U.S. chemical plants currently have potentially catastrophic vulnerabilities as terrorist
targets. The possible consequences of these vulnerabilities echo from the tragedies
of the Bhopal incident in 1984 to the terrorist attacks on 11 September 2001 and,
most recently, Hurricanes Katrina and Rita. Findings from a 2004 nationwide participatory
research study of 125 local union leaders at sites with very large volumes of highly
hazardous chemicals suggest that voluntary efforts to achieve chemical plant security
are not succeeding. Study respondents reported that companies had only infrequently
taken actions that are most effective in preventing or in preparing to respond to
a terrorist threat. In addition, companies reportedly often failed to involve key
stakeholders, including workers, local unions, and the surrounding communities, in
these efforts. The environmental health community thus has an opportunity to play
a key role in advocating for and supporting improvements in prevention of and preparation
for terrorist attacks. Policy-level recommendations to redress chemical site vulnerabilities
and the related ongoing threats to the nation’s security are as follows: a) specify detailed requirements for chemical site assessment and security; b) mandate audit inspections supported by significant penalties for cases of noncompliance;
c) require progress toward achieving inherently safer processes, including the minimizing
of storage of highly hazardous chemicals; d) examine and require additional effective actions in prevention, emergency preparedness,
and response and remediation; e) mandate and fund the upgrading of emergency communication systems; and f) involve workers and community members in plan creation and equip and prepare them
to prevent and respond effectively to an incident.
The Chernobyl accident in 1986 caused widespread radioactive contamination and enormous
concern. Twenty years later, the World Health Organization and the International Atomic
Energy Authority issued a generally reassuring statement about the consequences.
Accurate assessment of the consequences is important to the current debate on nuclear
Our objectives in this study were to evaluate the health impact of the Chernobyl
accident, assess the international response to the accident, and consider how to improve
responses to future accidents.
So far, radiation to the thyroid from radioisotopes of iodine has caused several
thousand cases of thyroid cancer but very few deaths; exposed children were most
susceptible. The focus on thyroid cancer has diverted attention from possible nonthyroid
effects, such as mini-satellite instability, which is potentially important. The
international response to the accident was inadequate and uncoordinated, and has been
unjustifiably reassuring. Accurate assessment of Chernobyl’s future health
effects is not currently possible in the light of dose uncertainties, current debates
over radiation actions, and the lessons from the late consequences of atomic bomb
Because of the uncertainties over the dose from and the consequences of the Chernobyl
accident, it is essential that investigations of its effects should be broadened and
supported for the long term. Because of the problems with the international response
Chernobyl, the United Nations should initiate an independent review of the actions
assignments of the agencies concerned, with recommendations for dealing with future
international-scale accidents. These should involve independent scientists and ensure
cooperation rather than rivalry.
The health sector component of the first U.S. National Assessment, published in 2000,
synthesized the anticipated health impacts of climate variability and change for five
categories of health outcomes: impacts attributable to temperature, extreme weather
events (e.g., storms and floods), air pollution, water- and food-borne diseases, and
vector- and rodent-borne diseases. The Health Sector Assessment (HSA) concluded that
climate variability and change are likely to increase morbidity and mortality risks
for several climate-sensitive health outcomes, with the net impact uncertain. The
objective of this study was to update the first HSA based on recent publications that
address the potential impacts of climate variability and change in the United States
for the five health outcome categories. The literature published since the first HSA
supports the initial conclusions, with new data refining quantitative exposure–response
relationships for several health end points, particularly for extreme heat events
and air pollution. The United States continues to have a very high capacity to plan
for and respond to climate change, although relatively little progress has been noted
in the literature on implementing adaptive strategies and measures. Large knowledge
gaps remain, resulting in a substantial need for additional research to improve our
understanding of how weather and climate, both directly and indirectly, can influence
human health. Filling these knowledge gaps will help better define the potential health
impacts of climate change and identify specific public health adaptations to increase
Although adverse health effects of particulate matter with a diameter of < 100 nm
(nanoparticles) have been proposed, molecular and/or experimental evidence for their
facilitation of lung inflammation in vivo is not fully defined.
In the present study we investigated the effects of nanoparticles on lung inflammation
related to bacterial endotoxin [lipopolysaccharide (LPS)] in mice.
We intratracheally administered vehicle, two sizes (14 nm, 56 nm) of carbon black
nanoparticles (4 mg/kg), LPS (2.5 mg/kg), or LPS plus nanoparticles and evaluated
parameters for lung inflammation and coagulation. Nanoparticles alone induced slight
lung inflammation and significant pulmonary edema compared with vehicle. Fourteen-nanometer
nanoparticles intensively aggravated LPS-elicited lung inflammation and pulmonary
edema that was concomitant with the enhanced lung expression of interleukin-1β (IL-1β),
macrophage inflammatory protein-1α (MIP-1α), macrophage chemoattractant protein-1,
MIP-2, and keratinocyte chemoattractant in overall trend, whereas 56-nm nanoparticles
did not show apparent effects. Immunoreactivity for 8-hydroxyguanosine, a marker for
oxidative stress, was more intense in the lungs from the LPS + 14-nm nanoparticle
group than in those from the LPS group. Circulatory fibrinogen levels were higher
in the LPS + plus 14-nm nanoparticle group than in the LPS group.
