Changes in Adipose Tissue and Circulating Concentrations of Persistent Organic Pollutants in Midlife Women.

Polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) are persistent organic pollutants (POPs) that bioaccumulate in adipose tissue. We investigated the relationship between change in central adiposity and changes in circulating concentrations of POPs over a 12-year period during the midlife. Serum concentrations of 34 PCBs and 19 OCPs were measured at four time points (1999/2000, 2002/03, 2005/06, 2009/11) in a cohort of midlife women, the Study of Women's Health Across the Nation. Linear mixed models were used to test the association between a change in waist circumference and a change in serum POP concentrations. Sixty-five women contributed 181 PCB observations. Fifty-nine women contributed 151 OCP observations. After adjustment for covariates (study site, race and ethnicity, age at baseline, parity), a one-inch (2.54 cm) increase in the change in waist circumference between visits was associated with a 4.9% decrease in the change in serum concentration of PCB 194 (95% CI: -8.0%, -1.6%). No associations were observed for other PCB congeners or the presence of OCPs. An increase in the difference in waist circumference over time was not associated with a change in the difference in serum concentrations of PCBs and OCPs except for PCB 194, possibly due to the high lipophilicity.

Environmental chemical-wide associations with immune biomarkers in US adults: A cross-sectional analysis.

Environmental chemical exposures influence immune system functions, and humans are exposed to a wide range of chemicals, termed the chemical "exposome". A comprehensive, discovery analysis of the associations of multiple chemical families with immune biomarkers is needed. In this study, we tested the associations between environmental chemical concentrations and immune biomarkers. We analyzed the United States cross-sectional National Health and Nutrition Examination Survey (NHANES 1999-2018). Chemical biomarker concentrations were measured in blood or urine (196 chemicals, 17 chemical families). Immune biomarkers included counts of lymphocytes, neutrophils, monocytes, basophils, eosinophils, red blood cells, white blood cells, and mean corpuscular volume. We conducted separate survey-weighted, multivariable linear regressions of each log2-transformed chemicals on immune measures, adjusted for relevant covariates. We accounted for multiple comparisons using a false discovery rate (FDR). Among 45,528 adult participants, the mean age was 45.7 years, 51.4% were female, and 69.3% were Non-Hispanic White. 71 (36.2%) chemicals were associated with at least one of the eight immune biomarkers. The most chemical associations (FDR<0.05) were observed with mean corpuscular volume (36 chemicals) and red blood cell counts (35 chemicals). For example, a doubling in the concentration of cotinine was associated with 0.16 fL (95% CI: 0.15, 0.17; FDR<0.001) increased mean corpuscular volume, and a doubling in the concentration of blood lead was associated with 61,736 increased red blood cells per µL (95% CI: 54,335, 69,138; FDR<0.001). A wide variety of chemicals, such as metals and smoking-related compounds, were highly associated with immune system biomarkers. This environmental chemical-wide association study identified chemicals from multiple families for further toxicological, immunologic, and epidemiological investigation.

Do we underestimate risk of cardiovascular mortality due to lead exposure?

BACKGROUND: Studies using data from the National Health and Nutrition Examination Survey-III (NHANES-III) have demonstrated significant prospective associations between blood lead levels and increased mortality. Bone lead represents cumulative lead burden and thus is a better biomarker for assessing chronic impacts, but its in vivo assessment requires special K-x-ray fluorescence (KXRF) instrumentation. Our team recently developed an algorithm predicting bone lead levels from a combination of blood lead levels, age and other socioeconomic and behavioral variables. We examined the associations of our algorithm-estimated bone lead levels and mortality in NHANES-III. METHODS: We included 11,628 adults followed up to December 31, 2019. Estimated tibia lead and patella lead levels were calculated using our prediction algorithms. We used survey-weighted Cox proportional hazards models to compute hazard ratios (HRs) and 95 % confidence intervals (CIs). RESULTS: During the median follow-up of 26.8 years, 4900 participants died (mortality rate = 1398 per 100,000 adults/year). Geometric means (95 % CIs) of blood lead, predicted tibia lead, and predicted patella lead were 2.69 µg/dL (2.54, 2.84), 6.73 µg/g (6.22, 7.25), and 16.3 µg/g (15.9, 16.8), respectively. The associations for all-cause mortality were similar between blood lead and bone lead. However, the associations for cardiovascular mortality were much greater with predicted bone lead markers compared to blood lead: for comparing participants at the 90th vs. 10th percentiles of exposure, HR = 3.32 (95 % CI: 1.93-5.73) for tibia lead, 2.42 (1.56-3.76) for patella lead, 1.63 (1.25-2.14) for blood lead. The population attributable fractions for cardiovascular disease mortality if everyone's lead concentrations were declined to the 10th percentiles were 45.8 % (95 % CI: 28.1-59.4) for tibia lead, 33.1 % (18.1-45.8) for patella lead, and 22.8 % (10.4-33.8) for blood lead. CONCLUSIONS: These findings suggest that risk assessment for cardiovascular mortality based on blood lead levels may underestimate the true mortality risk of lead exposure.

