A pilot study of several environmental endocrine disrupting chemicals in children with autism spectrum disorder in south China.

Autism spectrum disorders (ASD) is a group of heterogeneous neurodevelopmental disorders. Evidence has implied that environmental pollutants are important factors related to ASD. In this study, several environmental endocrine-disrupting chemicals, including parabens, benzophenone-type ultraviolet filters, hydroxyl polycyclic aromatic hydrocarbons, triclosan and tetrabromobisphenol A were analyzed in blood plasma in ASD children (n = 34) and the control children (n = 28). The results showed that parabens were the most concentrated chemicals (2.18 ng/mL, median value), followed by hydroxyl polycyclic aromatic hydrocarbons (0.73 ng/mL), benzophenone-type ultraviolet filters (0.14 ng/mL), triclosan (0.13 ng/mL) and tetrabromobisphenol A (0.03 ng/mL). ASD children accumulated significantly lower 2-hydroxy-4-methoxybenzophenone, 2,4-dihydroxybenzophenone, 4-hydroxybenzophenone and triclosan but higher 2-hydroxyphenanthrene and tetrabromobisphenol A than the control children (0.02/0.09 ng/mL of 2-hydroxy-4-methoxybenzophenone, p < 0.05; 0.04/0.07 ng/mL of 2,4-dihydroxybenzophenone, p < 0.05; 0.03/0.04 ng/mL of 4-hydroxybenzophenone, p < 0.05; 0.13/1.22 ng/mL of triclosan, p < 0.01; 0.03 ng/mL/not detected of 2-hydroxyphenanthrene, p < 0.05; 0.03/0.004 ng/mL of tetrabromobisphenol A, p < 0.05). Gender differences in certain environmental endocrine-disrupting chemicals were evident, and the differences were more inclined toward boys. Positive associations between 2-hydroxy-4-methoxybenzophenone and triclosan, and tetrabromobisphenol A and 2-hydroxyphenanthrene were found in ASD boys. Binary logistic regression analysis showed that the adjusted odds ratio value of 2-hydroxyphenanthrene in ASD boys was 11.0 (1.45-84.0, p < 0.05). This is the first pilot study on multiple environmental endocrine-disrupting chemicals in children with ASD in China.

Dermal exposure to the UV filter benzophenone-3 during early pregnancy affects fetal growth and sex ratio of the progeny in mice.

The aim of this study was to analyze whether dermal exposure to benzophenone 3 (BP-3) during pregnancy affects critical parameters of pregnancy, and whether this exposure may affect the outcome of a second pregnancy in mice. Pregnant mice were exposed to 50-mg BP-3/kg body weight/day or olive oil (vehicle) from gestation day (gd) 0 to gd6 by dermal exposure. High-frequency ultrasound imaging was used to follow up fetal and placental growth in vivo. Blood flow parameters in uterine and umbilical arteries were analyzed by Doppler measurements. Mice were killed at gd5, gd10, and gd14 on the first pregnancy, and at gd10 and 14 on the second pregnancy. The weight of the first and second progenies was recorded, and sex ratio was analyzed. BP-3 levels were analyzed in serum and amniotic fluid. BP-3 reduced the fetal weight at gd14 and feto-placenta index of first pregnancy, with 16.13% of fetuses under the 5th percentile; arteria uterina parameters showed altered pattern at gd10. BP-3 was detected in serum 4 h after the exposure at gd6, and in amniotic fluid at gd14. Offspring weight of first progeny was lower in BP-3 group. Placenta weights of BP-3 group were decreased in second pregnancy. First and second progenies of mothers exposed to BP-3 showed a higher percentage of females (female sex ratio). Dermal exposure to low dose of BP-3 during early pregnancy resulted in an intrauterine growth restriction (IUGR) phenotype, disturbed sex ratio and alterations in the growth curve of the offspring in mouse model.

