Environews
FOCUS | Climate Change Abatement Strategies: Which Way Is the Wind Blowing?
The potential human health effects of global climate disruption have been widely discussed, as have steps to abate the greenhouse gas emissions that would cause these effects. Historically, regulatory efforts aimed at reducing fossil fuel use have illustrated the need for market forces to get the job done, and almost everyone who is concerned about climate change mitigation favors putting a price on greenhouse gas emissions. The Focus article (p. A296) explores what strategy will yield the most mitigation bang for the investment buck.
SPHERES OF INFLUENCE | Beyond Mitigation: Planning for Climate Change Adaptation
Much of the scientific debate about climate change has revolved around the extent to which human activity is exacerbating naturally occurring global warming. Policy negotiations have therefore centered around mitigation strategies—specifically, whether greenhouse gas emissions must be curbed and, if so, to what extent. But the reality is sinking in that widespread region-specific climate change—whether anthropogenic, naturally occurring, or both—is happening now. The Spheres of Influence article (p. A306) describes how mitigation has begun sharing the global policy stage with a new challenge: adaptation to climate change that is already under way.
Commentary
RISK ASSESSMENT | FDA Conclusions Regarding Lead in Vitamins are Flawed
The U.S. Food and Drug Administration (FDA) determined the lead (Pb) content of 324 multivitamin/mineral products labeled for use by women and children and concluded that they did not pose a health hazard because Pb concentrations were below provisional total tolerable intake (PTTI) levels, developed in 1992. Miodovnik and Landrigan (p. 1021) review the the FDA’s conclusion and note that the PTTI levels assume a blood lead level (BLL) threshold of 10 µg/dL for adverse effects in children and pregnant or lactating women, despite accumulating evidence that chronic exposure of young children to BLLs < 10 µg/dL is associated with impairments in cognitive function and behavior. In addition, they note that the FDA analysis did not account for nonfood sources of Pb exposure such as lead house paint, the primary cause of elevated BLLs in children at this time. The authors argue that the FDA’s conclusions were unduly reassuring, and that current recommendations regarding acceptable levels of Pb in vitamins should be reconsidered.
Review
POPULATION HEALTH | Sustainable Control of Water-Related Infectious Diseases
Batterman et al. (p. 1023) argue that interventions to reduce water-related infectious disease have not been sustainable in many cases because they have focused on proximal causes and short-term solutions, without adequate consideration of distal causal factors or long-term strategies for implementing prevention and control efforts. The authors review historical practices in water-related infectious disease research and propose an interdisciplinary public health–oriented systems approach that draws from ecologic, anthropologic, engineering, political/economic, and public health fields. They suggest that the proposed research framework will address the complex and interrelated causes of water-related infectious disease and facilitate the development of sustainable programs for disease prevention and control.
RISK ASSESSMENT | Thyroid-Disrupting Chemicals: Interpreting Upstream Biomarkers of Adverse Outcomes
Epidemiologic and animal studies have demonstrated effects of environmental thyroid-disrupting chemicals (TDCs) on thyroid function that operate through different mechanisms. Miller et al. (p. 1033) review epidemiologic and experimental evidence concerning the role of thyroid hormones in nervous system development and cardiovascular outcomes in adults, relations between adverse outcomes and biomarkers of thyroid disruption, and societal implications of TDC-mediated outcomes. The authors note that effects of thyroid suppression have been observed at thyroid hormone levels within the “normal” range, and argue that relatively small effects of thyroid perturbation at the individual level can have profound implications at the societal level. They conclude that it is critical for human risk assessment strategies to incorporate new information as it becomes available, including information concerning regulatory mechanisms that affect thyroid hormone signaling and the role of individual TDCs and mixtures of TDCs in these processes.
Research
TOXICOLOGY | Prenatal Cigarette Smoke Exposure and Dyslipidemia in Adult Mice
Epidemiologic and toxicologic data suggest that prenatal and early postnatal exposure to cigarette smoke may increase the risk of cardiovascular disease (CVD) later in life. Ng et al. (p. 1042) exposed pregnant mice to mainstream cigarette smoke (MCS) or filtered air from gestational day 4 to parturition, and fed adult offspring a high-fat or normal diet to examine effects on body weight and lipid profiles. The authors report that body weight and plasma levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) were increased in adult female mice prenatally exposed to MCS relative to air-exposed females, and that weight gain, total cholesterol, and HDL levels were increased in response to the high-fat diet among adult male mice with prenatal MCS exposure relative to air-exposed males. The authors conclude that results provide support for effects of prenatal exposure to cigarette smoke on adult lipid profiles and body weight.
