A Clash of Old and New Scientific Concepts in Toxicity,with Important Implications for Public Health

Background

A core assumption of current toxicologic procedures used to establish health standards for chemical exposures is that testing the safety of chemicals at high doses can be used to predict the effects of low-dose exposures, such as those common in the general population. This assumption is based on the precept that “the dose makes the poison”: higher doses will cause greater effects.

Objectives

We challenge the validity of assuming that high-dose testing can be used to predict low-dose effects for contaminants that behave like hormones. We review data from endocrinology and toxicology that falsify this assumption and summarize current mechanistic understanding of how low doses can lead to effects unpredictable from high-dose experiments.

Discussion

Falsification of this assumption raises profound issues for regulatory toxicology. Many exposure standards are based on this assumption. Rejecting the assumption will require that these standards be reevaluated and that procedures employed to set health standards be changed. The consequences of these changes may be significant for public health because of the range of health conditions now plausibly linked to exposure to endocrine-disrupting contaminants.

Conclusions

We recommend that procedures to establish acceptable exposure levels for endocrine-disrupting compounds incorporate the inability for high-dose tests to predict low-dose results. Setting acceptable levels of exposure must include testing for health consequences at prevalent levels of human exposure, not extrapolations from the effects observed in high-dose experiments. Scientists trained in endocrinology must be engaged systematically in standard setting for endocrine-disrupting compounds.     

Effects of Low-Dose Bisphenol A on DNA Damage and Proliferation of Breast Cells: The Role of c-Myc

Background

Humans are exposed to low-dose bisphenol A (BPA) through plastic consumer products and dental sealants containing BPA. Although a number of studies have investigated the mammary gland effects after high-dose BPA exposure, the study findings differ. Furthermore, there has been a lack of mechanistic studies.

Objective

The objective of this study was to investigate the effect and the mechanism of low-dose BPA in mammary gland cells.

Methods

We evaluated DNA damage following BPA exposure using the comet assay and immunofluorescence staining, and used cell counting and three-dimensional cultures to evaluate effects on proliferation. We examined the expressions of markers of DNA damage and cell-cycle regulators by immunoblotting and performed siRNA-mediated gene silencing to determine the role of c-Myc in regulating BPA’s effects.

Results

Low-dose BPA significantly promoted DNA damage, up-regulated c-Myc and other cell-cycle regulatory proteins, and induced proliferation in parallel in estrogen receptor-α (ERα)-negative mammary cells. Silencing c-Myc diminished these BPA-induced cellular events, suggesting that c-Myc is essential for regulating effects of BPA on DNA damage and proliferation in mammary cells.

Conclusions

Low-dose BPA exerted c-Myc–dependent genotoxic and mitogenic effects on ERα-negative mammary cells. These findings provide significant evidence of adverse effects of low-dose BPA on mammary cells.

Citation

Pfeifer D, Chung YM, Hu MC. 2015. Effects of low-dose bisphenol A on DNA damage and proliferation of breast cells: the role of c-Myc. Environ Health Perspect 123:1271–1279; http://dx.doi.org/10.1289/ehp.1409199     

Global Burden of Aflatoxin-Induced Hepatocellular Carcinoma: A Risk Assessment

Background

Hepatocellular carcinoma (HCC), or liver cancer, is the third leading cause of cancer deaths worldwide, with prevalence 16–32 times higher in developing countries than in developed countries. Aflatoxin, a contaminant produced by the fungi Aspergillus flavus and Aspergillus parasiticus in maize and nuts, is a known human liver carcinogen.

Objectives

We sought to determine the global burden of HCC attributable to aflatoxin exposure.

Methods

We conducted a quantitative cancer risk assessment, for which we collected global data on food-borne aflatoxin levels, consumption of aflatoxin-contaminated foods, and hepatitis B virus (HBV) prevalence. We calculated the cancer potency of aflatoxin for HBV-postive and HBV-negative individuals, as well as the uncertainty in all variables, to estimate the global burden of aflatoxin-related HCC.

Results

Of the 550,000–600,000 new HCC cases worldwide each year, about 25,200–155,000 may be attributable to aflatoxin exposure. Most cases occur in sub-Saharan Africa, Southeast Asia, and China where populations suffer from both high HBV prevalence and largely uncontrolled aflatoxin exposure in food.