Effect of Sunscreen Application on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: A prior pilot study demonstrated the systemic absorption of 4 sunscreen active ingredients; additional studies are needed to determine the systemic absorption of additional active ingredients and how quickly systemic exposure exceeds 0.5 ng/mL as recommended by the US Food and Drug Administration (FDA). Objective: To assess the systemic absorption and pharmacokinetics of the 6 active ingredients (avobenzone, oxybenzone, octocrylene, homosalate, octisalate, and octinoxate) in 4 sunscreen products under single- and maximal-use conditions. Design, Setting, and Participants: Randomized clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) was conducted in 48 healthy participants. The study was conducted between January and February 2019. Interventions: Participants were randomized to 1 of 4 sunscreen products, formulated as lotion (n = 12), aerosol spray (n = 12), nonaerosol spray (n = 12), and pump spray (n = 12). Sunscreen product was applied at 2 mg/cm2 to 75% of body surface area at 0 hours on day 1 and 4 times on day 2 through day 4 at 2-hour intervals, and 34 blood samples were collected over 21 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone over days 1 through 21. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, homosalate, octisalate, and octinoxate over days 1 through 21. Results: Among 48 randomized participants (mean [SD] age, 38.7 [13.2] years; 24 women [50%]; 23 white [48%], 23 African American [48%], 1 Asian [2%], and 1 of unknown race/ethnicity [2%]), 44 (92%) completed the trial. Geometric mean maximum plasma concentrations of all 6 active ingredients were greater than 0.5 ng/mL, and this threshold was surpassed on day 1 after a single application for all active ingredients. For avobenzone, the overall maximum plasma concentrations were 7.1 ng/mL (coefficient of variation [CV], 73.9%) for lotion, 3.5 ng/mL (CV, 70.9%) for aerosol spray, 3.5 ng/mL (CV, 73.0%) for nonaerosol spray, and 3.3 ng/mL (CV, 47.8%) for pump spray. For oxybenzone, the concentrations were 258.1 ng/mL (CV, 53.0%) for lotion and 180.1 ng/mL (CV, 57.3%) for aerosol spray. For octocrylene, the concentrations were 7.8 ng/mL (CV, 87.1%) for lotion, 6.6 ng/mL (CV, 78.1%) for aerosol spray, and 6.6 ng/mL (CV, 103.9%) for nonaerosol spray. For homosalate, concentrations were 23.1 ng/mL (CV, 68.0%) for aerosol spray, 17.9 ng/mL (CV, 61.7%) for nonaerosol spray, and 13.9 ng/mL (CV, 70.2%) for pump spray. For octisalate, concentrations were 5.1 ng/mL (CV, 81.6%) for aerosol spray, 5.8 ng/mL (CV, 77.4%) for nonaerosol spray, and 4.6 ng/mL (CV, 97.6%) for pump spray. For octinoxate, concentrations were 7.9 ng/mL (CV, 86.5%) for nonaerosol spray and 5.2 ng/mL (CV, 68.2%) for pump spray. The most common adverse event was rash, which developed in 14 participants. Conclusions and Relevance: In this study conducted in a clinical pharmacology unit and examining sunscreen application among healthy participants, all 6 of the tested active ingredients administered in 4 different sunscreen formulations were systemically absorbed and had plasma concentrations that surpassed the FDA threshold for potentially waiving some of the additional safety studies for sunscreens. These findings do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients: A Randomized Clinical Trial.

Importance: The US Food and Drug Administration (FDA) has provided guidance that sunscreen active ingredients with systemic absorption greater than 0.5 ng/mL or with safety concerns should undergo nonclinical toxicology assessment including systemic carcinogenicity and additional developmental and reproductive studies. Objective: To determine whether the active ingredients (avobenzone, oxybenzone, octocrylene, and ecamsule) of 4 commercially available sunscreens are absorbed into systemic circulation. Design, Setting, and Participants: Randomized clinical trial conducted at a phase 1 clinical pharmacology unit in the United States and enrolling 24 healthy volunteers. Enrollment started in July 2018 and ended in August 2018. Interventions: Participants were randomized to 1 of 4 sunscreens: spray 1 (n = 6 participants), spray 2 (n = 6), a lotion (n = 6), and a cream (n = 6). Two milligrams of sunscreen per 1 cm2 was applied to 75% of body surface area 4 times per day for 4 days, and 30 blood samples were collected over 7 days from each participant. Main Outcomes and Measures: The primary outcome was the maximum plasma concentration of avobenzone. Secondary outcomes were the maximum plasma concentrations of oxybenzone, octocrylene, and ecamsule. Results: Among 24 participants randomized (mean age, 35.5 [SD, 1.5] years; 12 (50%] women; 14 [58%] black or African American; 14 [58%]), 23 (96%) completed the trial. For avobenzone, geometric mean maximum plasma concentrations were 4.0 ng/mL (coefficient of variation, 6.9%) for spray 1; 3.4 ng/mL (coefficient of variation, 77.3%) for spray 2; 4.3 ng/mL (coefficient of variation, 46.1%) for lotion; and 1.8 ng/mL (coefficient of variation, 32.1%). For oxybenzone, the corresponding values were 209.6 ng/mL (66.8%) for spray 1, 194.9 ng/mL (52.4%) for spray 2, and 169.3 ng/mL (44.5%) for lotion; for octocrylene, 2.9 ng/mL (102%) for spray 1, 7.8 ng/mL (113.3%) for spray 2, 5.7 ng/mL (66.3%) for lotion, and 5.7 ng/mL (47.1%) for cream; and for ecamsule, 1.5 ng/mL (166.1%) for cream. Systemic concentrations greater than 0.5 ng/mL were reached for all 4 products after 4 applications on day 1. The most common adverse event was rash, which developed in 1 participant with each sunscreen. Conclusions and Relevance: In this preliminary study involving healthy volunteers, application of 4 commercially available sunscreens under maximal use conditions resulted in plasma concentrations that exceeded the threshold established by the FDA for potentially waiving some nonclinical toxicology studies for sunscreens. The systemic absorption of sunscreen ingredients supports the need for further studies to determine the clinical significance of these findings. These results do not indicate that individuals should refrain from the use of sunscreen. Trial Registration: ClinicalTrials.gov Identifier: NCT03582215.