Heavy Metals and Trajectories of Anti-Müllerian Hormone During the Menopausal Transition.

BACKGROUND: Experimental and epidemiological studies have linked metals with women's reproductive aging, but the mechanisms are not well understood. Disrupted ovarian folliculogenesis and diminished ovarian reserve could be a pathway through which metals impact reproductive hormones and outcomes. OBJECTIVE: The study aimed to evaluate the associations of heavy metals with anti-Müllerian hormone (AMH), a marker of ovarian reserve. METHODS: The study included 549 women from the Study of Women's Health Across the Nation with 2252 repeated AMH measurements from 10 to 0 years before the final menstrual period (FMP). Serum AMH concentrations were measured using picoAMH ELISA. Urinary concentrations of arsenic, cadmium, mercury, and lead were measured using high-resolution inductively coupled plasma mass spectrometry. Multivariable linear mixed regressions modeled AMH as a function of time before the FMP interaction terms between metals and time to the FMP were also included. RESULTS: Adjusting for confounders, compared with those in the lowest tertile, women in the highest tertile of urinary arsenic or mercury concentrations had lower AMH concentrations at the FMP (percent change: -32.1%; 95% CI, -52.9 to -2.2, P-trend = .03 for arsenic; percent change: -40.7%; 95% CI, -58.9 to -14.5, P-trend = .005 for mercury). Higher cadmium and mercury were also associated with accelerated rates of decline in AMH over time (percent change per year: -9.0%; 95% CI, -15.5 to -1.9, P-trend = .01 for cadmium; -7.3%; 95% CI, -14.0 to -0.1, P-trend = .04 for mercury). CONCLUSION: Heavy metals including arsenic, cadmium, and mercury may act as ovarian toxicants by diminishing ovarian reserve in women approaching the FMP.

Manganese and Sleep Outcomes in United States Adults: Results from the 2017-2020 National Health and Nutrition Examination Survey (NHANES).

BACKGROUND: Manganese (Mn) is an essential micronutrient, but inadequate or excess Mn intake can have a detrimental impact on human health. Despite the essentiality, little is known about the relationship between Mn and sleep. OBJECTIVE: This study aimed to examine the relationship between blood Mn concentrations and sleep outcomes in US adults. METHODS: This cross-sectional study used data on blood Mn and sleep from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) (n = 8356, age ≥18 y). Multivariable logistic regression was used to examine associations between quintiles of blood Mn concentrations and subjective sleep outcomes (short sleep duration, late sleep midpoint, trouble sleeping, and obstructive sleep apnea [OSA] symptoms), adjusting for age, gender, body mass index, race/ethnicity, income, smoking, inflammation-adjusted serum ferritin concentration (iron status), caffeine, and alcohol intake. Gender-stratified models were used due to interactions with gender. RESULTS: The mean (SE) blood Mn concentration was 9.7 (0.1) µg/L in US adults. In males, a nonlinear association was noted in the relationship between blood Mn levels and short sleep duration on weekdays and weekends. The third Mn quintile (Q3) group had lower odds of short sleep duration (<7 h) on weekdays (odds ratio [OR]=0.6, 95% confidence interval [CI]: 0.4, 0.9) than the lowest Mn quintile (Q1, reference) after adjusting for covariates in males. The second Mn quintile (Q2) group had lower odds of late sleep midpoint on weekdays than Q1 (OR=0.6, 95% CI: 0.4, 0.8). In females, Q2 group had lower odds of OSA symptoms than Q1 (OR: 0.6, 95% CI: 0.4, 0.9). No relationship was noted between Mn and trouble sleeping. CONCLUSIONS: Gender differences exist in the association between Mn and sleep in adults. Q1 group had the poorest sleep outcomes, including higher odds of short sleep duration (in males), late sleep midpoint (in males), and OSA symptoms (in females).