Conclusions

Aflatoxin may play a causative role in 4.6–28.2% of all global HCC cases.     

Prenatal Exposure to Polychlorinated Biphenyls: A Neuropsychologic Analysis

Objectives

A large body of literature documents the effects of prenatal exposure to polychlorinated biphenyls (PCBs) on cognitive development of children. Despite this fact, no integrative synthesis has been published yet to identify the cognitive functions that are particularly affected. Our aim is to review this literature in an attempt to identify the cognitive profile associated with prenatal PCB exposure.

Data sources

Studies were identified by searching the PubMed database for articles published before June 2008. We reviewed data from nine prospective longitudinal birth cohorts for different aspects of cognition.

Data extraction

Associations between indicators of prenatal PCB exposure and performance on cognitive tasks reported in the selected studies are summarized and classified as general cognitive abilities, verbal or visual–spatial skills, memory, attention, and executive functions.

Data synthesis

The most consistent effects observed across studies are impaired executive functioning related to increased prenatal PCB exposure. Negative effects on processing speed, verbal abilities, and visual recognition memory are also reported by most studies. Converging results from different cohort studies in which exposure arises from different sources make it unlikely that co-exposure with another associated contaminant is responsible for the observed effects.

Conclusion

Prenatal PCB exposure appears to be related to a relatively specific cognitive profile of impairments. Failure to assess functions that are specifically impaired may explain the absence of effects found in some studies. Our findings have implications in the selection of cognitive assessment methods in future studies.     

Are Environmental Levels of Bisphenol A Associated with Reproductive Function in Fertile Men?

Background

Rodent and in vitro studies have demonstrated the estrogenicity of bisphenol A (BPA). However, few studies have examined the relationship between human exposure to BPA and male reproductive function.

Objectives

We investigated the relationships between environmental BPA exposure and reproductive parameters, including semen quality and male reproductive hormones, in prospectively recruited fertile men.

Methods

Participants (n = 375) were partners of pregnant women who participated in the Study for Future Families in four U.S. cities, and all of the men provided blood, semen, and urine samples. BPA was measured in urine. Serum samples were analyzed for reproductive hormones, including follicle-stimulating hormone, luteinizing hormone (LH), testosterone, inhibin B, estradiol, and sex hormone–binding globulin (SHBG), as well as the free androgen index (FAI). Semen analyses were performed according to World Health Organization criteria. Pearson correlations were used for unadjusted analyses, and multiple linear regression analyses were used to examine associations controlling for age, body mass index, smoking, ethnicity, urinary creatinine concentration, time of sample collection, and duration of abstinence.

Results

After multivariate adjustment, we observed no significant associations between any semen parameter and urinary BPA concentration. However, a significant inverse association was found between urinary BPA concentration and FAI levels and the FAI/LH ratio, as well as a significant positive association between BPA and SHBG.

Conclusions

Our results suggest that, in fertile men, exposure to low environmental levels of BPA may be associated with a modest reduction in markers of free testosterone, but any effects on reproductive function are likely to be small, and of uncertain clinical significance.     

The Short-Chain Fatty Acid Methoxyacetic Acid Disrupts Endogenous Estrogen Receptor-α–Mediated Signaling

Background

Ethylene glycol monomethyl ether (EGME) exposure is associated with impaired reproductive function. The primary metabolite of EGME is methoxyacetic acid (MAA), a short-chain fatty acid that inhibits histone deacetylase activity and alters gene expression.

Objective

Because estrogen signaling is necessary for normal reproductive function and modulates gene expression, the estrogen-signaling pathway is a likely target for MAA; however, little is known about the effects of MAA in this regard.

Methods

We evaluated the mechanistic effects of MAA on estrogen receptor (ER) expression and estrogen signaling using in vitro and in vivo model systems.

Results

MAA potentiates 17β-estradiol (E₂) stimulation of an estrogen-responsive reporter plasmid in HeLa cells transiently transfected with either a human ERα or ERβ expression vector containing a cytomegalovirus (CMV) promoter. This result is attributed to increased exogenous ER expression due to MAA-mediated activation of the CMV promoter. In contrast to its effects on exogenous ER, MAA decreases endogenous ERα expression and attenuates E₂-stimulated endogenous gene expression in both MCF-7 cells and the mouse uterus.