Fewer fluctuations, higher maximum concentration and better motor response of levodopa with catechol-O-methyltransferase inhibition.

Catechol-O-methyltransferase inhibitor addition to levodopa/carbidopa formulations improves motor symptoms and reduces levodopa fluctuations in patients with Parkinson's disease. Objectives were to investigate the effects of entacapone and tolcapone on plasma behaviour of levodopa, its metabolite 3-O-methyldopa and on motor impairment. 22 patients orally received levodopa/carbidopa first, then levodopa/carbidopa/entacapone and finally levodopa/carbidopa plus tolcapone within a 4.5 h interval twice. Maximum concentration, time to maximum level and bioavailability of levodopa did not differ between all conditions each with 200 mg levodopa application as a whole. Catechol-O-methyltransferase inhibition caused less fluctuations and higher baseline levels of levodopa after the first intake and less 3-O-methyldopa appearance. The maximum levodopa concentrations were higher after the second levodopa intake, particularly with catechol-O-methyltransferase inhibition. The motor response to levodopa was better with catechol-O-methyltransferase inhibition than without, tolcapone was superior to entacapone. More continuous levodopa brain delivery and lower 3-O-methyldopa bioavailability caused a better motor response during catechol-O-methyltransferase inhibition.

Metabolic disposition of the insect repellent DEET and the sunscreen oxybenzone following intravenous and skin administration in rats.

Insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone have shown a synergistic percutaneous enhancement when applied concurrently. Both compounds are extensively metabolized in vivo into a series of potentially toxic metabolites: 2 metabolites of DEET, N,N-diethyl-m-hydroxymethylbenzamide (DHMB) and N-ethyl-m-toluamide (ET), and 3 metabolites of oxybenzone, 2,4-dihydroxybenzophenone (DHB), 2,2-dihydroxy-4-methoxybenzophenone (DMB), and 2,3,4-trihydroxybenzophenone (THB). In this study, the metabolites were extensively distributed following intravenous and topical skin administration of DEET and oxybenzone in rats. Combined application enhanced the disposition of all DEET metabolites in the liver but did not consistently affect the distribution of oxybenzone metabolites. The DHMB appeared to be the major metabolite for DEET, while THB and its precursor DHB were the main metabolites for oxybenzone. Repeated once-daily topical application for 30 days led to higher concentrations of DEET metabolites in the liver. Hepatoma cell studies revealed a decrease in cellular proliferation from all metabolites as single and combined treatments, most notably at 72 hours. Increased accumulation of DHMB and ET in the liver together with an ability to reduce cellular proliferation at achievable plasma concentrations indicated that simultaneous exposure to DEET and oxybenzone might have the potential to precipitate adverse effects in a rat animal model.

Biotransformation of a novel antimitotic agent, I-387, by mouse, rat, dog, monkey, and human liver microsomes and in vivo pharmacokinetics in mice.

