Background: Industrial food animal production employs many of the same antibiotics or classes
of antibiotics that are used in human medicine. These drugs can be administered to
food animals in the form of free-choice medicated feeds (FCMF), where animals choose
how much feed to consume. Routine administration of these drugs to livestock selects
for microorganisms that are resistant to medications critical to the treatment of
clinical infections in humans.
Objectives: In this commentary, we discuss the history of medicated feeds, the nature of FCMF
use with regard to dose delivery, and U.S. policies that address antimicrobial drug
use in food animals.
Discussion: FCMF makes delivering a predictable, accurate, and intended dose difficult. Overdosing
can lead to animal toxicity; underdosing or inconsistent dosing can result in a failure
to resolve animal diseases and in the development of antimicrobial-resistant microorganisms.
Conclusions: The delivery of antibiotics to food animals for reasons other than the treatment of
clinically diagnosed disease, especially via free-choice feeding methods, should be
Objective: The purpose of this review is to evaluate the impact of recent epidemiologic literature
on the National Research Council (NRC) assessment of the lung and bladder cancer risks
from ingesting low concentrations (< 100 μg/L) of arsenic-contaminated water.
Data sources, extraction, and synthesis: PubMed was searched for epidemiologic studies pertinent to the lung and bladder cancer
risk estimates from low-dose arsenic exposure. Articles published from 2001, the date
of the NRC assessment, through September 2010 were included. Fourteen epidemiologic
studies on lung and bladder cancer risk were identified as potentially useful for
Conclusions: Recent epidemiologic studies that have investigated the risk of lung and bladder cancer
from low arsenic exposure are limited in their ability to detect the NRC estimates
of excess risk because of sample size and less than lifetime exposure. Although the
ecologic nature of the Taiwanese studies on which the NRC estimates are based present
certain limitations, the data from these studies have particular strengths in that
they describe lung and bladder cancer risks resulting from lifetime exposure in a
large population and remain the best data on which to conduct quantitative risk assessment.
Continued follow-up of a population in northeastern Taiwan, however, offers the best
opportunity to improve the cancer risk assessment for arsenic in drinking water. Future
studies of arsenic < 100 μg/L in drinking water and lung and bladder cancer should
consider adequacy of the sample size, the synergistic relationship of arsenic and
smoking, duration of arsenic exposure, age when exposure began and ended, and histologic
Background: Global climate change will have multiple effects on human health. Vulnerable populations—children,
the elderly, and the poor—will be disproportionately affected.
Objective: We reviewed projected impacts of climate change on children’s health, the pathways
involved in these effects, and prevention strategies.
Data sources: We assessed primary studies, review articles, and organizational reports.
Data synthesis: Climate change is increasing the global burden of disease and in the year 2000 was
responsible for > 150,000 deaths worldwide. Of this disease burden, 88% fell upon
children. Documented health effects include changing ranges of vector-borne diseases
such as malaria and dengue; increased diarrheal and respiratory disease; increased
morbidity and mortality from extreme weather; changed exposures to toxic chemicals;
worsened poverty; food and physical insecurity; and threats to human habitation. Heat-related
health effects for which research is emerging include diminished school performance,
increased rates of pregnancy complications, and renal effects. Stark variation in
these outcomes is evident by geographic region and socioeconomic status, and these
impacts will exacerbate health disparities. Prevention strategies to reduce health
impacts of climate change include reduction of greenhouse gas emissions and adaptation
through multiple public health interventions.
Conclusions: Further quantification of the effects of climate change on children’s health is needed
globally and also at regional and local levels through enhanced monitoring of children’s
environmental health and by tracking selected indicators. Climate change preparedness
strategies need to be incorporated into public health programs.
Background: Climate change is expected to have large impacts on health at low latitudes where
droughts and malnutrition, diarrhea, and malaria are projected to increase.
Objectives: The main objective of this study was to indicate a method to assess a range of plausible
health impacts of climate change while handling uncertainties in a unambiguous manner.
We illustrate this method by quantifying the impacts of projected regional warming
on diarrhea in this century.
