Identification and quantification of acetyl tributyl citrate (ATBC) metabolites using human liver microsomes and human urine.

Plasticizers are chemicals that make plastics flexible, and phthalates are commonly used. Due to the toxic effects of phthalates, there is increasing use of non-phthalate plasticizers like acetyl tributyl citrate (ATBC). ATBC has emerged as a safer alternative, yet concerns about its long-term safety persist due to its high leachability and potential endocrine-disrupting effects. This study aims to identify ATBC metabolites using human liver microsomes and suspect screening methods, and to explore potential urinary biomarkers for ATBC exposure. Using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry, we identified ATBC metabolites, including acetyl dibutyl citrate (ADBC), tributyl citrate (TBC), and dibutyl citrate (DBC). Urine samples from 15 participants revealed the presence of ADBC in 5, TBC in 11, and DBC in all samples, with DBC concentrations pointedly higher than the other metabolites. These metabolites show promise as biomarkers for ATBC exposure, though further validation with human data is required. Our results underscore the need for comprehensive studies on ATBC metabolism, exposure pathways, and urinary excretion to accurately assess human exposure levels.

Temporal trends in exposure to parabens, benzophenones, triclosan, and triclocarban in adult females in Kyoto, Japan, from 1993 to 2016.

Products used in daily life can contain chemicals such as parabens, benzophenones, triclosan, and triclocarban that have potential endocrine-disrupting effects. Little is known about the temporal trends of exposure levels to some of these chemicals in Japan. Our study assessed the intake and risk associated with exposure to commonly used chemicals. We measured the concentrations of five parabens, four benzophenones, and triclosan and triclocarban in 133 single spot urine samples. The urine samples were collected in 1993, 2000, 2003, 2009, 2011, and 2016 from healthy female residents in Kyoto, Japan. With the exception of methylparaben, ethylparaben, and butylparaben, there were no significant fluctuations in the concentrations of target chemicals over the study period; however, methylparaben, ethylparaben, and butylparaben showed temporal changes in concentrations. Methylparaben concentrations peaked in 2003 with a median value of 309 µg/g creatinine, ethylparaben concentrations peaked in 1993 with a median value of 17.3 µg/g creatinine, and butylparaben showed a decline, with the median values becoming non-detectable in 2009 and 2016. We calculated estimated daily intakes and hazard quotients for each chemical. In the analysis of total samples, 2.3% (3 samples) for butylparaben and 0.8% (1 sample) for propylparaben were found to surpass a hazard quotient of 1. Overall, 3% (n = 4) of the study participants exceeded a hazard index of 1. The potential health risks associated with exposure to butylparaben and propylparaben emphasize the need for further monitoring and research.

Potential adverse outcome pathway of neurodevelopmental toxicity, inflammatory response, and oxidative stress induction mediated by three alkyl organophosphate flame retardants in zebrafish larvae.

Following restrictions on polybrominated flame retardants, trimethyl phosphate (TMP), triethyl phosphate (TEP), and tris(2-butoxyethyl) phosphate (TBEP) have been frequently used as plasticizers for fire-resistant plastics. This study investigated the neurodevelopmental effects, inflammatory response, and oxidative stress induction of three alkyl organophosphate flame retardants using a zebrafish embryo/larvae model. After exposure of zebrafish embryos to TMP, TEP, and TBEP (0, 0.02, 0.2, 2, 20, and 200 µg L-1) for 96 h, survival, development, swimming behavior, changes in acetylcholinesterase (AChE) activity, dopamine, tumor necrosis factor-alpha (TNF-α), interleukin (IL), reactive oxygen species (ROS), and antioxidant enzyme activities were observed. Concentrations of TMP, TEP, and TBEP were also measured in the whole body of exposed larvae. Our results showed that exposure to 200 µg L-1 TEP and ≥20 µg L-1 TBEP significantly reduced larval body length; however, TMP had no significant effects on developmental parameters up to 200 µg L-1. After 96 h of exposure to TBEP, total distance moved, mean velocity, AChE, and dopamine concentrations were significantly decreased. Exposure to TEP and TBEP decreased the expression of genes that regulate central nervous system development (e.g. gap43 and mbpa), whereas ROS, antioxidant enzymes, TNF-α, and IL-1ß concentrations were significantly increased. Notably, pretreatment with an antioxidant N-acetylcysteine reduced neurotoxicity and oxidative stress caused by TEP and TBEP. The results of this study demonstrated that exposure to TEP and TBEP causes oxidative stress and has adverse effects on the neurobehavioral and immune system of zebrafish, leading to hypoactivity and ultimately impairing development.