Conclusions

These results illustrate the importance of careful experimental design and analysis when assessing the potential endocrine-disrupting properties of a compound to ensure biological responses are in concordance with in vitro analyses. Given the established role of the ER in normal reproductive function, the effects of MAA on the endogenous ER reported here are consistent with the reproductive abnormalities observed after EGME exposure and suggest that these toxicities may be due, at least in part, to attenuation of endogenous ER-mediated signaling.     

Pacific Ocean-wide profile of CYP1A1 expression, stable carbon and nitrogen isotope ratios, and organic contaminant burden in sperm whale skin biopsies

Background

Ocean pollution affects marine organisms and ecosystems as well as humans. The International Oceanographic Commission recommends ocean health monitoring programs to investigate the presence of marine contaminants and the health of threatened species and the use of multiple and early-warning biomarker approaches.

Objective

We explored the hypothesis that biomarker and contaminant analyses in skin biopsies of the threatened sperm whale (Physeter macrocephalus) could reveal geographical trends in exposure on an oceanwide scale.

Methods

We analyzed cytochrome P450 1A1 (CYP1A1) expression (by immunohistochemistry), stable nitrogen and carbon isotope ratios (as general indicators of trophic position and latitude, respectively), and contaminant burdens in skin biopsies to explore regional trends in the Pacific Ocean.

Results

Biomarker analyses revealed significant regional differences within the Pacific Ocean. CYP1A1 expression was highest in whales from the Galapagos, a United Nations Educational, Scientific, and Cultural Organization World Heritage marine reserve, and was lowest in the sampling sites farthest away from continents. We examined the possible influence of the whales’ sex, diet, or range and other parameters on regional variation in CYP1A1 expression, but data were inconclusive. In general, CYP1A1 expression was not significantly correlated with contaminant burdens in blubber. However, small sample sizes precluded detailed chemical analyses, and power to detect significant associations was limited.

Conclusions

Our large-scale monitoring study was successful at identifying regional differences in CYP1A1 expression, providing a baseline for this known biomarker of exposure to aryl hydrocarbon receptor agonists. However, we could not identify factors that explained this variation. Future oceanwide CYP1A1 expression profiles in cetacean skin biopsies are warranted and could reveal whether globally distributed chemicals occur at biochemically relevant concentrations on a global basis, which may provide a measure of ocean integrity.     

Investigating intergenerational differences in human PCB exposure due to variable emissions and reproductive behaviors

Background

Reproductive behaviors—such as age of childbearing, parity, and breast-feeding prevalence—have changed over the same historical time period as emissions of polychlorinated biphenyls (PCB) and may produce intergenerational differences in human PCB exposure.

Objectives

Our goal in this study was to estimate prenatal, postnatal, and lifetime PCB exposures for women at different ages according to year of birth, and to evaluate the impact of reproductive characteristics on intergenerational differences in exposure.

Methods

We used the time-variant mechanistic model CoZMoMAN to calculate human bioaccumulation of PCBs, assuming both hypothetical constant and realistic time-variant emissions.

Results

Although exposure primarily depends on when an individual was born relative to the emission history of PCBs, reproductive behaviors can have a significant impact. Our model suggests that a mother’s reproductive history has a greater influence on the prenatal and postnatal exposures of her children than it does on her own cumulative lifetime exposure. In particular, a child’s birth order appears to have a strong influence on their prenatal exposure, whereas postnatal exposure is determined by the type of milk (formula or breast milk) fed to the infant.

Conclusions

Prenatal PCB exposure appears to be delayed relative to the time of PCB emissions, particularly among those born after the PCB production phaseout. Consequently, the health repercussions of environmental PCBs can be expected to persist for several decades, despite bans on their production for > 40 years.     

Vascular Effects of Ultrafine Particles in Persons with Type 2 Diabetes

Background

Diabetes confers an increased risk for cardiovascular effects of airborne particles.

Objective

We hypothesized that inhalation of elemental carbon ultrafine particles (UFP) would activate blood platelets and vascular endothelium in people with type 2 diabetes.

