Table of Contents

Abstract

Background: The fungus Aspergillus fumigatus (A. fumigatus) is the leading cause of invasive mold infections, which cause severe disease and death in immunocompromised people. Use of triazole antifungal medications in recent decades has improved patient survival; however, triazole-resistant infections have become common in parts of Europe and are emerging in the United States. Triazoles are also a class of fungicides used in plant agriculture, and certain triazole-resistant A. fumigatus strains found causing disease in humans have been linked to environmental fungicide use.

Objectives: We examined U.S. temporal and geographic trends in the use of triazole fungicides using U.S. Geological Survey agricultural pesticide use estimates.

Discussion: Based on our analysis, overall tonnage of triazole fungicide use nationwide was relatively constant during 1992–2005 but increased $>4\text{-fold}$ during 2006–2016 to $2.9\hspace{0.17em}\text{million}\hspace{0.17em}\text{kg}$ in 2016. During 1992–2005, triazole fungicide use occurred mostly in orchards and grapes, wheat, and other crops, but recent increases in use have occurred primarily in wheat, corn, soybeans, and other crops, particularly in Midwest and Southeast states. We conclude that, given the chemical similarities between triazole fungicides and triazole antifungal drugs used in human medicine, increased monitoring for environmental and clinical triazole resistance in A. fumigatus would improve overall understanding of these interactions, as well as help identify strategies to mitigate development and spread of resistance. https://doi.org/10.1289/EHP7484

Abstract

Background: The twin pandemics of COVID-19 and systemic racism during 2020 have forced a conversation across many segments of our society, including the environmental health sciences (EHS) research community. We have seen the proliferation of statements of solidarity with the Black Lives Matter movement and commitments to fight racism and health inequities from academia, nonprofit organizations, governmental agencies, and private corporations. Actions must now arise from these promises. As public health and EHS scientists, we must examine the systems that produce and perpetuate inequities in exposure to environmental pollutants and associated health effects.

Objectives: We outline five recommendations the EHS research community can implement to confront racism and move our science forward for eliminating racial inequities in environmental health.

Discussion: Race is best considered a political label that promotes inequality. Thus, we should be wary of equating race with biology. Further, EHS researchers should seriously consider racism as a plausible explanation of racial disparities in health and consider structural racism as a factor in environmental health risk/impact assessments, as well as multiple explanations for racial differences in environmental exposures and health outcomes. Last, the EHS research community should develop metrics to measure racism and a set of guidelines on the use and interpretation of race and ethnicity within the environmental sciences. Numerous guidelines exist in other disciplines that can serve as models. By taking action on each of these recommendations, we can make significant progress toward eliminating racial disparities. https://doi.org/10.1289/EHP8186

Abstract

Background: Nitrate is a widespread groundwater contaminant and a leading cause of drinking water quality violations in California. Associations between nitrate exposure and select adverse birth outcomes have been suggested, but few studies have examined gestational exposures to nitrate and risk of preterm birth (before 37 wk gestation).

Objective: We investigated the association between elevated nitrate in drinking water and spontaneous preterm birth through a within-mother retrospective cohort study of births in California.

Methods: We acquired over 6 million birth certificate records linked with Office of Statewide Health Planning and Development hospital discharge data for California births from 2000–2011. We used public water system monitoring records to estimate nitrate concentrations in drinking water for each woman’s residence during gestation. After exclusions, we constructed a sample of 1,443,318 consecutive sibling births in order to conduct a within-mother analysis. We used separate conditional logistic regression models to estimate the odds of preterm birth at 20–31 and 32–36 wk, respectively, among women whose nitrate exposure changed between consecutive pregnancies.

Results: Spontaneous preterm birth at 20–31 wk was increased in association with tap water nitrate concentrations during pregnancy of 5 to $<10\mathrm{mg}/\mathrm{L}$ [odds ratio $\left(\text{OR}\right)=1.47$; 95% confidence interval (CI): 1.29, 1.67] and $\ge 10\mathrm{mg}/\mathrm{L}$ ($\text{OR}=2.52$; 95% CI: 1.49, 4.26) compared with $<5\mathrm{mg}/\mathrm{L}$ (as nitrogen). Corresponding estimates for spontaneous preterm birth at 32–36 wk were positive but close to the null for 5 to $<10\mathrm{mg}/\mathrm{L}$ nitrate ($\text{OR}=1.08$; 95% CI: 1.02, 1.15) and for $\ge 10\mathrm{mg}/\mathrm{L}$ nitrate ($\text{OR}=1.05$; 95% CI: 0.85, 1.31) vs. $<5\mathrm{mg}/\mathrm{L}$ nitrate. Our findings were similar in several secondary and sensitivity analyses, including in a conventional individual-level design.

