Table of Contents

Abstract

Background: The Global Burden of Disease (GBD) study, coordinated by the Institute for Health Metrics and Evaluation (IHME), produces influential, data-driven estimates of the burden of disease and premature death due to major risk factors. Expanded quantification of disease due to environmental health (EH) risk factors, including climate change, will enhance accuracy of GBD estimates, which will contribute to developing cost-effective policies that promote prevention and achieving Sustainable Development Goals.

Objectives: We review key aspects of the GBD for the EH community and introduce the Global Burden of Disease–Pollution and Health Initiative (GBD-PHI), which aims to work with IHME and the GBD study to improve estimates of disease burden attributable to EH risk factors and to develop an innovative approach to estimating climate-related disease burden—both current and projected.

Methods: We discuss strategies for improving GBD quantification of specific EH risk factors, including air pollution, lead, and climate change. We highlight key methodological challenges, including new EH risk factors, notably evidence rating and global exposure assessment.

Discussion: A number of issues present challenges to the scope and accuracy of current GBD estimates for EH risk factors. For air pollution, minimal data exist on the exposure–risk relationships associated with high levels of pollution; epidemiological studies in high pollution regions should be a research priority. For lead, the GBD’s current methods do not fully account for lead’s impact on neurodevelopment; innovative methods to account for subclinical effects are needed. Decisions on inclusion of additional EH risk–outcome pairs need to be guided by findings of systematic reviews, the size of exposed populations, feasibility of global exposure estimates, and predicted trends in exposures and diseases. Neurotoxicants, endocrine-disrupting chemicals, and climate-related factors should be high priorities for incorporation into upcoming iterations of the GBD study. Enhancing the scope and methods will improve the GBD’s estimates and better guide prevention policy. https://doi.org/10.1289/EHP5496

Abstract

Background: The substitution of bisphenol A (BPA) by bisphenol B (BPB), a very close structural analog, stresses the need to assess its potential endocrine properties.

Objective: This analysis aimed to investigate whether BPB has endocrine disruptive properties in humans and in wildlife as defined by the World Health Organization (WHO) definition used in the regulatory field, that is, a) adverse effects, b) endocrine activity, and c) plausible mechanistic links between the observed endocrine activity and adverse effects.

Methods: We conducted a systematic review to identify BPB adverse effects and endocrine activities by focusing on animal models and in vitro mechanistic studies. The results were grouped by modality (estrogenic, androgenic, thyroid hormone, steroidogenesis-related, or other endocrine activities). After critical analysis of results, lines of evidence were built using a weight-of-evidence approach to establish a biologically plausible link. In addition, the ratio of BPA to BPB potency was reported from studies investigating both bisphenols.

Results: Among the 36 articles included in the analysis, 3 subchronic studies consistently reported effects of BPB on reproductive function. In rats, the 28-d and 48-week studies showed alteration of spermatogenesis associated with a lower height of the seminiferous tubules, the alteration of several sperm parameters, and a weight loss for the testis, epididymis, and seminal vesicles. In zebrafish, the results of a 21-d reproductive study demonstrated that exposed fish had a lower egg production and a lower hatching rate and viability. The in vitro and in vivo mechanistic data consistently demonstrated BPB’s capacity to decrease testosterone production and to exert an estrogenic-like activity similar to or greater than BPA’s, both pathways being potentially responsible for spermatogenesis impairment in rats and fish.

Conclusion: The available in vivo, ex vivo, and in vitro data, although limited, coherently indicates that BPB meets the WHO definition of an endocrine disrupting chemical currently used in a regulatory context. https://doi.org/10.1289/EHP5200

Abstract

Background: Bisphenol A (BPA) is an endocrine disruptor that affects fetal growth in experimental studies. Bisphenol F (BPF) and bisphenol S (BPS), which have been substituted for BPA in some consumer products, have also shown endocrine-disrupting effects in experimental models. However, the effects of BPF and BPS on fetal growth in humans are unknown.

Objectives: Our goal was to investigate trimester-specific associations of urinary concentrations of BPA, BPF, and BPS with size at birth.

Methods: The present study included 845 pregnant women from Wuhan, China (2013–2015), who provided one urine sample in each of the first, second, and third trimesters. Linear regressions with generalized estimating equations were applied to estimate trimester-specific associations of urinary bisphenol concentrations with birth weight, birth length, and ponderal index. Linear mixed-effects models were used to identify potential critical windows of susceptibility to bisphenols by comparing the exposure patterns of newborns in the 10th percentile of each birth anthropometric measurement to that of those in the 90th percentile.