Blood-based biomarkers for Alzheimer's disease and cognitive function from mid- to late life.

INTRODUCTION: We investigated associations of Alzheimer's disease (AD) serum biomarkers with longitudinal changes in cognitive function from mid- to late life among women. METHODS: The study population included 192 women with the median age of 53.3 years at baseline, from the Study of Women's Health Across the Nation Michigan Cohort, followed up over 14 years. Associations between baseline serum amyloid ß (Aß)42, the Aß42/40 ratio, phosphorylated tau181 (p-tau181), and total tau with longitudinal changes in cognition were evaluated using linear mixed effects models. RESULTS: After adjusting for confounders, lower Aß42/40 ratios were associated with faster declines in the Digit Span Backward Test. Higher p-tau181 also showed a borderline statistically significant association with more rapid decline in the Symbol Digit Modalities Test. DISCUSSION: Our findings suggest that mid-life serum AD biomarkers could be associated with accelerated cognitive decline from mid- to late life in women. Future studies with larger samples are needed to validate and extend our findings. HIGHLIGHTS: This study investigates midlife serum AD biomarkers on longitudinal cognitive function changes in women. Mid-life serum AD biomarkers are associated with accelerated cognitive decline. A decrease in the Aß42/40 ratio was associated with a faster decline in the DSB score. A higher p-tau181 concentration was associated with a faster decline in the SDMT score.

Volatile Organic Compounds in Disposable Diapers and Baby Wipes in the US: A Survey of Products and Health Risks.

Many thousands of diapers are worn by young children and the elderly, who have thin and sensitive skin that is highly vulnerable to chemicals, including volatile organic compounds (VOCs) that may be ingredients of these products or present as inadvertent or residual components. The levels and potential health risks of VOCs in diapers have not been reported previously. In this study, we collected 31 disposable hygiene products in the US market based on market share and analyzed 98 target VOCs using purge and trap sampling and thermal desorption/gas chromatography/mass spectrometer analysis. Exposures and risks were modeled using reasonable upper level exposure scenarios. Adult diapers contained the highest total target VOC concentration (median level of 23.5 µg/g), and the predominant VOCs were alkanes. In some diapers, the estimated noncancer risk from these VOCs was sometimes very large (hazard quotient of 1609) due to n-heptane. Baby diapers contained several known or suspected carcinogens, including benzene and 1,4-dioxane, and the lifetime cancer risk from some diapers approached 1 per million under a worst-case scenario. Store-brand products had higher levels of VOCs than generic brands, and products labeled "organic" or "for sensitive skin" did not necessarily have lower levels. Our results show that toxic VOCs were found in all tested disposable diapers and wipes at trace levels, and risks from using some diapers in high use exposure scenarios are high enough to warrant additional attention and possibly corrective measures. We recommend eliminating and monitoring toxic ingredients and disclosing all chemicals that may be in these products.

Urinary concentrations of polycyclic aromatic hydrocarbon metabolites and childhood obesity.

Objectives: Existing literature provides limited information on the association between childhood obesity and polycyclic aromatic hydrocarbons (PAHs), which are potentially obesogenic. We examined the association between urinary concentrations of PAH metabolites and obesity in the Korean pediatric population. Methods: We analyzed the data of 2286 children/adolescents aged 3-17 years who participated in the Korean National Environmental Health Survey between 2015 and 2017. Urinary concentrations of 2-naphthol, 2-hydroxyfluorene, 1-hydroxyphenanthrene, and 1-hydroxypyrene were assayed using gas chromatography-mass spectrometry. Overweight/obesity was defined as a body mass index (BMI) for age ≥85th percentile. Multiple linear and logistic regression models were used to analyze the relationship of BMI z-score and overweight with urinary concentrations of PAH metabolites after adjusting for age, sex, household income, parental education level, physical activity, fast-food consumption, and environmental tobacco smoke exposure. Results: BMI z-score was positively associated with 2-naphthol concentrations in children aged 6-11 and 12-17 years and with 1-hydroxypyrene concentrations in children aged 6-11 years. In the overall population, a significant rise in odds ratios for overweight/obesity across 2-naphthol quartiles was noted. Specifically, the 3rd and 4th quartiles displayed odds ratios of 1.39 [1.03, 1.88] and 1.46 [1.08, 1.99] respectively, compared to the 1st quartile (P-for-trend = 0.006). Similar associations between 2-naphthol and overweight/obesity status were observed in the 6-11- and 12-17-year age groups. There was little evidence of an association between overweight/obesity and other PAH hydroxy derivatives. Conclusions: PAH exposure may be associated with increased childhood adiposity, a potential risk factor for adult obesity and adverse metabolic outcomes.

