Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-28 (of 28 Records) |
Query Trace: Rybak ME[original query] |
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Association between low maternal serum aflatoxin B1 exposure and adverse pregnancy outcomes in Mombasa, Kenya, 2017-2019: A nested matched case-control study
Osoro E , Awuor AO , Inwani I , Mugo C , Hunsperger E , Verani JR , Nduati R , Kinuthia J , Okutoyi L , Mwaengo D , Maugo B , Otieno NA , Mirieri H , Ombok C , Nyawanda B , Agogo GO , Ngere I , Zitomer NC , Rybak ME , Munyua P , Njenga K , Widdowson MA . Matern Child Nutr 2024 e13688 We examined the association between serum aflatoxin B1-lysine adduct (AFB1-lys) levels in pregnant women and adverse pregnancy outcomes (low birthweight, miscarriage and stillbirth) through a nested matched case-control study of pregnant women enroled at ≤28 weeks' gestation in Mombasa, Kenya, from 2017 to 2019. Cases comprised women with an adverse birth outcome, defined as either delivery of a singleton infant weighing <2500 g, or a miscarriage, or a stillbirth, while controls were women who delivered a singleton live infant with a birthweight of ≥2500 g. Cases were matched to controls at a ratio of 1:2 based on maternal age at enrolment, gestational age at enrolment and study site. The primary exposure was serum AFB1-lys. The study included 125 cases and 250 controls. The median gestation age when serum samples were collected was 23.0 weeks (interquartile range [IQR]: 18.1-26.0) and 23.5 (IQR: 18.1-26.5) among cases and controls, respectively. Of the 375 tested sera, 145 (38.7%) had detectable serum AFB1-lys: 36.0% in cases and 40.0% in controls. AFB1-lys adduct levels were not associated with adverse birth outcomes on multivariable analysis. Mid-upper arm circumference was associated with a 6% lower odds of adverse birth outcome for every unit increase (p = 0.023). Two-fifths of pregnant women had detectable levels of aflatoxin midway through pregnancy. However, we did not detect an association with adverse pregnancy outcomes, likely because of low serum AFB1-lys levels and low power, restricting meaningful comparison. More research is needed to understand the public health risk of aflatoxin in pregnant women to unborn children. |
Mutations in TAC1B: a novel genetic determinant of clinical fluconazole resistance in C. auris (preprint)
Rybak JM , Munoz JF , Barker KS , Parker JE , Esquivel BD , Berkow EL , Lockhart SR , Gade L , Palmer GE , White TC , Kelly SL , Cuomo CA , Rogers PD . bioRxiv 2020 2020.02.18.955534 Candida auris has emerged as a multidrug-resistant pathogen of great clinical concern. Approximately 90% of clinical C. auris isolates are resistant to fluconazole, the most commonly prescribed antifungal agent, yet it remains unknown what mechanisms underpin this fluconazole resistance. To identify novel mechanisms contributing to fluconazole resistance in C. auris, the fluconazole-susceptible C. auris clinical isolate AR0387 was passaged in media supplemented with fluconazole to generate derivative strains which had acquired increased fluconazole resistance in vitro. Comparative analysis of comprehensive sterol profiles, [3H]-fluconazole uptake, sequencing of C. auris genes homologous to genes known to contribute to fluconazole resistance in other species of Candida, and the relative expression of C. auris ERG11, CDR1, and MDR1 were performed. All fluconazole-evolved derivative strains were found to have acquired mutations in the zinc-cluster transcription factor-encoding gene, TAC1B, and a corresponding increase in CDR1 expression relative to the parental clinical isolate, AR0387. Mutations in TAC1B were also identified in a set of 304 globally distributed C. auris clinical isolates representing each of the four major clades. Introduction of the most common mutation found among fluconazole-resistant clinical isolates of C. auris into the fluconazole-susceptible isolate AR0387, was confirmed to increase fluconazole resistance by 8-fold, and the correction of the same mutation in a fluconazole-resistant isolate, AR0390, decreased fluconazole MIC by 16-fold. Taken together, these data demonstrate that C. auris can rapidly acquire resistance to fluconazole in-vitro, and that mutations in TAC1B significantly contribute to clinical fluconazole resistance.IMPORTANCE Candida auris is an emerging multidrug-resistant pathogen of global concern, known to be responsible for outbreaks on six continents and commonly resistant to antifungals. While the vast majority of clinical C. auris isolates are highly resistant to fluconazole, an essential part of the available antifungal arsenal, very little is known about the mechanisms contributing to resistance. In this work, we show that mutations in the transcription factor TAC1B significantly contribute to clinical fluconazole resistance. These studies demonstrate that mutations in TAC1B can arise rapidly in vitro upon exposure to fluconazole, and that a multitude of resistance-associated TAC1B mutations are present among the majority of fluconazole-resistant C. auris isolates from a global collection and appear specific to a subset of lineages or clades. Thus, identification of this novel genetic determinant of resistance significantly adds to the understanding of clinical antifungal resistance in C. auris. |
Rapid analysis of drugs: A pilot surveillance system to detect changes in the illicit drug supply to guide timely harm reduction responses - eight syringe services programs, Maryland, November 2021-August 2022
Russell E , Sisco E , Thomson A , Lopes J , Rybak M , Burnett M , Heilman D , Appley MG , Gladden RM . MMWR Morb Mortal Wkly Rep 2023 72 (17) 458-462 A record number of 2,912 drug overdose deaths occurred in Maryland during the 12-month period July 1, 2020-June 30, 2021. Illicitly manufactured fentanyl, fentanyl analogs, or both* were involved in 84% of these deaths.(†) Timely identification of illicit drug market changes (e.g., fentanyl rapidly replacing heroin) could improve the public health response, specifically communications about risks for novel psychoactive substances. During November 19, 2021-August 31, 2022, the National Institute of Standards and Technology (NIST)(§) tested 496 deidentified drug paraphernalia samples that staff members collected at eight Maryland syringe services programs (SSPs), also known as needle exchange programs,(¶) in partnership with the Maryland Department of Health Center for Harm Reduction Services (CHRS).** All test results were available within 48 hours. Among the 496 paraphernalia samples collected, 367 (74.0%) tested positive for an opioid, and 364 (99.2%) of these samples contained fentanyl or fentanyl analogs. Approximately four fifths of fentanyl-positive samples also tested positive for the veterinary medicine xylazine, a sedative that when combined with opioids might increase the potential for fatal respiratory depression and soft tissue infections when injected (1). For 248 of the 496 samples, SSP participants also completed a questionnaire about the drugs they had intended to purchase. Among the 212 participants who had intended to buy an opioid, 87.7% were exposed to fentanyl, fentanyl analogs, or both, and 85.8% were unknowingly exposed to xylazine. Results improved awareness of fentanyl and xylazine among SSP staff members and galvanized efforts to enhance SSPs' wound care services for participants experiencing soft tissue injuries possibly associated with injecting xylazine. Rapid analysis of drug paraphernalia can provide timely data on changing illicit drug markets that can be used to mitigate the harms of drug use more effectively. |
Assessing the impacts of preanalytical field sampling challenges on the reliability of serum aflatoxin B1-lysine measurements by use of LC-MS/MS
