the follow-up period. Exposures to air arsenic levels measured in micrograms/m3 were estimated from departmental air arsenic and workers urinary arsenic measurements. Relationships of different temporal variables with excess death rates are examined to judge qualitatively the implications of the multistage cancer process. Analysis to date indicates a late stage effect of arsenic although an additional early stage effect cannot be ruled out.     

The Risk of MTBE Relative to Other VOCs in Public Drinking Water in California

Ongoing publicity about methyl tertiary butyl ether (MTBE) suggests that this chemical is of greater concern than other contaminants commonly found in drinking water. The purpose of this article is to evaluate the available MTBE data in context with other volatile organic compounds (VOCs) that are detected in public drinking water sources in California. We find that of the 28 VOCs with a primary maximum contaminant level (MCL) in California, 21 were found in 50 or more drinking water sources from 1985 to 2002. Over the last 10 years, the most frequently detected VOCs were chloroform, tetrachloroethylene (PCE), and trichloroethylene (TCE), which were found in about 9-15% of all sampled drinking water sources. These same chemicals were found to have the highest mean detected concentrations over the last 5 years, ranging from 13 to 15 microg/L. Many VOCs were also found to routinely exceed state and federal drinking water standards, including benzene and carbon tetrachloride. By comparison, MTBE was found in approximately 1% of sampled drinking water sources for most years, and of those drinking water sources found to contain MTBE from 1998 to 2002, over 90% had detected concentrations below California's primary MCL of 13 microg/L. Relative to the other VOCs evaluated, MTBE has the lowest estimated California cancer potency value, and was found to pose one of the least cancer risks from household exposures to contaminated drinking water. These findings suggest that MTBE poses an insignificant threat to public drinking water supplies and public health in California, particularly when compared to other common drinking water contaminants.     

Treating and Drinking Well Water in the Presence of Health Risks from Arsenic Contamination: Results from a U.S. Hot Spot

The Safe Drinking Water Act of 1974 regulates water quality in public drinking water supply systems but does not pertain to private domestic wells, often found in rural areas throughout the country. The recent decision to tighten the drinking water standard for arsenic from 50 parts per billion (ppb) to 10 ppb may therefore affect some households in rural communities, but may not directly reduce health risks for those on private wells. The article reports results from a survey conducted in a U.S. arsenic hot spot, the rural area of Churchill County, Nevada. This area has elevated levels of arsenic in groundwater. We find that a significant proportion of households on private wells are consuming drinking water with arsenic levels that pose a health risk. The decision to treat tap water for those on private wells in this area is modeled, and the predicted probability of treatment is used to help explain drinking water consumption. This probability represents behaviors relating to the household's perception of risk.     

A Comparative Cancer Risk Evaluation of MTBE and Other Compounds (Including Naturally Occurring Compounds) in Drinking Water in New Hampshire

Methyl tert-butyl ether (MTBE) was added to gasoline in New Hampshire (NH) between 1995 and 2006 to comply with the oxygenate requirements of the 1990 Amendments to the Clean Air Act. Leaking tanks and spills released MTBE into groundwater, and as a result, MTBE has been detected in drinking water in NH. We conducted a comparative cancer risk assessment and a margin-of-safety (MOS) analysis for several constituents, including MTBE, detected in NH drinking water. Using standard risk assessment methods, we calculated cancer risks from exposure to 12 detected volatile organic compounds (VOCs), including MTBE, and to four naturally occurring compounds (i.e., arsenic, radium-226, radium-228, and radon-222) detected in NH public water supplies. We evaluated exposures to a hypothetical resident ingesting the water, dermally contacting the water while showering, and inhaling compounds volatilizing from water in the home. We then compared risk estimates for MTBE to those of the other 15 compounds. From our analysis, we concluded that the high-end cancer risk from exposure to MTBE in drinking water is lower than the risks from all the other VOCs evaluated and several thousand times lower than the risks from exposure to naturally occurring constituents, including arsenic, radium, and radon. We also conducted an MOS analysis in which we compared toxicological points of departure to the NH maximum contaminant level (MCL) of 13 µg/L. All of the MOSs were greater than or equal to 160,000, indicating a large margin of safety and demonstrating the health-protectiveness of the NH MCL for MTBE.     