Methods

In a randomized, double-blind, crossover trial, 19 subjects with type 2 diabetes inhaled filtered air or 50 μg/m³ elemental carbon UFP (count median diameter, 32 nm) by mouthpiece for 2 hr at rest. We repeatedly measured markers of vascular activation, coagulation, and systemic inflammation before and after exposure.

Results

Compared with air, particle exposure increased platelet expression of CD40 ligand (CD40L) and the number of platelet-leukocyte conjugates 3.5 hr after exposure. Soluble CD40L decreased with UFP exposure. Plasma von Willebrand factor increased immediately after exposure. There were no effects of particles on plasma tissue factor, coagulation factors VII or IX, or D-dimer.

Conclusions

Inhalation of elemental carbon UFP for 2-hr transiently activated platelets, and possibly the vascular endothelium, in people with type 2 diabetes.     

Prenatal Exposure to Bisphenol A at Environmentally Relevant Doses Adversely Affects the Murine Female Reproductive Tract Later in Life

Background

Exposure to endocrine-disrupting chemicals during critical developmental periods causes adverse consequences later in life; an example is prenatal exposure to the pharmaceutical diethylstilbestrol (DES). Bisphenol A (BPA), an environmental estrogen used in the synthesis of plastics, is of concern because its chemical structure resembles that of DES, and it is a “high-volume production” chemical with widespread human exposure.

Objectives

In this study we investigated whether prenatal BPA causes long-term adverse effects in female reproductive tissues in an experimental animal model previously shown useful in studying effects of prenatal DES.

Methods

Timed pregnant CD-1 mice were treated on days 9–16 of gestation with BPA (0.1, 1, 10, 100, or 1,000 μg/kg/day). After delivery, pups were held for 18 months; reproductive tissues were then evaluated.

Results

Ovarian cysts were significantly increased in the 1-μg/kg BPA group; ovarian cyst-adenomas were seen in the other three BPA-treated groups but not in corn-oil controls. We observed increased progressive proliferative lesions of the oviduct after BPA treatment, similar to those described in response to DES. Further, although not statistically different from the controls, prominent mesonephric (Wolffian) remnants and squamous metaplasia of the uterus, as well as vaginal adenosis, were present in BPA-treated mice, similar to lesions reported following DES treatment. More severe pathologies observed in some BPA-treated animals included atypical hyperplasia and stromal polyps of the uterus; sarcoma of the uterine cervix; and mammary adenocarcinoma. We did not observe these lesions in controls.

Conclusions

These data suggest that BPA causes long-term adverse reproductive and carcinogenic effects if exposure occurs during critical periods of differentiation.     

Central Neuroplasticity and Decreased Heart Rate Variability after Particulate Matter Exposure in Mice

Background

Epidemiologic studies show that exposure to fine particulate matter [aerodynamic diameter ≤ 2.5 μm (PM_2.5)] increases the total daily cardiovascular mortality. Impaired cardiac autonomic function, which manifests as reduced heart rate variability (HRV), may be one of the underlying causes. However, the cellular mechanism(s) by which PM_2.5 exposure induces decreased HRV is not known.

Objectives

We tested the hypothesis that exposure to PM_2.5 impairs HRV by decreasing the excitability of the cardiac vagal neurons in the nucleus ambiguus. We also detemined the effect of iron on PM-exposure–induced decrease in HRV.

Methods

We measured 24-hr HRV in time domains from electrocardiogram telemetry recordings obtained in conscious, freely moving mice after 3 days of exposure to PM_2.5 in the form of soot only or iron-soot. In parallel studies, we determined the intrinsic properties of identified cardiac vagal neurons, retrogradely labeled with a fluorescent dye applied to the sinoatrial node.

Results

Soot-only exposure decreased short-term HRV (root mean square of successive difference). With the addition of iron, all HRV parameters were significantly reduced. In nonexposed mice, vagal blockade significantly reduced all HRV parameters, suggesting that HRV is, in part, under vagal regulation in mice. Iron-soot exposure had no significant effect on resting membrane potential but decreased spiking responses of the identified cardiac vagal neurons to depolarizations (p < 0.05). The decreased spiking response was accompanied with a higher minimal depolarizing current required to evoke spikes and a lower peak discharge frequency.