3-(1H-Indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel indole compound with antitubulin action and potent antitumor activity in various preclinical models. I-387 avoids drug resistance mediated by P-glycoprotein and showed less neurotoxicity than vinca alkaloids during in vivo studies. We examined the pharmacokinetics and metabolism of I-387 in mice as a component of our preclinical development of this compound and continued interest in structure-activity relationships for antitubulin agents. After a 1 mg/kg intravenous dose, noncompartmental pharmacokinetic analysis in plasma showed that clearance (CL), volume of distribution at steady state (Vd(ss)), and terminal half-life (t(1/2)) of I-387 were 27 ml per min/kg, 5.3 l/kg, and 7 h, respectively. In the in vitro metabolic stability study, half-lives of I-387 were between 10 and 54 min by mouse, rat, dog, monkey, and human liver microsomes in the presence of NADPH, demonstrating interspecies variability. I-387 was most stable in rat liver microsomes and degraded quickly in monkey liver microsomes. Liquid chromatography-tandem mass spectrometry was used to identify phase I metabolites. Hydroxylation, reduction of a ketone group, and O-demethylation were the major metabolites formed by the liver microsomes of the five species. The carbonyl group of I-387 was reduced and identified as the most labile site in human liver microsomes. The results of these drug metabolism and pharmacokinetic studies provide the foundation for future structural modification of this pharmacophore to improve stability of drugs with potent anticancer effects in cancer patients.

Tissue disposition of the insect repellent DEET and the sunscreen oxybenzone following intravenous and topical administration in rats.

The insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone (OBZ) have been shown to produce synergistic permeation enhancement when applied concurrently in vitro and in vivo. The disposition of both compounds following intravenous administration (2 mg/kg of DEET or OBZ) and topical skin application (100 mg/kg of DEET and 40 mg/kg of OBZ) was determined in male Sprague-Dawley rats. Pharmacokinetic analysis was also conducted using compartmental and non-compartmental methods. A two-compartment model was deemed the best fit for intravenous administration. The DEET and oxybenzone permeated across the skin to accumulate in blood, liver and kidney following topical skin application. Combined use of DEET and oxybenzone accelerated the disappearance of both compounds from the application site, increased their distribution in the liver and significantly decreased the apparent elimination half-lives of both compounds (p < 0.05). Hepatoma cell studies revealed toxicity from exposure to all treatment concentrations, most notably at 72 h. Although DEET and oxybenzone were capable of mutually enhancing their percutaneous permeation and systemic distribution from topical skin application, there was no evidence of increased hepatotoxic deficits from concurrent application.

Novel simultaneous method for the determination of avobenzone and oxybenzone in human plasma by UHPLC-MS/MS with phospholipid removal pretreatment: An application to a sunscreen clinical trial.

Application of sunscreen is one of many ways to protect skin from the harmful effects of UV radiation. Sunscreen products are widely used and regulated as over-the-counter drug products in the United States. The U.S. Food and Drug Administration recommends an assessment of human systemic absorption of sunscreen active ingredients with a Maximal Usage Trial. The FDA conducted a clinical study to determine the systemic exposure of sunscreen active ingredients present in 4 commercially available sunscreen products of different formulation types under maximal usage conditions. To support this clinical study, a sensitive and specific LC-MS/MS method for the simultaneous determination of the two sunscreens avobenzone and oxybenzone in human plasma was developed. Phospholipid removal 96-well protein precipitation plates were used for sample clean-up and the extracted samples were chromatographed on an Ethylene-Bridged Hybrid (BEH) C18 column in isocratic flow using 10 mM ammonium formate in 0.1% formic acid and methanol (24:76, v/v) as a mobile phase. A triple quadrupole mass spectrometer in multiple reaction monitoring (MRM) mode was used to acquire data. The method was validated as per current FDA bioanalytical method validation guidance, in the ranges 0.20-12.00 ng/mL for avobenzone and 0.40-300.00 ng/mL for oxybenzone. The validated method was used toanalyzethese active ingredients in human clinical study samples.

Determination of 21 photoinitiators in human plasma by using high-performance liquid chromatography coupled with tandem mass spectrometry: A systemically validation and application in healthy volunteers.