Per- and Polyfluoroalkyl Substances (PFAS) and Lipid Trajectories in Women 45-56 Years of Age: The Study of Women's Health Across the Nation.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are associated with less favorable blood lipid profiles in epidemiological studies. However, little is known about the potential role of PFAS in longitudinal changes in lipids among midlife women even though women become more susceptible to metabolic alterations during the menopausal transition. OBJECTIVES: To examine associations of serum PFAS concentrations with longitudinal trajectories of blood total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in midlife women undergoing menopausal transition. METHODS: The sample included 1,130 women from the Study of Women's Health Across the Nation 45-56 y of age at baseline (1999-2000). We measured serum PFAS concentrations including linear perfluorooctanoic acid (n-PFOA), perfluorononanoic acid (PFNA), linear and branched perfluorooctanesulfonic acid (n-PFOS and Sm-PFOS, respectively), and perfluorohexanesulfonic acid (PFHxS) at baseline. We used k-means clustering to identify subgroups with different patterns of PFAS mixture. Blood lipids were measured annually or biannually through 2016 with an average follow-up of 14.8 y. We identified longitudinal trajectories of each lipid using latent class growth models. We used multinomial log-linear models adjusted for covariates to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of lipid trajectory classes by PFAS and their mixtures. RESULTS: Three distinct trajectories (low, middle, high) of total, LDL, and HDL cholesterol and two distinct trajectories (low and high) of triglycerides were identified. n-PFOS, Sm-PFOS, and PFHxS were positively associated with total and LDL cholesterol trajectories. n-PFOS was inversely associated with triglycerides trajectories. PFAS mixtures (high vs. low) showed positive associations with total and LDL cholesterol trajectories (high vs. low), showing ORs (95% CIs) of 1.69 (95% CI: 1.36, 2.12) and 1.79 (95% CI: 1.44, 2.22), respectively. DISCUSSION: Concentrations of serum PFAS were positively associated with trajectories of total and LDL cholesterol, providing a line of evidence supporting adverse effects of PFAS on lipid homeostasis. https://doi.org/10.1289/EHP12351.

Collagen Peptide Exerts an Anti-Obesity Effect by Influencing the Firmicutes/Bacteroidetes Ratio in the Gut.

Alterations in the intestinal microbial flora are known to cause various diseases, and many people routinely consume probiotics or prebiotics to balance intestinal microorganisms and the growth of beneficial bacteria. In this study, we selected a peptide from fish (tilapia) skin that induces significant changes in the intestinal microflora of mice and reduces the Firmicutes/Bacteroidetes ratio, which is linked to obesity. We attempted to verify the anti-obesity effect of selected fish collagen peptides in a high-fat-diet-based obese mouse model. As anticipated, the collagen peptide co-administered with a high-fat diet significantly inhibited the increase in the Firmicutes/Bacteroidetes ratio. It increased specific bacterial taxa, including Clostridium_sensu_stricto_1, Faecalibaculum, Bacteroides, and Streptococcus, known for their anti-obesity effects. Consequently, alterations in the gut microbiota resulted in the activation of metabolic pathways, such as polysaccharide degradation and essential amino acid synthesis, which are associated with obesity inhibition. In addition, collagen peptide also effectively reduced all obesity signs caused by a high-fat diet, such as abdominal fat accumulation, high blood glucose levels, and weight gain. Ingestion of collagen peptides derived from fish skin induced significant changes in the intestinal microflora and is a potential auxiliary therapeutic agent to suppress the onset of obesity.

Associations of healthy lifestyle and socioeconomic status with cognitive function in U.S. older adults.