Methods: We combined a range of linear regression coefficients to compute projections of future
climate change-induced increases in diarrhea using the results from five empirical
studies and a 19-member climate model ensemble for which future greenhouse gas emissions
were prescribed. Six geographical regions were analyzed.
Results: The model ensemble projected temperature increases of up to 4°C over land in the tropics
and subtropics by the end of this century. The associated mean projected increases
of relative risk of diarrhea in the six study regions were 8–11% (with SDs of 3–5%)
by 2010–2039 and 22–29% (SDs of 9–12%) by 2070–2099.
Conclusions: Even our most conservative estimates indicate substantial impacts from climate change
on the incidence of diarrhea. Nevertheless, our main conclusion is that large uncertainties
are associated with future projections of diarrhea and climate change. We believe
that these uncertainties can be attributed primarily to the sparsity of empirical
climate–health data. Our results therefore highlight the need for empirical data in
the cross section between climate and human health.
Background: The feminization of nature by endocrine-disrupting chemicals (EDCs) is a key environmental
issue affecting both terrestrial and aquatic wildlife. A crucial and as yet unanswered
question is whether EDCs have adverse impacts on the sustainability of wildlife populations.
There is widespread concern that intersex fish are reproductively compromised, with
potential population-level consequences. However, to date, only in vitro sperm quality data are available in support of this hypothesis.
Objective: The aim of this study was to examine whether wild endocrine-disrupted fish can compete
successfully in a realistic breeding scenario.
Methods: In two competitive breeding experiments using wild roach (Rutilus rutilus), we used DNA microsatellites to assign parentage and thus determine reproductive
success of the adults.
Results: In both studies, the majority of intersex fish were able to breed, albeit with varying
degrees of success. In the first study, where most intersex fish were only mildly
feminized, body length was the only factor correlated with reproductive success. In
the second study, which included a higher number of more severely intersex fish, reproductive
performance was negatively correlated with severity of intersex. The intersex condition
reduced reproductive performance by up to 76% for the most feminized individuals in
this study, demonstrating a significant adverse effect of intersex on reproductive
Conclusion: Feminization of male fish is likely to be an important determinant of reproductive
performance in rivers where there is a high prevalence of moderately to severely feminized
Background: Mechanisms of cardiovascular injuries from exposure to gas and particulate air pollutants
Objective: We sought to determine whether episodic exposure of rats to ozone or diesel exhaust
particles (DEP) causes differential cardiovascular impairments that are exacerbated
by ozone plus DEP.
Methods and results: Male Wistar Kyoto rats (10–12 weeks of age) were exposed to air, ozone (0.4 ppm),
DEP (2.1 mg/m3), or ozone (0.38 ppm) + DEP (2.2 mg/m3) for 5 hr/day, 1 day/week for 16 weeks, or to air, ozone (0.51 or 1.0 ppm), or DEP
(1.9 mg/m3) for 5 hr/day for 2 days. At the end of each exposure period, we examined pulmonary
and cardiovascular biomarkers of injury. In the 16-week study, we observed mild pulmonary
pathology in the ozone, DEP, and ozone + DEP exposure groups, a slight decrease in
circulating lymphocytes in the ozone and DEP groups, and decreased platelets in the
DEP group. After 16 weeks of exposure, mRNA biomarkers of oxidative stress (hemeoxygenase-1),
thrombosis (tissue factor, plasminogen activator inhibitor-1, tissue plasminogen activator,
and von Willebrand factor), vasoconstriction (endothelin-1, endothelin receptors A
and B, endothelial NO synthase) and proteolysis [matrix metalloprotease (MMP)-2, MMP-3, and tissue inhibitor of matrix metalloprotease-2] were increased by DEP and/or ozone
in the aorta, but not in the heart. Aortic LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1) mRNA and protein increased
after ozone exposure, and LOX-1 protein increased after exposure to ozone + DEP. RAGE (receptor for advanced glycation end products) mRNA increased in the ozone + DEP
group. Exposure to ozone or DEP depleted cardiac mitochondrial phospholipid fatty
acids (DEP > ozone). The combined effect of ozone and DEP exposure was less pronounced
than exposure to either pollutant alone. Exposure to ozone or DEP for 2 days (acute)
caused mild changes in the aorta.