A Probabilistic Arsenic Exposure Assessment for Children Who Contact CCA-Treated Playsets and Decks, Part 1: Model Methodology, Variability Results, and Model Evaluation

Concerns have been raised regarding the safety of young children who may contact arsenic residues while playing on and around chromated copper arsenate (CCA)-treated wood playsets and decks. Although CCA registrants voluntarily canceled the production of treated wood for residential use in 2003, the potential for exposure from existing structures and surrounding soil still poses concerns. The EPA's Office of Research and Development developed and applied the probabilistic Stochastic Human Exposure and Dose Simulation model for wood preservatives (SHEDS-Wood) to estimate children's absorbed dose of arsenic from CCA. Skin contact with, and nondietary ingestion of, arsenic in soil and wood residues were considered for the population of children in the United States who frequently contact CCA-treated wood playsets and decks. Model analyses were conducted to assess the range in population estimates and the impact of potential mitigation strategies such as the use of sealants and hand washing after play events. The results show predicted central values for lifetime annual average daily dose values for arsenic ranging from 10(-6) to 10(-5) mg/kg/day, with predicted 95th percentiles on the order of 10(-5) mg/kg/day. There were several orders of magnitude between lower and upper percentiles. Residue ingestion via hand-to-mouth contact was determined to be the most significant exposure route for most scenarios. Results of several alternative scenarios were similar to baseline results, except for the scenario with greatly reduced residue concentrations through hypothetical wood sealant applications; in this scenario, exposures were lower, and the soil ingestion route dominated. SHEDS-Wood estimates are typically consistent with, or within the range of, other CCA exposure models.     

Quantitative Links Between Arsenic Exposure and Influenza A (H1N1) Infection‐Associated Lung Function Exacerbations Risk

The objective of this study was to link arsenic exposure and influenza A (H1N1) infection‐induced respiratory effects to assess the impact of arsenic‐contaminated drinking water on exacerbation risk of A (H1N1)‐associated lung function. The homogeneous Poisson process was used to approximate the related processes between arsenic exposure and influenza‐associated lung function exacerbation risk. We found that (i) estimated arsenic‐induced forced expiratory volume in 1 second (FEV₁) reducing rates ranged from 0.116 to 0.179 mL/μg for age 15–85 years, (ii) estimated arsenic‐induced A (H1N1) viral load increasing rate was 0.5 mL/μg, (iii) estimated A (H1N1) virus‐induced FEV₁ reducing rate was 0.10 mL/logTCID50, and (iv) the relationship between arsenic exposure and A (H1N1)‐associated respiratory symptoms scores (RSS) can be described by a Hill model. Here we showed that maximum RSS at day 2 postinfection for Taiwan, West Bengal (India), and the United States were estimated to be in the severe range of 0.83, 0.89, and 0.81, respectively, indicating that chronic arsenic exposure and A (H1N1) infection together are most likely to pose potential exacerbations risk of lung function, although a 50% probability of lung function exacerbations risk induced by arsenic and influenza infection was within the mild and moderate ranges of RSS at day 1 and 2 postinfection. We concluded that avoidance of drinking arsenic‐containing water could significantly reduce influenza respiratory illness and that need will become increasingly urgent as the novel H1N1 pandemic influenza virus infects people worldwide.     

Assessing Risk‐Based Upper Limits of Melamine Migration from Food Containers

Melamine contamination of food has become a major food safety issue because of incidents of infant disease caused by exposure to this chemical. This study was aimed at establishing a safety limit in Taiwan for the degree of melamine migration from food containers. Health risk assessment was performed for three exposure groups (preschool children, individuals who dine out, and elderly residents of nursing homes). Selected values of tolerable daily intake (TDI) for melamine were used to calculate the reference migration concentration limit (RMCL) or reference specific migration limit (RSML) for melamine food containers. The only existing values of these limits for international standards today are 1.2 mg/L (0.2 mg/dm²) in China and 30 mg/L (5 mg/dm²) in the European Union. The factors used in the calculations included the specific surface area of food containers, daily food consumption rate, body weight, TDI, and the percentile of the population protected at a given migration concentration limit (MCL). The results indicate that children are indeed at higher risk of melamine exposure at toxic levels than are other groups and that the 95th percentile of MCL (specific surface area = 5) for children aged 1–6 years should be the RMCL (0.07 mg/dm²) for protecting the sensitive and general population.     