We investigated the complex relations of socioeconomic status (SES) and healthy lifestyles with cognitive functions among older adults in 1313 participants, aged 60 years and older, from the National Health and Nutrition Examination Survey 2011-2014. Cognitive function was measured using an average of the standardized z-scores of the Consortium to Establish a Registry for Alzheimer's Disease Word Learning and delayed recall tests, the Animal Fluency Test, and the Digit Symbol Substitution Test. Latent class analysis of family income, education, occupation, health insurance, and food security was used to define composite SES (low, medium, high). A healthy lifestyle score was calculated based on smoking, alcohol consumption, physical activity, and the Healthy-Eating-Index-2015. In survey-weighted multivariable linear regressions, participants with 3 or 4 healthy behaviors had 0.07 (95% CI 0.005, 0.14) standard deviation higher composite cognitive z-score, relative to those with one or no healthy behavior. Participants with high SES had 0.37 (95% CI 0.29, 0.46) standard deviation higher composite cognitive z-score than those with low SES. No statistically significant interaction was observed between healthy lifestyle score and SES. Our findings suggested that higher healthy lifestyle scores and higher SES were associated with better cognitive function among older adults in the United States.

The role of exposure to per- and polyfluoroalkyl substances in racial/ethnic disparities in hypertension: Results from the study of Women's health across the nation.

BACKGROUND: Racial/ethnic disparities in hypertension are a pressing public health problem. The contribution of environmental pollutants including PFAS have not been explored, even though certain PFAS are higher in Black population and have been associated with hypertension. OBJECTIVES: We examined the extent to which racial/ethnic disparities in incident hypertension are explained by racial/ethnic differences in serum PFAS concentrations. METHODS: We included 1058 hypertension-free midlife women with serum PFAS concentrations in 1999-2000 from the multi-racial/ethnic Study of Women's Health Across the Nation with approximately annual follow-up visits through 2017. Causal mediation analysis was conducted using accelerated failure time models. Quantile-based g-computation was used to evaluate the joint effects of PFAS mixtures. RESULTS: During 11,722 person-years of follow-up, 470 participants developed incident hypertension (40.1 cases per 1000 person-years). Black participants had higher risks of developing hypertension (relative survival: 0.58, 95% CI: 0.45-0.76) compared with White participants, which suggests racial/ethnic disparities in the timing of hypertension onset. The percent of this difference in timing that was mediated by PFAS was 8.2% (95% CI: 0.7-15.3) for PFOS, 6.9% (95% CI: 0.2-13.8) for EtFOSAA, 12.7% (95% CI: 1.4-22.6) for MeFOSAA, and 19.1% (95% CI: 4.2, 29.0) for PFAS mixtures. The percentage of the disparities in hypertension between Black versus White women that could have been eliminated if everyone's PFAS concentrations were dropped to the 10th percentiles observed in this population was 10.2% (95% CI: 0.9-18.6) for PFOS, 7.5% (95% CI: 0.2-14.9) for EtFOSAA, and 17.5% (95% CI: 2.1-29.8) for MeFOSAA. CONCLUSIONS: These findings suggest differences in PFAS exposure may be an unrecognized modifiable risk factor that partially accounts for racial/ethnic disparities in timing of hypertension onset among midlife women. The study calls for public policies aimed at reducing PFAS exposures that could contribute to reductions in racial/ethnic disparities in hypertension.

Phthalates and Incident Diabetes in Midlife Women: The Study of Women's Health Across the Nation (SWAN).

CONTEXT: Phthalates are hypothesized to contribute to diabetes, but longitudinal evidence in humans is limited. OBJECTIVE: We examined whether phthalate exposure was associated with a higher incidence of diabetes in a racially/ethnically diverse cohort of midlife women. METHODS: In the Study of Women's Health Across the Nation Multipollutant Study, we followed 1308 women without diabetes in 1999-2000 for 6 years. Eleven phthalate metabolites were measured in spot urine samples in 1999-2000 and 2002-2003. Incident diabetes was ascertained between 1999-2000 and 2005-2006. Cox proportional hazards models with time-varying exposure were used to estimate the hazard ratio (HR) of diabetes associated with each phthalate metabolite, adjusting for demographic, lifestyle, and health-related factors. Effect modification by race/ethnicity was examined with interaction terms. RESULTS: Sixty-one women developed diabetes over 6 years (cumulative incidence = 4.7%). Among all women, several high-molecular-weight phthalate metabolites were associated with a higher incidence of diabetes, but none were statistically significant. There was effect modification by race/ethnicity. Among White women, each doubling of the concentrations of mono-isobutyl phthalate (MiBP), monobenzyl phthalate, mono-carboxyoctyl phthalate, mono-carboxyisononyl phthalate (MCNP), and mono(3-carboxypropyl) phthalate was associated with a 30% to 63% higher incidence of diabetes (HR = 1.30, 95% CI, 1.03-1.65 for MCNP; HR = 1.63, 95% CI, 1.18-2.25 for MiBP). In contrast, phthalates were not associated with diabetes incidence in Black or Asian women. CONCLUSIONS: Some phthalate metabolites were associated with a higher incidence of diabetes over 6 years, but the associations were inconsistent across racial/ethnic groups. Whether phthalates cause diabetes requires further investigation.

