COVID-19 Is a Coronary Artery Disease Risk Equivalent and Exhibits a Genetic Interaction With ABO Blood Type.

BACKGROUND: COVID-19 is associated with acute risk of major adverse cardiac events (MACE), including myocardial infarction, stroke, and mortality (all-cause). However, the duration and underlying determinants of heightened risk of cardiovascular disease and MACE post-COVID-19 are not known. METHODS: Data from the UK Biobank was used to identify COVID-19 cases (n=10 005) who were positive for polymerase chain reaction (PCR+)-based tests for SARS-CoV-2 infection (n=8062) or received hospital-based International Classification of Diseases version-10 (ICD-10) codes for COVID-19 (n=1943) between February 1, 2020 and December 31, 2020. Population controls (n=217 730) and propensity score-matched controls (n=38 860) were also drawn from the UK Biobank during the same period. Proportional hazard models were used to evaluate COVID-19 for association with long-term (>1000 days) risk of MACE and as a coronary artery disease risk equivalent. Additional analyses examined whether COVID-19 interacted with genetic determinants to affect the risk of MACE and its components. RESULTS: The risk of MACE was elevated in COVID-19 cases at all levels of severity (HR, 2.09 [95% CI, 1.94-2.25]; P<0.0005) and to a greater extent in cases hospitalized for COVID-19 (HR, 3.85 [95% CI, 3.51-4.24]; P<0.0005). Hospitalization for COVID-19 represented a coronary artery disease risk equivalent since incident MACE risk among cases without history of cardiovascular disease was even higher than that observed in patients with cardiovascular disease without COVID-19 (HR, 1.21 [95% CI, 1.08-1.37]; P<0.005). A significant genetic interaction was observed between the ABO locus and hospitalization for COVID-19 (Pinteraction=0.01), with risk of thrombotic events being increased in subjects with non-O blood types (HR, 1.65 [95% CI, 1.29-2.09]; P=4.8×10-5) to a greater extent than subjects with blood type O (HR, 0.96 [95% CI, 0.66-1.39]; P=0.82). CONCLUSIONS: Hospitalization for COVID-19 represents a coronary artery disease risk equivalent, with post-acute myocardial infarction and stroke risk particularly heightened in non-O blood types. These results may have important clinical implications and represent, to our knowledge, one of the first examples of a gene-pathogen exposure interaction for thrombotic events.

Environmental pollutant risk factors for worse COVID-19 related clinical outcomes in predominately hispanic and latino populations.

BACKGROUND: Per- and poly-fluorinated compounds (PFAS) and heavy metals constitute two classes of environmental exposures with known immunotoxicant effects. In this pilot study, we aimed to evaluate the impact of exposure to heavy metals and PFAS on COVID-19 severity. We hypothesized that elevated plasma-PFAS concentrations and urinary heavy metal concentrations would be associated with increased odds of ICU admission in COVID-19 hospitalized individuals. METHODS: Using the University of Southern California Clinical Translational Sciences Institute (SC-CTSI) biorepository of hospitalized COVID-19 patients, urinary concentrations of 15 heavy metals and urinary creatinine were measured in n = 101 patients and plasma concentrations of 13 PFAS were measured in n = 126 patients. COVID-19 severity was determined based on whether a patient was admitted to the ICU during hospitalization. Associations of metals and PFAS with ICU admission were assessed using logistic regression models, controlling for age, sex, ethnicity, smoking status, and for metals, urinary dilution. RESULTS: The average age of patients was 55 ± 14.2 years. Among SC-CTSI participants with urinary measurement of heavy metals and blood measures of PFAS, 54.5% (n = 61) and 54.8% (n = 80) were admitted to the ICU, respectively. For heavy metals, we observed higher levels of Cd, Cr, and Cu in ICU patients. The strongest associations were with Cadmium (Cd). After accounting for covariates, each 1 SD increase in Cd resulted in a 2.00 (95% CI: 1.10-3.60; p = 0.03) times higher odds of admission to the ICU. When including only Hispanic or Latino participants, the effect estimates between cadmium and ICU admission remained similar. Results for PFAS were less consistent, with perfluorodecanesulfonic acid (PFDS) exhibiting a positive but non-significant association with ICU admission (Odds ratio, 95% CI: 1.50, 0.97-2.20) and perfluorodecanoic acid (PFDA) exhibiting a negative association with ICU admission (0.53, 0.31-0.88). CONCLUSIONS: This study supports the hypothesis that environmental exposures may impact COVID-19 severity.

Dose dependence of prenatal fluoride exposure associations with cognitive performance at school age in three prospective studies.