Conclusions: In animals exposed to ozone or DEP alone for 16 weeks, we observed elevated biomarkers
of vascular impairments in the aorta, with the loss of phospholipid fatty acids in
myocardial mitochondria. We conclude that there is a possible role of oxidized lipids
and protein through LOX-1 and/or RAGE signaling.
Background: Residents of Anniston, Alabama, live near a Monsanto plant that manufactured polychlorinated
biphenyls (PCBs) from 1929 to 1971 and are relatively heavily exposed.
Objectives: The goal of this study was to determine the relationship, if any, between blood pressure
and levels of total serum PCBs, several PCB groups with common actions or structure,
35 individual PCB congeners, and nine chlorinated pesticides.
Methods: Linear regression analysis was used to determine the relationships between blood pressure
and serum levels of the various contaminants after adjustment for age, body mass index,
sex, race, smoking, and exercise in 394 Anniston residents who were not taking antihypertensive
Results: Other than age, total serum PCB concentration was the strongest determinant of blood
pressure of the covariates studied. We found the strongest associations for those
PCB congeners that had multiple ortho chlorines. We found the associations over the full range of blood pressure as well
as in those subjects whose blood pressure was in the normal range. The chlorinated
pesticides showed no consistent relationship to blood pressure.
Conclusions: In this cross-sectional study, serum concentrations of PCBs, especially those congeners
with multiple ortho chlorines, were strongly associated with both systolic and diastolic blood pressure.
Background: The putative effects of postmenopausal hormone therapy on the association between
particulate matter (PM) air pollution and venous thromboembolism (VTE) have not been
assessed in a randomized trial of hormone therapy, despite its widespread use among
Objective: In this study, we examined whether hormone therapy modifies the association of PM
with VTE risk.
Methods: Postmenopausal women 50–79 years of age (n = 26,450) who did not have a history of VTE and who were not taking anticoagulants
were enrolled in the Women’s Health Initiative Hormone Therapy trials at 40 geographically
diverse U.S. clinical centers. The women were randomized to treatment with estrogen
versus placebo (E trial) or to estrogen plus progestin versus placebo (E + P trial).
We used age-stratified Cox proportional hazard models to examine the association between
time to incident, centrally adjudicated VTE, and daily mean PM concentrations spatially
interpolated at geocoded addresses of the participants and averaged over 1, 7, 30,
and 365 days.
Results: During the follow-up period (mean, 7.7 years), 508 participants (2.0%) had VTEs at
a rate of 2.6 events per 1,000 person-years. Unadjusted and covariate-adjusted VTE
risk was not associated with concentrations of PM < 2.5 μm (PM2.5) or < 10 μm (PM10)] in aerodynamic diameter and PM × active treatment interactions were not statistically
significant (p > 0.05) regardless of PM averaging period, either before or after combining data
from both trials [e.g., combined trial-adjusted hazard ratios (95% confidence intervals)
per 10 μg/m3 increase in annual mean PM2.5 and PM10, were 0.93 (0.54–1.60) and 1.05 (0.72–1.53), respectively]. Findings were insensitive
to alternative exposure metrics, outcome definitions, time scales, analytic methods,
and censoring dates.
Conclusions: In contrast to prior research, our findings provide little evidence of an association
between short-term or long-term PM exposure and VTE, or clinically important modification
by randomized exposure to exogenous estrogens among postmenopausal women.
Background: Receptors for advanced glycation end-products (RAGE) are cell-surface receptors expressed
by alveolar type I (ATI) epithelial cells and are implicated in mechanisms of alveolar
development and sustained pulmonary inflammation.
Objectives: In the present study, we tested the hypothesis that diesel particulate matter (DPM)
up-regulates RAGE in rat ATI-like R3/1 cells and human primary small airway epithelial
cells (SAECs), leading to an inflammatory response.