In the present study, a comprehensive and sensitive method for simultaneous determination of 21 PIs (nine benzophenones, eight amine co-initiators, and four thioxanthones) in human plasma using high-performance liquid chromatography coupled with tandem mass spectrometry was developed and validated. Two different pre-treatment approaches (liquid-liquid extraction (LLE) and LLE coupled with solid-phase extraction (SPE)) and eight extraction solvents were studied to optimize sample treatment to obtain good recoveries and reduce any matrix effects. The procedure of LLE+SPE was selected as final sample treatment procedure because it obtained higher recoveries as well as lower matrix effects than that performed by LLE alone. The recoveries of 21 target analytes at three spiked concentrations (0.05, 0.5, and 5 ng/mL) ranged from 81% to 109%. The intra- and inter-day relative standard deviations were between 2.5% and 13%. Accuracy and precision data indicated that the detection method was accurate and precise for most of the PIs. The linearities of the labeled dilution calibration curves at 10 concentration levels (iLOQ to 100 ng/mL or iLOQ to 200 ng/mL) were good with correlation coefficients ranged from 0.995 to 0.999. The method quantification limits were in the range of 1.7-16 pg/mL. The analytical method was applied to the analysis of PIs in 14 human plasma samples collected from pregnant women in Guangdong Province, China. Fifteen PIs were detected with total concentrations ranging from 318 to 2772 pg/mL. The ubiquitous contamination of human plasma with PIs suggests that there is widespread exposure to these compounds. Consequently, there should be increased awareness of these pollutants in the environment.

Tissue deposition of the insect repellent DEET and the sunscreen oxybenzone from repeated topical skin applications in rats.

Insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone are capable of enhancing skin permeation of each other when applied simultaneously. We carried out a cellular study in rat astrocytes and neurons to assess cell toxicity of DEET and oxybenzone and a 30-day study in Sprague-Dawley rats to characterize skin permeation and tissue disposition of the compounds. Cellular toxicity occurred at 1 µg/mL for neurons and 7-day treatment for astrocytes and neurons. DEET and oxybenzone permeated across the skin to accumulate in blood, liver, and brain after repeated topical applications. DEET disappeared from the application site faster than oxybenzone. Combined application enhanced the disposition of DEET in liver. No overt sign of behavioral toxicity was observed from several behavioral testing protocols. It was concluded that despite measurable disposition of the study compounds in vivo, there was no evidence of neurotoxicological deficits from repeated topical applications of DEET, oxybenzone, or both.

Phase I and pharmacokinetic study of the vascular-disrupting agent CKD-516 (NOV120401) in patients with refractory solid tumors.

We report a phase I pharmacological study of an oral formulation of CKD-516, a vascular-disrupting agent, in patients with refractory solid tumors. Twenty-seven patients (16 in the dose-escalation cohort and 11 in the expansion cohort) received a single daily dose (5-25 mg) of CKD-516 five days per week. Nausea (67%) and diarrhea (63%) were the most common treatment-related adverse events. The recommended phase II dose of oral CKD-516 was 20 mg/d (15 mg/d with a body surface area (BSA) <1.65 m2 ). Notably, S-516 half-lives in patients receiving 15-20 mg CKD-516/d significantly differed between patients with and without splenomegaly that is suggestive of portal hypertension associated with liver cirrhosis (6.1 vs 4.6 hours, respectively). Of 11 patients without splenomegaly who completed at least one cycle of a daily CKD-516 dose of either 15 or 20 mg, only one patient (9.1%) suffered from any dose-limiting toxicity. We conclude that a daily oral dose of 15 or 20 mg CKD-516 five days per week could be tolerable in patients without liver cirrhosis.

An FPSE-HPLC-PDA method for rapid determination of solar UV filters in human whole blood, plasma and urine.

This paper reports a novel fabric phase sorptive extraction-high performance liquid chromatography-photodiode array detection (FPSE-HPLC-PDA) method for the simultaneous extraction and analysis of six benzophenone derivative UV filters including benzophenone (BZ); 5-benzoyl-4-hydroxy-methoxybenzenesulfonic acid (BP-4); bis(4-hydroxyphenyl)methanone (4-DHB); bis(2,4-dihydroxyphenyl)methanone (BP-2); (2,4-dihydroxybenzophenone) (BP-1) and 2,2'-dihydroxy-4-methoxybenzophenone (DHMB) in human whole blood, plasma and urine samples. Chromatographic separation method was conducted using a Spherisorb ODS 1 (C18) column in isocratic elution mode with a run time <25 min. The FPSE-HPLC-PDA method was validated in the range from 0.1 to 10 µg/mL for all the UV filter compounds. Propyl 4-hydroxybenzoate (also known as propyl paraben) was used as the internal standard (IS). The limit of quantification was found to be 0.1 µg/mL and the weighted-matrix matched standard calibration curves of six UV filters showed a good linearity up to a concentration of 10 µg/mL. This new approach exhibits high potential for direct adaptation as a rapid, robust and green analytical tool for several applications, e.g. in the current sample preparation practices used in many bioanalytical fields including pharmacokinetics (PK), pharmacodynamics (PD), therapeutic drug monitoring (TDM), clinical and forensic toxicology, disease diagnosis and drug discovery. Additionally, in the present work was highlighted that applying innovative extraction and clean up procedures before instrumental analysis by means of a well-known, rugged, cheap, and diffused configurations (e.g. HPLC-PDA), could be possible to validate methods that shows analytical performances comparable to more expensive and complex instrumentations (e.g. LC-MS/MS) that require trained personnel, high maintenance costs and a deep knowledge of analytical problems that could be encountered.