The combined effects of preservative chemicals in consumer products: An analysis using embryonic and adult zebrafish.

Benzisothiazolinone (BIT) and propyl paraben (PP) are preservatives in cleaning products; however, their toxicities are not well understood. In this study, zebrafish embryos were exposed to BIT, PP, and mixtures of both for 96 h to investigate the effects on growth hormone (GH), insulin-like growth factor-1 (IGF-1), and the transcription of 19 genes related to the GH/IGFs axis. Concentrations of BIT and PP were measured in the whole body of larvae. Zebrafish pairs were also exposed to BIT, PP, and mixtures for 21 d to evaluate the effects on sex hormones, histology in gonad, and transcription of 22 genes related to the hypothalamus-pituitary-gonad axis and vitellogenin. The mixtures had potentiation effects on development, reproduction, hormones, and gene transcripts than individual exposure. Larvae exposed to 229 µg L-1 BIT, 64.5 µg L-1 PP, and mixtures showed reduced growth. Decreased GH and IGF-1 levels were supported by gene regulation associated with the GH/IGFs axis. In larvae, reactive oxygen species, superoxide dismutase, catalase, and glutathione peroxidase levels were increased under all exposures. The gonadosomatic index in males and number of eggs decreased after mixture exposure. In females exposed to mixtures, the percentage of atretic follicle in ovary was significantly increased. The significant decrease in testosterone in males and significant decrease in 17ß-estradiol in females exposed to mixtures suggest anti-estrogenic and anti-androgenic potential. Thus, preservative mixtures in consumer products may be more toxic than the individual substances, which is important for managing the risks of mixing preservatives.

Effects of two alternative plasticizers on the growth hormone-related endocrine system, neurodevelopment, and oxidative stress of zebrafish larvae.

In response to the restriction of phthalate plasticizers, acetyl tributyl citrate (ATBC) and acetyl triethyl citrate (ATEC) have been used in medical devices and food packaging. In the present study, the effects of ATBC and ATEC on the development, behavior, growth hormone (GH)-related endocrine system, neurotransmitters, and oxidative stress of zebrafish embryo or larvae were investigated. After exposure of zebrafish to ATBC and ATEC (0, 0.03, 0.3, 3, 30, and 300 µg/L) for 96 h, developmental toxicity, behavioral changes under light/dark condition, changes in hormones and genes involved in GH/insulin-like growth factors (IGFs) axis, changes in hormone, enzyme, and genes related to neurodevelopment, antioxidant enzymes activities were determined. Larvae exposed to 30 or 300 µg/L ATBC showed significant reductions in body length and moving distance and speed, whereas no significant effects on development and locomotor behavior were observed in larvae exposed to ATEC. The contents of GH and IGF-I were significantly reduced in larvae exposed to 3, 30, and 300 µg/L ATBC. Hormonal changes in fish exposed to ATBC are well supported by regulation of genes related to GH (gh1) and the activity of IGF-I (igf1). In fish exposed to ATBC, reduced acetylcholinesterase activity and down-regulation of genes related to the central nervous system development (ache, gap43, mbpa, and syn21) were observed. ATBC increased the production of reactive oxygen species and the levels of superoxide dismutase, catalase, and glutathione peroxidase. Notably, pre-treatment with the classic antioxidant N-acetylcysteine alleviated ATBC-induced GH-related endocrine disruption and neurotoxicity. Our observations showed that exposure to low levels of ATBC could disturb the regulatory systems of GH/IGFs axis and neurobehavior, ultimately leading to developmental inhibition and hypoactivity, and that increased oxidative stress plays a major role in these toxicities.