Conclusions

The data suggest that PM-induced neuroplasticity of cardiac vagal neurons may be one mechanism contributing to the cardiovascular consequences associated with PM_2.5 exposure seen in humans.     

Effects of in Utero Exposure to Arsenic during the Second Half of Gestation on Reproductive End Points and Metabolic Parameters in Female CD-1 Mice

Background

Mice exposed to high levels of arsenic in utero have increased susceptibility to tumors such as hepatic and pulmonary carcinomas when they reach adulthood. However, the effects of in utero arsenic exposure on general physiological functions such as reproduction and metabolism remain unclear.

Objectives

We evaluated the effects of in utero exposure to inorganic arsenic at the U.S. Environmental Protection Agency (EPA) drinking water standard (10 ppb) and at tumor-inducing levels (42.5 ppm) on reproductive end points and metabolic parameters when the exposed females reached adulthood.

Methods

Pregnant CD-1 mice were exposed to sodium arsenite [none (control), 10 ppb, or 42.5 ppm] in drinking water from gestational day 10 to birth, the window of organ formation. At birth, exposed offspring were fostered to unexposed dams. We examined reproductive end points (age at vaginal opening, reproductive hormone levels, estrous cyclicity, and fertility) and metabolic parameters (body weight changes, hormone levels, body fat content, and glucose tolerance) in the exposed females when they reached adulthood.

Results

Arsenic-exposed females (10 ppb and 42.5 ppm) exhibited early onset of vaginal opening. Fertility was not affected when females were exposed to the 10-ppb dose. However, the number of litters per female was decreased in females exposed to 42.5 ppm of arsenic in utero. In both 10-ppb and 42.5-ppm groups, arsenic-exposed females had significantly greater body weight gain, body fat content, and glucose intolerance.

Conclusion

Our findings revealed unexpected effects of in utero exposure to arsenic: exposure to both a human-relevant low dose and a tumor-inducing level led to early onset of vaginal opening and to obesity in female CD-1 mice.

Citation

Rodriguez KF, Ungewitter EK, Crespo-Mejias Y, Liu C, Nicol B, Kissling GE, Yao HH. 2016. Effects of in utero exposure to arsenic during the second half of gestation on reproductive end points and metabolic parameters in female CD-1 mice. Environ Health Perspect 124:336–343; http://dx.doi.org/10.1289/ehp.1509703     

Household Exposure to Paint and Petroleum Solvents,Chromosomal Translocations,and the Risk of Childhood Leukemia

Background

Few studies have examined the association between home use of solvents and paint and the risk of childhood leukemia.

Objectives

In this case–control study, we examined whether the use of paint and petroleum solvents at home before birth and in early childhood influenced the risk of leukemia in children.

Methods

We based our analyses on 550 cases of acute lymphoblastic leukemia (ALL), 100 cases of acute myeloid leukemia (AML), and one or two controls per case individually matched for sex, age, Hispanic status, and race. We conducted further analyses by cytogenetic subtype. We used conditional logistic regression techniques to adjust for income.

Results

ALL risk was significantly associated with paint exposure [odds ratio (OR) = 1.65; 95% confidence interval (CI), 1.26–2.15], with a higher risk observed when paint was used postnatally, by a person other than the mother, or frequently. The association was restricted to leukemia with translocations between chromosomes 12 and 21 (OR = 4.16; 95% CI, 1.66–10.4). We found no significant association between solvent use and ALL risk overall (OR = 1.15; 95% CI, 0.87–1.51) or for various cytogenetic subtypes, but we observed a significant association in the 2.0- to 5.9-year age group (OR = 1.55; 95% CI, 1.07–2.25). In contrast, a significant increased risk for AML was associated with solvent (OR = 2.54; 95% CI, 1.19–5.42) but not with paint exposure (OR = 0.64; 95% CI, 0.32–1.25).

Conclusions

The association of ALL risk with paint exposure was strong, consistent with a causal relationship, but further studies are needed to confirm the association of ALL and AML risk with solvent exposure.     

Long-Term Traffic-Related Exposures and Asthma Onset in Schoolchildren in Oslo,Norway

Background

Whether there is a causal relation between long-term exposure to traffic and asthma development is so far not clear. This may be explained by inaccurate exposure assessment.

