Environews
FOCUS | Trash or Treasure? Putting Coal Combustion Waste to Work
Each year, more than 131 million tons of coal combustion waste (CCW) is produced as coal is burned for energy in the United States. “Beneficial uses” of CCW as defined by state environmental agencies, which range from incorporation into construction materials such as concrete to use as a fill in abandoned mines, divert about 43% of this waste from landfills. This article (p. A490) describes some of the most common uses of CCW and discusses concerns regarding the potential for toxic leaching from building materials.
SPHERES OF INFLUENCE | Balancing Act: Creating the Right Regulation for
Coal Combustion Waste
Although a significant amount of coal combustion waste (CCW) is recycled, recent reports of CCW storage site breaches has led to a reevaluation of whether this waste poses a health hazard. For the third time the U.S. Environmental Protection Agency is considering classifying and regulating CCW under the Resource Conservation and Recovery Act, and other state- and federal-level regulatory changes also may soon affect the disposal and reuse of this material. This article (p. A498) looks at how tighter regulation could impact the recycling of CCW.
Commentaries
RISK ASSESSMENT | BPA Metabolism and Human Risk Assessment
Human experimental studies of bisphenol A (BPA) metabolism have reported rapid clearance of the hormonally active parent compound via glucuronide conjugation followed by urinary excretion of the inactive conjugated metabolite. BPA also undergoes glucuronide conjugation in rats, but the conjugated metabolite is excreted in bile or feces (vs. urine) and may be converted back to unconjugated BPA by hepatic β-glucuronidase enzymes, thus increasing the duration of internal exposure to hormonally active BPA. According to Ginsberg and Rice (p. 1639), this interspecies difference is used to support arguments against the human health relevance of low-dose BPA effects in rats. The authors dispute this assumption and argue that human risk assessment
models that assume rapid metabolic clearance ignore the potential for increased in utero exposure to active BPA due to metabolic deconjugation in the placenta and other tissues. The authors cite evidence to support this mechanism and conclude that potential risks of low-dose exposures should not be dismissed until effects of local deconjugation reactions are incorporated into risk assessment models.
RISK ASSESSMENT | Basic Research versus Guideline Studies on BPA
Tyl (p. 1644) responds to a previous commentary [Myers et al.; Environ Health Perspect 117:309–315 (2009)] that argued against the exclusive use of guideline-compliant studies performed using Good Laboratory Practices (GLPs) for bisphenol A (BPA) risk assessment. Tyl contrasts guideline-
compliant studies designed to detect reproducible effects of exposures using relevant doses, routes and animal models, with basic/exploratory research studies of unvalidated outcomes that are typically of shorter duration and smaller size. She also discusses how testing guidelines are developed and how new end points may be validated and incorporated; provides an overview of the methods and findings of guideline-compliant and exploratory animal studies of BPA; describes BPA pharmacokinetics in rats and humans and its relevance to study design; and presents responses to specific criticisms by Myers et al. Tyl argues that weight-of-evidence evaluations have consistently concluded that low-level oral BPA exposures do not adversely affect human developmental or reproductive health endpoints, but she also recommends increasing studies to validate “new” end points used in exploratory research.
RISK ASSESSMENT | A Clash of Old and New Concepts in Toxicology
Studies that use high-dose exposures to predict low-dose effects assume predictable monotonic dose–response trends that will produce quantitative, but not qualitative, differences in biological responses with decreasing exposure doses. Myers et al. (p. 1652) question this assumption with regard to endocrine-disrupting compounds (EDCs), citing established examples of nonmonotonic responses to hormonally active drugs and experimental evidence of nonmonotonic responses to EDCs to support their argument. Mechanisms that may explain nonmonotonic effects of EDCs include dose-dependent up- or down-regulation of hormone receptors, receptor saturation at high doses, and non–receptor-
mediated mechanisms of effect. The authors recommend that procedures to establish acceptable exposure levels for EDCs address the potential for nonmonotonic dose responses by testing for effects at prevalent levels of human exposure, and that scientists trained in endocrinology be engaged in setting regulatory standards for EDCs.