Single and mixture toxicity evaluation of avobenzone and homosalate to male zebrafish and H295R cells.

Avobenzone and homosalate are widely used in sunscreens to provide ultraviolet (UV) protection, either as single compounds or in combination. Some UV filters exhibit estrogenic or anti-androgenic activities, however, studies regarding their interactions and toxicity in mixtures are limited. In this study, the effect of the toxicity of a binary mixture comprising avobenzone (0.72 µg L-1) and homosalate (1.02 and 103 µg L-1) on steroid hormone biosynthesis were investigated using male zebrafish and human adrenocortical carcinoma (H295R) cells. In fish exposed to homosalate, a significant decrease in the gonadosomatic index, testosterone level, and transcription of several genes (e.g, hsd3b2, cyp17a1, and hsd17b1) and a significant increase in the hepatosomatic index, liver steatosis, 17ß-estradiol level, and transcription of vtg gene were observed. These results suggest that estrogenic and anti-androgenic effects of homosalate were mediated by the steroidogenic pathway. The presence of 0.72 µg L-1 of avobenzone augmented the anti-androgenic responses in male fish. The testosterone level in the H295R cells were significantly decreased after they were exposed to homosalate alone or in combination with avobenzone, which is consistent with observations in male zebrafish. Further studies need to be conducted to understand the endocrine disrupting properties of long-term exposure to substances typically used in sunscreens.

Temporal trends in bisphenol exposures and associated health risk among Japanese women living in the Kyoto area from 1993 to 2016.

BACKGROUND: Bisphenols, and especially bisphenol A, are widely used as components of epoxy resins and polycarbonate. Widespread detection and potential health risks have led to bisphenol A being replaced by other alternatives, including structurally similar bisphenol analogs. Several bisphenol analogs are suspected to have similar adverse health consequences. This study examined the temporal trends in bisphenol exposure among a group of Japanese women from 1993 to 2016, and assessed the associated health risks. METHODS: We used archived single spot urine samples of healthy Japanese women living in the Kyoto area (n = 133) collected in 1993, 2000, 2003, 2009, 2011, and 2016. We measured the concentrations of 10 bisphenols in these samples. RESULTS: A sharp increase in the detection rates of bisphenol F was observed after 2000. There was a distinct downward trend in urinary bisphenol A concentrations and an upward trend in bisphenol E concentrations after 2009. While the hazard index for all measured bisphenols was below 1 in all subjects, bisphenol F was determined as the most important risk driver after 2000, rather than bisphenol A. DISCUSSION: Trends of decreasing bisphenol A and increasing bisphenol E exposure especially after 2011, along with no significant change in the sum of all bisphenol analogs in urine, provide clear evidence that bisphenol A has been replaced by other bisphenols in the study population. We found no significant change in the total exposure to bisphenols during the study period. Bisphenol F might become the most important bisphenol in terms of risk, while cumulative risks due to all bisphenol exposure were deemed insignificant. Considering the accumulating evidence indicating adverse effects at lower exposure levels, further studies are warranted to assess exposure and risk from bisphenol A analogs.

Toxicokinetic analyses of naphthalene, fluorene, phenanthrene, and pyrene in humans after single oral administration.