Methods and Results: Using real-time reverse transcriptase polymerase chain reaction and immunoblotting,
we found that RAGE mRNA and protein are up-regulated in cells exposed to DPM for 2 hr. Use of a luciferase
reporter containing nuclear factor-κB (NF-κB) response elements revealed decreased
NF-κB activation in cells transfected with small interfering RNA (siRNA) for RAGE
(siRAGE) before DPM exposure compared with cells transfected with scrambled control
siRNA (siControl). In addition, immunostaining revealed diminished nuclear translocation
of NF-κB in DPM-exposed cells transfected with siRAGE compared with cells transfected
with siControl before DPM stimulation. Enzyme-linked immunosorbent assay demonstrated
that in R3/1 cells DPM induced secretion of monocyte chemoattractant protein-1 (MCP-1)
and interleukin-8 (IL-8), two cytokines induced by NF-κB and associated with leukocyte
chemotaxis during an inflammatory response. Incorporating siRAGE was sufficient to
significantly decrease DPM-induced MCP-1 and IL-8 secretion compared with cells transfected
Conclusions: These data offer novel insights into potential mechanisms whereby RAGE influences
pulmonary inflammation exacerbated by DPM exposure. Further research may demonstrate
that molecules involved in RAGE signaling are potential targets in lessening the degree
of particulate matter-induced exacerbations of inflammatory lung disease.
Background: Ocean pollution affects marine organisms and ecosystems as well as humans. The International
Oceanographic Commission recommends ocean health monitoring programs to investigate
the presence of marine contaminants and the health of threatened species and the use
of multiple and early-warning biomarker approaches.
Objective: We explored the hypothesis that biomarker and contaminant analyses in skin biopsies
of the threatened sperm whale (Physeter macrocephalus) could reveal geographical trends in exposure on an oceanwide scale.
Methods: We analyzed cytochrome P450 1A1 (CYP1A1) expression (by immunohistochemistry), stable
nitrogen and carbon isotope ratios (as general indicators of trophic position and
latitude, respectively), and contaminant burdens in skin biopsies to explore regional
trends in the Pacific Ocean.
Results: Biomarker analyses revealed significant regional differences within the Pacific Ocean.
CYP1A1 expression was highest in whales from the Galapagos, a United Nations Educational,
Scientific, and Cultural Organization World Heritage marine reserve, and was lowest
in the sampling sites farthest away from continents. We examined the possible influence
of the whales’ sex, diet, or range and other parameters on regional variation in CYP1A1
expression, but data were inconclusive. In general, CYP1A1 expression was not significantly
correlated with contaminant burdens in blubber. However, small sample sizes precluded
detailed chemical analyses, and power to detect significant associations was limited.
Conclusions: Our large-scale monitoring study was successful at identifying regional differences
in CYP1A1 expression, providing a baseline for this known biomarker of exposure to
aryl hydrocarbon receptor agonists. However, we could not identify factors that explained
this variation. Future oceanwide CYP1A1 expression profiles in cetacean skin biopsies
are warranted and could reveal whether globally distributed chemicals occur at biochemically
relevant concentrations on a global basis, which may provide a measure of ocean integrity.
Background: Perfluorinated carboxylic acids (PFCAs) are ubiquitous in human sera worldwide. Biotransformation
of the polyfluoroalkyl phosphate esters (PAPs) is a possible source of PFCA exposure,
because PAPs are used in food-contact paper packaging and have been observed in human
Objectives: We determined pharmacokinetic parameters for the PAP monoesters (monoPAPs) and PAP
diesters (diPAPs), as well as biotransformation yields to the PFCAs, using a rat model.
Methods: The animals were dosed intravenously or by oral gavage with a mixture of 4:2, 6:2,
8:2, and 10:2 monoPAP or diPAP chain lengths. Concentrations of the PAPs and PFCAs,
as well as metabolic intermediates and phase II metabolites, were monitored over time
in blood, urine, and feces.