Discussion: The results suggest that nitrate in drinking water is associated with increased odds of spontaneous preterm birth. Notably, we estimated modestly increased odds associated with tap water nitrate concentrations of 5 to $<10\mathrm{mg}/\mathrm{L}$ (below the federal drinking water standard of $10\mathrm{mg}/\mathrm{L}$) relative to $<5\mathrm{mg}/\mathrm{L}$. https://doi.org/10.1289/EHP8205

Abstract

Background: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and toxic environmental pollutant. Gestational exposure to TCDD has been linked to cognitive and motor deficits, and increased incidence of autism spectrum disorder (ASD) traits in children. Most animal studies of these neurodevelopmental effects involve acute TCDD exposure, which does not model typical exposure in humans.

Objectives: The aim of the study was to establish a dietary low-dose gestational TCDD exposure protocol and performed an initial characterization of the effects on offspring behavior, neurodevelopmental phenotypes, and gene expression.

Methods: Throughout gestation, pregnant C57BL/6J mice were fed a diet containing a low dose of TCDD ($9\text{\hspace{0.17em}ng}$ TCDD/kg body weight per day) or a control diet. The offspring were tested in a battery of behavioral tests, and structural brain alterations were investigated by magnetic resonance imaging. The dendritic morphology of pyramidal neurons in the hippocampal Cornu Ammonis (CA)1 area was analyzed. RNA sequencing was performed on hippocampi of postnatal day 14 TCDD-exposed and control offspring.

Results: TCDD-exposed females displayed subtle deficits in motor coordination and reversal learning. Volumetric difference between diet groups were observed in regions of the hippocampal formation, mammillary bodies, and cerebellum, alongside higher dendritic arborization of pyramidal neurons in the hippocampal CA1 region of TCDD-exposed females. RNA-seq analysis identified 405 differentially expressed genes in the hippocampus, enriched for genes with functions in regulation of microtubules, axon guidance, extracellular matrix, and genes regulated by SMAD3.

Discussion: Exposure to $9\text{\hspace{0.17em}ng}$ TCDD/kg body weight per day throughout gestation was sufficient to cause specific behavioral and structural brain phenotypes in offspring. Our data suggest that alterations in SMAD3-regulated microtubule polymerization in the developing postnatal hippocampus may lead to an abnormal morphology of neuronal dendrites that persists into adulthood. These findings show that environmental low-dose gestational exposure to TCDD can have significant, long-term impacts on brain development and function. https://doi.org/10.1289/EHP7352

Abstract

Background: Understanding the epidemic of chronic kidney disease of uncertain etiology may be critical for health policies and public health responses. Recent studies have shown that microplastics (MPs) contaminate our food chain and accumulate in the gut, liver, kidney, muscle, and so on. Humans manufacture many plastics-related products. Previous studies have indicated that particles of these products have several effects on the gut and liver. Polystyrene (PS)-MPs (PS-MPs) induce several responses, such as oxidative stress, and affect living organisms.

Objectives: The aim of this study was to investigate the effects of PS-MPs in kidney cells in vitro and in vivo.

Methods: PS-MPs were evaluated in human kidney proximal tubular epithelial cells (HK-2 cells) and male C57BL/6 mice. Mitochondrial reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, inflammation, and autophagy were analyzed in kidney cells. In vivo, we evaluated biomarkers of kidney function, kidney ultrastructure, muscle mass, and grip strength, and urine protein levels, as well as the accumulation of PS-MPs in the kidney tissue.