Variations in repeated serum concentrations of UV filters, phthalates, phenols and parabens during pregnancy.

BACKGROUND: Biobank serum samples from longitudinal mother-child cohorts have been used to estimate prenatal exposures to endocrine disrupting chemicals (EDCs). However, the knowledge about variations in serum concentrations of non-persistent chemicals during pregnancy is limited. OBJECTIVE: To describe the within- and between-person variations in serum concentrations of non-persistent chemicals and changes over trimesters, including phthalate metabolites, parabens, phenols, and UV filters. DESIGN: Longitudinal study with repeated blood samples from 128 healthy pregnant women during pregnancy. SETTING: Population based study at a University Hospital in Copenhagen 1999-2001. METHODS: 503 repetitive prenatal serum samples from 128 pregnant women taken at approximately gestational week 12, 20, 30 and 40 were analyzed for 7 UV filters, 32 metabolites of 15 phthalate diesters, 8 phenols and 7 parabens by LC-MS/MS. RESULTS: Ten of 32 phthalate metabolites from six out of 15 phthalate diesters, two of seven parabens, two of eight phenols and three of seven UV filters were measurable in more than half of the serum samples. Of these chemicals, mono­ethyl phthalate (MEP), mono­iso­nonyl phthalate (MiNP), mono­iso­decyl phthalate (MiDP), 4­methylbenzophenone (4­MBP), 4­hydroxybenzoephenone (4­HBP) and n­propyl paraben (nPrP) had intra-class correlation coefficients (ICC) above 0.4 in both adjusted and unadjusted analyses (0.427-0.795), indicating low within-person variation. The serum concentration of UV filters 4­MBP and 4­HBP significantly increased throughout pregnancy, also after adjusting for seasonal variation (4­HBP: effect estimates 0.142-0.437, p < 0.001. 4­MBP: effect estimates 0.156-0.458, p < 0.002.). CONCLUSION: MEP, MiNP, MiDP, 4­MBP, 4­HBP and nPrP were measurable in >50% of serum samples and showed low within-person variation. Thus, it is possible with acceptable accuracy to evaluate maternal exposure during pregnancy for these non-persistent chemicals using one or more biobank serum samples. The here presented adjusted ICC values can in addition be applied as adjustment of residual variation in future studies that evaluate outcomes related to prenatal exposures.

Pharmacokinetics and metabolism of benzophenone 2 in the rat.

Twelve derivatives of benzophenone (BP1-BP12) are widely used as UV-screens to protect industrial products from light induced damage. There is growing public concern about industrially produced chemicals that might interfere with hormonal signalling pathways, thus having potential adverse effects on human health. The derivative 2,2',4,4'-tetrahydroxybenzophenone (BP2) which is used in cosmetic products and in packaging materials, was previously shown to be an estrogenic endocrine active chemical (EAC). While the metabolisation of BP3 has been analyzed in vivo, according to our knowledge little is known about the pharmacokinetics of BP2. Therefore we performed a dose-response experiment with 5 dosages of BP2 which was applied per gavage to adult ovariectomised (ovx) rats for 5 days. Serum samples were analyzed via HPLC. Metabolites were further identified by Helix pomatia glucuronidase treatment and subsequent ion-trap-mass spectrometry. Additionally we analyzed the time dependent metabolisation and excretion of BP2 in a kinetic study. The parent compound BP2 is metabolised to glucuronide - and sulfate-conjugates. In the serum maximum levels of BP2, BP2-glucuronide and BP2-sulfate were observed already 30 min after BP2 application while highest concentrations of BP2 and its metabolites in urine were measured 120 min after treatment. It is suggested that this biotransformation occurs via a first-pass effect in the gut wall or the liver. Despite this rapid metabolisation and excretion, the amount of unconjugated BP2 was sufficient to induce a dose dependent estrogenic effect in the uterotrophic assay.

Sunscreens in human plasma and urine after repeated whole-body topical application.