Also see Science Selections, p. A310
INFECTIOUS DISEASE | Weather and West Nile Virus in the United States
Above-average temperatures have been implicated in the spread of West Nile Virus (WNV) into the western United States, and have been associated with increasing case loads in some areas. However, associations between precipitation and WNV incidence have been inconsistent, and meteorologic factors that might increase the incidence of this mosquito-borne illness have not been systematically studied over a wide geographic area. Soverow et al. (p. 1049) conducted a case–crossover study to estimate associations between WNV and temperature, dew point temperature, and precipitation among 16,298 human WNV cases reported to the Centers for Disease Control and Prevention from 2001 to 2005. The authors report that warmer temperatures, elevated humidity, and heavy precipitation appeared to increase the rate of human WNV infection in the United States. Results suggest that meteorologic factors may help inform disease surveillance efforts, and that changing weather patterns may increase the incidence or spread of WNV in the future.
Also see Science Selections, p. A310
TOXICOLOGY | Nongenomic Promoting Effect of Bisphenol A on Seminoma Cells
It has been suggested that fetal exposure to environmental estrogens may contribute to reduced fertility and testicular germ cell cancer, but many xenoestrogens, including bisphenol A (BPA), have only a weak affinity for the classic estrogen receptors. Bouskine et al. (p. 1053) studied effects of low concentrations of BPA on JKT-1 cell proliferation in vitro to explore the potential influence of environmentally relevant BPA exposures on male germ cell proliferation. BPA concentrations similar to those found in human fluids stimulated JKT-1 cell proliferaton, activated cAMP-dependent and cGMP-dependent protein kinase pathways, and triggered rapid phosphorylation of cAMP response-element–binding protein (CREB) and retinoblastoma protein (Rb). These nongenomic effects appeared to be mediated through a nonclassic membrane estrogen G-protein–coupled receptor (GPCR). The authors conclude that this GPCR-mediated nongenomic action represents a new basis for evaluating BPA and other xenoestrogens that may interfere with the developmental programming of fetal germ cell proliferation and/or differentiation at environmentally relevant doses.
REPRODUCTIVE HEALTH | Arsenic and Impaired Glucose Tolerance in Pregnancy
Gestational diabetes (GD) has negative health effects on mothers and their infants. Arsenic exposure has been associated with type 2 diabetes, but has not been evaluated as a risk factor for GD. Ettinger et al. (p. 1059) studied 532 women living near the Tar Creek Superfund Site to examine relations between impaired glucose tolerance (a determinant of GD) and arsenic levels in blood and hair samples collected at delivery. Arsenic concentrations ranged from 0.2 to 24.1 µg/L [parts per billion (ppb)] (mean 1.7 ± 1.5) in blood and 1.1 to 724.4 ng/g (ppb) (mean 27.4 ± 61.6) in hair. Almost 12% of women were classified as having impaired glucose tolerance (blood glucose > 140 mg/dL after a 1-hr 50-g oral glucose tolerance test at 24–28 weeks gestation). The adjusted odds ratio for impaired glucose tolerance among women in the highest versus lowest quartile of blood arsenic exposure was 2.8 (95% confidence interval, 1.1‒6.9). The authors conclude that relatively low levels of maternal arsenic exposure were associated with impaired glucose tolerance and that arsenic exposure during pregnancy may therefore be a risk factor for GD.