Results: Uptake of PS-MPs at different concentrations by HK-2 cells resulted in higher levels of mitochondrial ROS and the mitochondrial protein Bad. Cells exposed to PS-MPs had higher ER stress and markers of inflammation. MitoTEMPO, which is a mitochondrial ROS antioxidant, mitigated the higher levels of mitochondrial ROS, Bad, ER stress, and specific autophagy-related proteins seen with PS-MP exposure. Furthermore, cells exposed to PS-MPs had higher protein levels of LC3 and Beclin 1. PS-MPs also had changes in phosphorylation of mitogen-activated protein kinase (MAPK) and protein kinase B (AKT)/mitogen-activated protein kinase (mTOR) signaling pathways. In an in vivo study, PS-MPs accumulated and the treated mice had more histopathological lesions in the kidneys and higher levels of ER stress, inflammatory markers, and autophagy-related proteins in the kidneys after PS-MPs treatment by oral gavage.

Conclusions: The results suggest that PS-MPs caused mitochondrial dysfunction, ER stress, inflammation, and autophagy in kidney cells and accumulated in HK-2 cells and in the kidneys of mice. These results suggest that long-term PS-MPs exposure may be a risk factor for kidney health. https://doi.org/10.1289/EHP7612

Abstract

Background: During food animal production, animals are exposed to, colonized by, and sometimes infected with bacteria that may contaminate animal products with susceptible and multidrug-resistant organisms (MDRO). The United States’ Organic Foods Production Act resulted in decreased antibiotic use in some animal production operations. Some studies have reported that decreased antibiotic use is associated with reduced MDRO on meat.

Objectives: The aim of this study was to investigate associations of meat production and processing methods with MDRO and overall bacterial contamination of retail meats.

Methods: Bacterial contamination data from 2012 to 2017 for chicken breast, ground beef, ground turkey, and pork chops were downloaded from the National Antimicrobial Resistance Monitoring System. Poisson regression models with robust variance were used to estimate associations with MDRO contamination and any contamination (adjusted for year and meat type) overall, and according to bacteria genus (Salmonella, Campylobacter, Enterococcus, Escherichia coli) and meat type.

Results: A total of 39,349 retail meat samples were linked to 216 conventional, 123 split (conventional and organic), and three organic processing facilities. MDRO contamination was similar in conventionally produced meats processed at split vs. conventional facilities but was significantly lower in organically produced meats processed at split facilities $\left[\text{adjusted prevalance ratio\hspace{0.17em}}\right(\text{aPR})=0.43$; 95% CI: 0.30, 0.63]. Meat processed by split vs. conventional processors had higher or similar MDRO contamination for all tested bacterial genera except Campylobacter ($\text{aPR}=0.29$; 95% CI: 0.13, 0.64). The prevalence of any contamination was lower in samples processed at split vs. conventional facilities for aggregated samples ($\text{aPR}=0.70$; 95% CI: 0.68, 0.73) and all meat types and bacterial genera.

Discussion: Organically produced and processed retail meat samples had a significantly lower prevalence of MDRO than conventionally produced and processed samples had, whereas meat from split processors had a lower prevalence of any contamination than samples from conventional processors had. Additional studies are needed to confirm findings and clarify specific production and processing practices that might explain them. https://doi.org/10.1289/EHP7327

Abstract

Background: Epidemiological data link traffic-related air pollution (TRAP) to increased risk of Alzheimer’s disease (AD). Preclinical data corroborating this association are largely from studies of male animals exposed acutely or subchronically to high levels of isolated fractions of TRAP. What remains unclear is whether chronic exposure to ambient TRAP modifies AD risk and the influence of sex on this interaction.

Objectives: This study sought to assess effects of chronic exposure to ambient TRAP on the time to onset and severity of AD phenotypes in a preclinical model and to determine whether sex or genetic susceptibility influences outcomes.

Methods: Male and female TgF344-AD rats that express human AD risk genes and wildtype littermates were housed in a vivarium adjacent to a heavily trafficked tunnel in Northern California and exposed for up to 14 months to filtered air (FA) or TRAP drawn from the tunnel and delivered to animals unchanged in real time. Refractive particles in the brain and AD phenotypes were quantified in 3-, 6-, 10-, and 15-month-old animals using hyperspectral imaging, behavioral testing, and neuropathologic measures.