BACKGROUND: Fluoride may be a developmental neurotoxicant at elevated exposures. We merged new data from a prospective Odense Child Cohort (OCC) with results from two previous birth cohort studies from Mexico and Canada to characterize the dose-effect relationship in greater detail. METHODS: The OCC contributed 837 mother-child pairs to the total of >1500. We measured creatinine-adjusted urine-fluoride concentrations in maternal urine samples obtained during late pregnancy. Child IQ was determined at age 7 years using an abbreviated version of the Wechsler Intelligence Scales for Children. Findings from the three cohorts were used to calculate the joint benchmark concentration (BMC) and the lower confidence limit (BMCL) after adjustment for covariables. RESULTS: In the OCC, urine-fluoride concentrations varied between 0.08 and 3.04 mg/l (median 0.52 mg/l) but were not significantly associated with full-scale IQ at age 7 years (ß = 0.08; 95% confidence interval -1.14 to 1.30 for a doubling in exposure). No difference was apparent between boys and girls. In the OCC, the BMC was 0.92 mg/l, with a BMCL of 0.30 mg/l. The joint analysis of all three cohorts showed a statistically significant association between urine-fluoride and IQ, with a BMC of 0.45 mg/l (BMCL, 0.28 mg/l), slightly higher than the BMC previously reported for the two North American cohorts alone. CONCLUSIONS: As the BMCL reflects an approximate threshold for developmental neurotoxicity, the results suggest that pregnant women and children may need protection against fluoride toxicity.

Urinary fluoride levels and metal co-exposures among pregnant women in Los Angeles, California.

BACKGROUND: Fluoride is ubiquitous in the United States (US); however, data on biomarkers and patterns of fluoride exposure among US pregnant women are scarce. We examined specific gravity adjusted maternal urinary fluoride (MUFsg) in relation to sociodemographic variables and metal co-exposures among pregnant women in Los Angeles, California. METHODS: Participants were from the Maternal and Developmental Risks from Environmental and Social Stressors (MADRES) cohort. There were 293 and 490 women with MUFsg measured during first and third trimesters, respectively. An intra-class correlation coefficient examined consistency of MUFsg between trimesters. Kruskal-Wallis and Mann-Whitney U tests examined associations of MUFsg with sociodemographic variables. Covariate adjusted linear regression examined associations of MUFsg with blood metals and specific gravity adjusted urine metals among a subsample of participants within and between trimesters. A False Discovery Rate (FDR) correction accounted for multiple comparisons. RESULTS: Median (IQR) MUFsg was 0.65 (0.5) mg/L and 0.8 (0.59) mg/L, during trimesters one and three respectively. During both trimesters, MUFsg was higher among older participants, those with higher income, and White, non-Hispanic participants than Hispanic participants. MUFsg was also higher for White, non-Hispanic participants than for Black, non-Hispanic participants in trimester three, and for those with graduate training in trimester one. MUFsg was negatively associated with blood mercury in trimester one and positively associated with blood lead in trimester three. MUFsg was positively associated with various urinary metals, including antimony, barium, cadmium, cobalt, copper, lead, nickel, tin, and zinc in trimesters one and/or three. CONCLUSIONS: MUFsg levels observed were comparable to those found in pregnant women in Mexico and Canada that have been associated with poorer neurodevelopmental outcomes. Lower urinary fluoride levels among Hispanic and non-Hispanic Black participants in MADRES compared to non-Hispanic White participants may reflect lower tap water consumption or lower fluoride exposure from other sources. Additional research is needed to examine whether MUFsg levels observed among pregnant women in the US are associated with neurodevelopmental outcomes.

Characteristics associated with attitudes and behaviors towards mask wearing during the COVID-19 pandemic: The Trojan Pandemic Response Initiative.