Taken together, evidence indicates that nanoparticles can aggravate lung inflammation
related to bacterial endotoxin, which is more prominent with smaller particles. The
enhancement may be mediated, at least partly, via the increased local expression of
proinflammatory cytokines and via the oxidative stress. Furthermore, nanoparticles
can promote coagulatory disturbance accompanied by lung inflammation.
Extremes of temperature are associated with short-term increases in daily mortality.
We set out to identify subpopulations and mortality causes with increased susceptibility
to temperature extremes.
We conducted a case-only analysis using daily mortality and hourly weather data from
50 U.S. cities for the period 1989–2000, covering a total of 7,789,655 deaths. We
used distributions of daily minimum and maximum temperature in each city to define
extremely hot days (≥ 99th percentile) and extremely cold days (≤ 1st percentile),
respectively. For each (hypothesized) effect modifier, a city-specific logistic regression
model was fitted and an overall estimate calculated in a subsequent meta-analysis.
Older subjects [odds ratio (OR) = 1.020; 95% confidence interval (CI), 1.005–1.034],
diabetics (OR = 1.035; 95% CI, 1.010–1.062), blacks (OR = 1.037; 95% CI, 1.016–1.059),
and those dying outside a hospital (OR = 1.066; 95% CI, 1.036–1.098) were more susceptible
to extreme heat, with some differences observed between those dying from a cardiovascular
disease and other decedents. Cardiovascular deaths (OR = 1.053; 95% CI, 1.036–1.070),
and especially cardiac arrest deaths (OR =1.137; 95% CI, 1.051–1.230), showed a greater
relative increase on extremely cold days, whereas the increase in heat-related mortality
was marginally higher for those with coexisting atrial fibrillation (OR = 1.059; 95%
In this study we identified several subpopulations and mortality causes particularly
susceptible to temperature extremes. This knowledge may contribute to establishing
health programs that would better protect the vulnerable.
Methylmercury (MeHg) is a known neurotoxic agent, but the mechanisms by which MeHg
may act on reproductive pathways are relatively unknown. Several studies have indicated
potential changes in hormone levels as well as declines in vertebrates with increasing
dietary MeHg exposure.
The purpose of this study was to identify alterations in gene expression associated
with MeHg exposure, specifically those associated with previously observed changes
in reproduction and reproductive biomarkers. Fathead minnows, Pimephales promelas, were fed one of three diets that were similar to documented concentrations of MeHg
in the diets of wild invertivorous and piscivorous fish. We used a commercial macroarray
in conjunction with quantitative polymerase chain reaction to examine gene expression
in fish in relation to exposure to these environmentally relevant doses of MeHg.
Expression of genes commonly associated with endocrine disruption was altered with
Hg exposure. Specifically, we observed a marked up-regulation in vitellogenin mRNA
in individual Hg-exposed males and a significant decline in vitellogenin gene expression
in female fish with increasing Hg concentrations. Other genes identified by the macroarray
experiment included those associated with egg fertilization and development, sugar
metabolism, apoptosis, and electron transport. We also observed differences in expression
patterns between male and female fish not related to genes specifically associated
with reproduction, indicating a potential physiological difference in the reaction
of males and females to MeHg.
Gene expression data may provide insight into the mechanisms by which MeHg affects
reproduction in fish and indicate how MeHg differs in its effect from other heavy
metals and endocrine-disrupting compounds.
During August 2003, record high temperatures were observed across Europe, and France
was the country most affected. During this period, elevated ozone concentrations were
measured all over the country. Questions were raised concerning the contribution of
O3 to the health impact of the summer 2003 heat wave.
We used a time-series design to analyze short-term effects of temperature and O3 pollution on mortality. Counts of deaths were regressed on temperatures and O3 levels, controlling for possible confounders: long-term trends, season, influenza
outbreaks, day of the week, and bank holiday effects. For comparison with previous
results of the nine cities, we calculated pooled excess risk using a random effect
approach and an empirical Bayes approach.
For the nine cities, the excess risk of death is significant (1.01%; 95% confidence
interval, 0.58–1.44) for an increase of 10 μg/m3 in O3 level. For the 3–17 August 2003 period, the excess risk of deaths linked to O3 and temperatures together ranged from 10.6% in Le Havre to 174.7% in Paris. When
we compared the relative contributions of O3 and temperature to this joint excess risk, the contribution of O3 varied according to the city, ranging from 2.5% in Bordeaux to 85.3% in Toulouse.
We observed heterogeneity among the nine cities not only for the joint effect of O3 and temperatures, but also for the relative contribution of each factor. These results
confirmed that in urban areas O3 levels have a non-negligible impact in terms of public health.