Results: Particulate matter (PM) concentrations in TRAP exposure chambers fluctuated with traffic flow but remained below 24-h PM with aerodynamic diameter less than or equal to 2.5 micrometers (${\mathrm{PM}}_{2.5}$) U.S. National Ambient Air Quality Standards limits. Ultrafine PM was a predominant component of TRAP. Nano-sized refractive particles were detected in the hippocampus of TRAP animals. TRAP-exposed animals had more amyloid plaque deposition, higher hyperphosphorylated tau levels, more neuronal cell loss, and greater cognitive deficits in an age-, genotype-, and sex-dependent manner. TRAP-exposed animals also had more microglial cell activation, but not astrogliosis.

Discussion: These data demonstrate that chronic exposure to ambient TRAP promoted AD phenotypes in wildtype and genetically susceptible rats. TRAP effects varied according to age, sex, and genotype, suggesting that AD progression depends on complex interactions between environment and genetics. These findings suggest current ${\mathrm{PM}}_{2.5}$ regulations are insufficient to protect the aging brain. https://doi.org/10.1289/EHP8905

Abstract

Background: Studies have evaluated environmental exposure to toxic metals such as arsenic (As), cadmium (Cd), manganese (Mn), or lead (Pb) on birth size; however, information on potential effects of exposures to metal mixtures is limited.

Objectives: We assessed the association between metal mixtures (As, Cd, Mn, Pb) in umbilical cord blood and neonate size in Bangladeshi children.

Methods: In this birth cohort study, pregnant women who were $\ge 18\text{\hspace{0.17em}years}$ of age with an ultrasound-confirmed singleton pregnancy of $\le 16\mathrm{wk}$ gestation were recruited from two Bangladesh clinics between 2008 and 2011. Neonate size metrics were measured at the time of delivery. Metals in cord blood were measured using inductively coupled plasma mass spectrometry. We employed multivariable linear regression and Bayesian kernel machine regression (BKMR) to estimate associations of individual metals and metal mixtures with birth size parameters.

Results: Data from 1,088 participants was assessed. We found a significant negative association between metal mixture and birth length and head circumference when all metal concentrations were above the 60th and 55th percentiles, respectively, compared with the median. An interquartile range (IQR) increase in log Cd concentration {log[Cd (in micrograms per deciliter)] $\text{IQR}=2.51$} was associated with a 0.13-standard deviation (SD) decrease in mean birth length (95% CI: $-0.25$, $-0.02$) and a 0.17-SD decrease in mean head circumference (95% CI: $-0.28$, $-0.05$), based on linear regression models adjusted for covariates and the other metals. An IQR increase in log Mn concentration {log[Mn (in micrograms per deciliter)] $\text{IQR}=0.69$} was associated with a 0.07-SD decrease in mean birth weight (95% CI: $-0.15$, 0.002).

Discussion: Metal mixtures in cord blood were associated with reduced birth size in Bangladeshi children. Results from linear regression models adjusted and the BKMR mixtures analyses suggest adverse effects of Cd and Mn, as individual metal exposures, on birth size outcomes. https://doi.org/10.1289/EHP7502

Abstract

Background: Chronic exposure to air pollution may prime the immune system to be reactive, increasing inflammatory responses to immune stimulation and providing a pathway to increased risk for inflammatory diseases, including asthma and cardiovascular disease. Although long-term exposure to ambient air pollution has been associated with increased circulating markers of inflammation, it is unknown whether it also relates to the magnitude of inflammatory response.

Objectives: The aim of this study was to examine associations between chronic ambient pollution exposures and circulating and stimulated levels of inflammatory mediators in a cohort of healthy adults.

Methods: Circulating interleukin (IL)-6, C-reactive protein (CRP) ($n=392$), and lipopolysaccharide stimulated production of $\text{IL-}1\mathrm{\beta }$, IL-6, and tumor necrosis factor $\left(\text{TNF}\right)\text{-}\mathrm{\alpha }$ ($n=379$) were measured in the Adult Health and Behavior II cohort. Fine particulate matter [particulate matter with aerodynamic diameter less than or equal to 2.5 μm (${\mathrm{PM}}_{2.5}$)] and constituents [black carbon (BC), and lead (Pb), manganese (Mn), zinc (Zn), and iron (Fe)] were estimated for each residential address using hybrid dispersion land use regression models. Associations between pollutant exposures and inflammatory measures were examined using linear regression; models were adjusted for age, sex, race, education, smoking, body mass index, and month of blood draw.