Results: The diPAPs were bioavailable, with bioavailability decreasing as the chain length
increased from 4 to 10 perfluorinated carbons. The monoPAPs were not absorbed from
the gut; however, we found evidence to suggest phosphate-ester cleavage within the
gut contents. We observed biotransformation to the PFCAs for both monoPAP and diPAP
Conclusions: Using experimentally derived biotransformation yields, perfluorooctanoic acid (PFOA)
sera concentrations were predicted from the biotransformation of 8:2 diPAP at concentrations
observed in human serum. Because of the long human serum half-life of PFOA, biotransformation
of diPAP even with low-level exposure could over time result in significant exposure
to PFOA. Although humans are exposed directly to PFCAs in food and dust, the pharmacokinetic
parameters determined here suggest that PAP exposure should be considered a significant
indirect source of human PFCA contamination.
Background: Environmental and biomedical researchers frequently encounter laboratory data constrained
by a lower limit of detection (LOD). Commonly used methods to address these left-censored
data, such as simple substitution of a constant for all values < LOD, may bias parameter
estimation. In contrast, multiple imputation (MI) methods yield valid and robust parameter
estimates and explicit imputed values for variables that can be analyzed as outcomes
Objective: In this article we expand distribution-based MI methods for left-censored data to
a bivariate setting, specifically, a longitudinal study with biological measures at
two points in time.
Methods: We have presented the likelihood function for a bivariate normal distribution taking
into account values < LOD as well as missing data assumed missing at random, and we
use the estimated distributional parameters to impute values < LOD and to generate
multiple plausible data sets for analysis by standard statistical methods. We conducted
a simulation study to evaluate the sampling properties of the estimators, and we illustrate
a practical application using data from the Community Participatory Approach to Measuring
Farmworker Pesticide Exposure (PACE3) study to estimate associations between urinary
acephate (APE) concentrations (indicating pesticide exposure) at two points in time
and self-reported symptoms.
Results: Simulation study results demonstrated that imputed and observed values together were
consistent with the assumed and estimated underlying distribution. Our analysis of
PACE3 data using MI to impute APE values < LOD showed that urinary APE concentration
was significantly associated with potential pesticide poisoning symptoms. Results
based on simple substitution methods were substantially different from those based
on the MI method.
Conclusions: The distribution-based MI method is a valid and feasible approach to analyze bivariate
data with values < LOD, especially when explicit values for the nondetections are
needed. We recommend the use of this approach in environmental and biomedical research.
Background: Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is a high-energy, trinitrated cyclic
compound that has been used worldwide since World War II as an explosive in both military
and civilian applications. RDX can be released in the environment by way of waste
streams generated during the manufacture, use, and disposal of RDX-containing munitions
and can leach into groundwater from unexploded munitions found on training ranges.
For > 60 years, it has been known that exposure to high doses of RDX causes generalized
seizures, but the mechanism has remained unknown.
Objective: We investigated the mechanism by which RDX induces seizures.
Methods and results: By screening the affinity of RDX for a number of neurotransmitter receptors, we found
that RDX binds exclusively to the picrotoxin convulsant site of the γ-aminobutyric
acid type A (GABAA) ionophore. Whole-cell in vitro recordings in the rat basolateral amygdala (BLA) showed that RDX reduces the frequency
and amplitude of spontaneous GABAA receptor–mediated inhibitory postsynaptic currents and the amplitude of GABA-evoked
postsynaptic currents. In extracellular field recordings from the BLA, RDX induced
prolonged, seizure-like neuronal discharges.
Conclusions: These results suggest that binding to the GABAA receptor convulsant site is the primary mechanism of seizure induction by RDX and
that reduction of GABAergic inhibitory transmission in the amygdala is involved in
the generation of RDX-induced seizures. Knowledge of the molecular site and the mechanism
of RDX action with respect to seizure induction can guide therapeutic strategies,
allow more accurate development of safe thresholds for exposures, and help prevent
the development of new explosives or other munitions that could pose similar health
Background: Quantitative high-throughput screening (qHTS) assays are increasingly being used to
inform chemical hazard identification. Hundreds of chemicals have been tested in dozens
of cell lines across extensive concentration ranges by the National Toxicology Program
in collaboration with the National Institutes of Health Chemical Genomics Center.
Objectives: Our goal was to test a hypothesis that dose–response data points of the qHTS assays
can serve as biological descriptors of assayed chemicals and, when combined with conventional
chemical descriptors, improve the accuracy of quantitative structure–activity relationship
(QSAR) models applied to prediction of in vivo toxicity end points.