Persistent organohalogen pollutant (POP) exposure may have a negative impact on reproductive
function. The objective of this study was to assess the impact of POP exposure on
the male hypothalamo–pituitary–gonadal axis.
Participants included 184 Swedish fishermen and spouses of pregnant women from Greenland
(n = 258), Warsaw, Poland (n = 113), and Kharkiv, Ukraine (n = 194).
Serum levels of 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153) and dichlorodiphenyl dichloroethene
(p,p′-DDE) were determined in the four populations, showing different exposure patterns:
Swedish fishermen, high CB-153/low p,p′-DDE; Greenland, high CB-153/high p,p′-DDE; Warsaw, low CB-153/moderate p,p′-DDE; Kharkiv, low CB-153/high p,p′-DDE. Serum was also analyzed for testosterone, estradiol, sex hormone-binding globulin
(SHBG), inhibin B, luteinizing hormone (LH), and follicle-stimulating hormone (FSH).
Free testosterone levels were calculated based on testosterone and SHBG.
We found significant center-to-center variations in the associations between exposure
and the outcomes. The most pronounced effects were observed in Kharkiv, where statistically
significant positive associations were found between the levels of both CB-153 and
p,p′-DDE and SHBG, as well as LH. In Greenland, there was a positive association between
CB-153 exposure and LH. In the pooled data set from all four centers, there was positive
association between p,p′-DDE and FSH levels [β = 1.1 IU/L; 95% confidence interval (CI), 1.0–1.1 IU/L]. The
association between CB-153 levels and SHBG was of borderline statistical significance
(β = 0.90 nmol/L; 95% CI, −0.04 to 1.9 nmol/L).
Gonadotropin levels and SHBG seem to be affected by POP exposure, but the pattern
of endocrine response is the subject of considerable geographic variation.
Ambient air is polluted with a mixture of pulmonary toxicants. Previous studies indicate
that prior exposure to atmospheric oxidant pollutants such as ozone may significantly
alter the response to other pollutants, such as 1-nitronaphthalene (1-NN). 1-NN, a
component of the particulate exhaust from diesel engines, has been found at low concentrations
in ambient air. Using a metabolomic approach, we investigated inflammatory responses
in arachidonic and linoleic acid biochemical cascades (35 metabolites) and the expression
of 19 cytokines/chemokines at three time points (2, 6, and 24 hr) following exposure
to 1-NN with and without prior long-term O3 exposure. Long-term O3 exposure is associated with biochemical changes that have been shown to render the
lung resistant to further O3 exposure. This study indicates that airways of O3-tolerant rats exhibited a low level of chronic inflammation, rendering the lungs
more susceptible to other environmental pollutants such as 1-NN. Specifically, a 12.5-mg/kg
dose of 1-NN to O3-tolerant rats produced significantly higher levels of cysteinyl-leukotrienes in bronchiolar
lavage fluid even when compared to a 50-mg/kg dose of 1-NN in rats exposed to filtered
air. Collectively, these results indicate that the combination of exposures as encountered
in polluted ambient air are considerably more injurious to the lung than would be
anticipated from previous studies employing single exposures. The observed synergism
between O3 and 1-NN may be causally related to a shift in a T-helper 1 to T-helper 2 immune
response in the airways.
The inhalation of radon, a well-established human carcinogen, is the principal—and
omnipresent—source of radioactivity exposure for the general population of most countries.
Scientists have thus sought to assess the lung cancer risk associated with indoor
radon. Our aim here is to assess this risk in France, using all available epidemiologic
results and performing an uncertainty analysis.
We examined the exposure–response relations derived from cohorts of miners and from
joint analyses of residential case-control studies and considered the interaction
between radon and tobacco. The exposure data come from measurement campaigns conducted
since the beginning of the 1980s by the Institute for Radiation Protection and Nuclear
Safety and the Directorate-General of Health in France. We quantified the uncertainties
associated with risk coefficients and exposures and calculated their impact on risk
The estimated number of lung cancer deaths attributable to indoor radon exposure ranges
from 543 [90% uncertainty interval (UI), 75–1,097] to 3,108 (90% UI, 2,996–3,221),
depending on the model considered. This calculation suggests that from 2.2% (90% UI,
0.3–4.4) to 12.4% (90% UI, 11.9–12.8) of these deaths in France may be attributable
to indoor radon.
In this original work we used different exposure–response relations from several epidemiologic
studies and found that regardless of the relation chosen, the number of lung cancer
deaths attributable to indoor radon appears relatively stable. Smokers can reduce
their risk not only by reducing their indoor radon concentration but also by giving
Miners inhaling respirable coal dust (CD) frequently develop coal workers’ pneumoconiosis,
a dust-associated pneumoconiosis characterized by lung inflammation and variable fibrosis.