Zitomer NC , Rybak ME , Sternberg MR . Toxins (Basel) 2022 14 (9) Aflatoxin exposure is endemic in developing countries with warm, humid climates that promote toxigenic mold growth on crops and foodstuffs. Estimating human aflatoxin exposure is key to identifying and abating contamination sources. Serum aflatoxin B1 bound to albumin lysine (AFB1-lys) is a preferred exposure biomarker, but field sample collection, processing, transportation, and storage logistics are challenging. We validated an improved LC-MS/MS method for serum AFB1-lys and applied it to three field sampling challenges: transportation/storage (elevated temperature); collection/processing (hemolysis); and sample type substitution (heparinized plasma). Our new LC-MS/MS method had a LOD of 0.03 ng/mL, accuracy (mean spike recovery) of 112%, total imprecision (replicate pool measurements) 5% at 0.2 ng/mL, and results that were 95.1% similar (mean percentage similarity) to an established method. AFB1-lys in human serum spiked with serum from aflatoxin-dosed rats was stable for 14 days at both ambient (22.5 C) and elevated (38 C) temperatures. Simulated hemolysis (adding 0.25-3 mg hemoglobin) did not affect AFB1-lys accuracy at 0.5 ng/mL but caused 10-25% signal suppression. Heparinized plasma AFB1-lys was 99.0% similar to serum but interfered with albumin measurements (bromocresol green) causing spurious low bias. Further investigation is warranted, but our findings suggest that AFB1-lys is pre-analytically robust. |
Human aflatoxin exposure in Uganda: Estimates from a subset of the 2011 Uganda AIDS indicator survey (UAIS)
Zitomer NC , Awuor AO , Widdowson MA , Daniel JH , Sternberg MR , Rybak ME , Mbidde EK . Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2020 38 (1) 1-12 Aflatoxins are carcinogenic mycotoxins that contaminate a variety of crops worldwide. Acute exposure can cause liver failure, and chronic exposure can lead to stunting in children and liver cancer in adults. We estimated aflatoxin exposure across Uganda by measuring a serum biomarker of aflatoxin exposure in a subsample from the 2011 Uganda AIDS Indicator Survey, a nationally representative survey of HIV prevalence, and examined its association with geographic, demographic, and socioeconomic variables. We analysed a subsample of 985 serum specimens selected among HIV-negative participants from 10 survey-defined geographic regions for serum aflatoxin B1-lysine (AFB1-lys) by use of isotope dilution LC-MS/MS and calculated results normalised to serum albumin. We used statistical techniques for censored data to estimate geometric means (GMs), standard deviations, and percentiles. We detected serum AFB1-lys in 71.7% of specimens (LOD = 0.5 pg/mg albumin). Unadjusted GM AFB1-lys (pg/mg albumin) was 1.33 (95% CI: 1.21-1.47). Serum AFB1-lys was higher in males (GM: 1.57; 95% CI: 1.38-1.80) vs. females (GM: 1.12; 95% CI: 0.97-1.30) (P = .0019), and higher in persons residing in urban settings (GM: 2.83; 95% CI: 2.37-3.37) vs. rural (GM: 1.10; 95% CI: 0.99-1.23) (P < .0001). When we used a multivariable censored regression model to assess confounding and interactions among variables we found that survey region, gender, age, occupation, distance to marketplace, and number of meals per day were statistically significant predictors of aflatoxin exposure. While not nationally representative, our findings provide an improved understanding of the widespread burden of aflatoxin exposure throughout Uganda and identify key geographic, demographic, and socioeconomic factors that may modulate aflatoxin exposure risk. |
Mutations in TAC1B : a Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris.
Rybak JM , Munoz JF , Barker KS , Parker JE , Esquivel BD , Berkow EL , Lockhart SR , Gade L , Palmer GE , White TC , Kelly SL , Cuomo CA , Rogers PD . mBio 2020 11 (3) ![]() ![]() Candida auris has emerged as a multidrug-resistant pathogen of great clinical concern. Approximately 90% of clinical C. auris isolates are resistant to fluconazole, the most commonly prescribed antifungal agent, and yet it remains unknown what mechanisms underpin this fluconazole resistance. To identify novel mechanisms contributing to fluconazole resistance in C. auris, fluconazole-susceptible C. auris clinical isolate AR0387 was passaged in media supplemented with fluconazole to generate derivative strains which had acquired increased fluconazole resistance in vitro Comparative analyses of comprehensive sterol profiles, [(3)H]fluconazole uptake, sequencing of C. auris genes homologous to genes known to contribute to fluconazole resistance in other species of Candida, and relative expression levels of C. auris ERG11, CDR1, and MDR1 were performed. All fluconazole-evolved derivative strains were found to have acquired mutations in the zinc-cluster transcription factor-encoding gene TAC1B and to show a corresponding increase in CDR1 expression relative to the parental clinical isolate, AR0387. Mutations in TAC1B were also identified in a set of 304 globally distributed C. auris clinical isolates representing each of the four major clades. Introduction of the most common mutation found among fluconazole-resistant clinical isolates of C. auris into fluconazole-susceptible isolate AR0387 was confirmed to increase fluconazole resistance by 8-fold, and the correction of the same mutation in a fluconazole-resistant isolate, AR0390, decreased fluconazole MIC by 16-fold. Taken together, these data demonstrate that C. auris can rapidly acquire resistance to fluconazole in vitro and that mutations in TAC1B significantly contribute to clinical fluconazole resistance.IMPORTANCE Candida auris is an emerging multidrug-resistant pathogen of global concern, known to be responsible for outbreaks on six continents and to be commonly resistant to antifungals. While the vast majority of clinical C. auris isolates are highly resistant to fluconazole, an essential part of the available antifungal arsenal, very little is known about the mechanisms contributing to resistance. In this work, we show that mutations in the transcription factor TAC1B significantly contribute to clinical fluconazole resistance. These studies demonstrated that mutations in TAC1B can arise rapidly in vitro upon exposure to fluconazole and that a multitude of resistance-associated TAC1B mutations are present among the majority of fluconazole-resistant C. auris isolates from a global collection and appear specific to a subset of lineages or clades. Thus, identification of this novel genetic determinant of resistance significantly adds to the understanding of clinical antifungal resistance in C. auris. |
Evaluation of a 24-Hour Caffeine Intake Assessment Compared with Urinary Biomarkers of Caffeine Intake among Young Adults in Canada
Vanderlee L , Reid JL , White CM , Acton RB , Kirkpatrick SI , Pao CI , Rybak ME , Hammond D . J Acad Nutr Diet 2018 118 (12) 2245-2253.e1 BACKGROUND: Caffeine is a widely consumed stimulant, and caffeine-containing products are increasingly available on the market. Few tools are available to capture caffeine intake, particularly among young adults. To estimate caffeine consumption in the previous 24 hours, the 24-Hour Caffeine Intake Recall (CIR-24) was modeled after the Automated Self-Administered 24-Hour Dietary Assessment Tool, using a brand-specific database of caffeine-containing foods, beverages, and supplements. OBJECTIVE: To evaluate the accuracy of the CIR-24 compared with caffeine concentration biomarkers in urine and a caffeinated beverage intake frequency screener (CBQ) designed to assess usual intake among a young adult population in Canada. DESIGN/PARTICIPANTS: In all, 79 young adults, aged 18 to 29 years, provided 24-hour urine samples and completed the CIR-24 and CBQ. MAIN OUTCOME MEASURES: Excretion for caffeine and eight caffeine metabolites were quantified from urine samples using high-performance liquid chromatography-polarity switching electrospray ionization-tandem quadrupole mass spectrometry with stable isotope-labeled internal standards. STATISTICAL ANALYSES PERFORMED: Pearson correlations and weighted κ coefficients were calculated for the self-report tools and caffeine biomarkers. RESULTS: The CIR-24 was significantly positively associated with all caffeine biomarkers (r(p)=0.28 to 0.52, κ=0.39 to 0.59), and the CBQ was significantly positively associated with all but one biomarker (r(p)=0.21 to 0.40, κ=0.32 to 0.45). The CIR-24 yielded a higher mean intake of caffeine than the CBQ. There was strong linear correlation between the CIR-24 and CBQ (r(p)=0.60, P<0.001), but poor agreement in absolute caffeine consumed (t=2.83, P=0.006); quartile ranking concordance was 0.44 (P<0.001). The CIR-24 performed better than the CBQ across all biomarkers in both linear correlation and quartile ranking. CONCLUSIONS: Although both the CIR-24 and CBQ performed reasonably well in capturing caffeine intake compared with urinary biomarkers of caffeine consumption, the CIR-24 had stronger agreement than the CBQ. The results suggest that the CIR-24 is a promising tool for evaluating caffeine intake among this population. |
Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis
Harausz EP , Garcia-Prats AJ , Law S , Schaaf HS , Kredo T , Seddon JA , Menzies D , Turkova A , Achar J , Amanullah F , Barry P , Becerra M , Chan ED , Chan PC , Ioana Chiotan D , Crossa A , Drobac PC , Fairlie L , Falzon D , Flood J , Gegia M , Hicks RM , Isaakidis P , Kadri SM , Kampmann B , Madhi SA , Marais E , Mariandyshev A , Mendez-Echevarria A , Moore BK , Nargiza P , Ozere I , Padayatchi N , Ur-Rehman S , Rybak N , Santiago-Garcia B , Shah NS , Sharma S , Shim TS , Skrahina A , Soriano-Arandes A , van den Boom M , van der Werf MJ , van der Werf TS , Williams B , Yablokova E , Yim JJ , Furin J , Hesseling AC . PLoS Med 2018 15 (7) e1002591 BACKGROUND: An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. METHODS AND FINDINGS: To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%-19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%-48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15-20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0-8.3, p = 0.041 and aOR 5.9, 95% CI 1.7-20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician's perception of illness, with resulting potential for bias. CONCLUSIONS: This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated. |
Phenol concentrations during childhood and subsequent measures of adiposity among young girls
Deierlein AL , Wolff MS , Pajak A , Pinney SM , Windham GC , Galvez MP , Rybak M , Calafat AM , Kushi LH , Biro FM , Teitelbaum SL . Am J Epidemiol 2017 186 (5) 581-592 Phenolic compounds represent a class of environmental chemicals with potentially endocrine-disrupting capabilities. We investigated longitudinal associations between childhood exposure to phenols, from both manmade and natural sources, and subsequent measures of adiposity among girls enrolled in the Breast Cancer and the Environment Research Program between 2004 and 2007. Baseline (ages 6-8 years) urinary concentrations were obtained for creatinine and phenol metabolites: enterolactone, genistein, daidzein, benzophenone-3, bisphenol A, the sum of parabens (methyl, ethyl, and propyl parabens), 2,5-dichlorophenol, and triclosan. Body mass index (weight (kg)/height (m)2), waist circumference, and percent body fat were measured at annual or semiannual examinations through 2015 (n = 1,017). Linear mixed-effects regression was used to estimate how baseline concentrations of phenols (tertile groups) were related to changes in girls' adiposity measurements from ages 7 through 15 years. Enterolactone was inversely associated with body mass index, waist circumference, and percent body fat, while 2,5-dichlorophenol was positively associated with these measurements. A nonmonotonic association was observed for triclosan and girls' adiposity; however, it was due to effect modification by baseline overweight status. Triclosan was positively associated with adiposity only among overweight girls. These results suggest that exposure to specific phenols during childhood may influence adiposity through adolescence. |
Exposure to phytoestrogens in utero and age at menarche in a contemporary British cohort
Marks KJ , Hartman TJ , Taylor EV , Rybak ME , Northstone K , Marcus M . Environ Res 2017 155 287-293 Phytoestrogens are estrogenic compounds that occur naturally in plants. Phytoestrogens can cross the placenta, and animal studies have found associations between in utero exposure to phytoestrogens and markers of early puberty. We investigated the association between in utero exposure to phytoestrogens and early menarche (defined as <11.5 years of age at onset) using data from a nested case-control study within the Avon Longitudinal Study of Parents and Children, a longitudinal study involving families living in the South West of England. Concentrations of six phytoestrogens were measured in maternal urine samples collected during pregnancy. Logistic regression was used to explore associations between tertiles of phytoestrogen concentrations and menarche status, with adjustment for maternal age at menarche, maternal education, pre-pregnancy body mass index (BMI), child birth order, duration of breastfeeding, and gestational age at sample collection. Among 367 mother-daughter dyads, maternal median (interquartile range) creatinine-corrected concentrations (in microg/g creatinine) were: genistein 62.1 (27.1-160.9), daidzein 184.8 (88.8-383.7), equol 4.3 (2.8-9.0), O-desmethylangolensin (O-DMA) 13.0 (4.4-34.5), enterodiol 76.1 (39.1-135.8), and enterolactone 911.7 (448.1-1558.0). In analyses comparing those in the highest tertile relative to those in the lowest tertile of in utero phytoestrogen exposure, higher enterodiol levels were inversely associated with early menarche (odds ratio (OR)=0.47; 95% confidence interval (CI): 0.26-0.83), while higher O-DMA levels were associated with early menarche (OR=1.89; 95% CI: 1.04-3.42). These findings suggest that in utero exposure to phytoestrogens may be associated with earlier age at menarche, though the direction of association differs across phytoestrogens. |
Associations of urinary phthalate and phenol biomarkers with menarche among a multiethnic cohort of young girls
Wolff MS , Pajak A , Pinney SM , Windham GC , Galvez M , Rybak M , Silva MJ , Ye X , Calafat AM , Kushi LH , Biro FM , Teitelbaum SL . Reprod Toxicol 2016 67 56-64 To study potential environmental influences on puberty in girls, we investigated urinary biomarkers in relation to age at menarche. Phenols and phthalates were measured at baseline (6-8 years of age). Menarche was ascertained over 11 years for 1051 girls with menarche and biomarkers. Hazards ratios were estimated from Cox models adjusted for race/ethnicity and caregiver education (aHR, 95% confidence intervals [CI] for 5th vs 1st quintile urinary biomarker concentrations). 2,5-Dichlorophenol was associated with earlier menarche (aHR 1.34 [1.06-1.71]); enterolactone was associated with later menarche (aHR 0.82 [0.66-1.03]), as was mono-3-carboxypropyl phthalate (MCPP) (aHR 0.73 [0.59-0.91]); the three p-trends were <.05. Menarche differed by 4-7 months across this range. Enterolactone and MCPP associations were stronger in girls with below-median body mass index. These analytes were also associated with age at breast development in this cohort. Findings from this prospective study suggest that some childhood exposures are associated with pubertal timing. |
Caffeine concentrations in coffee, tea, chocolate, and energy drink flavored e-liquids