Objective

We investigated the associations of long-term traffic-related exposures with asthma onset assessed retrospectively and respiratory symptoms in 9- to 10-year-old children.

Methods

We collected information on respiratory outcomes and potential confounding variables by parental questionnaire in 2,871 children in Oslo. Nitrogen dioxide exposure was assessed by the EPISODE dispersion model and assigned at updated individual addresses during lifetime. Distance to major road was assigned at birth address and address by date of questionnaire. Cox proportional hazard regression and logistic regression were used.

Results

We did not find positive associations between any long-term traffic-related exposure and onset of doctor-diagnosed asthma. An interquartile range (IQR) increase of NO₂ exposure before asthma onset was associated with an adjusted risk ratio of 0.82 [95% confidence interval (CI), 0.67–1.02]. Handling early asthma cases (children < 4 years of age) with recovery during follow-up as noncases gave a less negative association. The associations for late asthma onset (≥ 4 years of age) were positive but not statistically significant. For current symptoms, an IQR increase of previous year’s NO₂ exposure was associated with adjusted odds ratios of 1.01 (95% CI, 0.83–1.23) for wheeze, 1.10 (95% CI, 0.79–1.51) for severe wheeze, and 1.01 (95% CI, 0.84–1.21) for dry cough.

Conclusions

We were not able to find positive associations of long-term traffic-related exposures with asthma onset or with current respiratory symptoms in 9- to 10-year-old children in Oslo.     

Traffic-Related Air Pollution and Incident Type 2 Diabetes: Results from the SALIA Cohort Study

Background

Cross-sectional and ecological studies indicate that air pollution may be a risk factor for type 2 diabetes, but prospective data are lacking.

Objective

We examined the association between traffic-related air pollution and incident type 2 diabetes.

Design

Between 1985 and 1994, cross-sectional surveys were performed in the highly industrialized Ruhr district (West Germany); a follow-up investigation was conducted in 2006 using data from the Study on the Influence of Air Pollution on Lung, Inflammation and Aging (SALIA) cohort.

Participants

1,775 nondiabetic women who were 54–55 years old at baseline participated in both baseline and follow-up investigations and had complete information available.

Materials and Methods

Using questionnaires, we assessed 16-year incidence (1990–2006) of type 2 diabetes and information about covariates. Complement factor C3c as marker for subclinical inflammation was measured at baseline. Individual exposure to traffic-related particulate matter (PM) and nitrogen dioxide was determined at different spatial scales.

Results

Between 1990 and 2006, 87 (10.5%) new cases of diabetes were reported among the SALIA cohort members. The hazards for diabetes were increased by 15–42% per interquartile range of PM or traffic-related exposure. The associations persisted when different spatial scales were used to assess exposure and remained robust after adjusting for age, body mass index, socioeconomic status, and exposure to several non–traffic-related sources of air pollution. C3c was associated with PM pollution at baseline and was a strong independent predictor of incident diabetes. Exploratory analyses indicated that women with high C3c blood levels were more susceptible for PM-related excess risk of diabetes than were women with low C3c levels.

Conclusions

Traffic-related air pollution is associated with incident type 2 diabetes among elderly women. Subclinical inflammation may be a mechanism linking air pollution with type 2 diabetes.

Relevance to clinical practice

Our study identifies traffic-related air pollution as a novel and potentially modifiable risk factor of type 2 diabetes.     

Association between GIS-Based Exposure to Urban Air Pollution during Pregnancy and Birth Weight in the INMA Sabadell Cohort

Background

There is growing evidence that traffic-related air pollution reduces birth weight. Improving exposure assessment is a key issue to advance in this research area.

Objective

We investigated the effect of prenatal exposure to traffic-related air pollution via geographic information system (GIS) models on birth weight in 570 newborns from the INMA (Environment and Childhood) Sabadell cohort.

Methods

We estimated pregnancy and trimester-specific exposures to nitrogen dioxide and aromatic hydrocarbons [benzene, toluene, ethylbenzene, m/p-xylene, and o-xylene (BTEX)] by using temporally adjusted land-use regression (LUR) models. We built models for NO₂ and BTEX using four and three 1-week measurement campaigns, respectively, at 57 locations. We assessed the relationship between prenatal air pollution exposure and birth weight with linear regression models. We performed sensitivity analyses considering time spent at home and time spent in nonresidential outdoor environments during pregnancy.