Many coal miners are also exposed to polycyclic aromatic hydrocarbon (PAH) components
of diesel engine exhaust and cigarette smoke, which may contribute to lung disease
in these workers. Recently, apoptosis was reported to play a critical role in the
development of another pneumoconiosis of miners, silicosis. In addition, CD was reported
to suppress cytochrome P450 1A1 (CYP1A1) induction by PAHs.
We investigated the hypothesis that apoptosis plays a critical role in lung injury
and down-regulation of CYP1A1 induction in mixed exposures to CD and PAHs. We exposed
rats intratracheally to 0.0, 2.5, 10.0, 20.0, or 40.0 mg/rat CD and, 11 days later,
to intraperitoneal β-naphthoflavone (BNF), a PAH. In another group of rats exposed
to CD and BNF, caspase activity was inhibited by injection of the pan-caspase inhibitor
Q-VD-OPH [quinoline-Val-Asp (OMe)-CH2-OPH].
In rats exposed to BNF, CD exposure increased alveolar expression of the proapoptotic
mediator Bax but decreased CYP1A1 induction relative to BNF exposure alone. Pan-caspase
inhibition decreased CD-associated Bax expression and apoptosis but did not restore
CYP1A1 activity. Further, CD-induced lung inflammation and alveolar epithelial cell
hypertrophy and hyperplasia were not suppressed by caspase inhibition.
Combined BNF and CD exposure increased Bax expression and apoptosis in the lung, but
Bax and apoptosis were not the major determinants of early lung injury in this model.
Spatial estimations are increasingly used to estimate geocoded ambient particulate
matter (PM) concentrations in epidemiologic studies because measures of daily PM concentrations
are unavailable in most U.S. locations. This study was conducted to a) assess the feasibility of large-scale kriging estimations of daily residential-level
ambient PM concentrations, b) perform and compare cross-validations of different kriging models, c) contrast three popular kriging approaches, and d ) calculate SE of the kriging estimations. We used PM data for PM with aerodynamic
diameter ≤10 μm (PM10) and aerodynamic diameter ≤ 2.5 μm (PM2.5) from the U.S. Environmental Protection
Agency for the year 2000. Kriging estimations were performed at 94,135 geocoded addresses
of Women’s Health Initiative study participants using the ArcView geographic information
system. We developed a semiautomated program to enable large-scale daily kriging estimation
and assessed validity of semivariogram models using prediction error (PE), standardized
prediction error (SPE), root mean square standardized (RMSS), and SE of the estimated
PM. National- and regional-scale kriging performed satisfactorily, with the former
slightly better. The average PE, SPE, and RMSS of daily PM10 semivariograms using regular ordinary kriging with a spherical model were 0.0629,
−0.0011, and 1.255 μg/m3, respectively; the average SE of the estimated residential-level PM10 was 27.36 μg/m3. The values for PM2.5 were 0.049, 0.0085, 1.389, and 4.13 μg/m3, respectively. Lognormal ordinary kriging yielded a smaller average SE and effectively
eliminated out-of-range predicted values compared to regular ordinary kriging. Semiautomated
daily kriging estimations and semivariogram cross-validations are feasible on a national
scale. Lognormal ordinary kriging with a spherical model is valid for estimating daily
ambient PM at geocoded residential addresses.
The hurricanes and flooding in New Orleans, Louisiana, in October and November 2005
resulted in damp conditions favorable to the dispersion of bioaerosols such as mold
spores and endotoxin.
Our objective in this study was to assess potential human exposure to bioaerosols
in New Orleans after the flooding of the city.
A team of investigators performed continuous airborne sampling for mold spores and
endotoxin outdoors in flooded and nonflooded areas, and inside homes that had undergone
various levels of remediation, for periods of 5–24 hr during the 2 months after the
The estimated 24-hr mold concentrations ranged from 21,000 to 102,000 spores/m3 in outdoor air and from 11,000 to 645,000 spores/m3 in indoor air. The mean outdoor spore concentration in flooded areas was roughly
double the concentration in nonflooded areas (66,167 vs. 33,179 spores/m3; p < 0.05). The highest concentrations were inside homes. The most common mold species
were from the genera of Cladosporium and Aspergillus/Penicillium; Stachybotrys was detected in some indoor samples. The airborne endotoxin concentrations ranged
from 0.6 to 8.3 EU (endo-toxin units)/m3 but did not vary with flooded status or between indoor and outdoor environments.
The high concentration of mold measured indoors and outdoors in the New Orleans area
is likely to be a significant respiratory hazard that should be monitored over time.
Workers and returning residents should use appropriate personal protective equipment
and exposure mitigation techniques to prevent respiratory morbidity and long-term
Exposure to air pollution and, more specifically, particulate matter (PM) is associated
with adverse health effects. However, the specific PM characteristics responsible
for biological effects have not been defined.
In this project we examined the composition, sources, and relative toxicity of samples
of PM with aerodynamic diameter ≥2.5 μm (PM2.5) collected from sites within the Southeastern Aerosol Research and Characterization
(SEARCH) air monitoring network during two seasons. These sites represent four areas
with differing sources of PM2.5, including local urban versus regional sources, urban areas with different contributions
of transportation and industrial sources, and a site influenced by Gulf of Mexico
We collected samples from each site during the winter and summer of 2004 for toxicity
testing and for chemical analysis and chemical mass balance–based source apportionment.