Lisko JG , Lee GE , Kimbrell JB , Rybak ME , Valentin-Blasini L , Watson CH . Nicotine Tob Res 2016 19 (4) 484-492 INTRODUCTION: Most electronic cigarettes (e-cigarettes) contain a solution of propylene glycol/glycerin and nicotine, as well as flavors. E-cigarettes and their associated e-liquids are available in numerous flavor varieties. A subset of the flavor varieties include coffee, tea, chocolate, and energy drink, which, in beverage form, are commonly recognized sources of caffeine. Recently, some manufacturers have begun marketing e-liquid products as energy enhancers that contain caffeine as an additive. METHODS: A Gas Chromatography-Mass Spectrometry (GC-MS) method for the quantitation of caffeine in e-liquids was developed, optimized and validated. The method was then applied to assess caffeine concentrations in 44 flavored e-liquids from cartridges, disposables, and refill solutions. Products chosen were flavors traditionally associated with caffeine (ie, coffee, tea, chocolate, and energy drink), marketed as energy boosters, or labeled as caffeine-containing by the manufacturer. RESULTS: Caffeine was detected in 42% of coffee-flavored products, 66% of tea-flavored products, and 50% of chocolate-flavored e-liquids (limit of detection [LOD] - 0.04 microg/g). Detectable caffeine concentrations ranged from 3.3 microg/g to 703 microg/g. Energy drink-flavored products did not contain detectable concentrations of caffeine. Eleven of 12 products marketed as energy enhancers contained caffeine, though in widely varying concentrations (31.7 microg/g to 9290 microg/g). CONCLUSIONS: E-liquid flavors commonly associated with caffeine content like coffee, tea, chocolate, and energy drink often contained caffeine, but at concentrations significantly lower than their dietary counterparts. Estimated daily exposures from all e-cigarette products containing caffeine were much less than ingestion of traditional caffeinated beverages like coffee. IMPLICATIONS: This study presents an optimized and validated method for the measurement of caffeine in e-liquids. The method is applicable to all e-liquid matrices and could potentially be used to ensure regulatory compliance for those geographic regions that forbid caffeine in e-cigarette products. The application of the method shows that caffeine concentrations and estimated total caffeine exposure from e-cigarette products is significantly lower than oral intake from beverages. However, because very little is known about the effects of caffeine inhalation, e-cigarette users should proceed with caution when using caffeine containing e-cigarette products. Further research is necessary to determine associated effects from inhaling caffeine. |
Evaluation of efficacy, acceptability and palatability of calcium montmorillonite clay used to reduce aflatoxin B1 dietary exposure in a crossover study in Kenya
Awuor AO , Montgomery J , Yard E , Martin C , Daniel J , Zitomer N , Rybak M , Lewis L , Phillips T , Romoser A , Elmore S , Oyugi E , Amwayi S , Bii C , Vulule J . Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2016 34 (1) 93-102 Acute aflatoxin exposure can cause death and disease (aflatoxicosis) in humans. Aflatoxicosis fatality rates have been documented to be as high as 40% in Kenya. The inclusion in the diet of calcium silicate 100 (ACCS100), a calcium montmorillonite clay, may reduce aflatoxin bioavailability; thus potentially decreasing the risk of aflatoxicosis. We investigated the efficacy, acceptability, and palatability of ACCS100 in a population in Kenya with recurring aflatoxicosis outbreaks. Healthy adult participants were enrolled in this double-blinded, cross-over clinical trial in 2014. Following informed consent, participants (n=50) were randomized to receive either ACCS100 (3g/day) or placebo (3g/day) for seven days. Treatments were switched following a five-day washout period. Urine samples were collected daily and assessed for urinary aflatoxin M1 (AFM1). Blood samples were collected at the beginning and end of the trial and assessed for aflatoxin B1-lysine adducts from serum albumin (AFB1-lys). AFM1 concentrations in urine; were significantly reduced while taking ACCS100 compared to calcium carbonate placebo (beta=0.49, 95% confidence limit: 0.32-0.75). The 20 day interval included both the placebo and ACCS100 treatments as well as a washout period. There were no statistically significant differences in reported taste, aftertaste, appearance, color, or texture by treatment. There were no statistically significant differences in self-reported adverse events by treatment. Most participants would be willing to take ACCS100 (98%) and give it to their children (98%). ACCS100 was effective, acceptable, and palatable. More work is needed to test ACCS100 among vulnerable populations and to determine if ACCS100 remains effective at the levels of aflatoxin exposure that induce aflatoxicosis. |
Determination of Aflatoxin B1 in Smokeless Tobacco Products by Use of UHPLC-MS/MS
Zitomer N , Rybak ME , Li Z , Walters MJ , Holman MR . J Agric Food Chem 2015 63 (41) 9131-8 This work developed a UHPLC-MS/MS method for the detection and quantitation of aflatoxins in smokeless tobacco products, which was then used to determine aflatoxin B1 concentrations in 32 smokeless tobacco products commercially available in the United States. Smokeless tobacco products were dried, milled, and amended with 13C17-labeled internal standards, extracted in water/methanol solution in the presence of a surfactant, isolated through use of immunoaffinity column chromatography, and reconstituted in mobile phase prior to UHPLC-MS/MS analysis. The method was capable of baseline separation of aflatoxins B1, B2, G1, and G2 in a 2.5 min run by use of a fused core C18 column and a water/methanol gradient. MS/MS transition (m/z) 313.3 --> 241.2 was used for aflatoxin B1 quantitation, with 313.3 --> 285.1 used for confirmation. The limit of detection (LOD) for aflatoxin B1 was 0.007 parts per billion (ppb). Method imprecision for aflatoxin B1 (expressed as coefficient of variation) ranged from 5.5 to 9.4%. Spike recoveries were 105-111%. Aflatoxin B1 concentrations in the smokeless tobacco products analyzed ranged from <LOD to 0.271 ppb (dry mass). Aflatoxin B1 was most frequently detected in dry snuffs and chews, whereas all moist snuff products tested were below LOD. The amounts of aflatoxin B1 detected were low relative to the 20 ppb regulatory limit established by the U.S. Food and Drug Administration for foods and feeds. |
Environmental phenols and pubertal development in girls
Wolff MS , Teitelbaum SL , McGovern K , Pinney SM , Windham GC , Galvez M , Pajak A , Rybak M , Calafat AM , Kushi LH , Biro FM . Environ Int 2015 84 174-180 Environmental exposures to many phenols are documented worldwide and exposures can be quite high (>1 microM of urine metabolites). Phenols have a range of hormonal activity, but knowledge of effects on child reproductive development is limited, coming mostly from cross-sectional studies. We undertook a prospective study of pubertal development among 1239 girls recruited at three U.S. sites when they were 6-8 years old and were followed annually for 7 years to determine age at first breast or pubic hair development. Ten phenols were measured in urine collected at enrollment (benzophenone-3, enterolactone, bisphenol A, three parabens (methyl-, ethyl-, propyl-), 2,5-dichlorophenol, triclosan, genistein, daidzein). We used multivariable adjusted Cox proportional hazards ratios (HR (95% confidence intervals)) and Kaplan-Meier survival analyses to estimate relative risk of earlier or later age at puberty associated with phenol exposures. For enterolactone and benzophenone-3, girls experienced breast development 5-6 months later, adjusted HR 0.79 (0.64-0.98) and HR 0.80 (0.65-0.98) respectively for the 5th vs 1st quintiles of urinary biomarkers (microg/g-creatinine). Earlier breast development was seen for triclosan and 2,5-dichlorophenol: 4-9 months sooner for 5th vs 1st quintiles of urinary concentrations (HR 1.17 (0.96-1.43) and HR 1.37 (1.09-1.72), respectively). Association of breast development with enterolactone, but not the other three phenols, was mediated by body size. These phenols may be antiadipogens (benzophenone-3 and enterolactone) or thyroid agonists (triclosan and 2,5-dichlorophenol), and their ubiquity and relatively high levels in children would benefit from further investigation to confirm these findings and to establish whether there are certain windows of susceptibility during which exposure can affect pubertal development. |