Reviews
POPULATION HEALTH | Global Status of DDT
The World Health Organization has recommended dichlorodiphenyltrichloroethane (DDT) for indoor residual spraying to control malaria when suitable alternatives are not available, and DDT is currently used for this purpose in approximately 14 countries. van den Berg (p. 1656) reviews the use of DDT and current evidence concerning its benefits and risks in relation to available alternatives. He argues that a comprehensive cost assessment of DDT versus its alternatives is needed that takes unintended effects on human health, the environment, and international trade into account. He also argues that integrated vector management can provide a viable framework for developing and implementing effective and sustainable alternatives to DDT.
RISK ASSESSMENT | The PPAR-α Activation MOA Hypothesis Revisited
Several environmental contaminants that cause liver tumors in rodents, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are peroxisome proliferator–activated receptor-α (PPAR-α) agonists. Evidence that PPAR-α activation is a necessary and sufficient cause of rodent hepatocarcinogenesis supports PPAR-α activation as the sole mode of action (MOA) for these agents, and evidence that humans are relatively insensitive to this MOA have led some agencies to conclude that PPAR-α agonists do not contribute to human carcinogensis. Guyton et al. (p. 1664) review evidence against the PPAR-α activation MOA hypothesis, including evidence that DEHP is hepatocarcinogenic in PPAR-α–null mice, and suggest that available information is inadequate to characterize human sensitivity to this rodent MOA. They conclude that the hypothesized MOA for PPAR-α activation should not be used as a primary basis for assessing human carcinogenic risk from PPAR-α agonists and discuss broader theoretical implications for the development, testing, and application of MOA hypotheses in human health risk assessment.
POPULATION HEALTH | Environmental Health Indicators of Climate Change
It is generally believed that increases in temperature and other weather changes will occur over time, even under optimistic scenarios for greenhouse gas reduction. English et al. (p. 1673) discuss the need for accurate surveillance data and indicators of vulnerability and preparedness to predict human health impacts and develop successful mitigation and adaptation strategies. The authors identify potential surveillance indicators (e.g., climate-sensitive health outcomes; environmental and vulnerability indicators; and mitigation, adaptation, and policy indicators) and review available data sources. They conclude that data are available for many of the proposed measures but sensitivity and utility need to be evaluated. They also note that additional efforts are needed to increase data quality and availability and to develop new surveillance databases, especially for climate-sensitive morbidity.
Also see Science Selections, p. A504
Research
TOXICOLOGY | Cardiopulmonary Toxicity of Roadside PM
Exposure to traffic-derived particulate matter (PM) has been associated with respiratory and cardiovascular outcomes, but potential health effects may vary for different types of PM. Cho et al. (p. 1682) sampled airborne PM in three size ranges (ultrafine, < 0.1 µm; fine, 0.1–2.5 µm; and coarse, 2.5–10 µm) collected 20 m and 275 m from an interstate highway in North Carolina to characterize chemical composition of PM and evaluate cardiopulmonary effects in mice exposed via pharyngeal aspiration. Size-fractionated samples from the two sampling sites were similar with regard to composition and toxicologic effects, but there were clear differences in composition and outcomes according to PM size: Course PM was associated with pulmonary inflammation, and ultrafine PM was associated with cardiac ischemia–reperfusion injury. The authors recommend additional research to characterize dose effects, real-time exposures, and effects of gas-phase components.
EXPOSURE SCIENCE | Nationwide Spatial Modeling of PM10 and NO2
Exposure assessment for epidemiologic studies of air pollution is often limited to city-specific average measures or modeled estimates for limited geographic areas. Hart et al. (p. 1690) derived nationwide generalized additive models (GAMs) using smooth spatial surfaces of available monitoring data and geographic information system (GIS)-derived covariates to estimate annual residential exposures to nitrogen dioxide (NO2) and particulate matter < 10 µm in diameter (PM10) for 53,822 Trucking Industry Particle Study (TrIPS) participants. Model performance was evaluated by cross-validation and comparisons with simpler inverse distance-weighting models. Final models for both pollutants included distance to road, elevation, and land-use variables; the final NO2 model also included population density and distance to and emissions from the nearest nitrogen oxides–emitting power plant. Overall, GAMs performed better than the inverse-distance models. The authors conclude that the models provide reasonably accurate and unbiased estimates of annual PM10 and NO2 exposures for research on health effects of chronic air pollution.