Also see Science Selections, p. A310
EPIDEMIOLOGY | Exposure to Traffic and Risk of Rheumatoid Arthritis
Consistent associations between cigarette smoking and rheumatoid arthritis (RA) may be mediated by chronic inflammation and oxidative stress. Hart et al. (p. 1065) studied 90,297 U.S. women in the Nurses’ Health Study to determine whether particulate air pollution, another potential cause of systemic inflammation, might also be a risk factor for RA. The authors used Cox proportional hazard models to estimate the association between incident RA (between 1976 and 2004) and residential proximity to roads, a proxy measure of exposure to traffic-related air pollution. Women living within 50 m of a road had an increased risk of RA compared with women living ≥ 200 m from a road [adjusted hazard ratio (HR) = 1.31; 95% confidence interval (CI), 0.98–1.74], with a somewhat stronger association estimated for nonsmokers [HR = 1.62 (95% CI, 1.04–2.52)]. However, women living 50–200 m from a road did not appear to have an increased risk of RA relative to other women. The authors conclude that results were consistent with an effect of traffic-related air pollution on RA, but recommend that more specific measures of exposure be used in future research.
REPRODUCTIVE HEALTH | Organochlorinated Pollutants and Endometriosis
Persistent organochlorine pollutants have been hypothesized to play a role in the etiology of endometriosis, a common gynecologic disease characterized by the ectopic growth of endometrial tissue. However, results of epidemiologic studies have been inconsistent. Porpora et al. (p. 1070) conducted a hospital-based study of 80 cases with histologically confirmed endometriosis and 78 controls with other benign gynecologic conditions to examine relations between endometriosis and serum concentrations of 11 polychlorinated biphenyl (PCB) cogeners (including 4 dioxin-like PCBs that act as ligands for the aryl hydrocarbon receptor), 1,1-dichloro-2,2-bis(4-chlorophenyl)-ethene (p,p′-DDE), and hexachlorobenzene (HCB), and with 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity equivalent concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs. The authors report that endometriosis was associated with serum concentrations of several individual PCB cogeners, total serum PCBs (odds ratio = 5.63; 95% confidence interval, 2.25–14.10 for the highest versus lowest tertile of exposure), and serum p,p′-DDE.
DIABETES | Organochlorine Exposures and Incident Diabetes
Exposure to persistent organic pollutants (POPs) has been associated with diabetes in cross-sectional studies, but relatively few studies have examined associations with incident diabetes. Turyk et al. (p. 1076) studied self-reported onset of diabetes in association with serum levels of p,p′‑diphenyldichloroethene (DDE) and polychlorinated biphenyl (PCB) cogeners in a cohort of 471 adult Great Lake sport fish consumers followed from the early 1990s through 2005 (average follow-up, 8.4 years; 36 cases of incident diabetes reported). In addition, they compared annual percent changes in DDE and PCB-132/153 by diabetes status in 293 participants to determine whether diabetes might be noncausally linked with POPs through differences in metabolism. The authors report that serum DDE was associated with incident diabetes, and that annual percent change in DDE and PCB-132/153 was comparable between diabetics and other cohort participants.
EXPOSURE SCIENCE | PFOA Levels in an Exposed Community
Perfluorooctanoic acid (PFOA) is a compound used in manufacturing (e.g., to make Teflon) that is considered a probable human carcinogen by the U.S. Environmental Protection Agency.Steenland et al. (p. 1083) evaluated factors associated with serum PFOA levels among 64,251 participants in the C8 Health Project, a study of former or current mid-Ohio Valley residents near a West Virginia chemical plant that released large quantities of PFOA into the environment. The authors report that mean serum PFOA level among study participants was substantially higher than population estimates for the United States (83.0 ng/mL vs. 4–5 ng/mL), and that the strongest predictors of serum levels were current or former employment at the chemical plant and current or past residence in a contaminated water district. Other predictors included male sex, local vegetable consumption, and very young or old age.
HUMAN TOXICOLOGY | Cardiopulmonary Effects of Coarse PM in Healthy Young Adults
Exposure to fine particulate matter (PM) air pollution [aerodynamic diameter ≤ 2.5 µm (PM2.5)] has been associated with mortality and morbidity, but associations with coarse PM (PM2.5–10) have been less consistent. Graff et al. (p. 1089) compared pulmonary, cardiac, and hematologic end points before exposure, immediately after exposure, and again 20 hr after exposure to coarse concentrated ambient particles (CAPs; mean concentration 89.0 µg/m3, range 23.7–159.6 µg/m3) or filtered air in 14 healthy young volunteers (mean age, 25 years). The authors report that coarse CAP exposure was not associated with changes in pulmonary function, but was associated with a small increase in polymorphonuclear neutrophils in bronchoalveolar lavage fluid, decreased tissue plasminogen activator in peripheral blood, and decreased heart rate variability 20 hr after exposure. They conclude that the mild physiologic changes observed after exposure to coarse CAPs at environmentally relevant levels were similar to effects previously observed in response to fine CAP exposures, but note that findings need to be replicated in future studies.