We also collected PM2.5 downwind of a series of prescribed forest burns. We assessed the toxicity of the
samples by instillation into rat lungs and assessed general toxicity, acute cytotoxicity,
and inflammation. Statistical dose–response modeling techniques were used to rank
the relative toxicity and compare the seasonal differences at each site. Projection-to-latent-surfaces
(PLS) techniques examined the relationships among sources, chemical composition, and
toxicologic end points.
Results and conclusions
Urban sites with high contributions from vehicles and industry were most toxic.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly lipophilic chemical that distributes into adipose tissue,
especially at low doses. However, at high doses TCDD sequesters in liver because it
induces cytochrome P450 1A2 (CYP1A2) that binds TCDD. A physiologically based pharmacokinetic
(PBPK) model was developed that included an inducible elimination rate of TCDD in
the Sprague-Dawley rat. Objectives of this work were to characterize the influence
of induction of CYP1A2 and adipose tissue mass fraction on the terminal elimination
half-life (t1/2) of TCDD using this PBPK model. When the model assumes a fixed elimination of TCDD,
t1/2 increases with dose, due to hepatic sequestration. Because experimental data indicate
that the t1/2 of TCDD decreases with dose, the model was modified to include an inducible elimination
rate. The PBPK model was then used to compare the t1/2 after an increase of adipose tissue mass fraction from 6.9 to 70%. The model suggests
that at low exposures, increasing adipose tissue mass increases the terminal t1/2. However, at higher exposures, as CYP1A2 is induced, the relationship between adipose
tissue mass and t1/2 reaches a plateau. This demonstrates that an inducible elimination rate is needed
in a PBPK model in order to describe the pharmacokinetics of TCDD. At low exposures
these models are more sensitive to parameters related to partitioning into adipose
Arsenic is both a human carcinogen and a chemotherapeutic agent, but the mechanism
of neither arsenic-induced carcinogenesis nor tumor selective cytotoxicity is clear.
Using a model cell line in which p53 expression is regulated exogenously in a tetracycline-off
system (TR9-7 cells), our laboratory has shown that arsenite disrupts mitosis and
that p53-deficient cells [p53(−)], in contrast to p53-expressing cells [p53(+)], display greater sensitivity to arsenite-induced mitotic arrest and apoptosis.
Our goal was to examine the role p53 plays in protecting cells from arsenite-induced
p53(+) and p53(−) cells were synchronized in G2 phase using Hoechst 33342 and released from synchrony in the presence or absence
of 5 μM sodium arsenite.
Mitotic index analysis demonstrated that arsenite treatment delayed exit from G2 in p53(+) and p53(−) cells. Arsenite-treated p53(+) cells exited mitosis normally, whereas p53(−) cells exited mitosis with delayed kinetics. Microarray analysis performed on mRNAs
of cells exposed to arsenite for 0 and 3 hr after release from G2 phase synchrony showed that arsenite induced inhibitor of DNA binding-1 (ID1) differentially
in p53(+)and p53(−) cells. Immunoblotting con-firmed that ID1 induction was more extensive and sustained
in p53(+) cells.
p53 promotes mitotic exit and leads to more extensive ID1 induction by arsenite. ID1
is a dominant negative inhibitor of transcription that represses cell cycle regulatory
genes and is elevated in many tumors. ID1 may play a role in the survival of arsenite-treated
p53(+) cells and contribute to arsenic carcinogenicity.
This report summarizes the Brazilian experience on the design and implementation of
environmental health, with contributions from Argentina, Canada, and Cuba, presented
at the International Symposium on the Development of Indicators for Environmental
Health Integrated Management, held in Recife, Pernambuco, Brazil, on 17–18 June 2004.
The methodology for the development of environmental health indicators has been used
as a reference in the implementation of environmental health surveillance in Brazil.
This methodology has provided tools and processes to facilitate the understanding
and to measure the determinants of risks to environmental health, to help decision
makers control those risks.
Polyvinyl chloride (PVC) materials have been linked to asthma in several epidemiologic
studies, but the possible causal factors remain unknown.
We challenged 10 subjects experimentally to degraded PVC products under controlled
conditions. All of the subjects had previously experienced respiratory symptoms suspected
to be caused by this kind of exposure in their work place. Five subjects had doctor-diagnosed
The subjects were exposed to degraded PVC material in an exposure chamber; a challenge
with ceramic tile was used as the control test. We followed exhaled nitric oxide,
nasal NO, lung functions, cytokines [tumor necrosis factor-α (TNF-α), interleukin-4
(IL-4), IL-6, and IL-12] and NO in nasal lavage fluid (NAL) during and after the exposures.
We also measured 2-ethylhexanol in exhaled breath samples and NAL.