EPIDEMIOLOGY | PM2.5 and PM10–2.5 Exposures, Mortality, and CHD
There is growing evidence that fine particulate matter air pollution [< 2.5 µm in diameter (PM2.5)] increases mortality and cardiovascular disease, but less is known about coarse PM
[2.5–10 µm (PM10–2.5)]. Puett et al. (p. 1697) evaluated chronic PM2.5 and PM10-2.5 in association with all-cause mortality and fatal and nonfatal incident coronary heart disease (CHD) among 66,250 Nurses’ Health Study participants living in metropolitan areas of the northeastern and midwestern United States. Exposures were estimated according to current residence using geographic information systems–based spatial smoothing models. PM2.5 exposure was positively associated with all-cause mortality and fatal CHD, both before and after adjusting for individual- and community-level confounders, but adjusted estimates did not support associations with PM10–2.5. The authors note that stronger associations with exposures in the prior 12 months than exposures in the more distant past suggest that reducing PM2.5 air pollution could lead to relatively rapid improvements in human health.
TOXICOLOGY | MAA Disrupts Estrogen Receptor-α Signaling
Reproductive effects of ethylene glycol monomethyl ether may be mediated by its primary metabolite, methoxyacetic acid (MAA), a short-chain fatty acid that inhibits histone deacetylase activity and alters gene expression. Henley et al. (p. 1702) investigated effects of MAA on the estrogen-signaling pathway, which they hypothesized would contribute to reproductive effects. MAA potentiated 17β-estradiol (E2) stimulation of an estrogen-responsive reporter plasmid in estrogen receptor (ER)-negative HeLa cells following transfection with human ERα or ERβ expression vectors, but this was an artifact of MAA-mediated activation of the cytomegalovirus (CMV) promoter rather than a direct effect on ER expression. In contrast, MAA exposure decreased endogenous ERα expression and attenuated E2-stimulated endogenous gene expression in ER-positive MCF-7 cells and in vivo in the mouse uterus. The authors conclude that modest effects on ER expression were consistent with MAA-mediated effects on endogenous ER-mediated signaling, but they suggest that other mechanisms probably contribute to MAA-mediated effects on reproduction as well. Spurious effects caused by MAA-mediated CMV promoter activation also highlight the importance of careful experimental design and analysis.
EXPOSURE SCIENCE | Human Exposure to HBCD via Dust and Food
Hexabromocyclododecane (HBCD), a flame retardant used in polystyrene insulation and textiles, can migrate into the environment, contaminating indoor dust and foods. Exposure through diet or ingestion of contaminated dust may lead to adverse health outcomes, but the combined contributions of dust and dietary sources to HBCD exposure have not been investigated. Roosens et al. (p. 1707) estimated dietary exposures to three HBCD isomers (ΣHBCDs) in 16 Belgian university students by measuring levels in duplicate samples of meals eaten during 1 week. In addition, HBCDs were measured in bedroom dust and serum samples from each participant. Serum ΣHBCD levels and estimated intakes via diet and dust were consistent with the low end of ranges reported for other populations, and estimated exposure via dust, but not diet, was significantly correlated with serum levels. Findings reinforce dust ingestion as an important source of exposure, but the authors note that dietary assessments over longer periods may be necessary to accurately estimate intake if consumption of highly contaminated food items is irregular.
EPIDEMIOLOGY | Aircraft Noise Exposure and Saliva Cortisol
Increased stress has been proposed as an underlying cause of associations between exposure to aircraft noise and cardiovascular outcomes. Selander et al. (p. 1713) measured saliva cortisol levels as a biomarker of stress among 439 participants in the HYENA (Hypertension and Exposure to Noise near Airports) study, a cross-sectional study of adults living near one of seven airports in six European countries. Morning cortisol levels were significantly elevated in women with an average 24-hr sound level > 60 dB versus ≤ 50 dB, resulting in an estimated relative increase of 34%. The positive association persisted for women with high noise exposure regardless of their self-reported level of annoyance, but the association appeared to be stronger among employed versus retired women. In contrast, aircraft noise exposure was not associated with cortisol levels in men. The authors conclude that the association between morning saliva cortisol levels and aircraft noise in women may be relevant to cardiovascular effects of noise.