Urine excretion of caffeine and select caffeine metabolites is common in the US population and associated with caffeine intake
Rybak ME , Sternberg MR , Pao CI , Ahluwalia N , Pfeiffer CM . J Nutr 2015 145 (4) 766-774 BACKGROUND: Caffeine is a widely consumed psychoactive stimulant and is of epidemiologic interest. Major sources of caffeine are challenging to standardize, and the use of biomarkers is proposed as an alternative means of assessing intake. OBJECTIVE: We described urine caffeine and caffeine metabolite concentrations (n = 2466) and excretion rates (n = 2261) in the US population ≥6 y by age, sex, race-ethnicity, and caffeine intake (from foods, beverages, and dietary supplements). METHODS: We measured caffeine and 14 of its metabolites in spot urine samples from the cross-sectional NHANES 2009-2010 by use of LC-tandem mass spectrometry. RESULTS: Caffeine and its metabolites were detectable in the urine of most persons, generally at concentrations ≥1 mumol/L. Median concentrations (95% CI) ranged from 0.560 (0.497, 0.620) micromol/L to 58.6 (48.6, 67.2) micromol/L; median excretion rates from 0.423 (0.385, 0.468) nmol/min to 46.0 (40.7, 50.2) nmol/min. Urine concentrations and excretion rates for 9 analytes (caffeine, theophylline, paraxanthine, 1-methylxanthine, 1-methyluric acid, 1,3-dimethyluric acid, 1,7-dimethyluric acid, 1,3,7-trimethyluric acid, and 5-acetylamino-6-amino-3-methyluracil) had moderate correlations with caffeine intake (Spearman rho = 0.55-0.68, P < 0.0001); the remaining analytes had low correlations (rho = 0.15-0.33, P < 0.0001). We observed larger differences in geometric mean concentrations and excretion rates between the highest vs. lowest quartiles of caffeine intake for these 9 compounds than the rest. Consistent with dietary caffeine intake, we observed that urine concentrations and excretion rates for most compounds were significantly (P < 0.05) higher in men than women, non-Hispanic whites than Hispanics and non-Hispanic blacks, and highest in persons aged 40-59 y. CONCLUSION: Excretion of caffeine and its metabolites in urine is common in the US population. According to the observed associations between spot urine concentrations or excretion rates with caffeine intake, several of these compounds show promise as potential biomarkers of caffeine intake. |
Caffeine intake in children in the United States and 10-y trends: 2001-2010
Ahluwalia N , Herrick K , Moshfegh A , Rybak M . Am J Clin Nutr 2014 100 (4) 1124-32 BACKGROUND: Because of the increasing concern of the potential adverse effects of caffeine intake in children, recent estimates of caffeine consumption in a representative sample of children are needed. OBJECTIVES: We provide estimates of caffeine intake in children in absolute amounts (mg) and in relation to body weight (mg/kg) to examine the association of caffeine consumption with sociodemographic factors and describe trends in caffeine intake in children in the United States. DESIGN: We analyzed caffeine intake in 3280 children aged 2-19 y who participated in a 24-h dietary recall as part of the NHANES, which is a nationally representative survey of the US population with a cross-sectional design, in 2009-2010. Trends over time between 2001 and 2010 were examined in 2-19-y-old children (n = 18,530). Analyses were conducted for all children and repeated for caffeine consumers. RESULTS: In 2009-2010, 71% of US children consumed caffeine on a given day. Median caffeine intakes for 2-5-, 6-11-, and 12-19-y olds were 1.3, 4.5, and 13.6 mg, respectively, and 4.7, 9.1, and 40.6 mg, respectively, in caffeine consumers. Non-Hispanic black children had lower caffeine intake than that of non-Hispanic white counterparts. Caffeine intake correlated positively with age; this association was independent of body weight. On a given day, 10% of 12-19-y-olds exceeded the suggested maximum caffeine intake of 2.5 mg/kg by Health Canada. A significant linear trend of decline in caffeine intake (in mg or mg/kg) was noted overall for children aged 2-19 y during 2001-2010. Specifically, caffeine intake declined by 3.0 and 4.6 mg in 2-5- and 6-11-y-old caffeine consumers, respectively; no change was noted in 12-19-y-olds. CONCLUSION: A majority of US children including preschoolers consumed caffeine. Caffeine intake was highest in 12-19-y-olds and remained stable over the 10-y study period in this age group. |
Higher urinary lignan concentrations in women but not men are positively associated with shorter time to pregnancy
Mumford SL , Sundaram R , Schisterman EF , Sweeney AM , Barr DB , Rybak ME , Maisog JM , Parker DL , Pfeiffer CM , Louis GM . J Nutr 2014 144 (3) 352-8 Phytoestrogens have been associated with subtle hormonal changes, although effects on fecundity are unknown. Our objective was to evaluate the association between male and female urinary phytoestrogen (isoflavone and lignan) concentrations and time to pregnancy (TTP) in a population-based cohort of 501 couples desiring pregnancy and discontinuing contraception. Couples were followed for 12 mo or until pregnancy. Fecundability ORs (FORs) and 95% CIs were estimated after adjusting for age, body mass index, race, site, creatinine, supplement use, and physical activity in relation to female, male, and joint couple concentrations. Models included the phytoestrogen of interest and the sum of the remaining individual phytoestrogens. FORs <1 denote a longer TTP and FORs >1 a shorter TTP. Urinary lignan concentrations were higher, on average, among female partners of couples who became pregnant during the study compared with women who did not become pregnant (median enterodiol: 118 vs. 80 nmol/L; P < 0.10; median enterolactone: 990 vs. 412 nmol/L; P < 0.05) and were associated with significantly shorter TTP in models based on both individual and couples' concentrations (couples' models: enterodiol FOR, 1.13; 95% CI: 1.02, 1.26; enterolactone FOR, 1.11; 95% CI: 1.01, 1.21). Male lignan concentrations were not associated with TTP, nor were isoflavone concentrations. Sensitivity analyses showed that associations observed are unlikely to be explained by potential unmeasured confounding by lifestyle or other nutrients. Our results suggest that female urinary lignan concentrations at levels characteristic of the U.S. population are associated with a shorter TTP among couples who are attempting to conceive, highlighting the importance of dietary influences on fecundity. |
Development of a Standard Reference Material for metabolomics research