Evaluating the Risk of Liver Cancer in Humans Exposed to Trichloroethylene Using Physiological Models

Trichloroethylene (TCE) is a widespread environmental pollutant. TCE is classified as a rodent carcinogen by the U.S. Environmental Protection Agency (EPA). Using the rodent cancer bioassay findings and estimates of metabolized dose, the EPA has estimated lifetime exposure cancer risks for humans that ingest TCE in drinking water or inhale TCE. In this study, a physiologically based pharmacokinetic (PB-PK) model for mice was used to simulate selected gavage and inhalation bioassays with TCE. Plausible dose-metrics thought to be linked with the mechanism of action for TCE carcinogenesis were selected. These dose-metrics, adjusted to reflect an average amount per day for a lifetime, were metabolism of TCE (AMET, mg/kg/day) and systemic concentration of TCA (AUCTCA, mg/L/day). These dose-metrics were then used in a linearized multistage model to estimate AMET and AUCTCA values that correspond to liver cancer risks of 1 in 1 million in mice. A human PB-PK model for TCE was then used to predict TCE concentrations in drinking water and air that would provide AMET and AUCTCA values equal to the predicted mice AMET and AUCTCA values that correspond to liver cancer risks of 1 in 1 million. For the dose-metrics, AMET and AUCTCA, the TCE concentrations in air were 10.0 and 0.1 ppb TCE (continuous exposure), respectively, and in water, 7 and 4 μg TCE/L, respectively.     

Assessing human health response in life cycle assessment using ED10s and DALYs: part 1--Cancer effects.

Life cycle assessment (LCA) is a framework for comparing products according to their total estimated environmental impact, summed over all chemical emissions and activities associated with a product at all stages in its life cycle (from raw material acquisition, manufacturing, use, to final disposal). For each chemical involved, the exposure associated with the mass released into the environment, integrated over time and space, is multiplied by a toxicological measure to estimate the likelihood of effects and their potential consequences. In this article, we explore the use of quantitative methods drawn from conventional single-chemical regulatory risk assessments to create a procedure for the estimation of the cancer effect measure in the impact phase of LCA. The approach is based on the maximum likelihood estimate of the effect dose inducing a 10% response over background, ED10, and default linear low-dose extrapolation using the slope betaED10 (0.1/ED10). The calculated effects may correspond to residual risks below current regulatory compliance requirements that occur over multiple generations and at multiple locations; but at the very least they represent a "using up" of some portion of the human population's ability to accommodate emissions. Preliminary comparisons are performed with existing measures, such as the U.S. Environmental Protection Agency's (U.S. EPA's) slope factor measure q1*. By analyzing bioassay data for 44 chemicals drawn from the EPA's Integrated Risk Information System (IRIS) database, we explore estimating ED10 from more readily available information such as the median tumor dose rate TD50 and the median single lethal dose LD50. Based on the TD50, we then estimate the ED10 for more than 600 chemicals. Differences in potential consequences, or severity, are addressed by combining betaED10 with the measure disability adjusted life years per affected person, DALYp. Most of the variation among chemicals for cancer effects is found to be due to differences in the slope factors (betaED10) ranging from 10(-4) up to 10(4) (risk of cancer/mg/kg-day).     

An Analysis of the Uncertainties in Estimates of Radon-Induced Lung Cancer

A recent report by the National Academy of Sciences estimates that the radiation dose to the bronchial epithelium, per working level month (WLM) of radon daughter exposure, is about 30% lower for residential exposures than for exposures received in underground mines. Adjusting the previously published BEIR IV radon risk model accordingly, the unit risk for indoor exposures of the general population is about 2.2 x 10(-4) lung cancer deaths (lcd)/WLM. Using results from EPA's National Residential Radon Survey, the average radon level is estimated to be about 1.25 pCi/L, and the annual average exposure about 0.242 WLM. Based on these estimates, 13,600 radon-induced lcd/yr are projected for the United States. A quantitative uncertainty analysis was performed, which considers: statistical uncertainties in the epidemiological studies of radon-exposed miners; the dependence of risk on age at, and time since, exposure; the extrapolation of risk estimates from mines to homes based on comparative dosimetry; and uncertainties in the radon daughter levels in homes and in the average residential occupancy. Based on this assessment of the uncertainties in the unit risk and exposure estimates, an uncertainty range of 7000-30000 lcd/yr is derived.     