EPIDEMIOLOGY | Arsenic and Lung Cancer in New England
Exposure to high concentrations of arsenic is an established risk factor for skin, bladder, and lung cancers, but associations with low to moderate exposure to As in drinking water (< 100 µg/L) have been inconsistent. Heck et al. (p. 1718) evaluated toenail As concentration (an indication of exposure over the prior year) and lung cancer among 223 cases and 238 control participants in the New England Lung Cancer Study, a population-based study of incident primary lung cancer. The authors report that high (≥ 0.114 µg/g) versus low (< 0.05 µg/g) As exposure was associated with small-cell and squamous-cell lung cancer [adjusted odds ratio (OR) 2.75; 95% CI,
1.00–7.57]. Participants with a history of chronic lung disease and high toenail As were at increased risk (OR 4.78; 95% CI, 1.87–12.2) relative to those with lung disease or high As only (OR 1.31; 95% CI, 0.45–3.84 and OR 1.02; 95% CI, 0.62–1.69, respectively). Results suggest that relatively low levels of As exposure may increase the risk of specific lung cancer subtypes, but findings must be confirmed in larger populations.
EPIDEMIOLOGY | Cobalamin and Arsenic Metabolism
Chronic arsenic exposure through contaminated drinking water is a risk factor for cancers, cardiovascular disease, and neurologic impairment. Metabolic conversion of inorganic As (iAs) to dimethylarsinic acid (DMA) reduces toxicity and facilitates urinary As (uAs) elimination, but the intermediate metabolite monomethylarsonic (MMA) may have increased cytoxic and genotoxic effects. Adequate folate facilitates iAs methylation to DMA and MMA and appears to enhance urinary elimination, but the potential influence of cobalamin, which also facilitates methylation, is unclear. Hall et al. (p. 1724) conducted a cross-sectional study of uAs metabolites (%iAs, %MMA, and %DMA) among 778 Bangladeshi adults, many of whom were exposed to elevated As and were classified as cobalamin deficient. Cobalamin-deficient participants had increased %iAs and %MMA relative to cobalamin-sufficient participants, with stronger associations observed among those with adequate versus deficient folate levels. The authors conclude that cobalamin appeared to facilitate iAs methylation to potentially toxic MMA metabolites in participants with adequate folate.
POPULATION HEALTH | Heat Vulnerability Mapping
Projected increases in the frequency, duration, and intensity of heat waves highlight the need for effective warning systems and intervention plans to reduce morbidity and mortality. Reid et al. (p. 1730) developed a cumulative heat vulnerability index to identify high-risk populations in 39,794 urban census tracts based on characteristics previously shown to predict adverse responses to heat, including demographic characteristics, air conditioning, diabetes prevalence (as a surrogate measure of comorbidity), and vegetation cover (classified using satellite images). The authors report that variability was largely explained by differences in social/environmental vulnerability (education, poverty, race, green space), social isolation, air conditioning prevalence, and the proportion of elderly and diabetic residents. Vulnerability indices were highest for Northeast and Pacific Coast regions and lowest in the Southeastern United States. The authors conclude that the index may be applied to other populations after validation with health outcomes data, but different predictors may be needed to identify vulnerable populations in rural areas.
TOXICOGENOMICS | Screening for Genotoxic Chemicals Using DT40 Cell Lines
Current genotoxicity assays often have limited specificity and sensitivity, and most do not provide information on specific genotoxic effects and mechanisms. Ji et al. (p. 1737) describe a novel bioassay that identifies genotoxic effects by comparing cell proliferation kinetics between wild-type and DNA-repair–deficient mutant clones of the chicken DT40 B-lymphocyte line. The assay takes advantage of the fact that unrepaired DNA damage delays proliferation by interfering with DNA replication. In addition, variation in effects according to clone-specific deficiencies in DNA repair pathways can be used to investigate the specific type(s) of genotoxic damage produced by a given chemical. The authors report that the assay identified genotoxic effects of γ-ray and ultraviolet (UV) light exposures that were consistent with expectations, and that results based on cellular proliferation over 48 hr were comparable with results based on a colony-formation assay that took more than a week to complete. In addition, the assay was used to characterize two types of DNA lesions (chromosomal breaks and UV photoproduct-like damage) caused by exposure to sodium metaarsenite. The authors conclude that the new bioassay is a reliable and sensitive screening tool for identifying and characterizing genotoxic effects of environmental mutagens.