Phinney KW , Ballihaut G , Bedner M , Benford BS , Camara JE , Christopher SJ , Davis WC , Dodder NG , Eppe G , Lang BE , Long SE , Lowenthal MS , McGaw EA , Murphy KE , Nelson BC , Prendergast JL , Reiner JL , Rimmer CA , Sander LC , Schantz MM , Sharpless KE , Sniegoski LT , Tai SS , Thomas JB , Vetter TW , Welch MJ , Wise SA , Wood LJ , Guthrie WF , Hagwood CR , Leigh SD , Yen JH , Zhang NF , Chaudhary-Webb M , Chen H , Fazili Z , Lavoie DJ , McCoy LF , Momin SS , Paladugula N , Pendergrast EC , Pfeiffer CM , Powers CD , Rabinowitz D , Rybak ME , Schleicher RL , Toombs BM , Xu M , Zhang M , Castle AL . Anal Chem 2013 85 (24) 11732-8 ![]() The National Institute of Standards and Technology (NIST), in collaboration with the National Institutes of Health (NIH), has developed a Standard Reference Material (SRM) to support technology development in metabolomics research. SRM 1950 Metabolites in Human Plasma is intended to have metabolite concentrations that are representative of those found in adult human plasma. The plasma used in the preparation of SRM 1950 was collected from both male and female donors, and donor ethnicity targets were selected based upon the ethnic makeup of the U.S. population. Metabolomics research is diverse in terms of both instrumentation and scientific goals. This SRM was designed to apply broadly to the field, not toward specific applications. Therefore, concentrations of approximately 100 analytes, including amino acids, fatty acids, trace elements, vitamins, hormones, selenoproteins, clinical markers, and perfluorinated compounds (PFCs), were determined. Value assignment measurements were performed by NIST and the Centers for Disease Control and Prevention (CDC). SRM 1950 is the first reference material developed specifically for metabolomics research. |
Determination of urine caffeine and its metabolites by use of high-performance liquid chromatography-tandem mass spectrometry: estimating dietary caffeine exposure and metabolic phenotyping in population studies
Rybak ME , Pao CI , Pfeiffer CM . Anal Bioanal Chem 2013 406 (3) 771-84 We have developed and validated a high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for determining urine caffeine and 14 caffeine metabolites suitable for estimating caffeine exposure and metabolic phenotyping in population studies. Sample preparation consisted solely of a series of simple reagent treatments at room temperature. Stable isotope-labeled analogs were used as internal standards for all analytes. We developed rapid LC-MS/MS separations for both positive and negative ion mode electrospray ionizations to maximize measurement sensitivity. Limits of detection were 0.05-0.1 mumol/L depending on the analytes. Method imprecision, based on total coefficients of variation, was generally <7 % when analyte concentration was >1 mumol/L. Analyte recoveries were typically within 10 % of being quantitative (100 %), and good agreement was observed among analytes measured across different MS/MS transitions. We applied this method to the analysis of a convenience set of human urine samples (n = 115) and were able to detect a majority of the analytes in ≥99 % of samples as well as calculate caffeine metabolite phenotyping ratios for cytochrome P450 1A2 and N-acetyltransferase 2. Whereas existing LC-MS/MS methods are limited in number of caffeine metabolites for which they are validated, or are designed for studies in which purposely elevated caffeine levels are expected, our method is the first of its kind designed specifically for the rapid, sensitive, accurate, and precise measurement of urine caffeine and caffeine metabolites at concentrations relevant to population studies. |
Dietary flavonol intake is associated with age of puberty in a longitudinal cohort of girls
Mervish NA , Gardiner EW , Galvez MP , Kushi LH , Windham GC , Biro FM , Pinney SM , Rybak ME , Teitelbaum SL , Wolff MS . Nutr Res 2013 33 (7) 534-42 Lignans and flavonols are dietary phytoestrogens found at high concentrations in the Western Diet. They have potential to influence the timing of puberty. We hypothesized that greater consumption of these 2 phytoestrogens would be related to later age at pubertal onset among girls. Pubertal assessment and 24-hour diet recall data were available for 1178 girls, ages 6 to 8 years (mean 7.3 years) in the Breast Cancer and Environment Research Project Puberty Study. Lignan and flavonol intakes were mainly derived from fruit and vegetable consumption. Average consumption was 6.5 mg/d for flavonols and 0.6 mg/d for lignans. Highest flavonol consumption (>5 mg/d) was associated with later breast development (adjusted hazards ratio [HR]: 0.74, 95% CI: [0.61-0.91]) compared to 2 to 5 mg/d (adjusted HR: 0.84, 95% CI: [0.70-1.0]) and <2 mg/d (referent group; P-trend = .006). Flavonol intake was not associated with pubic hair development. Lignan intake was not associated with either breast or pubic hair development. Dietary intake was only weakly correlated with urinary enterolactone, a biomarker for lignans (RS = 0.13). Consistent with biologic properties of phytoestrogens that indicate hormonal activity, their consumption may be associated with reproductive end points, even in childhood. |
Human aflatoxin exposure in Kenya, 2007: a cross-sectional study
Yard EE , Daniel JH , Lewis LS , Rybak ME , Paliakov EM , Kim AA , Montgomery JM , Bunnell R , Abudo MU , Akhwale W , Breiman RF , Sharif SK . Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2013 30 (7) 1322-31 Aflatoxins contaminate approximately 25% of agricultural products worldwide. They can cause liver failure and liver cancer. Kenya has experienced multiple aflatoxicosis outbreaks in recent years, often resulting in fatalities. However, the full extent of aflatoxin exposure in Kenya has been unknown. Our objective was to quantify aflatoxin exposure across Kenya. We analysed aflatoxin levels in serum specimens from the 2007 Kenya AIDS Indicator Survey - a nationally representative, cross-sectional serosurvey. KAIS collected 15,853 blood specimens. Of the 3180 human immunodeficiency virus-negative specimens with ≥1 mL sera, we randomly selected 600 specimens stratified by province and sex. We analysed serum specimens for aflatoxin albumin adducts by using isotope dilution MS/MS to quantify aflatoxin B1-lysine, and normalised with serum albumin. Aflatoxin concentrations were then compared by demographic, socioeconomic and geographic characteristics. We detected serum aflatoxin B1-lysine in 78% of serum specimens (range = <LOD-211 pg/mg albumin, median = 1.78 pg/mg albumin). Aflatoxin exposure did not vary by sex, age group, marital status, religion or socioeconomic characteristics. Aflatoxin exposure varied by province (p < 0.05); it was highest in Eastern (median = 7.87 pg/mg albumin) and Coast (median = 3.70 pg/mg albumin) provinces and lowest in Nyanza (median = <LOD) and Rift Valley (median = 0.70 pg/mg albumin) provinces. Our findings suggest that aflatoxin exposure is a public health problem throughout Kenya, and it could be substantially impacting human health. Wide-scale, evidence-based interventions are urgently needed to decrease exposure and subsequent health effects. |
The CDC's second National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population is a valuable tool for researchers and policy makers
Pfeiffer CM , Sternberg MR , Schleicher RL , Haynes BM , Rybak ME , Pirkle JL . J Nutr 2013 143 (6) 938S-47S The CDC's National Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population (Nutrition Report) is a serial publication that provides ongoing assessment of the population's nutritional status. The Nutrition Report presents data on blood and urine biomarker concentrations (selected water- and fat-soluble vitamins and nutrients, trace elements, dietary bioactive compounds) from a representative sample of the population participating in the NHANES. The Second Nutrition Report (released in 2012) contains reference information (means and percentiles) for 58 biomarkers measured during all or part of 2003-2006, stratified by age, sex, and race-ethnicity. Where available, we presented cutoff-based prevalence data during 2003-2006 and data on changes in biomarker concentrations or prevalence since 1999. Blood vitamin concentrations were generally higher in older (≥60 y) than in younger (20-39 y) adults and lower in Mexican Americans and non-Hispanic blacks than in non-Hispanic whites. Nearly 80% of Americans (aged ≥6 y) were not at risk of deficiencies in any of the 7 vitamins studied (vitamins A, B-6, B-12, C, D, and E and folate). Deficiency rates varied by age, sex, and race-ethnicity. Approximately 90% of women (aged 12-49 y) were not at risk of iron deficiency, but only 68% were not at risk of deficiencies in iron and all 7 vitamins. Young women (20-39 y) had median urine iodine concentrations bordering on insufficiency. First-time data are presented on plasma concentrations of 24 saturated and mono- and polyunsaturated fatty acids. Tabulation and graphical presentation of NHANES data in the Second Nutrition Report benefits those organizations involved in developing and evaluating nutrition policy. |