EPIDEMIOLOGY | Asthma and Brevetoxin Exposure
Fleming et al. (p. 1095) previously reported changes in asthma symptoms and pulmonary function tests (PFTs) after exposure to brevetoxins in Florida red tide (Karenia brevis bloom) aerosols. In this article the authors examined self-reported health effects in 87 asthmatic study participants using personal and ambient air samplers to characterize brevetoxin exposures. The authors report that 1 hr of exposure to brevetoxin concentrations > 57 ng/m3 was associated with significant increases in self-reported respiratory symptoms and total symptom scores, but not with changes in PFT results. The authors conclude that adverse health effects may be associated with exposures to very low concentrations of brevetoxins among asthmatics.
TOXICOLOGY | Auditory Function after Developmental Exposure to PCBs and/or MeHg
Auditory deficits have been observed in association with polychlorinated biphenyl (PCB) and methylmercury (MeHg) exposure in animal models and humans, but combined effects of PCBs and MeHg during development have not been evaluated. Powers et al. (p. 1101) exposed female rats to PCBs (1 or 3 mg/kg in corn oil), MeHg (1.5 or 4.5 ppm in drinking water), or PCBs and MeHg beginning 4 weeks before gestation through postnatal day 21, and measured auditory function in their adult offspring. PCB-exposed rats had reduced auditory function compared with unexposed controls based on distortion product otoacoustic emission and auditory brainstem response testing, but that auditory function among rats exposed to MeHg alone was comparable with controls. In contrast with expectations, auditory deficits in rats with joint exposure to MeHg and PCBs were attenuated compared with deficits observed in rats exposed to PCBs alone. The authors conclude that developmental exposure to PCBs was associated with permanent hearing deficits in adult rats that were consistent with a cochlear site of action.
TOXICOLOGY | Arsenic and Immune Response Gene Expression
Chronic exposure to arsenic in drinking water has been associated with lung disease and other adverse health outcomes. Kozul et al. (p. 1108) examined mRNA and protein expression changes in the lungs of mice exposed to environmentally relevant concentrations of As in food or drinking water (10 or 100 ppb) for 5–6 weeks to evaluate overall effects and specifically assess the hypothesis that As alters immune function. Relative to As-unexposed mice, the As-exposed mice demonstrated significant changes in the expression of genes relevant to the innate immune response (including genes for interleukin 1β, interleukin 1 receptor and several toll-like receptors, cytokines and cytokine receptors) in cell adhesion and migration, channels, receptors, differentiation, and proliferation. The authors conclude that chronic low-dose As exposure at the current U.S. drinking-water standard may alter the regulation of innate immunity and contribute to altered disease risk, particularly in lungs.
TOXICOLOGY | A Mouse Model for Adjuvant Effects of Particulate Matter
Ambient particulate matter (PM) has been shown to enhance allergic sensitization in humans and animals. Li et al. (p. 1116) explored the underlying mechanism and role of PM components in the adjuvant effect of PM using an intranasal ovalbumin (OVA) sensitization model to contrast allergic airway inflammation among mice exposed to concentrated ambient ultrafine particles (UFPs; PM with aerodynamic diameter < 0.15 um), fine ambient PM (< 2.5 um), carbon black particles, or vehicle only. Ambient UFPs had a higher polycyclic aromatic hydrocarbon content and oxidant potential than fine PM, and elicited enhanced allergic inflammatory responses in the upper and lower respiratory tract that were partially suppressed by the antioxidant N-acetyl cysteine. The authors conclude that the adjuvant effects of ambient UFPs were determined by their oxidant potential, and suggest that redox-active organic chemicals on the surface of UFPs may increase inflammatory responses by altering the redox equilibrium of the mucosal immune system.