Results: Medians (25th–75th percentiles) of urinary concentrations of BPA, BPF, and BPS were 1.40 (0.19–3.85), 0.65 (0.34–1.39), and 0.38 (0.13–1.11) ng/mL, respectively. Urinary BPA concentrations in different trimesters were inversely, but not significantly, associated with birth weight and ponderal index. Urinary concentrations of BPF and BPS during some trimesters were associated with significantly lower birth weight, birth length, or ponderal index, with significant trend p-values ($p_{\text{trend}}<0.05$) across quartiles of BPF and BPS concentrations. The observed associations were unchanged after additionally adjusting for other bisphenols. In addition, newborns in the 10th percentile of each birth anthropometry measure had higher BPF and BPS exposures during pregnancy than newborns in the 90th percentile of each outcome.

Conclusions: Prenatal exposure to BPF and BPS was inversely associated with size at birth in this cohort. Replication in other populations is needed. https://doi.org/10.1289/EHP4664

Abstract

Background: Particulate matter (PM) is a complex mixture. Geographic variations in PM may explain the lack of consistent associations with breast cancer.

Objective: We aimed to evaluate the relationship between air pollution, PM components, and breast cancer risk in a United States-wide prospective cohort.

Methods: We estimated annual average ambient residential levels of particulate matter $<2.5\mathrm{\mu }\mathrm{m}$ and $<10\mathrm{\mu }\mathrm{m}$ in aerodynamic diameter (${\mathrm{PM}}_{2.5}$ and ${\mathrm{PM}}_{10}$, respectively) and nitrogen dioxide (${\mathrm{NO}}_2$) using land-use regression for 47,433 Sister Study participants (breast cancer–free women with a sister with breast cancer) living in the contiguous United States. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk associated with an interquartile range (IQR) increase in pollutants. Predictive k-means were used to assign participants to clusters derived from ${\mathrm{PM}}_{2.5}$ component profiles to evaluate the impact of heterogeneity in the ${\mathrm{PM}}_{2.5}$ mixture. For ${\mathrm{PM}}_{2.5}$, we investigated effect measure modification by component cluster membership and by geographic region without regard to air pollution mixture.

Results: During follow-up ($\text{mean}=8.4\mathrm{y}$), 2,225 invasive and 623 ductal carcinoma in situ (DCIS) cases were identified. ${\mathrm{PM}}_{2.5}$ and ${\mathrm{NO}}_2$ were associated with breast cancer overall [$\text{HR}=1.05$ (95% CI:0.99, 1.11) and 1.06 (95% CI:1.02, 1.11), respectively] and with DCIS but not with invasive cancer. Invasive breast cancer was associated with ${\mathrm{PM}}_{2.5}$ only in the Western United States [$\text{HR}=1.14$ (95% CI:1.02, 1.27)] and ${\mathrm{NO}}_2$ only in the Southern United States [$\text{HR}=1.16$ (95% CI:1.01, 1.33)]. ${\mathrm{PM}}_{2.5}$ was associated with a higher risk of invasive breast cancer among two of seven identified composition-based clusters. A higher risk was observed [$\text{HR}=1.25$ (95% CI: 0.97, 1.60)] in a California-based cluster characterized by low S and high Na and nitrate (${\mathrm{NO}}_3^{-}$) fractions and for another Western United States cluster [$\text{HR}=1.60$ (95% CI: 0.90, 2.85)], characterized by high fractions of Si, Ca, K, and Al.

Conclusion: Air pollution measures were related to both invasive breast cancer and DCIS within certain geographic regions and PM component clusters. https://doi.org/10.1289/EHP5131

Abstract

Background: Per- and polyfluoroalkyl substances (PFASs) are common industrial and consumer product chemicals with widespread human exposures that have been linked to adverse health effects. PFASs are commonly detected in foods and food-contact materials (FCMs), including fast food packaging and microwave popcorn bags.

Objectives: Our goal was to investigate associations between serum PFASs and consumption of restaurant food and popcorn in a representative sample of Americans.

Methods: We analyzed 2003–2014 serum PFAS and dietary recall data from the National Health and Nutrition Examination Survey (NHANES). We used multivariable linear regressions to investigate relationships between consumption of fast food, restaurant food, food eaten at home, and microwave popcorn and serum levels of perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorohexanesulfonic acid (PFHxS), and perfluorooctanesulfonic acid (PFOS).