Results: There were no significant correlations between circulating and stimulated measures of inflammation. Significant positive associations were found between exposure to ${\mathrm{PM}}_{2.5}$ and BC with stimulated production of IL-6, $\text{IL-}1\mathrm{\beta }$, and $\text{TNF-}\mathrm{\alpha }$. Pb, Mn, Fe, and Zn exposures were positively associated with stimulated production of $\text{IL-}1\mathrm{\beta }$ and $\text{TNF-}\mathrm{\alpha }$. No pollutants were associated with circulating IL-6 or CRP levels.

Discussion: Exposure to ${\mathrm{PM}}_{2.5}$, BC, Pb, Mn, Fe, and Zn was associated with increased production of inflammatory mediators by stimulated immune cells. In contrast, pollutant exposure was not related to circulating markers of inflammation. These results suggest that chronic exposure to some pollutants may prime immune cells to mount larger inflammatory responses, possibly contributing to increased risk for inflammatory disease. https://doi.org/10.1289/EHP7089

Abstract

Background: Epidemiologic studies indicate that early life arsenic exposures are linked to an increased risk of cardiovascular diseases. Different oxidation and methylation states of arsenic exist in the environment and are formed in vivo via the action of arsenic ($+3$ oxidation state) methyltransferase (As3MT). Methylated arsenicals are pro-atherogenic postnatally, but pre- and perinatal effects are unclear. This is particularly important because methylated arsenicals are known to cross the placenta.

Objectives: We tested the effects of early life exposure to inorganic and methylated arsenicals on atherosclerotic plaque formation and its composition in apolipoprotein E knock-out (${\text{apoE}}^{-/-}$) mice and evaluated whether ${\text{apoE}}^{-/-}$ mice lacking As3MT expression were susceptible to this effect.

Methods: We exposed ${\text{apoE}}^{-/-}$ or ${\text{apoE}}^{-/-}{/\mathrm{As}3\text{MT}}^{-/-}$ mice to $200\text{\hspace{0.17em}ppb}$ inorganic or methylated arsenic in the drinking water from conception to weaning and assessed atherosclerotic plaques in the offspring at 18 wk of age. Mixed regression models were used to estimate the mean difference in each outcome relative to controls, adjusting for sex and including a random effects term to account for within-litter clustering.

Results: Early life exposure to inorganic arsenic, and more profoundly methylated arsenicals, resulted in significantly larger plaques in the aortic arch and sinus in both sexes. Lipid levels in these plaques were higher without a substantial difference in macrophage numbers. Smooth muscle cell content was not altered, but collagen content was lower. Importantly, there were sex-specific differences in these observations, where males had higher lipids and lower collagen in the plaque, but females did not. In mice lacking As3MT, arsenic did not alter the plaque size, although the size was highly variable. In addition, control ${\text{apoE}}^{-/-}{/\mathrm{As}3\text{MT}}^{-/-}$ mice had significantly larger plaque size compared with control ${\text{apoE}}^{-/-}$.

Conclusion: This study shows that early life exposure to inorganic and methylated arsenicals is pro-atherogenic with sex-specific differences in plaque composition and a potential role for As3MT in mice. https://doi.org/10.1289/EHP8171

Abstract

Background: Exposure to secondhand smoke (SHS) is a risk factor for developing sporadic forms of sporadic dementia. A human tau (htau) mouse model is available that exhibits age-dependent tau dysregulation, neurofibrillary tangles, neuronal loss, neuroinflammation, and oxidative stress starting at an early age (3–4 months) and in which tau dysregulation and neuronal loss correlate with synaptic dysfunction and cognitive decline.

Objective: The goal of this study was to assess the effects of chronic SHS exposure (10 months’ exposure to $\sim 30{\mathrm{mg}/\mathrm{m}}^3$) on behavioral and cognitive function, metabolism, and neuropathology in mice.