BACKGROUND: Attitudes and behaviors towards mask wearing may influence the ability to reduce transmission of COVID-19 and other diseases. METHODS: University students, staff, and faculty (N = 9653) responded to an email invitation to complete electronic surveys (November 2021 and April 2022). Surveys included 19 items measuring attitudes and behaviors towards mask wearing from the Understanding America Study. Linear mixed models including variables for sex, age group, division, race and ethnicity, political affiliation, and history of COVID-19, were used to estimate the mean difference of the mean score for attitudes and behavior between Time 1 (November 2021) and Time 2 (April 2022). RESULTS: Participants were mostly female (62.1%), students (70.6%), White (39.5%) and Asian (34.7%). More than half identified their political affiliation as Democrat (65.5%). Characteristic variable-by-time interactions for difference in mean mask attitude scores difference were significant at Time 1 (T1) and Time 2 (T2) between Black and White participants (B = 0.18 (0.05), 95% CI: 0.07, 0.28, p = 0.001), Asian and White participants (B = 0.07 (0.02), 95% CI: 0.03-0.12, p = 0.001), participants with self-reported history of COVID-19 and no history of COVID-19 (B= -0.13 (0.02), 95% CI: -0.07, -0.18, p < 0.0001), females and males (B = 0.07 (0.02), 95% CI: 0.03, 0.11, p = 0.001), Republicans and Democrats (B= -0.18 (0.04), 95%CI: -0.26, -0.10, p < 0.0001) and Independents and Democrats (B= -0.10 (0.03), 95%CI: -0.15, -0.05, p < 0.0001). Mean difference in mean scores for mask behaviors at Time and Time 2 were significant between participants with COVID-19 and participants who did not have COVID-19 (B= -0.12 (0.04), 95% CI: -0.19, -0.04, p = 0.004), students compared to faculty and staff (B=-0.22 (0.05), -0.32, -0.12, p < 0.0001), between Republicans and Democrats (B-= -0.16 (0.07), 95% CI: -0.28, -0.03, p = 0.020, and between Independents and Democrats (B=-0.08 (0.04), 95% CI: -0.16, -0.002, p = 0.04). CONCLUSION: Race and ethnicity, political affiliation, and division may affect attitudes and behaviors in mask wearing. Further investigation into how characteristics influence public health measures such as mask wearing is needed to contain the spread of the COVID-19 virus, other infectious diseases, and future pandemics.

Trust in science and scientists among university students, staff, and faculty of a large, diverse university in Los Angeles during the COVID-19 pandemic, the Trojan Pandemic Response Initiative.

BACKGROUND: Mistrust in science and scientists may adversely influence the rate of COVID-19 vaccination and undermine public health initiatives to reduce virus transmission. METHODS: Students, staff and faculty responded to an email invitation to complete an electronic survey. Surveys included 21-items from the Trust in Science and Scientists Inventory questionnaire. Responses were coded so higher scores indicated a higher trust in science and scientists, A linear regression model including sex, age group, division, race and ethnicity, political affiliation, and history of COVID-19, was used to determine variables significantly associated with trust in science and scientists scores at the p < 0.05 level. RESULTS: Participants were mostly female (62.1%), Asian (34.7%) and White (39.5%) and students (70.6%). More than half identified their political affiliation as Democrat (65%). In the final regression model, all races and ethnicities had significantly lower mean trust in science and scientists scores than White participants [Black ([Formula: see text]= -0.42, 95% CI: -0.55, -0.43, p < 0.001); Asian ([Formula: see text]= -0.20, 95% CI: -0.24, -0.17, p < 0.001); Latinx ([Formula: see text]= -0.22, 95% CI: -0.27, -0.18, p < 0.001); Other ([Formula: see text]= -0.19, 95% CI: -0.26, -0.11, p < 0.001)]. Compared to those identifying as Democrat, all other political affiliations had significantly lower mean scores. [Republican ([Formula: see text] =-0.49, 95% CI: -0.55, -0.43, p < 0.0001); Independent ([Formula: see text] =-0.29, 95% CI: -0.33, -0.25, p < 0.0001); something else ([Formula: see text] =-0.19, 95% CI: -0.25, -0.12, p < 0.0001)]. Having had COVID-19 ([Formula: see text]= -0.10, 95% CI: -0.15, -0.06, p < 0.001) had significantly lower scores compared to those who did not have COVID-19. CONCLUSION: Despite the setting of a major research University, trust in science is highly variable. This study identifies characteristics that could be used to target and curate educational campaigns and university policies to address the COVID19 and future pandemics.

In Utero Exposure to Mercury Is Associated With Increased Susceptibility to Liver Injury and Inflammation in Childhood.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of liver disease in children. Mercury (Hg), a ubiquitous toxic metal, has been proposed as an environmental factor contributing to toxicant-associated fatty liver disease. APPROACH AND RESULTS: We investigated the effect of prenatal exposure to Hg on childhood liver injury by combining epidemiological results from a multicenter mother-child cohort with complementary in vitro experiments on monocyte cells that are known to play a key role in liver immune homeostasis and NAFLD. We used data from 872 mothers and their children (median age, 8.1 years; interquartile range [IQR], 6.5-8.7) from the European Human Early-Life Exposome cohort. We measured Hg concentration in maternal blood during pregnancy (median, 2.0 µg/L; IQR, 1.1-3.6). We also assessed serum levels of alanine aminotransferase (ALT), a common screening tool for pediatric NAFLD, and plasma concentrations of inflammation-related cytokines in children. We found that prenatal Hg exposure was associated with a phenotype in children that was characterized by elevated ALT (≥22.1 U/L for females and ≥25.8 U/L for males) and increased concentrations of circulating IL-1ß, IL-6, IL-8, and TNF-α. Consistently, inflammatory monocytes exposed in vitro to a physiologically relevant dose of Hg demonstrated significant up-regulation of genes encoding these four cytokines and increased concentrations of IL-8 and TNF-α in the supernatants. CONCLUSIONS: These findings suggest that developmental exposure to Hg can contribute to inflammation and increased NAFLD risk in early life.