Results: Calories of food eaten at home in the past 24 h had significant inverse associations with serum levels of all five PFASs; these associations were stronger in women. Consumption of meals from fast food/pizza restaurants and other restaurants was generally associated with higher serum PFAS concentrations, based on 24-h and 7-d recall, with limited statistical significance. Consumption of popcorn was associated with significantly higher serum levels of PFOA, PFNA, PFDA, and PFOS, based on 24-h and 12-month recall, up to a 63% (95% CI: 34, 99) increase in PFDA among those who ate popcorn daily over the last 12 months.

Conclusions: Associations between serum PFAS and popcorn consumption may be a consequence of PFAS migration from microwave popcorn bags. Inverse associations between serum PFAS and food eaten at home—primarily from grocery stores—is consistent with less contact between home-prepared food and FCMs, some of which contain PFASs. The potential for FCMs to contribute to PFAS exposure, coupled with concerns about toxicity and persistence, support the use of alternatives to PFASs in FCMs. https://doi.org/10.1289/EHP4092

Abstract

Background: Pregnancy is a sensitive condition during which adverse environmental exposures should be monitored thoroughly and minimized whenever possible. In particular, the hormone balance during gestation is delicate, and disturbance may cause acute or chronic long-term health effects. A potential endocrine disruption may be provoked by in utero exposure to xenoestrogens mimicking endogenous estrogens. The mycoestrogen zearalenone (ZEN), a toxic fungal secondary metabolite and mycotoxin found frequently in food and feed, constitutes a prominent example.

Objectives: We performed a comprehensive assessment of the transfer as well as phase I and phase II metabolism of ZEN at the human placental barrier.

Methods: Human placentas were perfused with $1\mathrm{\mu }\mathrm{M}$ ($318\mathrm{\mu }\mathrm{g}/\mathrm{L}$) ZEN for 6 h. Samples from the maternal and fetal compartment, placental tissue, and fetal plasma were analyzed by a highly sensitive UHPLC-MS/MS assay to detect ZEN as well as nine key metabolites ($\mathrm{\alpha }\text{-zearalenol}$, $\mathrm{\beta }\text{-zearalenol}$, zearalanone, $\mathrm{\alpha }\text{-zearalanol}$, $\mathrm{\beta }\text{-zearalanol}$, ZEN-14-glucuronide, $\mathrm{\alpha }\text{-zearalenol-}14\text{-glucuronide}$, $\mathrm{\beta }\text{-zearalenol-}14\text{-glucuronide}$, ZEN-14-sulfate).

Results: The model revealed a fast maternofetal transfer of ZEN across the human placental barrier. We also unraveled phase I and phase II metabolism of the parent toxin ZEN into the approximately 70-times more estrogenic $\mathrm{\alpha }\text{-zearalenol}$ and the less active ZEN-14-sulfate conjugate, which are effectively released into the maternal and fetal circulation in considerable amounts.

Conclusions: Our findings suggest that exposure to ZEN (such as through consumption of ZEN-contaminated cereal-based products) during pregnancy may result in in utero exposure of the fetus, not only to ZEN but also some of its highly estrogenically active metabolites. In the light of the known affinity of ZEN and potentially co-occurring xenoestrogens to the estrogen receptor, and our results demonstrating placental transfer of ZEN and its metabolites in an ex vivo model, we recommend further research and more comprehensive assessment of gestational exposures in women. https://doi.org/10.1289/EHP4860

Abstract

Background: Pregnant women and children are especially vulnerable to exposures to food contaminants, and a balanced diet during these periods is critical for optimal nutritional status.

Objectives: Our objective was to study the association between diet and measured blood and urinary levels of environmental contaminants in mother–child pairs from six European birth cohorts ($n=818$ mothers and 1,288 children).

Methods: We assessed the consumption of seven food groups and the blood levels of organochlorine pesticides, polybrominated diphenyl ethers, polychlorinated biphenyls (PCBs), per- and polyfluoroalkyl substances (PFAS), and heavy metals and urinary levels of phthalate metabolites, phenolic compounds, and organophosphate pesticide (OP) metabolites. Organic food consumption during childhood was also studied. We applied multivariable linear regressions and targeted maximum likelihood based estimation (TMLE).