TOXICOLOGY | Role of JNK and p38 MAPKs in Chromium Toxicity
Potassium dichromate [Cr(VI)] exposure has been associated with a variety of diseases in humans and with developmental abnormalities in animal models. Cr(VI) activates cellular signaling factors, including the mitogen-activated protein kinases (MAPKs) c-Jun N-terminal kinase (JNK)1/2 and p38, but activation patterns vary depending on the experimental system, dose, and timing of Cr(IV) exposure. Chen et al. (p. 1124) studied the contribution of individual MAPKs to Cr(VI) toxicity in mouse embryonic stem (ES) cells, including wild type cells and cells deficient in MAP kinase kinases (MAP2Ks) that mediate JNK and p38 activation. ES treated with 50 µM Cr(VI) demonstrated rapid phosphorylation (activation) of MAPKs and their respective downstream transcription factors, that antioxidant pretreatment blocked Cr(VI)-mediated MAPK activation and cytotoxicity, and that MAP2K4/7-dependent JNK activation reduced acute Cr(VI) toxicity whereas MAP2K4-dependent p38 activation increased it. In addition, low-dose Cr(VI) (0.1 µM) inhibited cardiomyocyte development in wild-type cells, but not MAP2K7-deficient cells, and also resulted in MAP2K4/7-dependent JNK activation and MAP2K4-dependent p38 activation. The authors conclude that effects of Cr(VI) are dependent on the actions of specific MAPKs.
ALTERNATIVE MODEL DEVELOPMENT | Human Neurospheres for Developmental Neurotoxicity Testing
Developmental neurotoxicity (DNT) is a serious threat to human health, but relatively few environmental chemicals have been evaluated for DNT, in part because current testing guidelines recommend time- and cost-intensive rodent studies that require large numbers of animals. Therefore, alternative testing strategies that reduce animal experiments and the time and cost of screening have been advocated. Moors et al. (p. 1131) developed a three-dimensional test system for DNT screening using human neural progenitor cells (hNPCs) grown as neurospheres, and established in vitro assays to detect disturbances in basic processes of brain development. According to the authors, the neurospheres imitated basic processes of brain development, including proliferation, differentiation, and migration. In addition, they demonstrated effects of known developmental toxicants (methylmercury chloride and mercury chloride) on migration and proliferation and on caspase-independent apoptosis in response to oxidative stress. The authors conclude that the human neurosphere system is a promising method for medium-throughput screening to identify DNT hazards that affect basic processes of brain development.
TOXICOGENOMICS | Genomewide Analysis of the Aryl Hydrocarbon Receptor Regulatory Network
The aryl hydrocarbon receptor (AHR) has been thought to exist as an inactive cytosolic complex that translocates to the nucleus to induce gene transcription only after activation by xenobiotic ligands. However, there is increasing evidence that AHR may influence homeostatic and developmental processes through endogenous mechanisms in the absence of xenobiotic stimulation. Sartor et al. (p. 1139) conducted a genomewide analysis of AHR gene targets in mouse hepatoma cells that integrated chromatin immunoprecipitation/chip and global gene expression signatures with a prior functional knowledge to develop a comprehensive model of AHR regulatory functions. The authors report that in the absence of xenobiotic stimulation, naďve AHR was bound to an extensive array of gene clusters relevant to multiple morphogenetic and developmental programs. In contrast, ligand activation (e.g., by benzo[a]pyrene) displaced the receptor from these targets to xenobiotic metabolism gene promoters. They conclude that AHR-mediated effects of xenobiotics result from down-regulation of endogenous AHR-mediated mechanisms as well as up-regulation of xenobiotic metabolism genes, and suggest that early exposure to xenobiotic AHR ligands may disrupt normal development and alter gene expression into adulthood.
HEALTH POLICY | Assessing the Impact of Extramural Asthma Research
There has been growing demand for measures to assess the effectiveness of publicly funded research programs, but research impact assessments traditionally have focused on short-term outcomes related to research publications. Liebow et al. (p. 1147) evaluated the impact of extramural asthma research using a framework based on existing data and expert judgment that characterizes impact in terms of publications, clinical applications of findings, community interventions, and technology developments. The authors discuss gaps and limitations in data needed to evaluate research impacts, but conclude that with modifications of current data structures and improved linkages among databases, it will be possible to determine longer-term impacts of research programs and improve the quality and effectiveness of funded research.