Polycyclic aromatic hydrocarbons (PAHs) are generated by incomplete combustion of organic matter. They have health effects in multiple organs and can cause lung, skin, and bladder cancers in humans. Although data regarding their toxicity is available, information on the absorption, distribution, metabolism, and excretion of PAHs in humans is very limited. In the present study, deuterium-labeled naphthalene (Nap), fluorene (Flu), phenanthrene (Phe), and pyrene (Pyr) were orally administered as a single dose (0.02-0.04 mg/kg) to eight healthy adults. Both serum and urine samples were monitored for 72 h after the exposure. Parent compounds and PAH metabolites (monohydroxy-PAHs; OH-PAHs) were measured by headspace-solid phase microextraction coupled with gas chromatography-mass spectrometry and high-performance liquid chromatography-tandem mass spectrometry, respectively. Based on the time-concentration profiles in serum and urine, non-compartmental analysis was performed, and two-compartment models were constructed and validated for each PAH. Subsequently, all of the parent compounds were rapidly absorbed (Tmax: 0.25 to 1.50 h) after oral administration and excreted in urine with a biological half-life (T1/2) of 1.01 to 2.99 h. The fractional urinary excretion (Fue) of OH-PAHs ranged from 0.07 % to 11.3 %; their T1/2 values ranged from 3.4 to 11.0 h. The two-compartment models successfully described the toxicokinetic characteristics of each PAH and its metabolites. Fue and the two-compartment models could be useful tools for exposure simulation or dose-reconstruction of PAHs. The results of this study will provide useful information for interpreting biomonitoring data of PAHs.

Thyroid hormone disrupting potentials of benzisothiazolinone in embryo-larval zebrafish and rat pituitary GH3 cell line.

Benzisothiazolinone (BIT), one of the most widely used antimicrobial agents in consumer products, has frequently been detected in the water environment. The present study was conducted to determine the adverse effects of BIT on the thyroid neuroendocrine system of zebrafish embryos/larvae. Rat pituitary (GH3) cell line was employed to support the underlying mechanism of thyroid hormone disrupting effects. Significant coagulation and hatching delay were observed in embryos exposed to 30 µg/L of BIT, which in turn remarkably decreased hatchability and larval survival. In BIT-exposed larvae, tshß, tshr, and trh genes were significantly upregulated along with a decrease in thyroxine and triiodothyronine content, indicating that BIT decreased thyroid hormones and increased thyrotropin-releasing hormone and thyroid stimulating hormone secretion through a feedback circuit. The downregulation of trα and deio2 genes in the zebrafish larvae suggests the inhibition of thyroid hormone receptors and deiodination. Similar to the results in zebrafish, upregulation of tshß and downregulation of trα, trß, deio1, and deio2 genes were observed in GH3 cells. Our observations suggest that BIT can decrease the level of thyroid hormones by influencing central regulation, receptor binding, and deiodination.

Pharmacokinetics of transdermal methyl-, ethyl-, and propylparaben in humans following single dermal administration.

Parabens are common chemicals used as preservatives in foods, cosmetics, and personal care products. Although transdermal exposure to parabens occurs, studies on human pharmacokinetics (PK) following dermal exposure to parabens are scarce. In this study, the PK following dermal exposure to parabens was determined and compared with our previous findings on oral exposure. A paraben mixture cream containing 0.8% deuterated methyl-, ethyl-, and propylparaben (MeP-d4 0.26%; EtP-d4 0.26%, and PrP-d4 0.28%) was dermally applied to the whole arm of five male volunteers at a dose of 24 g/person over 30 min. Blood and urine samples were collected at several intervals over the course of 48 h to measure the levels of MeP-d4, EtP-d4, and PrP-d4 and their conjugated metabolites using HPLC-MS/MS. As a result of non-compartmental analysis, the average peak values of total (sum of conjugated and unconjugated metabolites) MeP-d4, EtP-d4, and PrP-d4 were reached at 7.8 h, 10.5 h, and 5.3 h, indicating a slower absorption rate compared to that of oral exposure (<2 h). The terminal elimination half-lives of MeP-d4, EtP-d4, and PrP-d4 were 12.2 h, 12.0 h, and 9.3 h, respectively. Fractional urinary excretion (Fue) of total MeP-d4, EtP-d4, and PrP-d4 was 1.7%, 2.3%, and 1.9%, respectively. The Fue of total and unconjugated PrP-d4 following dermal exposure was five times lower and three times higher, respectively, compared with those after oral exposure, suggesting that PrP is relatively less metabolized to the conjugated form after dermal exposure. Taken together, dermal exposure to paraben leads to a longer apparent half-life and results in higher proportions of biologically active unconjugated parabens in the systemic circulation as compared to oral exposure. This study provides insights into the kinetic properties of parabens and their metabolites in humans.