Results: Maternal high ($\ge 4\text{times}/\text{week}$) versus low ($<2\text{times}/\text{week}$) fish consumption was associated with 15% higher PCBs [geometric mean (GM) $\text{ratio}=1.15$; 95% confidence interval (CI): 1.02, 1.29], 42% higher perfluoroundecanoate (PFUnDA) ($\text{GM}\text{ratio}=1.42$; 95% CI: 1.20, 1.68), 89% higher mercury (Hg) ($\text{GM}\text{ratio}=1.89$; 95% CI: 1.47, 2.41) and a 487% increase in arsenic (As) ($\text{GM}\text{ratio}=4.87$; 95% CI: 2.57, 9.23) levels. In children, high ($\ge 3\text{times}/\text{week}$) versus low ($<1.5\text{times}/\text{week}$) fish consumption was associated with 23% higher perfluorononanoate (PFNA) ($\text{GM}\text{ratio}=1.23$; 95% CI: 1.08, 1.40), 36% higher PFUnDA ($\text{GM}\text{ratio}=1.36$; 95% CI: 1.12, 1.64), 37% higher perfluorooctane sulfonate (PFOS) ($\text{GM}\text{ratio}=1.37$; 95% CI: 1.22, 1.54), and $>200\%$ higher Hg and As [$\text{GM}\text{ratio}=3.87$ (95% CI: 1.91, 4.31) and $\text{GM}\text{ratio}=2.68$ (95% CI: 2.23, 3.21)] concentrations. Using TMLE analysis, we estimated that fish consumption within the recommended 2–3 times/week resulted in lower PFAS, Hg, and As compared with higher consumption. Fruit consumption was positively associated with OP metabolites. Organic food consumption was negatively associated with OP metabolites.

Discussion: Fish consumption is related to higher PFAS, Hg, and As exposures. In addition, fruit consumption is a source of exposure to OPs. https://doi.org/10.1289/EHP5324

Abstract

Background: Piperonyl butoxide (PBO) is a pesticide synergist used in residential, commercial, and agricultural settings. PBO was recently found to inhibit Sonic hedgehog (Shh) signaling, a key developmental regulatory pathway. Disruption of Shh signaling is linked to birth defects, including holoprosencephaly (HPE), a malformation of the forebrain and face thought to result from complex gene–environment interactions.

Objectives: The impact of PBO on Shh signaling in vitro and forebrain and face development in vivo was examined.

Methods: The influence of PBO on Shh pathway transduction was assayed in mouse and human cell lines. To examine its teratogenic potential, a single dose of PBO ($22–\mathrm{1,800}\mathrm{mg}/\mathrm{kg}$) was administered by oral gavage to $\mathrm{C}57\text{BL}/6\mathrm{J}$ mice at gestational day 7.75, targeting the critical period for HPE. Gene–environment interactions were investigated using $Sh{h}^{+/-}$ mice, which model human HPE-associated genetic mutations.

Results: PBO attenuated Shh signaling in vitro through a mechanism similar to that of the known teratogen cyclopamine. In utero PBO exposure caused characteristic HPE facial dysmorphology including dose-dependent midface hypoplasia and hypotelorism, with a lowest observable effect level of $67\mathrm{mg}/\mathrm{kg}$. Median forebrain deficiency characteristic of HPE was observed in severely affected animals, whereas all effective doses disrupted development of Shh-dependent transient forebrain structures that generate cortical interneurons. Normally silent heterozygous Shh null mutations exacerbated PBO teratogenicity at all doses tested, including $33\mathrm{mg}/\mathrm{kg}$.

Discussion: These findings demonstrate that prenatal PBO exposure can cause overt forebrain and face malformations or neurodevelopmental disruptions with subtle or no craniofacial dysmorphology in mice. By targeting Shh signaling as a sensitive mechanism of action and examining gene–environment interactions, this study defined a lowest observable effect level for PBO developmental toxicity in mice more than 30-fold lower than previously recognized. Human exposure to PBO and its potential contribution to etiologically complex birth defects should be rigorously examined. https://doi.org/10.1289/EHP5260

Abstract

Background: The autonomic nervous system plays a key role in maintaining homeostasis and responding to external stimuli. In adults, exposure to fine particulate matter (${\mathrm{PM}}_{2.5}$) has been associated with reduced heart rate variability (HRV), an indicator of cardiac autonomic control.