Role of renal function in the association of drinking water fluoride and plasma fluoride among adolescents in the United States: NHANES, 2013-2016.

CONTEXT: While fluoride has been added to drinking water and dental products for decades in order to prevent tooth decay, there are growing concerns about its potential toxicity. Given that fluoride is primarily excreted in urine, an important question that has not been examined is whether among those whose drinking water is fluoridated, impaired renal function is associated with higher levels of circulating fluoride. OBJECTIVE: To examine the association between drinking water and plasma fluoride and its modification by renal function. DESIGN, SETTING, AND PARTICIPANTS: Participants in the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2016 with measures of fluoride in plasma and drinking water and renal function. These measures were only available in adolescent age 12-19 years. OUTCOMES: Plasma fluoride levels and their modification by strata of renal function, measured by the estimated glomerular filtration rate (eGFR). RESULTS: Among 1841 healthy adolescents, a 10 ml/min/1.73 m (Penman et al., 1997) lower eGFR and a 1 mg/L higher drinking water fluoride concentration were associated with a 0.02 (95%CI -0.02, -0.03) umol/L and 0.23 (95%CI 0.15,0.30) umol/L higher adjusted plasma fluoride level, respectively. The association of water and plasma fluoride levels was most robust among those with lower renal function (multiplicative interaction p value < 0.001). For adolescents in the lowest eGFR quartile, a 1 mg/L higher drinking water fluoride concentration was associated with a 0.35 (95%CI 0.21,0.48) umol/L higher plasma fluoride level, compared to 0.20 (95%CI 0.14,0.26) umol/L in the highest eGFR quartile. Restriction to those with measurable plasma fluoride levels yielded similar results. CONCLUSIONS: Water fluoridation results in higher plasma fluoride levels in those with lower renal function. How routine water fluoridation may affect the many millions of Americans with Chronic Kidney Disease, who are particularly susceptible to heavy metal and mineral accumulation, needs to be further investigated.

Prenatal maternal pesticide exposure in relation to sleep health of offspring during adolescence.

STUDY OBJECTIVES: The neurobiological processes involved in establishing sleep regulation are vulnerable to environmental exposures as early as seven weeks of gestation. Studies have linked in utero pesticide exposure to childhood sleep-disordered breathing. However, the impact of in utero pesticide exposure on the sleep health of adolescents remains unexplored. MATERIALS AND METHODS: Data from 137 mother-adolescent pairs from a Mexico City cohort were analyzed. We used maternal urinary 3-phenoxybenzoic acid (3-PBA, pyrethroid metabolite) and 3, 5, 6-trichloro-2-pyridinol (TCPy, chlorpyrifos metabolite) from trimester three to estimate in utero pesticide exposure. Among adolescents, we obtained repeated measures of objectively assessed sleep duration, midpoint, and fragmentation using wrist-actigraphy devices for 7 consecutive days in 2015 and 2017. Unstratified and sex-stratified associations between maternal urinary 3-PBA and TCPy and adolescent sleep measures were examined using generalized linear mixed models (GLMMs). We also examined the interactive effects of maternal pesticide exposure and offspring sex on sleep outcomes. RESULTS: 3-PBA and TCPy were detected in 44.4% and 93% of urine samples, respectively. Adjusted findings demonstrated that higher exposure to maternal TCPy was associated with longer sleep duration and later sleep timing. Findings from interaction tests between maternal pesticide exposure and offspring sex were not statistically significant, although adjusted sex-stratified findings showed that the association between TCPy with duration and midpoint was evident only among female offspring. To illustrate, those in the highest tertile of exposure had a 59 minute (95% CI: 12.2, 104.8) (p, trend = 0.004) longer sleep duration and a 0.6 hour (95% CI: 0.01, 1.3) (p, trend = 0.01) later sleep midpoint. We found no significant associations between 3-PBA and sleep outcomes. CONCLUSION: Within a cohort of mother-adolescent pairs, we found associations between maternal prenatal pesticide exposure and longer sleep duration and later sleep timing among adolescent offspring. Further, this association may be female-specific.

Domain-specific effects of prenatal fluoride exposure on child IQ at 4, 5, and 6-12 years in the ELEMENT cohort.