On the morning after the PVC exposure, subjects reported respiratory tract symptoms
significantly more often than they did after the control test (50% vs. 0%, respectively;
p = 0.029; n = 10). We did not detect any changes in lung functions or levels of exhaled NO, nasal
NO, or NO in NAL after PVC challenge compared with the control test. Cytokine levels
increased after both exposures, with no statistically significant difference between
situations. All of the exhaled breath samples collected during the PVC exposure contained
PVC flooring challenge can evoke respiratory tract symptoms in exposed subjects. Our
results do not support the hypothesis that PVC materials themselves evoke immediate
asthmatic reactions. The chamber test used is well suited to this type of exposure
Otitis media is one of the most common infections in young children. Although exposure
to environmental tobacco smoke is a known risk factor associated with otitis media,
little information is available regarding the potential association with air pollution.
We set out to study the relationship between exposure to traffic-related air pollution
and otitis media in two birth cohorts.
Individual estimates of outdoor concentrations of traffic-related air pollutants—nitrogen
dioxide, fine particles [particulate matter with aerodynamic diameters ≤ 2.5 μm (PM2.5)], and elemental carbon—were calculated for home addresses of approximately 3,700
and 650 infants from birth cohort studies in the Netherlands and Germany, respectively.
Air pollution exposure was analyzed in relation to physician diagnosis of otitis media
in the first 2 years of life.
Odds ratios (adjusted for known major risk factors) for otitis media indicated positive
associations with traffic-related air pollutants. An increase in 3 μg/m3 PM2.5, 0.5 μg/m3 elemental carbon, and 10 μg/m3 NO2 was associated with odds ratios of 1.13 (95% confidence interval, 1.00–1.27), 1.10
(1.00–1.22), and 1.14 (1.03–1.27) in the Netherlands and 1.24 (0.84–1.83), 1.10 (0.86–1.41),
and 1.14 (0.87–1.49) in Germany, respectively.
These findings indicate an association between exposure to traffic-related air pollutants
and the incidence of otitis media. Given the ubiquitous nature of air pollution exposure
and the importance of otitis media to children’s health, these findings have significant
public health implications.
We conducted a longitudinal study to assess the exposure of 23 elementary school–age
children to pyrethroid pesticides, using urinary pyrethroid metabolites as exposure
biomarkers. We substituted most of the children’s conventional diets with organic
food items for 5 consecutive days and collected two daily spot urine samples, first
morning and before bedtime voids, throughout the 15-day study period. We analyzed
urine samples for five common pyrethroid metabolites. We found an association between
the parents’ self-reported pyrethroid use in the residential environment and elevated
pyrethroid metabolite levels found in their children’s urine. Children were also exposed
to pyrethroids through their conventional diets, although the magnitude was smaller
than for the residential exposure. Children’s ages appear to be significantly associated
with pyrethroids exposure, which is likely attributed to the use of pyrethroids around
the premises or in the facilities where older children engaged in the outdoor activities.
We conclude that residential pesticide use represents the most important risk factor
for children’s exposure to pyrethroid insecticides. Because of the wide use of pyrethroids
in the United States, the findings of this study are important for both children’s
pesticide exposure assessment and environmental public health.
We previously demonstrated that among 54 infants in neonatal intensive care units,
exposure to polyvinyl chloride plastic medical devices containing the plasticizer
di(2-ethylhexyl) phthalate (DEHP) is associated with urinary concentrations of mono(2-ethylhexyl)
phthalate (MEHP), a DEHP metabolite. In this follow-up report, we studied the neonates’
exposure to DEHP-containing devices in relation to urinary concentrations of two other
DEHP metabolites, and to urinary concentrations of metabolites of dibutyl phthalate
(DBP) and benzylbutyl phthalate (BzBP), phthalates found in construction materials
and personal care products.
A priori, we classified the intensiveness of these 54 infants’ exposure to DEHP-containing
medical products. We measured three metabolites of DEHP in infants’ urine: MEHP and
two of its oxidative metabolites, mono(2-ethyl-5-hydroxylhexyl) phthalate (MEHHP)
and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP). We also measured monobutyl phthalate
(MBP), a metabolite of DBP, and monobenzyl phthalate (MBzP), a metabolite of BzBP.
Intensiveness of DEHP-containing product use was monotonically associated with all
three DEHP metabolites. Urinary concentrations of MEHHP and MEOHP among infants in
the high-DEHP-intensiveness group were 13–14 times the concentrations among infants
in the low-intensiveness group (p ≤ 0.007). Concentrations of MBP were somewhat higher in the medium-and high-DEHP-intensiveness
group; MBzP did not vary by product use group. Incorporating all phthalate data into
a structural equation model confirmed the specific monotonic association between intensiveness
of product use and biologic measures of DEHP.
Inclusion of the oxidative metabolites MEHHP and MEOHP strengthened the association
between intensiveness of product use and biologic indices of DEHP exposure over that
observed with MEHP alone.