Methods: We obtained cell viability qHTS concentration–response data for 1,408 substances assayed
in 13 cell lines from PubChem; for a subset of these compounds, rodent acute toxicity
half-maximal lethal dose (LD50) data were also available. We used the k nearest neighbor classification and random forest QSAR methods to model LD50 data using chemical descriptors either alone (conventional models) or combined with
biological descriptors derived from the concentration–response qHTS data (hybrid models).
Critical to our approach was the use of a novel noise-filtering algorithm to treat
Results: Both the external classification accuracy and coverage (i.e., fraction of compounds
in the external set that fall within the applicability domain) of the hybrid QSAR
models were superior to conventional models.
Conclusions: Concentration–response qHTS data may serve as informative biological descriptors of
molecules that, when combined with conventional chemical descriptors, may considerably
improve the accuracy and utility of computational approaches for predicting in vivo animal toxicity end points.
Background: Dysregulation of positive and negative selection, antigen presentation, or apoptosis
in the thymus can lead to immunosuppression or autoimmunity. Diethylstilbestrol (DES),
dexamethasone (DEX), cyclophosphamide (CPS), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are immunosuppressive chemicals that induce similar immunotoxic effects
in the thymus, however, the mechanism of toxicity is purported to be different for
Objectives: We hypothesized that genomic analysis of thymus after chemical-induced atrophy would
yield transcriptional profiles that suggest pathways of toxicity associated with reduced
Methods: Female B6C3F1 mice were exposed to these immunosuppressive agents and changes in gene
expression and immune cell subpopulations were evaluated.
Results: All four chemicals induced thymic atrophy and changes in both the relative proportion
and absolute number of CD3+, CD4+/CD8−, CD4−/CD8+, and CD4+/CD8+ thymocytes. The most significant impact of exposure to DEX, DES, and CPS was modulation
of gene expression in the T-cell receptor (TCR) complex and TCR and CD28 signaling
pathways; this could represent a common mechanism of action and play a pivotal role
in lineage commitment and development of T cells. Up-regulation of genes associated
with the antigen presentation and dendritic cell maturation pathways was the most
distinctive effect of TCDD exposure. These elements, which were also up-regulated
by DEX and DES, contribute to positive and negative selection.
Conclusions: Genomic analysis revealed gene expression changes in several pathways that are commonly
associated with xenobiotic-induced immune system perturbations, particularly those
that contribute to the development and maturation of thymic T cells.
Background: In humans, persistent organic pollutants (POPs) are stored primarily in adipose tissue.
Their total body burden and their contribution to obesity-associated diseases remain
Objectives: We characterized POP total body burden and their redistribution in obese individuals
before and after drastic weight loss and compared these values with a variety of molecular,
biological, and clinical parameters.
Methods: Seventy-one obese subjects were enrolled and underwent bariatric surgery. Blood and
adipose tissue samples were obtained at different times from these individuals as
well as from 18 lean women.
Results: POP content (17 dioxins/furans and 18 polychlorinated biphenyl congeners) in different
adipose tissue territories was similar, allowing us to assess total POP body burden
from a single biopsy. Total POP body burden was 2 to 3 times higher in obese than
in lean individuals. We also found increased expression of some POP target genes in
obese adipose tissue. Drastic weight loss led to increased serum POPs and, within
6–12 months, to a significant 15% decrease in total polychlorinated biphenyl body
burden. Importantly, serum POP levels were positively correlated with liver toxicity
markers and lipid parameters, independently of age and body mass index.
Conclusions: POP content in adipose tissue and serum correlate with biological markers of obesity-related
dysfunctions. Drastic weight loss leads to a redistribution of POPs and to a moderate
decrease of their total body burden.
Background: Although studies have found that diabetes mellitus (DM) modifies the impact of exposures
from air pollution on cardiovascular outcomes, information is limited regarding DM
as an air pollution-associated outcome.