Objectives: Our goal was to investigate the associations of exposure to fine particulate matter (${\mathrm{PM}}_{2.5}$) with HRV as an indicator of cardiac autonomic control during early development.

Methods: We studied 237 maternal–infant pairs in a Boston-based birth cohort. We estimated daily residential ${\mathrm{PM}}_{2.5}$ using satellite data in combination with land-use regression predictors. In infants at 6 months of age, we measured parasympathetic nervous system (PNS) activity using continuous electrocardiogram monitoring during the Repeated Still-Face Paradigm, an experimental protocol designed to elicit autonomic reactivity in response to maternal interaction and disengagement. We used multivariable linear regression to examine average ${\mathrm{PM}}_{2.5}$ exposure across pregnancy in relation to PNS withdrawal and activation, indexed by changes in respiration-corrected respiratory sinus arrhythmia (${\text{RSA}}_{\mathrm{c}}$)—an established metric of HRV that reflects cardiac vagal tone. We examined interactions with infant sex using cross-product terms.

Results: In adjusted models we found that a 1-unit increase in ${\mathrm{PM}}_{2.5}$ (in micrograms per cubic meter) was associated with a 3.53% decrease in baseline ${\text{RSA}}_{\mathrm{c}}$ (95% CI: $-6.96$, 0.02). In models examining ${\text{RSA}}_{\mathrm{c}}$ change between episodes, higher ${\mathrm{PM}}_{2.5}$ was generally associated with reduced PNS withdrawal during stress and reduced PNS activation during recovery; however, these associations were not statistically significant. We did not observe a significant interaction between ${\mathrm{PM}}_{2.5}$ and sex.

Discussion: Prenatal exposure to ${\mathrm{PM}}_{2.5}$ may disrupt cardiac vagal tone during infancy. Future research is needed to replicate these preliminary findings. https://doi.org/10.1289/EHP4434

Abstract

Background: Ambient fine particulate air pollution with aerodynamic diameter $\le 2.5\mathrm{\mu }\mathrm{m}$ (${\mathrm{PM}}_{2.5}$) is an important contributor to the global burden of disease. Information on the shape of the concentration–response relationship at low concentrations is critical for estimating this burden, setting air quality standards, and in benefits assessments.

Objectives: We examined the concentration–response relationship between ${\mathrm{PM}}_{2.5}$ and nonaccidental mortality in three Canadian Census Health and Environment Cohorts (CanCHECs) based on the 1991, 1996, and 2001 census cycles linked to mobility and mortality data.

Methods: Census respondents were linked with death records through 2016, resulting in 8.5 million adults, 150 million years of follow-up, and 1.5 million deaths. Using annual mailing address, we assigned time-varying contextual variables and 3-y moving-average ambient ${\mathrm{PM}}_{2.5}$ at a $1\times 1\mathrm{km}$ spatial resolution from 1988 to 2015. We ran Cox proportional hazards models for ${\mathrm{PM}}_{2.5}$ adjusted for eight subject-level indicators of socioeconomic status, seven contextual covariates, ozone, nitrogen dioxide, and combined oxidative potential. We used three statistical methods to examine the shape of the concentration–response relationship between ${\mathrm{PM}}_{2.5}$ and nonaccidental mortality.

Results: The mean 3-y annual average estimate of ${\mathrm{PM}}_{2.5}$ exposure ranged from 6.7 to $8.0{\mathrm{\mu }\mathrm{g}/\mathrm{m}}^3$ over the three cohorts. We estimated a hazard ratio (HR) of 1.053 [95% confidence interval (CI): 1.041, 1.065] per $10{\text{-}\mathrm{\mu }\mathrm{g}/\mathrm{m}}^3$ change in ${\mathrm{PM}}_{2.5}$ after pooling the three cohort-specific hazard ratios, with some variation between cohorts (1.041 for the 1991 and 1996 cohorts and 1.084 for the 2001 cohort). We observed a supralinear association in all three cohorts. The lower bound of the 95% CIs exceeded unity for all concentrations in the 1991 cohort, for concentrations above $2{\mathrm{\mu }\mathrm{g}/\mathrm{m}}^3$ in the 1996 cohort, and above $5{\mathrm{\mu }\mathrm{g}/\mathrm{m}}^3$ in the 2001 cohort.