Longitudinal behavioral changes and factors related to reinforced risk aversion behavior among patients with chronic kidney disease during the COVID-19 pandemic.

In patients with chronic kidney disease (CKD), coronavirus disease 2019 (COVID-19) has a higher mortality rate than the general population; therefore, prevention is vital. To prevent COVID-19 infection, it is important to study individuals' risk aversion behavior. The objective of this study was to understand how the behavioral characteristics of physical distancing, hygiene practice, and exercise changed in patients with CKD during the COVID-19 pandemic and to identify the characteristics of patients who showed weakened or strengthened behavioral changes. We analyzed data from the Study on Kidney Disease and Environmental Chemicals (Clinical Trial No. NCT04679168), that examined a prospective cohort of patients with CKD. This cohort included patients with CKD who visited the participating hospitals for the first time between June and October 2020 and the second time between October 2020 and January 2021. Data on demographics, socio-economic details, and behavioral characteristics were collected through a questionnaire survey. Using a multivariable logistic regression model, we identified whether COVID-19 infection risk perception and previous strong behavioral changes affected behavioral changes during the first and second visits. A total of 277 patients (33.2% females) were included in the analysis. Nine out of 12 behaviors were reinforced at the first visit, and five out of nine reinforced behaviors were weakened at the second visit. A high-risk perception of COVID-19 infection was not associated with the tendency of overall behavioral reinforcement or maintaining behaviors in an enhanced state at the second visit. Strong behavioral changes at the patients' first visit to the hospital were associated with a tendency to strengthen or maintain reinforced behaviors at the second visit (adjusted odds ratio 1.99, 95% confidence interval 1.19-3.34; P = 0.009). Even if the initial COVID-19 risk perception is high, behavioral changes worsen over time. Individuals who showed more active behavioral changes at the beginning of the COVID-19 pandemic tended to maintain reinforced behavior over time. Continuous education and monitoring are needed to maintain changed behaviors, especially in patients with a high initial COVID-19 risk perception.

Exposure to phthalate esters in Japanese females in Kyoto, Japan from 1993 to 2016: Temporal trends and associated health risks.

Phthalates are used as plasticizers in many products used in daily life worldwide. Due to industrial and economic developments, exposure among general population to phthalates may vary geographically and temporally. However, studies are lacking for investigating temporal changes in phthalate exposure in the Japanese population. In the present study, the temporal trends in exposure to various phthalates were assessed among a group of Japanese adult female population over 1993-2016 and derived associated risks. For this purpose, urine samples of healthy Japanese females in Kyoto, Japan (N = 132) collected in 1993, 2000, 2003, 2009, 2011, and 2016, were employed and measured for the concentrations of 18 phthalate metabolites. Over this period, the detection rates of mono(3-carboxypropyl) phthalate (MCPP) and monoisobutyl phthalate (MiBP) decreased, and the geometric means of the urinary concentrations of mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) showed a significant decreasing trend. Cumulative risk due to exposure to dibutyl phthalate (DBP), diisobutyl phthalate (DiBP), butyl benzyl phthalate (BBP), and di-2-ethylhexyl phthalate (DEHP) showed a dramatic decrease only between 1993 and 2000. The maximum hazard quotient (HQM) was attributed to DEHP in most subjects regardless of sampling year. This study showed the temporal trend of the exposure of Japanese females to several phthalate esters over two decades. As of the late 2010's, DEHP was still the predominant component of phthalate ester exposure in the population. The HI value, however, indicates that direct risk due to phthalate exposure was unlikely among the studied population.

Within- and between-person variability of urinary phthalate metabolites and bisphenol analogues over seven days: Considerations of biomonitoring study design.