BACKGROUND: The three chemical ultraviolet absorbers benzophenone-3 (BP-3), octyl-methoxycinnamate (OMC) and 3-(4-methylbenzylidene) camphor (4-MBC) are commercially used in sunscreens worldwide. Apart from sun protection, they may possess endocrine-disrupting effects in animals and in vitro. For all three compounds, only sporadic measurements of percutaneous absorption and excretion after topical application in humans have been described. METHODS: In this study, 32 healthy volunteers, 15 young males and 17 postmenopausal females, were exposed to daily whole-body topical application of 2 mg/cm(2) of sunscreen formulation at 10% (w/w) of each for 4 days. Blood concentrations were measured at 0, 1, 2, 3, 4, 24 and 96 h and urine concentrations at 0, 24, 48, 72 and 96 h. RESULTS: Almost all three sunscreens were undetectable in plasma and urine before the first application. One to 2 h after the first application, all three sunscreens were detectable in plasma. The maximum median plasma concentrations were 187 ng/mL BP-3, 16 ng/mL 4-MBC and 7 ng/mL OMC for females and 238 ng/mL BP-3, 18 ng/mL 4-MBC and 16 ng/mL OMC for men. In the females, urine levels of 44 ng/mL BP-3 and 4 ng/mL of 4-MBC and 6 ng/mL OMC were found, and in the males, urine levels of 81 ng/mL BP-3, 4 ng/mL of 4-MBC and OMC were found. In plasma, the 96-h median concentrations were higher compared with the 24-h concentrations for 4-MBC and OMC in men and for BP-3 and 4-MBC in females.

Presence of benzophenones commonly used as UV filters and absorbers in paired maternal and fetal samples.

BACKGROUND: Previous studies have demonstrated widespread exposure of humans to certain benzophenones commonly used as UV filters or UV absorbers; some of which have been demonstrated to have endocrine disrupting abilities. OBJECTIVES: To examine whether benzophenones present in pregnant women pass through the placental barrier to amniotic fluid and further to the fetal blood circulation. METHODS: A prospective study of 200 pregnant women with simultaneously collected paired samples of amniotic fluid and maternal serum and urine. In addition, unique samples of human fetal blood (n=4) obtained during cordocentesis: and cord blood (n=23) obtained at delivery, both with paired maternal samples of serum and urine collected simultaneously, were used. All biological samples were analyzed by TurboFlow-liquid chromatography - tandem mass spectrometry for seven different benzophenones. RESULTS: Benzophenone-1 (BP-1), benzophenone-3 (BP-3), 4-methyl-benzophenone (4-MBP), and 4-hydroxy-benzophenone (4-HBP) were all detectable in amniotic fluid and cord blood samples and except 4-HBP also in fetal blood; albeit at a low frequency. BP-1 and BP-3 were measured at ~10-times lower concentrations in fetal and cord blood compared to maternal serum and 1000-times lower concentration compared to maternal urine levels. Therefore BP-1 and BP-3 were only detectable in the fetal circulation in cases of high maternal exposure indicating some protection by the placental barrier. 4-MBP seems to pass into fetal and cord blood more freely with a median 1:3 ratio between cord blood and maternal serum levels. Only for BP-3, which the women seemed to be most exposed to, did the measured concentrations in maternal urine and serum correlate to concentrations measured in amniotic fluid. Thus, for BP-3, but not for the other tested benzophenones, maternal urinary levels seem to be a valid proxy for fetal exposure. CONCLUSIONS: Detectable levels of several of the investigated benzophenones in human amniotic fluid as well as in fetal and cord blood calls for further investigations of the toxicokinetic and potential endocrine disrupting properties of these compounds in order for better assessment of the risk to the developing fetus.

In vivo schistosomicidal activity of 7-epiclusianone and its quantification in the plasma of healthy and Schistosoma mansoni infected mice using UPLC-MS/MS.