Discussion: In a very large population-based cohort with up to 25 y of follow-up, ${\mathrm{PM}}_{2.5}$ was associated with nonaccidental mortality at concentrations as low as $5{\mathrm{\mu }\mathrm{g}/\mathrm{m}}^3$. https://doi.org/10.1289/EHP5204

Abstract

Background: The rapidly increasing dissemination of carbapenem-resistant Enterobacteriaceae (CRE) in both humans and animals poses a global threat to public health. However, the transmission of CRE between humans and animals has not yet been well studied.

Objectives: We investigated the prevalence, risk factors, and drivers of CRE transmission between humans and their backyard animals in rural China.

Methods: We conducted a comprehensive sampling strategy in 12 villages in Shandong, China. Using the household [residents and their backyard animals (farm and companion animals)] as a single surveillance unit, we assessed the prevalence of CRE at the household level and examined the factors associated with CRE carriage through a detailed questionnaire. Genetic relationships among human- and animal-derived CRE were assessed using whole-genome sequencing–based molecular methods.

Results: A total of 88 New Delhi $\text{metallo-}\mathrm{\beta }\text{-lactamases}$–type carbapenem-resistant Escherichia coli (NDM-EC), including 17 from humans, 44 from pigs, 12 from chickens, 1 from cattle, and 2 from dogs, were isolated from 65 of the 746 households examined. The remaining 12 NDM-EC were from flies in the immediate backyard environment. The NDM-EC colonization in households was significantly associated with a) the number of species of backyard animals raised/kept in the same household, and b) the use of human and/or animal feces as fertilizer. Discriminant analysis of principal components (DAPC) revealed that a large proportion of the core genomes of the NDM-EC belonged to strains from hosts other than their own, and several human isolates shared closely related core single-nucleotide polymorphisms and $bl{a}_{\text{NDM}}$ genetic contexts with isolates from backyard animals.

Conclusions: To our knowledge, we are the first to report evidence of direct transmission of NDM-EC between humans and animals. Given the rise of NDM-EC in community and hospital infections, combating NDM-EC transmission in backyard farm systems is needed. https://doi.org/10.1289/EHP5251

Abstract

Background: Previous studies suggest that prenatal exposure to phthalates, ubiquitous synthetic chemicals, may adversely affect neurodevelopment. However, data are limited on how phthalates affect cognition, executive function, and behavioral function into adolescence.

Objective: We aimed to investigate associations of prenatal phthalate exposure with neurodevelopment in childhood and adolescence in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study.

Methods: We examined associations between maternal urinary phthalate metabolite concentrations measured twice during pregnancy and a range of neurodevelopmental outcomes from ages 7 through 16 y in the CHAMACOS birth cohort ($n=334$). We used age-specific linear regression models and generalized estimating equation models to assess longitudinal effects and examined differences by sex.

Results: Phthalate metabolites were detected in 88%–100% of samples, depending on the metabolite. Associations of phthalates with neurodevelopmental outcomes were largely null with some noteworthy patterns. Higher prenatal concentrations of metabolites of low-molecular weight phthalates ($\mathrm{\Sigma }\text{LMW}$) were associated with more self-reported hyperactivity [$\mathrm{\beta }=0.8$, 95% confidence interval (CI): 0.1, 1.4 per 2-fold increase in $\mathrm{\Sigma }\text{LMW}$ phthalates], attention problems ($\mathrm{\beta }=1.5$, 95% CI: 0.7, 2.2), and anxiety ($\mathrm{\beta }=0.9$, 95% CI: 0.0, 1.8) at age 16. We observed sex-specific differences for the sums of high-molecular-weight and di(2-ethylhexyl) metabolites and cognitive outcomes (e.g., $\mathrm{\beta }$ for Full-Scale IQ for $\text{boys}=-1.9$, 95% CI: $-4.1$, 0.3 and $-1.7$, 95% CI: $-3.8$, 0.3, respectively; $\mathrm{\beta }$ for $\text{girls}=1.8$, 95% CI: 0.1, 3.4 and 1.6, 95% CI: 0.0, 3.2, respectively; $p\text{-int}=0.01$ for both).

Conclusion: We found predominantly null associations of prenatal phthalates with neurodevelopment in CHAMACOS, and weak associations of $\mathrm{\Sigma }\text{LMW}$ phthalates with internalizing and externalizing behaviors in adolescence. No previous studies have examined associations of prenatal phthalate exposure with neurodevelopment into adolescence, an important time for manifestations of effects. https://doi.org/10.1289/EHP5165

Abstract

Background: The timing of puberty is highly sensitive to environmental factors, including endocrine disruptors. Among them, bisphenol A (BPA) has been previously analyzed as potential modifier of puberty. Yet, disparate results have been reported, with BPA advancing, delaying, or being neutral in its effects on puberty onset. Likewise, mechanistic analyses addressing the central and peripheral actions/targets of BPA at puberty remain incomplete and conflictive.