Results

In the overall cohort, neither NO₂ nor BTEX exposure was significantly associated with birth weight in any of the exposure periods. When considering only women who spent < 2 hr/day in nonresidential outdoor environments, the estimated reductions in birth weight associated with an interquartile range increase in BTEX exposure levels were 77 g [95% confidence interval (CI), 7–146 g] and 102 g (95% CI, 28–176 g) for exposures during the whole pregnancy and the second trimester, respectively. The effects of NO₂ exposure were less clear in this subset.

Conclusions

The association of BTEX with reduced birth weight underscores the negative role of vehicle exhaust pollutants in reproductive health. Time–activity patterns during pregnancy complement GIS-based models in exposure assessment.     

Prenatal and Early,but Not Late,Postnatal Exposure of Mice to Sidestream Tobacco Smoke Increases Airway Hyperresponsiveness Later in Life

Background

Cigarette smoke exposure in utero and during early postnatal development increases the incidence of asthma and airway hyperresponsiveness (AHR) later in life, suggesting that a possible critical period of developmental sensitivity exists in the prenatal and early postnatal periods.

Objective

We investigated mechanisms of susceptibility during critical developmental periods to sidestream smoke (SS) exposure and evaluated the possible effects of SS on neural responses.

Methods

We exposed three different age groups of mice to either SS or filtered air (FA) for 10 consecutive days beginning on gestation day (GD) 7 by maternal exposure or beginning on postnatal day (PND) 2 or PND21 by direct inhalation. Lung function, airway substance P (SP) innervation, and nerve growth factor (NGF) levels in broncho alveolar lavage fluid were measured after a single SS exposure on PND59.

Results

Methacholine (MCh) dose response for lung resistance (R_L) was significantly elevated, and dynamic pulmonary compliance (C_dyn) was significantly decreased, in the GD7 and PND2 SS exposure groups compared with the FA groups after SS exposure on PND59. At the same time points, the percent area of SP nerve fibers in tracheal smooth muscle and the levels of NGF were significantly elevated. MCh dose–response curves for R_L and C_dyn, SP nerve fiber density, and the level of NGF were not significantly changed in the PND21 exposure group after SS exposure on PND59.

Conclusions

These results suggest that a critical period of susceptibility to SS exposure exists in the prenatal and early postnatal period of development in mice that results in increased SP innervation, increased NGF levels in the airway, and enhanced MCh AHR later in life.     

Urinary,Circulating, and Tissue Biomonitoring Studies Indicate Widespread Exposure to Bisphenol A

Background

Bisphenol A (BPA) is one of the highest-volume chemicals produced worldwide, and human exposure to BPA is thought to be ubiquitous. Thus, there are concerns that the amount of BPA to which humans are exposed may cause adverse health effects. Importantly, results from a large number of biomonitoring studies are at odds with the results from two toxicokinetic studies.

Objective

We examined several possibilities for why biomonitoring and toxicokinetic studies could come to seemingly conflicting conclusions.

Data sources

We examined > 80 published human biomonitoring studies that measured BPA concentrations in human tissues, urine, blood, and other fluids, along with two toxicokinetic studies of human BPA metabolism.

Data extraction and synthesis

The > 80 biomonitoring studies examined included measurements in thousands of individuals from several different countries, and these studies overwhelmingly detected BPA in individual adults, adolescents, and children. Unconjugated BPA was routinely detected in blood (in the nanograms per milliliter range), and conjugated BPA was routinely detected in the vast majority of urine samples (also in the nanograms per milliliter range). In stark contrast, toxicokinetic studies proposed that humans are not internally exposed to BPA. Some regulatory agencies have relied solely on these toxicokinetic models in their risk assessments.

Conclusions

Available data from biomonitoring studies clearly indicate that the general population is exposed to BPA and is at risk from internal exposure to unconjugated BPA. The two toxicokinetic studies that suggested human BPA exposure is negligible have significant deficiencies, are directly contradicted by hypothesis-driven studies, and are therefore not reliable for risk assessment purposes.