BACKGROUND: The tetraprenylated benzophenone 7-epiclusianone (7-epi) is a substance isolated from the fruits of Garcinia brasiliensis and in vitro studies have demonstrated that 7-epi is effective against Schistosoma mansoni adult worms. HYPOTHESIS/PURPOSE: Here we report the in vivo evaluation of 7-epi and its pharmacokinetic in healthy and Schistosoma mansoni infected mice. STUDY DESIGN AND METHODS: In this work, we assayed the schistosomicidal activity of 7-epi at the dose of 100 mg/kg and 300 mg/kg body weight/day in S. mansoni experimentally infected mice. Besides, two groups of animals were treated and a detailed analysis of plasma samples was performed by liquid chromatography coupled to mass spectrometry (LC-MS/MS). RESULTS: The worm burden showed a reduction in the infected mice after treatment with 300 mg/kg for five days (p < .05). And we found an increase of AUC0-∞ (20846 vs. 32438 ng.h/ml) and a decrease of total apparent clearance (0.006 vs. 0.004 l/h/kg) of 7- epi in the infected group compared to the healthy group. Consequently, the half-life increased (1.73 vs. 6.11 h) and Cmax was reduced (5427.5 vs. 3321.0 ng/ml) in the infected group compared to the healthy group. In addition, histopathological investigations were performed analysing liver samples from healthy and infected mice. CONCLUSION: The results showed significant schistosomicidal in vivo activity at 300 mg/kg. In addition, livers from S. mansoni infected mice showed a greater number of egg granulomas and the changes in the pharmacokinetic parameters in this group could be associated with the pathology of the murine experimental schistosomiasis.

Simultaneous Quantitation of 2-Hydroxy-4-Methoxybenzophenone, a Sunscreen Ingredient, and its Metabolites in Harlan Sprague Dawley Rat Plasma Following Perinatal Dietary Exposure.

2-Hydroxy-4-methoxybenzophenone (HMB) is a common ingredient in sunscreens and other personal care products and thus significant potential exists for human exposure. HMB was nominated to the National Toxicology Program (NTP) for testing due to its high exposure through consumer products and inadequate toxicological data at the time, which also included increasing concern for the potential effects of HMB on reproduction and development. HMB is metabolized to numerous metabolites in vivo and in vitro including 2,4-dihydroxybenzophenone (DHB), 2,3,4-trihydroxybenzophenone (THB) and 2,5-dihydroxy-4-methoxybenzophenone (2,5-DHMB) as well as their corresponding glucuronide and/or sulfate conjugates. In this study, we have developed and validated a liquid chromatography-tandem mass spectrometry method to quantitate free (unconjugated) HMB and DHB, and total (combined conjugated and unconjugated) HMB, DHB, THB and 2,5-DHMB. The method was successfully applied to quantitate these analytes in plasma from postnatal day 28 and 56 male and female Harlan Sprague Dawley rat pups following perinatal dietary exposure to 0 (control), 3,000, 10,000 and 30,000 ppm HMB beginning on gestational Day 6. All determined analyte concentrations increased with increasing dose and were significantly higher than the controls at both timepoints. All the total analytes were quantified in all plasma samples and total concentrations were considerably higher than free, suggesting extensive conjugation. Mean concentrations of total HMB and DHB were higher (~100-300-fold) than the free HMB and DHB concentrations, and total concentrations in plasma were approximately HMB≈DHB > 2,5-DHMB¼THB. Free and total analyte plasma concentrations were not sex-dependent and in general, both free and total analytes were detected in the control samples. Comparison of our rat data, using the internal dose, with human data available in the literature suggests that the rat doses used in our studies were within 4-fold of the human dose.

People with diabetes, respiratory, liver or mental disorders, higher urinary antimony, bisphenol A, or pesticides had higher food insecurity: USA NHANES, 2005-2006.

This study was aimed to examine the prevalence of food insecurity and what social, health, and environmental characteristics could constitute such situation in a national and population-based setting. Data was retrieved from the National Health and Nutrition Examination Survey, 2005-2006. Information on demographics, lifestyle factors, self-reported ever medical conditions in the past and self-reported food security conditions in the last 12 months calculated on the household level was obtained by household interview. Bloods and urines (subsample) were collected at the interview as well. Only adults aged 20 years and above (n = 4979) were included for statistical analysis in the present study. Chi-square test, t test, and survey-weighted logistic regression modeling were performed. Three thousand eight hundred thirty-four (77.9%) people were with full food security, 466 (9.5%) people were with marginal food security and 624 (12.7%) people were with low or very low food security. Being younger, having higher ratios of family income to poverty thresholds (due to low level of education or lack of financial support), having prior asthma, arthritis, chronic bronchitis, depression, diabetes, eczema, emphysema or liver problems, having higher levels of serum cotinine, urinary antimony, bisphenol A, pesticides, or having lower levels of urinary Benzophenone-3 were associated with food insecurity. In addition to socioeconomic and smoking conditions, evidence on people with several prior health conditions and being exposed to environmental chemicals and food insecurity is further provided. Future social, health and environmental policy, and programs protecting people from food insecurity by considering both health and environmental factors mentioned above would be suggested.