PHYTOCHEMICALS | ER-Dependent Actions of Cucurma comosa Diarylheptanoids
Biological mechanisms underlying the estrogenic activity of diarylheptanoid phytoestrogens isolated from Curcuma comosa Roxb. have not been characterized, despite their use in dietary supplements and potential therapeutic applications. Winuthayanon et al. (p. 1155) used established in vitro and in vivo model systems to characterize the estrogenic mechanisms and activity of 3 naturally occurring diarylheptanoids: [(3S)-1,7-diphenyl-(6E)-6-hepten-3-ol (D1), 1,7-diphenyl-(6E)-6-hepten-3-one (D2), and (3R)-1,7-diphenyl-(4E,6E)-4,6-heptadien-3-ol (D3)]. The authors report that all 3 diarylheptanoids up-regulated estrogen-responsive genes through an estrogen receptor (ER)–dependent mechanism in vitro, but only D3 caused ER-dependent increases in uterine weight and epithelial cell proliferation in vivo. In addition, they report that D3 activated estrogen responsive genes through both classic and nonclassic [estrogen response element (ERE)-independent] mechanisms, and that its biologic action was selective for ERα. Results suggest that diarylheptanoids act as ER agonists, and that potential target tissues may extend beyond the reproductive tract.
Children's Health
HEALTH POLICY | Economic Benefits of Lead Hazard Control
Lead paint used in homes before 1978 is the primary source of lead exposure among children in the United States today. Gould (p. 1162) conducted a cost–benefit analysis to quantify the social and economic benefits of household lead paint hazard control. The author contrasted the estimated cost of lead paint hazard control ($1–$11 billion) with estimated benefits that would result from reductions in health care costs ($11‒$53 billion), special education ($30‒$146 million), attention deficit–hyperactivity disorder ($267 million), and the direct costs of crime ($1.7 billion), and increases in lifetime earnings ($165‒233 billion) and tax revenue ($25‒$35 billion). On the basis of these estimates, the author concludes that each dollar invested in lead paint hazard control would result in a return of $17‒$221, or a net savings of $181‒269 billion.
Also see Science Selections, p. A311
EPIDEMIOLOGY | Pediatric Asthma Symptoms and Traffic-Related PM2.5
The U.S. EPA air quality standard for ambient fine particles [particulate matter ≤ 2.5 µm diameter (PM2.5)] is based on total mass rather than PM composition or sources. Gent et al. (p. 1168) collected information on daily symptoms and medication use over 12 months from 149 children with asthma to assess health effects of specific components or sources of PM2.5. Particle samples from a monitor located within 27 km of participants’ residences were analyzed for trace elements and elemental carbon to determine daily contributions from six particle sources defined using factor analysis/apportionment. Mean PM2.5 over the 4-year study was above the U.S. annual standard (17.0 vs. 15.0 µg/m3), with the majority attributed to the “motor vehicle” (42%) and “road dust” (12%) source categories. According to the authors, total PM2.5 was not associated with asthma symptoms or medication use, but 5-µg/m3 increases in motor vehicle or road dust PM2.5 (same day or 3-day average) were associated with increased wheeze, shortness of breath, and short-acting inhaler use.
FETAL/CHILD DEVELOPMENT | Brominated Flame Retardant and Genitourinary Conditions
In 1973–1974, Michigan residents were accidentally exposed to polybrominated biphenyl (PBB), a suspected endocrine-disrupting compound, in contaminated animal and dairy products. Small et al. (p. 1175) conducted a prospective study of associations between PBB exposure during pregnancy (based on maternal serum PBB-153 levels at enrollment or model-based estimates) and male genitourinary (GU) conditions in 464 sons of exposed women. GU conditions were reported by 33 sons or their parents, including 13 hernias, 10 hydroceles, 9 cases of cryptorchidism, 5 hypospadias, and 1 varicocele (4 with hernia and hydrocele, 1 with hernia and cryptorchidism.) The authors report that PBB exposure was not associated with hypospadias or cryptorchidism (conditions thought to be associated with estrogenic exposures) but was associated with hernia or hydocele, and suggest that these results may indicate effects through antiandrogenic or other mechanisms.