Urine was used as a part of a human biomonitoring study based on the excretion kinetics of less-persistent contaminants, such as phthalates and bisphenol A (BPA). Despite the advantages of being non-invasive and easy to collect, urine can show a large variability of concentrations of phthalate metabolites and BPA within a person depending on sampling time. Therefore, it is essential to assess the variability of urinary concentrations for comprehensive sampling design in the context of exposure and risk assessments. In this study, 18 phthalate metabolites and eight BPs were measured in all spot urine (n = 401) collected from 12 participants for seven consecutive days to evaluate within- and between-person variabilities. The intraclass correlation coefficients (ICCs) for all spot urines were poor for monomethyl phthalate (ICC: 0.002) and BPA (0.121) but were moderate for monoethyl phthalate (0.514) and monobenzyl phthalate (0.462). Based on the results of di (2-ethylhexyl) phthalate (DEHP) metabolites, the half-life and differences in metabolic capability seem to affect the ICCs. Urinary mono (2-ethylhexyl) phthalate (MEHP), a primary metabolite of DEHP, was suggested as a short-term exposure marker of DEHP in our study. Creatinine- and specific gravity-adjusted concentrations of phthalate metabolites and BPs resulted in increased ICCs, implying requirements for randomly collected spot urine. Most analytes in the first morning voids (FMVs) were correlated significantly with those in the daily composites, suggesting the feasibility of FMVs to estimate the daily exposure dose. This study facilitates a more comprehensive sampling design and data interpretation strategy for human biomonitoring studies.

First snapshot on behavioral characteristics and related factors of patients with chronic kidney disease in South Korea during the COVID-19 pandemic (June to October 2020).

BACKGROUND: The recent novel coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented changes in behavior. We evaluated the current status of precautionary behavior and physical activity in chronic kidney disease (CKD) patients during the COVID-19 pandemic. METHODS: A population of CKD patients (n = 306) registered in the Study on Kidney Disease and Environmental Chemicals (SKETCH, Clinical Trial No. NCT04679168) cohort recruited from June 2020 to October 2020 was included in the study. We conducted a questionnaire survey related to risk perception of COVID-19, precautionary behavior, and physical activity. RESULTS: There were 187 patients (61.1%) with estimated glomerular filtration rate of <45 mL/min/1.73 m2 . This population showed a higher degree of risk perception for COVID-19 than the general population. Age was the most significant determinant of risk perception among CKD patients. During the pandemic, social distancing and hygiene-related behavior were significantly increased (p < 0.001). The frequency of exercise was decreased only in those who took regular exercise, without diabetes, or with a lower Charlson comorbidity index (CCI) (p < 0.001), with no change among the other groups. Socioeconomic status and comorbidities significantly affected behavioral characteristics regardless of the category. Education and income were significantly associated with precautionary behaviors such as staying at home and hand sanitizer use. Patients with higher CCI status significantly increased frequency of exercise (adjusted odds ratio, 2.10; 95% confidence interval, 1.01-4.38). CONCLUSION: CKD patients showed higher risk perception with active precautionary behavioral changes than the general population. Healthcare providers should be aware of the characteristics to comprise precautionary behavior without reducing physical activity.

Effects of methylisothiazolinone and octylisothiazolinone on development and thyroid endocrine system in zebrafish larvae.

Methylisothiazolinone (MIT) and octylisothiazolinone (OIT) are used as preservatives and biocides to prevent product decay or deterioration. In the present study, developmental toxicity and the effect on the thyroid endocrine system were investigated in zebrafish embryos exposed to MIT and OIT for 96 h. Coagulation was significantly increased when zebrafish embryos were exposed to a concentration of 300 µg/L MIT and ≥ 0.3 µg/L OIT, resulting in a significant decrease in hatchability and larvae survival. The body length in zebrafish larvae exposed to 30 µg/L OIT was significantly shorter than that of the control group. The whole-body levels of triiodothyronine and thyroxine were significantly decreased in larvae exposed to MIT and OIT. Significant upregulation of crh, trh, tshß, and tshr genes and downregulation of trαa, tg, ttr, and deio2 genes were observed in fish exposed to two isothiazolinones. The expression of dre-miR-193b and dre-miR-499 was significantly increased in zebrafish larvae exposed to MIT and OIT, indicating that epigenetic deregulation of miRNAs modulated genes involved in thyroid hormone regulation. OIT has a higher magnitude of toxicity than MIT, corresponding to the observed changes in thyroid hormones and developmental toxicity.