Objectives: Using two prospective cohorts, the Nurses’ Health Study (NHS) and the Health Professionals
Follow-Up Study (HPFS), we investigated the relationship of incident type 2 DM with
exposures to particulate matter (PM) <2.5 μm (PM2.5), PM <10 μm (PM10), and PM between 2.5 and 10 μm in aerodynamic diameter (PM10–2.5) in the previous 12 months and the distance to roadways.
Methods: Cases were reported and confirmed through biennial and supplemental questionnaires
of diagnosis and treatment information. During follow-up from 1989 to 2002, questionnaires
provided information on time-varying covariates and updated addresses. Addresses were
geocoded and used to assign air pollution exposures from spatiotemporal statistical
Results: Among participants living in metropolitan areas of the northeastern and midwestern
United States, there were 3,784 incident cases of DM in the NHS, and 688 cases in
the HPFS. Pooled results from random effects meta-analysis of cohort-specific models
adjusted for body mass index and other known risk factors produced hazard ratios (HRs)
for incident DM with interquartile range (IQR) increases in average PM during the
12 months before diagnosis of 1.03 [95% confidence interval (CI), 0.96–1.10] for PM2.5, 1.04 (95% CI, 0.99–1.09) for PM10, and 1.04 (95% CI, 0.99–1.09) for PM10–2.5. Among women, the fully adjusted HR for living < 50 m versus ≥ 200 m from a roadway
was 1.14 (95% CI, 1.03–1.27).
Conclusions: Overall, results did not provide strong evidence of an association between exposure
to PM in the previous 12 months and incident DM; however, an association with distance
to road (a proxy marker of exposure to traffic-related pollution) was shown among
Background: Exposure to environmental toxicants is associated with numerous disease outcomes,
many of which involve underlying immune and inflammatory dysfunction.
Objectives: To address the gap between environmental exposures and immune dysfunction, we investigated
the association of two endocrine-disrupting compounds (EDCs) with markers of immune
Methods: Using data from the 2003–2006 National Health and Nutrition Examination Survey, we
compared urinary bisphenol A (BPA) and triclosan levels with serum cytomegalovirus
(CMV) antibody levels and diagnosis of allergies or hay fever in U.S. adults and children
≥ 6 years of age. We used multivariate ordinary least squares linear regression models
to examine the association of BPA and triclosan with CMV antibody titers, and multivariate
logistic regression models to investigate the association of these chemicals with
allergy or hay fever diagnosis. Statistical models were stratified by age (< 18 years
and ≥ 18 years).
Results: In analyses adjusted for age, sex, race, body mass index, creatinine levels, family
income, and educational attainment, in the ≥ 18-year age group, higher urinary BPA
levels were associated with higher CMV antibody titers (p < 0.001). In the < 18-year age group, lower levels of BPA were associated with higher
CMV antibody titers (p < 0.05). However, triclosan, but not BPA, showed a positive association with allergy
or hay fever diagnosis. In the < 18-year age group, higher levels of triclosan were
associated with greater odds of having been diagnosed with allergies or hay fever
(p < 0.01).
Conclusions: EDCs such as BPA and triclosan may negatively affect human immune function as measured
by CMV antibody levels and allergy or hay fever diagnosis, respectively, with differential
consequences based on age. Additional studies should be done to investigate these
Background: Previous studies have reported positive associations between maternal exposure to
air pollutants and several adverse birth outcomes. However, there have been no studies
assessing the association between environmental levels of hazardous air pollutants,
such as benzene, and neural tube defects (NTDs), a common and serious group of congenital
Objective: Our goal was to conduct a case–control study assessing the association between ambient
air levels of benzene, toluene, ethylbenzene, and xylene (BTEX) and the prevalence
of NTDs among offspring.
Methods: The Texas Birth Defects Registry provided data on NTD cases (spina bifida and anencephaly)
delivered between 1999 and 2004. The control group was a random sample of unaffected
live births, frequency matched to cases on year of birth. Census tract–level estimates
of annual BTEX levels were obtained from the U.S. Environmental Protection Agency
1999 Assessment System for Population Exposure Nationwide. Restricted cubic splines
were used in mixed-effects logistic regression models to determine associations between
each pollutant and NTD phenotype.