TOXICOGENOMICS | Diesel Exhaust Particles and Airway MicroRNA Expression
MicroRNAs (miRNAs) are small, evolutionarily conserved noncoding RNAs that regulate gene expression and have been implicated in disease pathogenesis. More than 500 miRNAs have been identified, but little is known about mechanisms that control their expression. Jardim et al. (p. 1745) hypothesized that respiratory effects of particulate matter (PM) air pollution may be mediated by altered miRNA expression in airway epithelial cells and used microarray profile analysis and quantitative real-time polymerase chain reaction assays to evaluate miRNA expression in differentiated human bronchial epithelial cells exposed to diesel exhaust particles (DEP). The authors report that 197 of 313 detectable
miRNAs (62.9%) were up- or down-regulated after DEP exposure, and a molecular network analysis indicated that exposure was associated with inflammatory response pathways and a strong tumorigenic disease signature. The authors conclude that effects of DEP and other environmental pollutants on miRNA expression may contribute to adverse health effects.
Also see Science Selections, p. A504
EXPOSURE SCIENCE | Neighborhood Walkability and Air Pollution
Ambient air pollution and physical inactivity are risk factors for adverse health outcomes. Marshall et al. (p. 1752) evaluated joint geographic distributions of nitric oxide (NO) concentrations (a marker for vehicle emissions estimated using a land-use regression model), ozone (O3) concentrations (based on ambient monitoring data), and a neighborhood walkability score (based on land-use mix, street connectivity, and residential density) for 49,702 postal codes in Vancouver (British Columbia, Canada). Areas near the city center and lower income neighborhoods tended to have higher walkability scores, higher NO, and lower O3 concentrations than other areas. Neighborhoods characterized by low pollution and high walkability were generally higher income areas located near the city center, whereas neighborhoods with high pollution and low walkability were typically middle income communities located far from the city center. The authors suggest that these methods can be extended and used to facilitate efforts to optimize the built environment to improve health.
Also see Science Selections, p. A505
EXPOSURE SCIENCE | Longitudinal Mercury Monitoring in Japanese and Korean Women (United States)
Fish consumption guidelines to limit mercury exposure have not accounted for the potential influence of intraindividual variability and seasonal or temporal changes in the amounts and types of fish consumed. Tsuchiya et al. (p. 1760) examined changes in Hg exposure over time according to self-reported fish intake and hair Hg levels measured in Korean (n = 108) and Japanese (n = 106) women participating in the Arsenic Mercury Intake Biometric Study (AMIBS). There was little change in the fish species most responsible for Hg intakes and little variability in hair Hg levels over the 14-month study. In addition, fish consumption estimates based on an open-ended survey of diet over the previous year were more consistent with hair Hg levels than estimates based on 2-week recall surveys. The authors conclude that information on fish consumption obtained at a single point in time may provide an adequate basis for fish consumption guidelines, but caution that longer follow-up may be needed to capture variability over time.
EPIDEMIOLOGY | Black Carbon, Oxidative Stress, and Blood Pressure
Inconsistent associations between air pollution and blood pressure (BP) may reflect variation in particulate matter (PM) components, as well as variation in study designs and populations. Mordukhovich et al. (p. 1767) analyzed data from the Veterans Administration Normative Aging Study cohort to estimate associations between BP and exposure to black carbon (BC, a traffic-related combustion by-product; n = 461, 1,067 observations) or fine PM [aerodynamic diameter ≤ 2.5 µm (PM2.5); n = 457, 949 observations] measured at a monitoring station near the study center. A 1‑SD increase in BC concentration (0.43 µg/m3, 7-day moving average) was associated with a 1.5‑mmHg increase in systolic BP [95% CI, 0.1–2.8]
and a 0.9-mmHg increase in diastolic BP (95% CI, 0.2–1.6). Associations were not observed with a 1‑SD increase in PM2.5 (4.98 µg/m3), and the authors did not detect statistical interactions between BC and common polymorphisms in genes related to antioxidative defense (GSTM1, GSTP1, GSTT1, NQO1, catalase, and HMOX‑1). The authors conclude that BC may be primarily responsible for associations observed between PM and blood pressure.