Reproducibility of the Dose-Response Curve of Steroid-Induced Cleft Palate in Mice

Pregnant CD-1 mice were exposed to cortisone acetate at doses ranging from 20 to 100 mg/kg/ day on days 10-13 by oral and intramuscular routes. Multiple replicate assays were conducted under identical conditions to assess the reproducibility of the dose–response curve for cleft palate. The data were fitted to the probit, logistic, multistage or Armitage-Doll, and Weibull dose-response model separately for each route of exposure. The curves were then tested for parallel slopes (probit and logistic models) or coincidence of model parameters (multistage and Weibull models). The 19 replicate experiments had a wide range of slope estimates, wider for the oral than for the intramuscular experiments. For all models and both routes of exposure the null hypothesis of equality of slopes was rejected at a significant level of p < 0.001. For the intramuscular group of replicates, rejection of slope equality could in part be explained by not maintaining a standard dosing regime. The rejection of equivalence of dose-response curves from replicate studies showed that it is difficult to reproduce dose-response data of a single study within the limits defined by the dose-response model. This has important consequences for quantitative risk assessment, public health measures, or development of mechanistic theories which are typically based on a single animal bioassay.     

Evaluating the Potential for a Helicobacter pylori Drinking Water Guideline

Helicobacter pylori is a microaerophilic, gram‐negative bacterium that is linked to adverse health effects including ulcers and gastrointestinal cancers. The goal of this analysis is to develop the necessary inputs for a quantitative microbial risk assessment (QMRA) needed to develop a potential guideline for drinking water at the point of ingestion (e.g., a maximum contaminant level, or MCL) that would be protective of human health to an acceptable level of risk while considering sources of uncertainty. Using infection and gastric cancer as two discrete endpoints, and calculating dose‐response relationships from experimental data on humans and monkeys, we perform both a forward and reverse risk assessment to determine the risk from current reported surface water concentrations of H. pylori and an acceptable concentration of H. pylori at the point of ingestion. This approach represents a synthesis of available information on human exposure to H. pylori via drinking water. A lifetime risk of cancer model suggests that a MCL be set at <1 organism/L given a 5‐log removal treatment because we cannot exclude the possibility that current levels of H. pylori in environmental source waters pose a potential public health risk. Research gaps include pathogen occurrence in source and finished water, treatment removal rates, and determination of H. pylori risks from other water sources such as groundwater and recreational water.     

Premature Deaths,Statistical Lives,and Years of Life Lost: Identification,Quantification, and Valuation of Mortality Risks

Mortality effects of exposure to air pollution and other environmental hazards are often described by the estimated number of “premature” or “attributable” deaths and the economic value of a reduction in exposure as the product of an estimate of “statistical lives saved” and a “value per statistical life.” These terms can be misleading because the number of deaths advanced by exposure cannot be determined from mortality data alone, whether from epidemiology or randomized trials (it is not statistically identified). The fraction of deaths “attributed” to exposure is conventionally derived as the hazard fraction (R – 1)/R, where R is the relative risk of mortality between high and low exposure levels. The fraction of deaths advanced by exposure (the “etiologic” fraction) can be substantially larger or smaller: it can be as large as one and as small as 1/e (≈0.37) times the hazard fraction (if the association is causal and zero otherwise). Recent literature reveals misunderstanding about these concepts. Total life years lost in a population due to exposure can be estimated but cannot be disaggregated by age or cause of death. Economic valuation of a change in exposure-related mortality risk to a population is not affected by inability to know the fraction of deaths that are etiologic. When individuals facing larger or smaller changes in mortality risk cannot be identified, the mean change in population hazard is sufficient for valuation; otherwise, the economic value can depend on the distribution of risk reductions.     

Cancer Fatalities from Waterborne Radon (Rn-222)

A model of the biokinetics of radon in the human body following ingestion is developed from existing data. Calculations of the probability of cancer fatality from use of radon-laden water in the home then are presented. The pathways of emanation and ingestion are examined and shown to lead to roughly equal risks. The probability of fatal cancer resulting from lifetime use of water at a radon concentration of 1 pCi/L is shown to be 1 X 10(-6), with a reasonable range between 2 X 10(-7) and 5 X 10(-6). The allowed concentration consistent with an excess risk of 10(-4) then is approximately 100 pCi/L, which is exceeded in a significant fraction of U.S. water supplies. The lifetime number of premature deaths due to waterborne radon in the U.S. is estimated to lie between 5000 and 125,000, with a best estimate of 25,000.     