OBJECTIVE: Prenatal exposure to fluoride has been associated with adverse neurodevelopmental outcomes. However, the neuropsychological profile of fluoride's developmental neurotoxicity at low levels and the stability of this relationship across childhood has not been characterized. We investigated the longitudinal and domain specific effect of prenatal fluoride exposure on IQ among children ages 4, 5, and 6-12 years in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort. METHODS: We measured the average of maternal urinary fluoride at each trimester of pregnancy adjusted for creatinine (MUFCRE). Children were administered the McCarthy Scales of Children's Abilities at ages 4 (N = 386) and 5 (N = 308), and the Wechsler Abbreviated Scale of Intelligence at age 6-12 (N = 278). We used generalized estimating equation (GEE) models to estimate the population averaged effect of MUFCRE concentration on longitudinal General Cognitive Index (GCI)/Full-Scale IQ (FSIQ), Verbal IQ (VIQ), and Performance IQ (PIQ) scores (N = 348). We tested for possible interactions between MUFCRE and child sex as well as for MUFCRE and time point on children's IQ. All models controlled for relevant available covariates. RESULTS: The mean/median MUFCRE concentration was 0.90/0.83 mg/L (SD = 0.39; IQR, 0.64-1.11 mg/L). A 0.5 mg/L increase in MUFCRE predicted an average 2.12-point decrease in GCI/FSIQ (95% CI: -3.49, -0.75) and 2.63-point decrease in PIQ (95% CI: -3.87, -1.40). MUFCRE was marginally associated with VIQ across time (B = -1.29, 95% CI: -2.60, 0.01). No interactions between MUFCRE and child sex or MUFCRE and time were observed. CONCLUSION: The negative association between prenatal fluoride exposure and longitudinal IQ was driven by decrements in non-verbal intelligence (i.e. PIQ), suggesting that visual-spatial and perceptual reasoning abilities may be more impacted by prenatal fluoride exposure as compared to verbal abilities.

Serum antioxidant status and mortality from influenza and pneumonia in US adults.

OBJECTIVE: We examined the association between serum antioxidant status and mortality from influenza and pneumonia in US adults. DESIGN: Serum concentrations of antioxidants included vitamin C, vitamin A, vitamin E, sum of α- and ß-carotene, ß-cryptoxanthin, lutein + zeaxanthin and lycopene. We computed total antioxidant capacity (TAC) as a measure of composite antioxidant status in serum. Survey-weighted Cox proportional hazard models were used to compute hazard ratios (HR) and 95 % CI comparing quartiles of each antioxidant and TAC. SETTING: Data from the US National Health and Nutrition Examination Survey (NHANES)-III. PARTICIPANTS: A total of 7428 NHANES-III participants ≥45 years of age. RESULTS: With a weighted-median follow-up of 16·8 years, 154 participants died from influenza/pneumonia. After adjustment for covariates, serum vitamin C, the sum of α- and ß-carotene and TAC were nonlinearly associated with influenza/pneumonia mortality, with the statistically significant smallest HR at the third quartile v. the first quartile (HR = 0·38 (95 % CI: 0·19, 0·77), 0·29 (0·16, 0·51) and 0·30 (0·15, 0·59), respectively). HR comparing the fourth v. the first quartiles were weaker and nonsignificant: 0·57 (95 % CI: 0·27, 1·17), 0·70 (0·41, 1·19) and 0·65 (0·31, 1·35), respectively. Serum lycopene had a monotonic association with influenza/pneumonia mortality (HR = 0·43 (95 % CI: 0·23, 0·83) comparing the fourth v. the first quartile, Pfor trend = 0·01). CONCLUSIONS: The current study suggests that antioxidant intake as reflected by serum concentrations may reduce mortality risk from influenza or pneumonia in the US general population. These findings warrant further confirmation in other populations with different settings (e.g. a shorter-term association with influenza infection).

Did prioritizing essential workers help to achieve racial/ethnic equity in early COVID-19 vaccine distribution? The LA pandemic surveillance cohort study.