Sociodemographic and lifestyle variables are compound- and class-specific correlates of urine phytoestrogen concentrations in the U.S. population
Rybak ME , Sternberg MR , Pfeiffer CM . J Nutr 2013 143 (6) 986S-94S Isoflavones and lignans are plant-derived dietary compounds generally believed to be beneficial to human health. We investigated the extent to which sociodemographic (age, sex, race-ethnicity, education, and income) and lifestyle variables (smoking, alcohol consumption, BMI, physical activity, and dietary supplement use) were correlates of spot urine concentration for daidzein, genistein, O-desmethylangolensin (DMA), equol, enterodiol, and enterolactone in the U.S. population aged ≥20 y (NHANES 2003-2006). We performed correlation analyses with continuous variables and calculated stratified unadjusted geometric means for each sociodemographic and lifestyle variable. We used bivariate significance testing and covariate adjustment by use of multiple regression models to identify influential variables and used beta coefficients to estimate relative effects. Urine creatinine was also included in our analyses because of its use in correcting for variable dilution in spot urine samples. We observed many significant (P < 0.05) associations with the sociodemographic and lifestyle variables that withstood covariate adjustment. Smoking was a significant correlate of urine DMA and enterolactone, with concentrations at least 25% lower in smokers vs. nonsmokers. Consumers of 1 daily alcoholic drink vs. none were estimated to have 18-21% lower urine equol and DMA concentrations. A 25% increase in BMI was associated with a 21% lower urine enterolactone concentration, and increasing physical activity was associated with a >6% higher urine enterolactone concentration. Dietary supplement use was not significantly associated with any of the urine phytoestrogens. Overall, we found that relationships between sociodemographic and lifestyle variables and urine phytoestrogen concentration were highly compound and class specific. |
Dietary supplement use and smoking are important correlates of biomarkers of water-soluble vitamin status after adjusting for sociodemographic and lifestyle variables in a representative sample of U.S. adults
Pfeiffer CM , Sternberg MR , Schleicher RL , Rybak ME . J Nutr 2013 143 (6) 957S-65S Biochemical indicators of water-soluble vitamin (WSV) status were measured in a nationally representative sample of the U.S. population in NHANES 2003-2006. To examine whether demographic differentials in nutritional status were related to and confounded by certain variables, we assessed the association of sociodemographic (age, sex, race-ethnicity, education, income) and lifestyle (dietary supplement use, smoking, alcohol consumption, BMI, physical activity) variables with biomarkers of WSV status in adults (aged ≥20 y): serum and RBC folate, serum pyridoxal-5'-phosphate (PLP), serum 4-pyridoxic acid, serum total cobalamin (vitamin B-12), plasma total homocysteine (tHcy), plasma methylmalonic acid (MMA), and serum ascorbic acid. Age (except for PLP) and smoking (except for MMA) were generally the strongest significant correlates of these biomarkers (|r| ≤ 0.43) and together with supplement use explained more of the variability compared with the other covariates in bivariate analysis. In multiple regression models, sociodemographic and lifestyle variables together explained from 7 (vitamin B-12) to 29% (tHcy) of the biomarker variability. We observed significant associations for most biomarkers (≥6 of 8) with age, sex, race-ethnicity, supplement use, smoking, and BMI and for some biomarkers with PIR (5 of 8), education (1 of 8), alcohol consumption (4 of 8), and physical activity (5 of 8). We noted large estimated percentage changes in biomarker concentrations between race-ethnic groups (from -24 to 20%), between supplement users and nonusers (from -12 to 104%), and between smokers and nonsmokers (from -28 to 8%). In summary, age, sex, and race-ethnic differentials in biomarker concentrations remained significant after adjusting for sociodemographic and lifestyle variables. Supplement use and smoking were important correlates of biomarkers of WSV status. |
Phytoestrogen biomonitoring: an extractionless LC-MS/MS method for measuring urinary isoflavones and lignans by use of atmospheric pressure photoionization (APPI)
Parker DL , Rybak ME , Pfeiffer CM . Anal Bioanal Chem 2011 402 (3) 1123-36 We present here a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying phytoestrogenic isoflavones (daidzein, equol, genistein, and O-desmethylangolensin) and lignans (enterodiol and enterolactone) in urine without the use of extraction or the preconcentration techniques inherent in existing methods. The development of this concept was made possible by use of atmospheric pressure photoionization (APPI); an ionization technique that we found to improve analyte sensitivity relative to electrospray ionization and atmospheric pressure chemical ionization for this particular group of compounds. The analytical performance of this method was equal to or exceeded that of comparable methods. Between-run coefficients of variation (CVs) across three quality control (QC) pool levels analyzed in duplicate over 20 days were 3.1-5.8% CV; within-run CVs were 2.3-6.0%. Accuracy, as determined by average spike recovery in QC pools, was generally within +/-10% of being quantitative (100%). Relative limits of detection were 0.04-0.4 ng/mL urine, with absolute detection limits as low as 0.1 pg. This method was applied to the analysis of >2,500 urine specimens for the 2005-2006 Centers for Disease Control and Prevention's National Health and Nutrition Examination Survey (NHANES). The method was capable of quantifying these compounds in 95-100% of study samples. This work is the first ever report of using APPI for the LC-MS/MS determination of these compounds in urine. It is also the first method of its kind to do so without any need for analyte extraction or preconcentration prior to analysis. |
NTP-CERHR expert panel report on the developmental toxicity of soy infant formula
McCarver G , Bhatia J , Chambers C , Clarke R , Etzel R , Foster W , Hoyer P , Leeder JS , Peters JM , Rissman E , Rybak M , Sherman C , Toppari J , Turner K . Birth Defects Res B Dev Reprod Toxicol 2011 92 (5) 421-68 Soy infant formula contains soy protein isolates and is fed to infants as a supplement to or replacement for human milk or cow milk. Soy protein isolates contains estrogenic isoflavones (phytoestrogens) that occur naturally in some legumes, especially soybeans. Phytoestrogens are nonsteroidal, estrogenic compounds. In plants, nearly all phytoestrogens are bound to sugar molecules and these phytoestrogen-sugar complexes are not generally considered hormonally active. Phytoestrogens are found in many food products in addition to soy infant formula, especially soy-based foods such as tofu, soy milk, and in some over-the-counter dietary supplements. Soy infant formula was selected for National Toxicology Program (NTP) evaluation because of (1) the availability of large number of developmental toxicity studies in laboratory animals exposed to the isoflavones found in soy infant formula (namely, genistein) or other soy products, as well as few studies on human infants fed soy infant formula, (2) the availability of information on exposures in infants fed soy infant formula, and (3) public concern for