Combining Occurrence and Toxicity Information to Identify Priorities for Drinking-Water Mixture Research

Characterizing all possible chemical mixtures in drinking water is a potentially overwhelming project, and the task of assessing each mixture's net toxicity even more daunting. We propose that analyzing occurrence information on mixtures in drinking water may help to narrow the priorities and inform the approaches taken by researchers in mixture toxicology. To illustrate the utility of environmental data for refining the mixtures problem, we use a recent compilation of national ground-water-quality data to examine proposed U.S. Environmental Protection Agency (EPA) and Agency for Toxic Substances and Disease Registry (ATSDR) models of noncancer mixture toxicity. We use data on the occurrence of binary and ternary mixtures of arsenic, cadmium, and manganese to parameterize an additive model and compute hazard index scores for each drinking-water source in the data set. We also use partially parameterized interaction models to perform a bounding analysis estimating the interaction potential of several binary and ternary mixtures for which the toxicological literature is limited. From these results, we estimate a relative value of additional toxicological information for each mixture. For example, we find that according to the U.S. EPA's interaction model, the levels of arsenic and cadmium found in U.S. drinking water are unlikely to have synergistic cardiovascular effects, but the same mixture's potential for synergistic neurological effects merits further study. Similar analysis could in future be used to prioritize toxicological studies based on their potential to reduce scientific and regulatory uncertainty. Environmental data may also provide a means to explore the implications of alternative risk models for the toxicity and interaction of complex mixtures.     

Associations Between Morbidity and Alternative Measures of Particulate Matter

This paper explores the association between acute respiratory morbidity and different measures of exposure to airborne particulate matter, including sulfates, total suspended particulates, and fine and inhalable particulates. Regression analysis was used to test for the impacts of these alternative measures of particulate matter on respiratory morbidity using the 1979-1981 annual Health Interview Surveys and EPA's Inhalable Particle Monitoring Network. The general results indicate that, of the surrogate measures for particulate matter, sulfates appear to have the greatest association with morbidity. To the extent that sulfuric acid aerosols are correlated with airborne sulfates, the results suggest that respiratory impairment sufficient to lead to days of reduced activity may be related to the existence of acidity in the air. These findings are consistent with the results of ecological studies reporting an association between mortality and exposures to fine particles and sulfates.     

Can Long-Term Exposure Distributions Be Predicted from Short-Term Measurements?

A method for estimating long-term distributions of exposure based on repeated short-term measurements within the same population is developed. If the short-term measurements span seasonal variation, and if the distributions are log-normal or nearly so, then long-term distributions can be estimated from as few as two visits to the same population. The method is illustrated using examples drawn from EPA's TEAM Study of exposures to volatile organic compounds.     

The Rise and Fall of a Regulator: Adventure Sports in the United Kingdom

Following a tragic accident in 1993 involving the deaths of teenagers while kayaking a new regulatory regime was imposed upon some adventure sports providers in the United Kingdom. In particular, a new regulatory body, the Adventure Activities Licensing Authority (AALA), was established to oversee the sector. Yet in 2010, a government‐sponsored review recommended that AALA be abolished and this recommendation has been quickly accepted by government. This article explores the background to these developments through documentation, interviews with those affected by the AALA regime, and court cases. Evidence reported here, perhaps surprising, is that AALA itself is seen in a very positive light by many, even those it regulates. What may have happened is that AALA became caught up in a wider debate about the place and management of risk in life beyond the workplace, which has been simmering in the United Kingdom for a decade or more, and of which it fell foul. It may also be that adventure sports, because they entail voluntary engagement with high consequence hazards, starkly expose serious questions about the application of conventional, factory‐originated risk assessment approaches to life in general.     

Application of a QMRA Framework to Inform Selection of Drinking Water Interventions in the Developing Context

The aim of this study was to develop a modified quantitative microbial risk assessment (QMRA) framework that could be applied as a decision support tool to choose between alternative drinking water interventions in the developing context. The impact of different household water treatment (HWT) interventions on the overall incidence of diarrheal disease and disability adjusted life years (DALYs) was estimated, without relying on source water pathogen concentration as the starting point for the analysis. A framework was developed and a software tool constructed and then implemented for an illustrative case study for Nepal based on published scientific data. Coagulation combined with free chlorine disinfection provided the greatest estimated health gains in the short term; however, when long‐term compliance was incorporated into the calculations, the preferred intervention was porous ceramic filtration. The model demonstrates how the QMRA framework can be used to integrate evidence from different studies to inform management decisions, and in particular to prioritize the next best intervention with respect to estimated reduction in diarrheal incidence. This study only considered HWT interventions; it is recognized that a systematic consideration of sanitation, recreation, and drinking water pathways is important for effective management of waterborne transmission of pathogens, and the approach could be expanded to consider the broader water‐related context.