Associations of Healthy Lifestyle and Socioeconomic Status with Cognitive Function in U.S. Older Adults.

We investigated the complex relations of socioeconomic status (SES) and healthy lifestyles with cognitive functions among older adults in 1,313 participants, aged 60 years and older, from the National Health and Nutrition Examination Survey 2011-2014. Cognitive function was measured using an average of the standardized z-scores of the Consortium to Establish a Registry for Alzheimer’s Disease Word Learning and delayed recall tests, the Animal Fluency Test, and the Digit Symbol Substitution Test. Latent class analysis of family income, education, occupation, health insurance, and food security was used to define composite SES (low, medium, high). A healthy lifestyle score was calculated based on smoking, alcohol consumption, physical activity, and the Healthy-Eating-Index-2015. In survey-weighted multivariable linear regressions, participants with 3 or 4 healthy behaviors had 0.07 (95% CI: 0.005, 0.14) standard deviation higher composite cognitive z-score, relative to those with one or no healthy behavior. Participants with high SES had 0.37 (95% CI: 0.29, 0.46) standard deviation higher composite cognitive z-score than those with low SES. No statistically significant interaction was observed between healthy lifestyle score and SES. Our findings suggested that higher healthy lifestyle scores and higher SES were associated with better cognitive function among older adults in the United States.

Improving the Prediction of Death from Cardiovascular Causes with Multiple Risk Markers.

Background: Traditional risk factors including demographics, blood pressure, cholesterol, and diabetes status are successfully able to predict a proportion of cardiovascular disease (CVD) events. Whether including additional routinely measured factors improves CVD prediction is unclear. To determine whether a comprehensive risk factor list, including clinical blood measures, blood counts, anthropometric measures, and lifestyle factors, improves prediction of CVD deaths beyond traditional factors. Methods: The analysis comprised of 21,982 participants aged 40 years and older (mean age=59.4 years at baseline) from the National Health and Nutrition Examination Survey (NHANES) from 2001 to 2016 survey cycles. Data were linked with the National Death Index mortality data through 2019 and split into 80:20 training and testing sets. Relative to the traditional risk factors (age, sex, race/ethnicity, smoking status, systolic blood pressure, total and high-density lipoprotein cholesterol, antihypertensive medications, and diabetes), we compared models with an additional 22 clinical blood biomarkers, 20 complete blood counts, 7 anthropometric measures, 51 dietary factors, 13 cardiovascular health-related questions, and all 113 predictors together. To build prediction models for CVD mortality, we performed Cox proportional hazards regression, elastic-net (ENET) penalized Cox regression, and random survival forest, and compared classification using C-index and net reclassification improvement. Results: During follow-up (median, 9.3 years), 3,075 participants died; 30.9% (1,372/3,075) deaths were from cardiovascular causes. In Cox proportional hazards models with traditional risk factors (C-index=0.850), CVD mortality classification improved with incorporation of clinical blood biomarkers (C-index=0.867), blood counts (C-index=0.861), and all predictors (C-index=0.871). Net CVD mortality reclassification improved 13.2% by adding clinical blood biomarkers and 12.2% by adding all predictors. Results for ENET-penalized Cox regression and random survival forest were similar. No improvement was observed in separate models for anthropometric measures, dietary nutrient intake, or cardiovascular health-related questions. Conclusions: The addition of clinical blood biomarkers and blood counts substantially improves CVD mortality prediction, beyond traditional risk factors. These biomarkers may serve as an important clinical and public health screening tool for the prevention of CVD deaths.