Children's Health
EPIDEMIOLOGY | Traffic Pollution: Preeclampsia and Preterm Birth
Preeclampsia, a major cause of maternal and perinatal morbidity and mortality, complicates 2–8% of pregnancies. Evidence of adverse effects of air pollution on pregnancy outcomes has been reported, but effects of traffic-related pollutants have not been studied extensively, despite the potential for greater toxicity and spatial variation in exposure. Wu et al. (p. 1773) examined preeclampsia and preterm delivery (< 37 weeks gestation) in association with residential exposure to traffic-generated nitrogen oxides (NOx) and particulate matter ≤ 2.5 µm in aerodynamic diameter (PM2.5) among 81,186 singleton births in California, with exposures over the entire pregnancy estimated using a line-source dispersion model (CALINE4). Preeclampsia was increased among women in the highest versus lowest quartile range of NOx [adjusted odds ratio (OR) = 1.33; 95% CI, 1.18–1.49] and PM2.5 exposures (OR = 1.42; 95% CI, 1.26–1.59); preterm births, particularly births < 30 weeks gestation, were also associated with these exposures (NOx OR = 2.28; 95% CI, 2.15–2.42 and PM2.5 OR = 1.81; 95% CI, 1.71–1.92). The authors conclude that results provide further support for adverse effects of air pollution on reproductive outcomes.
Also see Science Selections, p. A505
EPIDEMIOLOGY | Air Pollution and Wheeze in Young Children
Associations between air pollution and respiratory symptoms and morbidity in children have been reported by multiple studies, but relatively few have examined associations in very young children, and none have examined associations with gastrointestinal illnesses. Orazzo et al. (p. 1780) conducted a case–crossover study of ambient air pollution [particulate matter (PM), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone, and carbon monoxide (CO)] and emergency room visits for wheezing and gastroenteric illness (acute enteric disease with diarrhea and vomiting) in children 0–2 years of age from six Italian cities. CO and SO2 were most strongly associated with wheezing, with a 2.7% increase (95% CI,
0.5–4.9) estimated in association with a 1.04-µg/m3 increase in 7-day average CO and a 3.4% (95% CI, 1.5–5.3) increase with a 8.0-µg/m3 increase in SO2. The authors found positive associations with visits for wheezing for PM and NO2 and a significant association between the 3-day moving average CO level and gastroenteric disorders. Results are consistent with adverse health effects of air pollution in children 0–2 years of age, but the authors conclude that additional research is needed to investigate underlying mechanisms.
EPIDEMIOLOGY | Anogenital Distance from Birth to 2 Years
Anogenital distance (AGD), a sexually dimorphic trait in rodents and humans, is considered a reliable marker of androgen and antiandrogen effects in rodents, but data on AGD in humans are sparse and longitudinal changes during infancy have not been assessed. Thankamony et al. (p. 1786) measured AGD in 463 male and 426 female full-term infants living in the United Kingdom and assessed changes over time based on 2,168 longitudinal AGD measurements (median of two measurements per infant). The authors suggest that these findings may be used as normative data for population studies of effects of environmental chemicals on genital development.
EPIDEMIOLOGY | Truck Traffic and Allergy in a Global Study of Children
Multiple studies have reported associations between traffic-related air pollution and allergic outcomes in children, but most have been conducted only among children in developed countries. Brunekreef et al. (p. 1791) describe associations between truck traffic on the street of residence and symptoms of asthma, rhinoconjunctivitis, and eczema among 13- to 14-year-old children (n = 315,572 from 110 centers in 46 countries) and 6- to 7-year-old children
(n = 197,515 from 70 centers in 29 countries) in the third phase of the International Study of Asthma and Allergies in Childhood (ISAAC). The frequency of truck traffic was associated with the prevalence of asthma, rhinoconjunctivitis, and eczema symptoms. Adjusted odds ratios (95% CIs) for “current wheeze” and “almost the whole day” versus “never” truck traffic were 1.35 (1.23–1.49) for 13- to 14-year-olds and 1.35 (1.22–1.48) for 6- to 7-year-olds, with remarkably similar associations estimated throughout the world. The authors conclude that findings merit further investigation given increasing exposure of the world’s children to traffic.