We analyzed the chest radiographs (CXRs) of 249 clinically healthy children, 230 from
southwest Mexico City and 19 from Tlaxcala. In contrast to children from Tlaxcala,
children from southwest Mexico City were chronically exposed to ozone levels exceeding
the U.S. National Ambient Air Quality Standards for an average of 4.7 hr/day and to
concentrations of particulate matter (PM) with aerodynamic diameters ≤2.5 μm (PM2.5) above the annual standard. CXRs of Mexico City children demonstrated bilateral hyperinflation
(151 of 230) and increased linear markings (121 of 230). Hyperinflation and interstitial
markings were significantly more common in Mexico City children (p < 0.0002 and 0.00006 respectively). Mexico City boys had a higher probability of
developing interstitial markings with age (p = 0.004). Computed tomography (CT) scans were obtained in 25 selected Mexico City
children with abnormal CXRs. Mild bronchial wall thickening was seen in 10 of 25,
prominent central airways in 4 of 25, air trapping in 8 of 21, and pulmonary nodules
in 2 of 21. Only 7.8% of Mexico City children had abnormal lung function tests based
on predicted values. These findings are consistent with bronchiolar, peribronchiolar,
and/or alveolar duct inflammation, possibly caused by ozone, PM, and lipopolysaccharide
exposure. The epidemiologic implications of these findings are important for children
residing in polluted environments, because bronchiolar disease could lead to chronic
pulmonary disease later in life.
To explore possible associations between autism spectrum disorders (ASD) and environmental
exposures, we linked the California autism surveillance system to estimated hazardous
air pollutant (HAP) concentrations compiled by the U.S. Environmental Protection Agency.
Subjects included 284 children with ASD and 657 controls, born in 1994 in the San
Francisco Bay area. We assigned exposure level by census tract of birth residence
for 19 chemicals we identified as potential neurotoxicants, developmental toxicants,
and/or endocrine disruptors from the 1996 HAPs database. Because concentrations of
many of these were highly correlated, we combined the chemicals into mechanistic and
structural groups, calculating summary index scores. We calculated ASD risk in the
upper quartiles of these group scores or individual chemical concentrations compared
with below the median, adjusting for demographic factors.
The adjusted odds ratios (AORs) were elevated by 50% in the top quartile of chlorinated
solvents and heavy metals [95% confidence intervals (CIs), 1.1–2.1], but not for aromatic
solvents. Adjusting for these three groups simultaneously led to decreased risks for
the solvents and increased risk for metals (AORs for metals: fourth quartile = 1.7;
95% CI, 1.0–3.0; third quartile = 1.95; 95% CI, 1.2–3.1). The individual compounds
that contributed most to these associations included mercury, cadmium, nickel, trichloroethylene,
and vinyl chloride.
Our results suggest a potential association between autism and estimated metal concentrations,
and possibly solvents, in ambient air around the birth residence, requiring confirmation
and more refined exposure assessment in future studies.
Trichloroethylene (TCE) is a common environmental contaminant at hazardous waste sites
and in ambient and indoor air. Assessing the human health risks of TCE is challenging
because of its inherently complex metabolism and toxicity and the widely varying perspectives
on a number of critical scientific issues. Because of this complexity, the U.S. Environmental
Protection Agency (EPA) drew upon scientific input and expertise from a wide range
of groups and individuals in developing its 2001 draft health risk assessment of TCE.
This scientific outreach, which was aimed at engaging a diversity of perspectives
rather than developing consensus, culminated in 2000 with 16 state-of-the-science
articles published together as an Environmental Health Perspectives supplement. Since that time, a substantial amount of new scientific research has
been published that is relevant to assessing TCE health risks. Moreover, a number
of difficult or controversial scientific issues remain unresolved and are the subject
of a scientific consultation with the National Academy of Sciences coordinated by
the White House Office of Science and Technology Policy and co-sponsored by a number
of federal agencies, including the U.S. EPA. The articles included in this mini-monograph
provide a scientific update on the most prominent of these issues: the pharmacokinetics
of TCE and its metabolites, mode(s) of action and effects of TCE metabolites, the
role of peroxisome proliferator–activated receptor in TCE toxicity, and TCE cancer
Much progress has been made in understanding the complex pharmacokinetics of trichloroethylene
(TCE). Qualitatively, it is clear that TCE is metabolized to multiple metabolites
either locally or into systemic circulation. Many of these metabolites are thought
to have toxicologic importance. In addition, efforts to develop physiologically based
pharmacokinetic (PBPK) models have led to a better quantitative assessment of the
dosimetry of TCE and several of its metabolites. As part of a mini-monograph on key
issues in the health risk assessment of TCE, this article is a review of a number
of the current scientific issues in TCE pharmacokinetics and recent PBPK modeling
efforts with a focus on literature published since 2000. Particular attention is paid
to factors affecting PBPK modeling for application to risk assessment. Recent TCE
PBPK modeling efforts, coupled with methodologic advances in characterizing uncertainty
and variability, suggest that rigorous application of PBPK modeling to TCE risk assessment
appears feasible at least for TCE and its major oxidative metabolites trichloroacetic
acid and trichloroethanol. However, a number of basic structural hypotheses such as
enterohepatic recirculation, plasma binding, and flow- or diffusion-limited treatment
of tissue distribution require additional evaluation and analysis. Moreover, there
are a number of metabolites of potential toxicologic interest, such as chloral, dichloroacetic
acid, and those derived from glutathione conjugation, for which reliable pharmacokinetic
data is sparse because of analytical difficulties or low concentrations in systemic
circulation. It will be a challenge to develop reliable dosimetry for such cases.