Associations Between Repeated Measures of Urinary Phthalate Metabolites With Hormones and Timing of Natural Menopause.

Phthalates, ubiquitous endocrine-disrupting chemicals, may affect ovarian folliculogenesis and steroidogenesis. We examined the associations of urinary phthalate metabolites with hormones including estradiol, testosterone, follicle-stimulating hormone (FSH), sex hormone-binding globulin (SHBG), and anti-Müllerian hormone (AMH), and timing of natural menopause in midlife women. Data were from 1189 multiracial/multiethnic women aged 45 to 56 years without hormone therapy from the Study of Women's Health Across the Nation (SWAN). Urinary concentrations of 12 phthalate metabolites and hormones were repeatedly measured in 1999 to 2000 and 2002 to 2003, resulting in a total of 2111 observations. Linear mixed-effect models were used to calculate percentage differences (%D) and 95% CIs in serum concentrations of estradiol, testosterone, FSH, SHBG, and AMH. Cox proportional-hazards models were used to calculate hazard ratios (HRs) and 95% CIs of natural menopause. We observed statistically significant associations of phthalate metabolites with lower testosterone concentrations: MCOP with testosterone (%D: -2.08%; 95% CI, -3.66 to -0.47) and MnBP with testosterone (%D: -1.99%; 95% CI, -3.82 to -0.13), after adjusting for multiple comparisons with false discovery rates less than 5%. Lower AMH concentrations were also found with higher MECPP (%D: -14.26%; 95% CI, -24.10 to -3.14), MEHHP (%D: -15.58%; 95% CI, -24.59 to -5.50), and MEOHP (%D: -13.50%; 95% CI, -22.93 to -2.90). No associations were observed for other hormones or timing of natural menopause. These results suggest that exposure to phthalates may affect circulating levels of testosterone and diminish the ovarian reserve in midlife women. Given the widespread exposure, reduced exposure to phthalates may be a key step to prevent reproductive effects of phthalates.

Associations between mercury exposure with blood pressure and lipid levels: A cross-sectional study of dental professionals.

Mercury (Hg) exposure is a public health problem worldwide that is now being addressed through the Minamata Convention on Mercury. Fish containing methylmercury and dental amalgam containing elemental Hg are the major sources of exposure for most populations. There is some evidence that methylmercury impacts cardiovascular and metabolic health, primarily in populations with high exposure levels. Studies of elemental Hg and these outcomes are relatively rare. We aimed to examine associations between Hg exposure (both elemental and methylmercury) and blood pressure, as well as cholesterol and triglyceride levels. In 2012, we recruited dental professionals attending the Health Screening Program at the American Dental Association (ADA) Annual Session in California. Total Hg levels in hair and blood samples were analyzed as indicators of methylmercury exposure and in urine as an indicator of primarily elemental Hg exposure (n = 386; mean ± sd age 55 ± 11 years). We measured blood pressure (systolic and diastolic) and lipid profiles (total cholesterol, high-density lipoprotein cholesterol [HDL], low-density lipoprotein cholesterol [LDL] and triglycerides). The geometric means (geometric standard deviations) for blood, hair, and urine Hg were 3.64 (2.39) µg/L, 0.60 (2.91) µg/g, and 1.30 (2.44) µg/L, respectively. For every one µg/L increase in specific gravity-adjusted urine Hg, LDL increased by 2.31 mg/dL (95% CI = 0.09, 4.54), in linear regression adjusting for BMI, race, sex, polyunsaturated fatty acid intake from fish consumption, smoking status, and use of cholesterol-lowering medication. No significant associations between Hg biomarkers and blood pressure or hair or blood Hg with lipid levels were observed. Results suggest that elemental Hg exposure may influence LDL concentrations in adults with low-level exposure, and this relationship merits further study in other populations.

Isomer-Specific Serum Concentrations of Perfluorooctane Sulfonic Acid among U.S. Adults: Results from the National Health and Nutrition Examination Survey (NHANES) and the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS).