effects on infant or child development. On October 2, 2008 (73 FR 57360), the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) announced its intention to conduct an updated review of soy infant formula to complete a previous evaluation that was initiated in 2005. Both the current and previous evaluations relied on expert panels to assist the NTP in developing its conclusions on the potential developmental effects associated with the use of soy infant formula, presented in the NTP Brief on Soy Infant Formula. The initial expert panel met on March 15 to 17, 2006, to reach conclusions on the potential developmental and reproductive toxicities of soy infant formula and its predominant isoflavone constituent genistein. The expert panel reports were released for public comment on May 5, 2006 (71 FR 28368). On November 8, 2006 (71 FR 65537), CERHR staff released draft NTP Briefs on Genistein and Soy Formula that provided the NTP's interpretation of the potential for genistein and soy infant formula to cause adverse reproductive and/or developmental effects in exposed humans. However, CERHR did not complete these evaluations, finalize the briefs, or issue NTP Monographs on these substances based on this initial evaluation. Between 2006 and 2009, a substantial number of new publications related to human exposure or reproductive and/or developmental toxicity were published for these substances. Thus, CERHR determined that updated evaluations of genistein and soy infant formula were needed. However, the current evaluation focuses only on soy infant formula and the potential developmental toxicity of its major isoflavone components, e.g. genistein, daidzein (and estrogenic metabolite, equol), and glycitein. This updated evaluation does not include an assessment on the potential reproductive toxicity of genistein following exposures during adulthood as was carried out in the 2006 evaluation. CERHR narrowed the scope of the evaluation because the assessment of reproductive effects of genistein following exposure to adults was not considered relevant to the consideration of soy infant formula use in infants during the 2006 evaluation. To obtain updated information about soy infant formula for the CERHR evaluation, the PubMed (Medline) database was searched from February 2006 to August 2009 with genistein/genistin, daidzein/daidzin, glycitein/glycitin, equol, soy, and other relevant keywords. References were also identified from the bibliographies of published literature. The updated expert panel report represents the efforts of a 14-member panel of government and nongovernment scientists, and was prepared with assistance from NTP staff. The finalized report, released on January 15, 2010 (75 FR 2545), reflects consideration of public comments received on a draft report that was released on October 19, 2009, for public comment and discussions that occurred at a public meeting of the expert panel held December 16 to 18, 2009 (74 FR 53509). The finalized report presents conclusions on (1) the strength of scientific evidence that soy infant formula or its isoflavone constituents are developmental toxicants based on data from in vitro, animal, or human studies; (2) the extent of exposures in infants fed soy infant formula; (3) the assessment of the scientific evidence that adverse developmental health effects may be associated with such exposures; and (4) knowledge gaps that will help establish research and testing priorities to reduce uncertainties and increase confidence in future evaluations. The Expert Panel expressed minimal concern for adverse developmental effects in infants fed soy infant formula. This level of concern represents a "2" on the five-level scale of concern used by the NTP that ranges from negligible concern ("1") to serious concern ("5"). The Expert Panel Report on Soy Infant Formula was considered extensively by NTP staff in preparing the 2010 NTP Brief on Soy Infant Formula, which represents the NTP's opinion on the potential for exposure to soy infant formula to cause adverse developmental effects in humans. The NTP concurred with the expert panel that there is minimal concern for adverse effects on development in infants who consume soy infant formula. This conclusion was based on information about soy infant formula provided in the expert panel report, public comments received during the course of the expert panel evaluation, additional scientific information made available since the expert panel meeting, and peer reviewer critiques of the draft NTP Brief by the NTP Board of Scientific Counselors (BSC) on May 10, 2010 (Meeting materials are available at http://ntp.niehs.nih.gov/go/9741.). The BSC voted in favor of the minimal concern conclusion with 7 yes votes, 3 no votes, and 0 abstentions. One member thought that the conclusion should be negligible concern and two members thought that the level of concern should be higher than minimal concern. The NTP's response to the May 10, 2010 review ("peer-review report") is available on the NTP website at http://ntp.niehs.nih.gov/go/9741. The monograph includes the NTP Brief on Soy Infant Formula as well as the entire final Expert Panel Report on Soy Infant Formula. Public comments received as part of the NTP's evaluation of soy infant formula and other background materials are available at http://cerhr.niehs.nih.gov/evals/index.html. Reports can be obtained from the web site (http://cerhr.niehs.nih.gov/) or from: Kristina A. Thayer, PhD, NIEHS/NTP K2-04, PO Box 12233, Research Triangle Park, NC 27709. E-mail: thayer@niehs.nih.gov. Birth Defects Res (Part B) 92:421-468, 2011. (c) 2011 Wiley Periodicals, Inc. |
Investigation of relationships between urinary biomarkers of phytoestrogens, phthalates, and phenols and pubertal stages in girls
Wolff MS , Teitelbaum SL , Pinney SM , Windham G , Liao L , Biro F , Kushi LH , Erdmann C , Hiatt RA , Rybak ME , Calafat AM . Environ Health Perspect 2010 118 (7) 1039-46 BACKGROUND: Hormonally active environmental agents may alter the course of pubertal development in girls, which is controlled by steroids and gonadotropins. OBJECTIVES: We investigated associations of concurrent exposures from three chemical classes (phenols, phthalates, and phytoestrogens) with pubertal stages in a multiethnic longitudinal study of 1,151 girls from New York City, New York, greater Cincinnati, Ohio, and northern California who were 6-8 years of age at enrollment (2004-2007). METHODS: We measured urinary exposure biomarkers at visit 1 and examined associations with breast and pubic hair development (present or absent, assessed 1 year later) using multivariate adjusted prevalence ratios (PR) and 95% confidence intervals (CIs). Modification of biomarker associations by age-specific body mass index percentile (BMI%) was investigated, because adipose tissue is a source of peripubertal hormones. RESULTS: Breast development was present in 30% of girls, and 22% had pubic hair. High-molecular-weight phthalate (high MWP) metabolites were weakly associated with pubic hair development [adjusted PR, 0.94 (95% CI, 0.88-1.00), fifth vs. first quintile]. Small inverse associations were seen for daidzein with breast stage and for triclosan and high MWP with pubic hair stage; a positive trend was observed for low-molecular-weight phthalate biomarkers with breast and pubic hair development. Enterolactone attenuated BMI associations with breast development. In the first enterolactone quintile, for the association of high BMI with any development, the PR was 1.34 (95% CI, 1.23-1.45 vs. low BMI). There was no BMI association in the fifth, highest quintile of enterolactone. CONCLUSIONS: Weak hormonally active xenobiotic agents investigated in this study had small associations with pubertal development, mainly among those agents detected at highest concentrations. |
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