Objective: We aimed to provide a comprehensive characterization of the impact of early BPA exposures, especially at low, real-life doses, on the postnatal development of hypothalamic Kiss1/NKB neurons, and its functional consequences on female pubertal maturation.

Methods: Pregnant CD1 female mice were orally administered BPA at 5, 10, or $40\mathrm{\mu }\mathrm{g}/\mathrm{kg}$ body weight (BW)/d from gestational day 11 to postnatal day 8 (PND8). Vaginal opening, as an external marker of puberty onset, was monitored daily from PND19 to PND30 in the female offspring. Blood and brain samples were collected at PND12, 15, 18, 21, and 30 for measuring circulating levels of gonadotropins and analyzing the hypothalamic expression of Kiss1/kisspeptin and NKB.

Results: Perinatal exposure to BPA, in a range of doses largely below the no observed adverse effect level (NOAEL; $5\mathrm{mg}/\mathrm{kg}$ BW/d, according to the FDA), was associated with pubertal differences in the female progeny compared with those exposed to vehicle alone, with an earlier age of vaginal opening but consistently lower levels of circulating luteinizing hormone. Mice treated with BPA exhibited a persistent, but divergent, impairment of Kiss1 neuronal maturation, with more kisspeptin cells in the rostral (RP3V) hypothalamus but consistently fewer kisspeptin neurons in the arcuate nucleus (ARC). Detailed quantitative analysis of the ARC population, essential for pubertal development, revealed that mice treated with BPA had persistently lower Kiss1 expression during (pre)pubertal maturation, which was associated with lower Tac2 (encoding NKB) levels, even at low doses ($5\mathrm{\mu }\mathrm{g}/\mathrm{kg}$ BW/d), in the range of the tolerable daily intake (TDI), recently updated by the European Food Safety Authority.

Conclusions: Our data attest to the consistent, but divergent, effects of gestational exposures to low concentrations of BPA, via the oral route, on phenotypic and neuroendocrine markers of puberty in female mice, with an unambiguous impact on the developmental maturation not only of Kiss1, but also of the NKB system, both essential regulators of puberty onset. https://doi.org/10.1289/EHP5570

Abstract

Background: Long-term exposure to particulate matter (PM) in ambient air has been associated with cardiovascular mortality, but few studies have considered incident disease in relation to PM from different sources.

Objectives: We aimed to study associations between long-term exposure to different types of PM and sources, and incident ischemic heart disease (IHD) and stroke in three Swedish cities.

Methods: Based on detailed emission databases, monitoring data, and high-resolution dispersion models, we calculated source contributions to PM with aerodynamic diameter $\le 10\mathrm{\mu }\mathrm{m}$ (${\mathrm{PM}}_{10}$), PM with aerodynamic diameter $\le 2.5\mathrm{\mu }\mathrm{m}$ (${\mathrm{PM}}_{2.5}$), and black carbon (BC) from road wear, traffic exhaust, residential heating, and other sources in Gothenburg, Stockholm, and Umeå. Registry data for participants from four cohorts were used to obtain incidence of IHD and stroke for first hospitalization or death. We constructed time windows of exposure for same-year, 1- to 5-y, and 6- to 10-y averages preceding incidence from annual averages at residential addresses. Risk estimates were based on random effects meta-analyses of cohort-specific Cox proportional hazard models.

Results: We observed 5,166 and 3,119 incident IHD and stroke cases, respectively, in 114,758 participants. Overall, few consistent associations were observed between the different air pollution measures and IHD or stroke incidence. However, same-year levels of ambient locally emitted BC (range: $0.01-4.6{\mathrm{\mu }\mathrm{g}/\mathrm{m}}^3$) were associated with a 4.0% higher risk of incident stroke per interquartile range (IQR), $0.30{\mathrm{\mu }\mathrm{g}/\mathrm{m}}^3$ [95% confidence interval (CI): 0.04, 7.8]. This association was primarily related to BC from traffic exhaust. ${\mathrm{PM}}_{10}$ (range: $4.4-52{\mathrm{\mu }\mathrm{g}/\mathrm{m}}^3$) and ${\mathrm{PM}}_{2.5}$ (range: $2.9-22{\mathrm{\mu }\mathrm{g}/\mathrm{m}}^3$) were not associated with stroke. Associations with incident IHD were observed only for ${\mathrm{PM}}_{2.5}$ exposure from residential heating.