BACKGROUND: Most US states and counties prioritized essential workers for early access to COVID-19 vaccines due to their heightened occupational risk. Racial/ethnic groups most impacted by COVID-19 are overrepresented among essential workers. This study estimates the effects of prioritizing essential workers on racial/ethnic equity in COVID-19 vaccination. METHODS: Survey data were collected from 5500 Los Angeles County adult residents in March and April 2021. Multivariate regression models were used to assess marginal changes in probabilities of vaccination attributable to essential worker status by race/ethnicity. These probabilities were multiplied by population proportions of essential workers in each racial/ethnic group to estimate the effects of prioritizing essential workers on vaccine equity in the population. RESULTS: While Latinos (24.9%), Blacks (22.4%), and Asians (21.4%) were more likely to be prioritized essential workers than Whites (14.3%), their marginal gains in vaccine uptake due to their essential worker status did not significantly differ from that of Whites. At the population-level, prioritizing vaccines for essential workers increased the probabilities of vaccination by small and similar amounts among Asians (5.3%; 95% confidence interval [CI]: 3.3%, 7.5%), Blacks (4.0%; 95% CI: 1.7%, 6.5%), Latinos (3.7%; 95% CI: 2.3%, 5.1%), and Whites (2.9%; 95% CI :1.9%, 3.9%). CONCLUSIONS: Prioritizing essential workers did not provide proportionally greater early vaccine uptake benefits to racial/ethnic groups that were disproportionately affected by COVID-19. Early prioritization of essential workers during vaccine campaigns is an important but insufficient strategy for reducing racial/ethnic disparities in early vaccine uptake. Additional strategies addressing access and trust are needed to achieve greater equity in vaccine distribution.

A Benchmark Dose Analysis for Maternal Pregnancy Urine-Fluoride and IQ in Children.

As a guide to establishing a safe exposure level for fluoride exposure in pregnancy, we applied benchmark dose modeling to data from two prospective birth cohort studies. We included mother-child pairs from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort in Mexico and the Maternal-Infant Research on Environmental Chemicals (MIREC) cohort in Canada. Maternal urinary fluoride concentrations (U-F, in mg/L, creatinine-adjusted) were measured in urine samples obtained during pregnancy. Children were assessed for intelligence quotient (IQ) at age 4 (n = 211) and between six and 12 years (n = 287) in the ELEMENT cohort, and three to four years (n = 407) in the MIREC cohort. We calculated covariate-adjusted regression coefficients and their standard errors to assess the association of maternal U-F concentrations with children's IQ measures. Assuming a benchmark response of 1 IQ point, we derived benchmark concentrations (BMCs) and benchmark concentration levels (BMCLs). No deviation from linearity was detected in the dose-response relationships, but boys showed lower BMC values than girls. Using a linear slope for the joint cohort data, the BMC for maternal U-F associated with a 1-point decrease in IQ scores was 0.31 mg/L (BMCL, 0.19 mg/L) for the youngest boys and girls in the two cohorts, and 0.33 mg/L (BMCL, 0.20 mg/L) for the MIREC cohort and the older ELEMENT children. Thus, the joint data show a BMCL in terms of the adjusted U-F concentrations in the pregnant women of approximately 0.2 mg/L. These results can be used to guide decisions on preventing excess fluoride exposure in pregnant women.

Association between cumulative childhood blood lead exposure and hepatic steatosis in young Mexican adults.

BACKGROUND: Exposure to environmental toxicants may play a role in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD). Cumulative exposure to lead (Pb) has chronic and permanent effects on liver function. Pediatric populations are vulnerable to the toxic effects of Pb, even at low exposure levels. The purpose of the study was to estimate the association between cumulative Pb exposure during childhood and hepatic steatosis biomarkers in young Mexican adults. METHODS: A subsample of 93 participants from the ELEMENT cohort were included in this study. Childhood blood samples were collected annually from ages 1-4 years and were used to calculate the Cumulative Childhood Blood Lead Levels (CCBLL). Hepatic steatosis during adulthood was defined as an excessive accumulation of hepatic triglycerides (>5%) determined using Magnetic Resonance Imaging (MRI). Liver enzymes were also measured at this time, and elevated liver enzyme levels were defined as ALT (≥30 IU/L), AST (≥30 IU/L), and GGT (≥40 IU/L). Adjusted linear regression models were fit to examine the association between CCBLL (quartiles) and the hepatic steatosis in young adulthood. RESULTS: In adulthood, the mean age was 21.4 years, 55% were male. The overall prevalence of hepatic steatosis by MRI was 19%. Elevate levels of the enzymes ALT, AST, and GGT were present in 25%, 15%, and 17% of the sample, respectively. We found a positive association between the highest quartile of CCBLL with the steatosis biomarkers of hepatic triglycerides (Q4 vs. Q1: ß = 6.07, 95% CI: 1.91-10.21), elevated ALT (Q4 vs. Q1: ß = 14.5, 95% CI: 1.39-27.61) and elevated AST (Q4 vs. Q1: ß = 7.23, 95% CI: 0.64-13.82). No significant associations were found with GGT. CONCLUSIONS: Chronic Pb exposure during early childhood is associated with a higher levels of hepatic steatosis biomarkers and hepatocellular injury in young adulthood. More actions should be taken to eliminate sources of Pb during the first years of life.