Methods: Wild-type (WT) and htau female and male mice were exposed to SHS (90% side stream, 10% main stream) using the SCIREQ® inExpose™ system or air control for 168 min per day, for 312 d, 7 d per week. The exposures continued during the days of behavioral and cognitive testing. In addition to behavioral and cognitive performance and neuropathology, the lungs of mice were examined for pathology and alterations in gene expression.

Results: Mice exposed to chronic SHS exposure showed the following genotype-dependent responses: a) lower body weights in WT, but not htau, mice; b) less spontaneous alternation in WT, but not htau, mice in the Y maze; c) faster swim speeds of WT, but not htau, mice in the water maze; d) lower activity levels of WT and htau mice in the open field; e) lower expression of brain PHF1, TTCM1, $\text{IGF}1\mathrm{\beta }$, and HSP90 protein levels in WT male, but not female, mice; and f) more profound effects on hippocampal metabolic pathways in WT male than female mice and more profound effects in WT than htau mice.

Discussion: The brain of WT mice, in particular WT male mice, might be especially susceptible to the effects of chronic SHS exposure. In WT males, independent pathways involving ascorbate, flavin adenine dinucleotide, or palmitoleic acid might contribute to the hippocampal injury following chronic SHS exposure. https://doi.org/10.1289/EHP8428

Abstract

Background: Maternal smoking during pregnancy is related to altered DNA methylation in infant umbilical cord blood. The extent to which low levels of smoke exposure among nonsmoking pregnant women relates to offspring DNA methylation is unknown.

Objective: This study sought to evaluate relationships between maternal prenatal plasma cotinine levels and DNA methylation in umbilical cord blood in newborns using the Infinium HumanMethylation 450K BeadChip.

Methods: Participants from the Newborn Epigenetics Study cohort who reported not smoking during pregnancy had verified low levels of cotinine from maternal prenatal plasma (0 $\text{ng}/\mathrm{mL}$ to $<4\text{\hspace{0.17em}ng}/\mathrm{mL}$), and offspring epigenetic data from umbilical cord blood were included in this study ($n=79$). Multivariable linear regression models were fit to the data, controlling for cell proportions, age, race, education, and parity. Estimates represent changes in response to any $1\text{-ng}/\mathrm{mL}$ unit increase in exposure.

Results: Multivariable linear regression models yielded 29,049 CpGs that were differentially methylated in relation to increases in cotinine at a 5% false discovery rate. Top CpGs were within or near genes involved in neuronal functioning (PRKG1, DLGAP2, BSG), carcinogenesis (FHIT, HSPC157) and inflammation (AGER). Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses suggest cotinine was related to methylation of gene pathways controlling neuronal signaling, metabolic regulation, cell signaling and regulation, and cancer. Further, enhancers associated with transcription start sites were enriched in altered CpGs. Using an independent sample from the same study population ($n=115$), bisulfite pyrosequencing was performed with infant cord blood DNA for two genes within our top 20 hits (AGER and PRKG1). Results from pyrosequencing replicated epigenome results for PRKG1 (cg17079497, $\text{estimate}=-1.09$, $\text{standard error\hspace{0.17em}}\left(\text{SE}\right)=0.45$, $p=0.018$) but not for AGER (cg09199225; $\text{estimate}=-0.16$, $\text{SE}=0.21$, $p=0.44$).

Discussion: Secondhand smoke exposure among nonsmoking women may alter DNA methylation in regions involved in development, carcinogenesis, and neuronal functioning. These novel findings suggest that even low levels of smoke exposure during pregnancy may be sufficient to alter DNA methylation in distinct sites of mixed umbilical cord blood leukocytes in pathways that are known to be altered in cord blood from pregnant active smokers. https://doi.org/10.1289/EHP8099

Abstract

Background: Glyphosate (GLY) is the most heavily used herbicide in the world. Despite nearly ubiquitous exposure, few studies have examined prenatal GLY exposure and potentially adverse pregnancy outcomes. Preterm birth (PTB) is a risk factor for neonatal mortality and adverse health effects in childhood.

Objectives: We examined prenatal exposure to GLY and a highly persistent environmental degradate of GLY, aminomethylphosphonic acid (AMPA), and odds of PTB in a nested case–control study within the ongoing Puerto Rico Testsite for Exploring Contamination Threats (PROTECT) pregnancy cohort in northern Puerto Rico.