Electrochemical fluorination manufacture of perfluorooctane sulfonic acid (PFOS), one of the most studied per- and polyfluoroalkyl substances, produces mixtures of linear and branched isomers, but little is known about human exposure to linear or branched PFOS isomers. We examined determinants affecting isomer-specific patterns of PFOS in serum in two adult populations in the United States, the National Health and Nutrition Examination Survey (NHANES) and the Study of Women's Health Across the Nation Multi-Pollutant Study (SWAN-MPS). After adjusting for demographic variables, fish consumption (in both populations), a glomerular filtration rate above 90 mL/min/1.73 m2 (observed in NHANES; not tested in SWAN-MPS), premenopausal status (only observed in SWAN-MPS), and less consumption of processed food (observed in SWAN-MPS; not tested in NHANES) were associated with a higher proportion of linear PFOS. Non-Hispanic Black and Asian participants were likely to have a higher proportion of linear PFOS than non-Hispanic White participants in both populations. Our findings suggest that isomer-specific patterns of PFOS serum concentrations in humans vary depending on population characteristics that affect PFOS exposure and excretion. Consideration of specific PFOS isomers in future human biomonitoring and epidemiologic studies can provide useful insight to better understand PFOS exposure.

Exposure to heavy metals and hormone levels in midlife women: The Study of Women's Health Across the Nation (SWAN).

Exposure to heavy metals may alter the circulating levels of sex hormones. However, epidemiologic studies on heavy metals and sex hormones have been limited, and results have been inconsistent. We assessed the associations of heavy metals assayed in urine, including arsenic, cadmium, lead, and mercury, with repeated measures of serum estradiol (E2), follicle-stimulating hormone (FSH), testosterone, and sex hormone-binding globulin (SHBG) levels in the Study of Women's Health Across the Nation Multi-Pollutant Study. The sample included 1355 White, Black, Chinese, and Japanese women, aged 45-56 years at baseline (1999-2000), whose serum hormone levels were repeatedly measured through 2017. Urinary metal concentrations were measured at baseline. Linear mixed effect models were used to calculate percent changes in serum hormone levels per doubling of urinary metal concentrations, adjusting for demographics, socioeconomic status, lifestyle, health-related factors, and urinary creatinine. After multivariable adjustment, a doubling of urinary metal concentration was associated with lower E2 levels by 2.2% (95% CI: 4.0%, -0.3%) for mercury and 3.6% (95% CI: 5.7%, -1.6%) for lead; higher FSH levels by 3.4% (95% CI: 0.9%, 5.9%) for lead; and higher SHBG levels by 3.6% (95% CI: 1.3%, 5.9%) for cadmium. The overall joint effect using the Bayesian kernel machine regression showed that metal mixtures were inversely associated with E2 and positively associated with FSH levels. No association was found between metals and testosterone levels. Results from this prospective cohort study demonstrate that environmental heavy metal exposures, including cadmium, mercury, and lead, may disturb circulating levels of E2, FSH, and SHBG in midlife women.

Predicting cumulative lead (Pb) exposure using the Super Learner algorithm.

Chronic lead (Pb) exposure causes long term health effects. While recent exposure can be assessed by measuring blood lead (half-life 30 days), chronic exposures can be assessed by measuring lead in bone (half-life of many years to decades). Bone lead measurements, in turn, have been measured non-invasively in large population-based studies using x-ray fluorescence techniques, but the method remains limited due to technical availability, expense, and the need for licensing radioactive materials used by the instruments. Thus, we developed prediction models for bone lead concentrations using a flexible machine learning approach--Super Learner, which combines the predictions from a set of machine learning algorithms for better prediction performance. The study population included 695 men in the Normative Aging Study, aged 48 years and older, whose bone (patella and tibia) lead concentrations were directly measured using K-shell-X-ray fluorescence. Ten predictors (blood lead, age, education, job type, weight, height, body mass index, waist circumference, cumulative cigarette smoking (pack-year), and smoking status) were selected for patella lead and 11 (the same 10 predictors plus serum phosphorus) for tibia lead using the Boruta algorithm. We implemented Super Learner to predict bone lead concentrations by calculating a weighted combination of predictions from 8 algorithms. In the nested cross-validation, the correlation coefficients between measured and predicted bone lead concentrations were 0.58 for patella lead and 0.52 for tibia lead, which has improved the correlations obtained in previously-published linear regression-based prediction models. We evaluated the applicability of these prediction models to the National Health and Nutrition Examination Survey for the associations between predicted bone lead concentrations and blood pressure, and positive associations were observed. These bone lead prediction models provide reasonable accuracy and can be used to evaluate health effects of cumulative lead exposure in studies where bone lead is not measured.