Dietary fluoride intake over the course of pregnancy in Mexican women.

OBJECTIVE: To estimate dietary fluoride intake (F) over the course of pregnancy and the overall adjusted difference in dietary F intake by pregnancy stages and levels of compliance with dietary recommendations. DESIGN: Secondary data analysis from a longitudinal pregnancy cohort study in a population exposed to fluoridated salt. Women were followed during the early, middle and late stages of their pregnancy (n 568). The dietary intake of recommended prenatal nutrients according to Mexican dietary guidelines and F intake (mg/d) was estimated with a validated FFQ. Data were summarised with descriptive statistics. Levels of F intake were compared with the USA's Institute of Medicine adequate intake (AI) of 3 mg/d for pregnancy. Adjusted differences in F intake by pregnancy stages and levels of compliance with recommendations were estimated using random effects models. SETTING: Mexico City. PARTICIPANTS: Women participating in the Early Life Exposures in Mexico to ENvironmental Toxicants (ELEMENT) project, from 2001 to 2003. RESULTS: Median dietary F intake throughout pregnancy ranged from 0·64 (interquartile range (IQR) 0·38) in the early to 0·70 (IQR 0·42) in the middle, and 0·72 (IQR 0·44) mg/d in the late stage (0·01 mg F/kg per d). Corresponding adjusted intakes of F were 0·72 (95 % CI 0·70, 0·74), 0·76 (95 % CI 0·74, 0·77) and 0·80 (95 % CI 0·78, 0·82) mg/d. Women who were moderately and highly compliant with Mexican dietary recommendations ingested, on average, 0·04 and 0·14 mg F/d more than non-compliant women (P < 0·005). CONCLUSIONS: Dietary F intake was below current AI, was greater with the progression of pregnancy and in women who were moderately and highly compliant with dietary recommendations.

Association of Dietary Fluoride Intake and Diet Variables with Dental Caries in Adolescents from the ELEMENT Cohort Study.

To examine the association of dietary fluoride intake, total carbohydrate consumption and other key dietary variables with dental caries experience among adolescents, a cross-sectional analysis was conducted in a sample of 402 participants from the Early Life Exposures in Mexico to Environmental Toxicants cohort. The presence and severity of dental caries were assessed using the International Caries Detection and Assessment System (ICDAS) to calculate the number of decayed, missing, and filled teeth or surfaces (D1MFT/D4MFT). The dietary intake of fluoride, energy, carbohydrates, and food groups was estimated using a validated food frequency questionnaire (FFQ). Multivariate zero-inflated negative binomial regression models and negative binomial regression models were run to estimate the association of fluoride intake (mg/day) and total carbohydrate intake (g/day) with the D1MFT/D4MFT index. We found that 80% of the adolescents experienced dental caries (D1MFT >0), with 30% presenting cavitated lesions (D4MFT >0). The mean scores for D1MFT and D4MFT were 6.2 (SD 5.3) and 0.67 (SD 1.3), respectively. The median intake of fluoride estimated by the FFQ was 0.015 mg/kg/day. This intake was statistically higher in participants with a D4MFT = 0 compared to those with a D4MFT >0 (0.90 vs. 0.82 mg/day; 0.016 vs. 0.014 mg/kg/day; p < 0.05). For D1MFT, D1MFS, D4MFT, and D4MFS scores, a higher fluoride consumption (mg/day) from foods and beverages was associated with a statistically significant reduction in the number of lesions. The reported frequency of consumption of sugary foods in a whole day was statistically higher in those with D1MFT >0 than in those with D1MFT = 0 (p < 0.05). The total carbohydrate intake (g/day) was positively associated with dental caries experience. We conclude that a higher fluoride intake through foods and beverages is associated with a lower dental caries experience among adolescents; this effect was seen even when the dietary intake of fluoride was 0.015 mg/kg/day, which is lower than the average intake recommendation. In contrast, a higher total carbohydrate intake and the frequency of intake of sugary foods were associated with a higher dental caries experience, with no apparent threshold for the effects.

Lagged kernel machine regression for identifying time windows of susceptibility to exposures of complex mixtures.