Results: Mothers living in census tracts with the highest benzene levels were more likely to
have offspring with spina bifida than were women living in census tracts with the
lowest levels (odds ratio = 2.30; 95% confidence interval, 1.22–4.33). No significant
associations were observed between anencephaly and benzene or between any of the NTD
phenotypes and toluene, ethylbenzene, or xylene.
Conclusion: In the first study to assess the relationship between environmental levels of BTEX
and NTDs, we found an association between benzene and spina bifida. Our results contribute
to the growing body of evidence regarding air pollutant exposure and adverse birth
Background: Childhood lead exposure adversely affects neurodevelopment. However, few studies have
examined changes in human brain metabolism that may underlie known adverse cognitive
and behavioral outcomes.
Objective: We examined the association between mean childhood blood lead levels and in vivo brain metabolite concentrations as adults, determined by proton magnetic resonance
spectroscopy (MRS) in a birth cohort with documented low-to-moderate lead exposure.
Methods: Adult participants from the Cincinnati Lead Study [n = 159; mean age (± SD), 20.8 ± 0.9 years] completed a quantitative, short-echo proton
MRS protocol evaluating seven regions to determine brain concentrations of N-acetyl aspartate (NAA), creatine and phosphocreatine (Cr), cholines (Cho), myo-inositol,
and a composite of glutamate and glutamine (GLX). Correlation and multiple linear
regression analyses were conducted.
Results: Mean childhood blood lead levels were associated with regionally specific brain metabolite
concentrations adjusted for age at imaging and Full-Scale intelligence quotient. Adjusted
analyses estimated for a unit (micrograms per deciliter) increase in mean childhood
blood lead concentrations, a decrease of NAA and Cr concentration levels in the basal
ganglia, a decrease of NAA and a decrease of Cho concentration levels in the cerebellar
hemisphere, a decrease of GLX concentration levels in vermis, a decrease of Cho and
a decrease of GLX concentration levels in parietal white matter, and a decrease of
Cho concentration levels in frontal white matter.
Conclusions: Gray-matter NAA reductions associated with increasing childhood blood lead levels
suggest that sustained childhood lead exposure produces an irreversible pattern of
neuronal dysfunction, whereas associated white-matter choline declines indicate a
permanent alteration to myelin architecture.
Background: Identifying windows of vulnerability to environmental toxicants is an important area
in children’s health research.
Objective: We compared and contrasted statistical approaches that may help identify windows of
vulnerability by formally testing differences in exposure effects across time of exposure,
incorporating continuous time metrics for timing of exposure, and efficiently incorporating
Methods: We considered four methods: 1) window-specific and simultaneously adjusted regression;
2) multiple informant models; 3) using features of individual exposure patterns to
predict outcomes; and 4) models of population exposure patterns depending on the outcome.
We illustrate them using a study of prenatal vulnerability to lead in relation to
Bayley’s Mental Development Index at 24 months of age (MDI24).
Results: The estimated change in MDI24 score with a 1-loge-unit increase in blood lead during the first trimester was −2.74 [95% confidence
interval (CI), −5.78 to 0.29] based on a window-specific regression. The corresponding
change in MDI24 was −4.13 (95% CI, −7.54 to −0.72) based on a multiple informant model;
estimated effects were similar across trimesters (p = 0.23). Results from method 3 suggested that blood lead levels in early pregnancy
were significantly associated with reduced MDI24, but decreasing blood leads over
the course of pregnancy were not. Method 4 results indicated that blood lead levels
before 17 weeks of gestation were lower among children with MDI24 scores in the 90th
versus the 10th percentile (p = 0.08).
Conclusions: Method 2 is preferred over method 1 because it enables formal testing of differences
in effects across a priori–defined windows (e.g., trimesters of pregnancy). Methods 3 and 4 are preferred over
method 2 when there is large variability in the timing of exposure assessments among
participants. Methods 3 and 4 yielded smaller p-values for tests of the hypothesis that not only level but also timing of lead exposure
are relevant predictors of MDI24; systematic power comparisons are warranted.