Trichloroethylene (TCE) exposure has been associated with increased risk of liver
and kidney cancer in both laboratory animal and epidemiologic studies. The U.S. Environmental
Protection Agency 2001 draft TCE risk assessment concluded that it is difficult to
determine which TCE metabolites may be responsible for these effects, the key events
involved in their modes of action (MOAs), and the relevance of these MOAs to humans.
In this article, which is part of a mini-monograph on key issues in the health risk
assessment of TCE, we present a review of recently published scientific literature
examining the effects of TCE metabolites in the context of the preceding questions.
Studies of the TCE metabolites dichloroacetic acid (DCA), trichloroacetic acid (TCA),
and chloral hydrate suggest that both DCA and TCA are involved in TCE-induced liver
tumorigenesis and that many DCA effects are consistent with conditions that increase
the risk of liver cancer in humans. Studies of S-(1,2-dichlorovinyl)-l-cysteine have revealed a number of different possible cell signaling effects that
may be related to kidney tumorigenesis at lower concentrations than those leading
to cytotoxicity. Recent studies of trichloroethanol exploring an alternative hypothesis
for kidney tumorigenesis have failed to establish the formation of formate as a key
event for TCE-induced kidney tumors. Overall, although MOAs and key events for TCE-induced
liver and kidney tumors have yet to be definitively established, these results support
the likelihood that toxicity is due to multiple metabolites through several MOAs,
none of which appear to be irrelevant to humans.
Peroxisome proliferator–activated receptor α (PPARα) is thought to be involved in
several different diseases, toxic responses, and receptor pathways. The U.S. Environmental
Protection Agency 2001 draft trichloroethylene (TCE) risk assessment concluded that
although PPAR may play a role in liver tumor induction, the role of its activation
and the sequence of subsequent events important to tumorigenesis are not well defined,
particularly because of uncertainties concerning the extraperoxisomal effects. In
this article, which is part of a mini-monograph on key issues in the health risk assessment
of TCE, we summarize some of the scientific literature published since that time on
the effects and actions of PPARα that help inform and illustrate the key scientific
questions relevant to TCE risk assessment. Recent analyses of the role of PPARα in
gene expression changes caused by TCE and its metabolites provide only limited data
for comparison with other PPARα agonists, particularly given the difficulties in interpreting
results involving PPARα knockout mice. Moreover, the increase in data over the last 5 years from the broader
literature on PPARα agonists presents a more complex array of extraperoxisomal effects
and actions, suggesting the possibility that PPARα may be involved in modes of action
(MOAs) not only for liver tumors but also for other effects of TCE and its metabolites.
In summary, recent studies support the conclusion that determinations of the human
relevance and susceptibility to PPARα-related MOA(s) of TCE-induced effects cannot
rely on inferences regarding peroxisome proliferation per se and require a better
understanding of the interplay of extraperoxisomal events after PPARα agonism.
A large body of epidemiologic evidence exists for exploring causal associations between
cancer and trichloroethylene (TCE) exposure. The U.S. Environmental Protection Agency
2001 draft TCE health risk assessment concluded that epidemiologic studies, on the
whole, support associations between TCE exposure and excess risk of kidney cancer,
liver cancer, and lymphomas, and, to a lesser extent, cervical cancer and prostate
cancer. As part of a mini-monograph on key issues in the health risk assessment of
TCE, this article reviews recently published scientific literature examining cancer
and TCE exposure and identifies four issues that are key to interpreting the larger
body of epidemiologic evidence: a) relative sensitivity of cancer incidence and mortality data; b) different classifications of lymphomas, including non-Hodgkin lymphoma; c) differences in data and methods for assigning TCE exposure status; and d) different methods employed for causal inferences, including statistical or meta-analysis
approaches. The recent epidemiologic studies substantially expand the epidemiologic
database, with seven new studies available on kidney cancer and somewhat fewer studies
available that examine possible associations at other sites. Overall, recently published
studies appear to provide further support for the kidney, liver, and lymphatic systems
as targets of TCE toxicity, suggesting, as do previous studies, modestly elevated
(typically 1.5–2.0) site-specific relative risks, given exposure conditions in these
studies. However, a number of challenging issues need to be considered before drawing
causal conclusions about TCE exposure and cancer from these data.
EHP publishes on a continuous publication basis, which means each article is published online immediately upon completion.