The impact of neurotoxic chemical mixtures on children's health is a critical public health concern. It is well known that during early life, toxic exposures may impact cognitive function during critical time intervals of increased vulnerability, known as windows of susceptibility. Knowledge on time windows of susceptibility can help inform treatment and prevention strategies, as chemical mixtures may affect a developmental process that is operating at a specific life phase. There are several statistical challenges in estimating the health effects of time-varying exposures to multi-pollutant mixtures, such as: multi-collinearity among the exposures both within time points and across time points, and complex exposure-response relationships. To address these concerns, we develop a flexible statistical method, called lagged kernel machine regression (LKMR). LKMR identifies critical exposure windows of chemical mixtures, and accounts for complex non-linear and non-additive effects of the mixture at any given exposure window. Specifically, LKMR estimates how the effects of a mixture of exposures change with the exposure time window using a Bayesian formulation of a grouped, fused lasso penalty within a kernel machine regression (KMR) framework. A simulation study demonstrates the performance of LKMR under realistic exposure-response scenarios, and demonstrates large gains over approaches that consider each time window separately, particularly when serial correlation among the time-varying exposures is high. Furthermore, LKMR demonstrates gains over another approach that inputs all time-specific chemical concentrations together into a single KMR. We apply LKMR to estimate associations between neurodevelopment and metal mixtures in Early Life Exposures in Mexico and Neurotoxicology, a prospective cohort study of child health in Mexico City.

Dietary patterns, bone lead and incident coronary heart disease among middle-aged to elderly men.

BACKGROUND: Most absorbed lead ends up in the bone, where it can be measured as a biomarker of cumulative exposure, elevations of which have been shown to predict a higher risk of coronary heart disease (CHD). Knowledge about the role of dietary patterns is critical to the development of effective interventions for the cardiovascular toxicity of cumulative lead exposure. METHODS: 594 men, free of CHD at baseline, were followed from August 1991 to June 2011 in the Normative Aging Study. Bone lead concentrations were measured by K-shell-X-ray fluorescence. Dietary patterns were identified using principal components analysis. Two dietary patterns were identified: a 'prudent' pattern characterized by high intake of fruit, vegetables, legumes, tomatoes, poultry, and seafood; and a 'Western' pattern, with high intake of red meat, processed meat, refined grains, high-fat dairy products, high-energy drinks, fries, butter and eggs. Cox proportional hazard models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. Effect modification on the multiplicative scale was examined through cross-product interaction terms. RESULTS: 137 men developed incident CHD events during 5071 person-years of follow-up. After adjusting for age, body mass index, total energy intake, smoking status, total cholesterol to high-density lipoprotein ratio, education and occupation, an HR of incident CHD was 1.64 (95% CI: 1.27-2.11) with each doubling in patella lead concentration in the low prudent diet group (< median prudent score); and the HR decreased to 1.07 (95% CI: 0.86-1.34) in the high prudent diet (≥ median prudent score) (p-for-interaction = 0.01), suggesting protective effects of prudent diet against lead-related CHD. By contrast, the association between tibia lead and CHD was non-significantly larger in the low Western diet group (HR = 1.43, 95% CI: 1.14-1.80) compared with the high Western diet group (HR = 1.08, 95% CI: 0.86-1.34) (p-for-interaction = 0.06). No significant effect modifications were detected by Western diet in the patella lead-CHD association and by prudent diet in the tibia lead-CHD association. CONCLUSIONS: Prudent diet may reduce the risk of development of CHD in relation to patella lead. However, these findings need to be interpreted with caution, given the modest sample size.

Fluoride exposure and pubertal development in children living in Mexico City.

BACKGROUND: Previous animal and ecological studies have provided evidence for an earlier sexual maturation in females in relation to fluoride exposure; however, no epidemiological studies have examined the association between fluoride exposure and pubertal development in both boys and girls using individual-level biomarkers of fluoride. Capitalizing on an ongoing Mexican birth cohort study, we examined the association between concurrent urinary fluoride levels and physical markers of pubertal development in children. METHODS: We conducted a cross-sectional study of 157 boys and 176 girls at age 10-17 years living in Mexico City. We used ion-selective electrode-based diffusion methods to assess fluoride levels in urine, adjusting for urinary specific gravity. Pubertal stages were evaluated by a trained physician. Associations of fluoride with pubertal stages and age at menarche were studied using ordinal regression and Cox proportional-hazard regression, respectively. RESULTS: In the entire sample, the geometric mean and interquartile range (IQR) of urinary fluoride (specific gravity adjusted) were 0.59 mg/L and 0.31 mg/L, respectively. In boys, our analysis showed that a one-IQR increase in urinary fluoride was associated with later pubic hair growth (OR = 0.71, 95% CI: 0.51-0.98, p = 0.03) and genital development (OR = 0.71, 95% CI: 0.53-0.95, p = 0.02). No significant associations were found in girls, although the direction was negative. CONCLUSIONS: Childhood fluoride exposure, at the levels observed in our study, was associated with later pubertal development among Mexican boys at age 10-17 years. Further research is needed to confirm these findings.