Discussion: Few consistent associations were observed between different particulate components and IHD or stroke. However, long-term residential exposure to locally emitted BC from traffic exhaust was associated with stroke incidence. The comparatively low exposure levels may have contributed to the paucity of associations. https://doi.org/10.1289/EHP4757

Abstract

Background: The question of whether exposure to bisphenol A (BPA) contributes to the development of type 2 diabetes is still unresolved. Most epidemiological evidence on the association between BPA and diabetes is from cross-sectional studies or longitudinal studies with single urinary measurements. No prospective study has examined exposure to BPA analogs such as bisphenol S (BPS) in relation to incident type 2 diabetes.

Objectives: We aimed to investigate whether exposure to BPA and BPS, assessed at up to two time points, was associated with the incidence of type 2 diabetes.

Methods: We performed a case–cohort study on 755 participants without diabetes at baseline and followed-up over 9 y as part of the French prospective cohort Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.). BPA-glucuronide (BPA-G) and BPS-glucuronide (BPS-G) were assessed in fasting spot urine samples collected during the health examinations at baseline and 3 y later. Associations with incident diabetes were examined using Prentice-weighted Cox regression models adjusted for potential confounders.

Results: A total of 201 incident cases of type 2 diabetes were diagnosed over the follow-up, including 30 in the subcohort. Compared with participants with the lowest average BPA exposure (below the first quartile), participants in the second, third, and fourth quartile groups of exposure had a near doubling of the risk of type 2 diabetes, with a hazard ratio $\left(\text{HR}\right)=$ 2.56 (95% CI: 1.16, 5.65), 2.35 (95% CI: 1.07, 5.15), and 1.56 (95% CI: 0.68, 3.55), respectively. The detection of BPS-G in urine at one or both time points was associated with incident diabetes, with an $\text{HR}=$ 2.81 (95% CI: 1.74, 4.53).

Discussion: This study shows positive associations between exposure to BPA and BPS and the incidence of type 2 diabetes, independent of traditional diabetes risk factors. Our results should be confirmed by recent, population-based observational studies in different populations and settings. Overall, these findings raise concerns about using BPS as a BPA substitute. Further research on BPA analogs is warranted. https://doi.org/10.1289/EHP5159

Abstract

Background: The geographic range of the tick Amblyomma americanum, a vector of diseases of public health significance such as ehrlichiosis, has expanded from the southeast of the United States northward during the 20th century. Recently, populations of this tick have been reported to be present close to the Canadian border in Michigan and New York states, but established populations are not known in Canada. Previous research suggests that changing temperature patterns with climate change may influence tick life cycles and permit northward range expansion of ticks in the northern hemisphere.

Objectives: We aimed to estimate minimal temperature conditions for survival of A. americanum populations at the northern edge of the tick’s range and to investigate the possibility of range expansion of A. americanum into northern U.S. states and southern Canada in the coming decades.

Methods: A simulation model of the tick A. americanum was used, via simulations using climate data from meteorological stations in the United States and Canada, to estimate minimal temperature conditions for survival of A. americanum populations at the northern edge of the tick’s range.

Results: The predicted geographic scope of temperature suitability [$\ge \mathrm{3,285}$ annual cumulative degree days (DD) $>0°\mathrm{C}$] included most of the central and eastern U.S. states east of longitude 110°W, which is consistent with current surveillance data for the presence of the tick in this region, as well as parts of southern Quebec and Ontario in Canada. Regional climate model output raises the possibility of northward range expansion into all provinces of Canada from Alberta to Newfoundland and Labrador during the coming decades, with the greatest northward range expansion (up to $\mathrm{1,000}\mathrm{km}$ by the year 2100) occurring under the greenhouse gas (GHG) emissions of Representative Concentration Pathway (RCP) 8.5. Predicted northward range expansion was reduced by approximately half under the reduced GHG emissions of RCP4.5.

Discussion: Our results raise the possibility of range expansion of A. americanum into northern U.S. states and southern Canada in the coming decades, and conclude that surveillance for this tick, and the diseases it transmits, would be prudent. https://doi.org/10.1289/EHP5668