Methods: GLY and AMPA in urine samples collected at $18\pm 2$ (Visit 1) and $26\pm 2$ (Visit 3) wk gestation (53 cases/194 randomly selected controls) were measured using gas chromatography tandem mass spectrometry. Multivariable logistic regression was used to estimate associations with PTB (delivery $<37\mathrm{wk}$ completed gestation).

Results: Detection rates in controls were 77.4% and 77.5% for GLY and 52.8% and 47.7% for AMPA, and geometric means (geometric standard deviations) were 0.44 (2.50) and 0.41 $\left(2.56\right)\mathrm{\mu }\mathrm{g}/\mathrm{L}$ for GLY and 0.25 (3.06) and 0.20 $\left(2.87\right)\mathrm{\mu }\mathrm{g}/\mathrm{L}$ for AMPA, for Visits 1 and 3, respectively. PTB was significantly associated with specific gravity–corrected urinary GLY and AMPA at Visit 3, whereas associations with levels at Visit 1 and the Visits 1–3 average were largely null or inconsistent. Adjusted odds ratios (ORs) for an interquartile range increase in exposure at Visit 3 were 1.35 (95% CI: 0.99, 1.83) and 1.67 (95% CI: 1.26, 2.20) for GLY and AMPA, respectively. ORs for Visit 1 and the visit average were closer to the null.

Discussion: Urine GLY and AMPA levels in samples collected near the 26th week of pregnancy were associated with increased odds of PTB in this modestly sized nested case–control study. Given the widespread use of GLY, multiple potential sources of AMPA, and AMPA’s persistence in the environment, as well as the potential for long-term adverse health effects in preterm infants, further investigation in other populations is warranted. https://doi.org/10.1289/EHP7295

Abstract

Background: The epidemiological literature of associations between atmospheric pollutant exposure and breast cancer incidence has recently strongly evolved.

Objectives: We aimed to perform a) a meta-analysis of studies considering this relationship, correcting for publication bias and taking menopausal status and cancer hormone responsiveness into account; and b) for the pollutants most likely to affect breast cancer, an assessment of the corresponding number of attributable cases in France and of the related economic costs.

Methods: We conducted a literature review and random-effects meta-analyses of epidemiological studies examining the association of fine particulate matter with aerodynamic diameter less than or equal to $2.5\mathrm{\mu }\mathrm{m}$ (${\mathrm{PM}}_{2.5}$), particulate matter with aerodynamic diameter less than or equal to 10 μm (${\mathrm{PM}}_{10}$), and ${\mathrm{NO}}_2$ long-term exposure with breast cancer incidence; additional analyses were stratified on menopausal status and on tumor hormone responsiveness status. The resulting dose–response functions were combined with modeled atmospheric pollutant exposures in 2013 for France, cancer treatments costs, lost productivity, and years of life lost, to estimate the number of breast cancers attributable to atmospheric pollution and related economic costs in France.

Results: The review identified 32, 27, and 36 effect estimates for ${\mathrm{PM}}_{2.5}$, ${\mathrm{PM}}_{10}$, and ${\mathrm{NO}}_2$, respectively. The meta-analytical relative risk estimates of breast cancer corrected for publication bias were 1.006 [95% confidence interval (CI): 0.941, 1.076], 1.047 (95% CI: 0.984, 1.113), and 1.023 (95% CI: 1.005, 1.041), respectively. ${\mathrm{NO}}_2$ estimated effects appeared higher in premenopausal than in postmenopausal women and higher for hormone responsive positive ($\text{ER}+/\text{PR}+$) than negative ($\text{ER}–/\text{PR}–$) breast cancers. Assuming a causal effect of ${\mathrm{NO}}_2$, we estimated that 1,677 (95% CI: 374, 2,914) new breast cancer cases were attributable to ${\mathrm{NO}}_2$ annually in France, or 3.15% (95% CI: 0.70, 5.48) of the incident cases. The corresponding tangible and intangible costs were estimated to be €$825\text{\hspace{0.17em}million}$ (low, high: 570, 1,080) per year.

Conclusion: These findings suggest that decreasing long-term ${\mathrm{NO}}_2$ exposure or correlated air pollutant exposures could lower breast cancer risk. https://doi.org/10.1289/EHP8419