Urinary Concentrations of Major Phthalate and Alternative Plasticizer Metabolites in Children of Thailand, Indonesia, and Saudi Arabia, and Associated Risks.

Phthalates are widely used in consumer products and are well-known for adverse endocrine outcomes. Di-(2-ethylhexyl) phthalate (DEHP), one of the most extensively used phthalates, has been rapidly substituted with alternative plasticizers in many consumer products. The aim of this study was to assess urinary phthalate and alternative plasticizer exposure and associated risks in children of three Asian countries with different geographical, climate, and cultural characteristics. Children were recruited from elementary schools of Saudi Arabia (n = 109), Thailand (n = 104), and Indonesia (n = 89) in 2017-2018, and their urine samples were collected. Metabolites of major phthalates and alternative plasticizers were measured in the urine samples by HPLC-MS/MS. Urinary metabolite levels differed substantially between the three countries. Metabolite levels of diisononyl phthalate (DiNP), diisodecyl phthalate (DiDP), di(2-ethylhexyl) terephthalate (DEHTP), and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) were the highest in Saudi children: Median urinary concentrations of oxo-MiNP, OH-MiDP, 5cx-MEPTP, and OH-MINCH were 8.3, 8.4, 128.0, and 2.9 ng/mL, respectively. Urinary DEHP metabolite concentrations were the highest in the Indonesian children. The hazard index (HI) derived for the plasticizers with antiandrogenicity based reference doses (RfDAA) was >1 in 86%, 80%, and 49% of the Saudi, Indonesian, and Thai children, respectively. DEHP was identified as a common major risk driver for the children of all three countries, followed by DnBP and DiBP depending on the country. Among alternative plasticizers, urinary DEHTP metabolites were detected at levels comparable to those of DEHP metabolites or higher among the Saudi children, and about 4% of the Saudi children exceeded the health based human biomonitoring (HBM)-I value. Priority plasticizers that were identified among the children of three countries warrant refined exposure assessment for source identification and relevant exposure reduction measures.

Placental Transfer and Composition of Perfluoroalkyl Substances (PFASs): A Korean Birth Panel of Parent-Infant Triads.

Exposure to perfluoroalkyl substances (PFASs) is of public concern due to their persistent exposure and adverse health effects. Placental transfer of PFASs is an important excretion pathway of these chemicals in pregnant women and exposure route in fetuses. We measured PFAS concentrations in maternal, paternal, and umbilical cord serum collected from 62 pregnant Korean women and matched biological fathers of the fetuses. Placental transfer rates (cord to maternal serum ratio) of PFASs were also calculated. Demographics and pregnancy-related factors determining the placental transfer rates were identified using linear regression models. Maternal, paternal, and cord serum showed different PFASs compositions. Among the PFASs, perfluorooctane sulfonate (PFOS) showed the highest concentrations in maternal and paternal serum, while perfluorooctanoic acid (PFOA) showed the highest concentration in cord serum. There was a higher proportion of perfluoroalkyl carboxylic acids (PFCAs) with 9-12 carbon chains than those with 13-14 carbon chains in maternal and paternal serum, but this proportion was in the opposite direction in cord serum. PFOA and perfluorohexane sulfonate (PFHxS) had higher placental transfer rates (means of 0.32 and 0.36, respectively) than PFOS (mean of 0.12), which is in line with the results of previous studies. Gestational age and birth weight were positively associated with placental transfer rate of PFOA, PFHxS, and PFOS, while pre-pregnant BMI and weight were inversely associated with PFOS. This study showed that placental transfer of PFASs differs by compounds and is associated with pregnancy-related factors. Further studies on novel PFASs are warranted for Korean pregnant women.

Ecological Risk Assessment of Amoxicillin, Enrofloxacin, and Neomycin: Are Their Current Levels in the Freshwater Environment Safe?

Veterinary pharmaceuticals may cause unexpected adverse effects on non-target aquatic species. While these pharmaceuticals were previously identified as priority compounds in ambient water, their ecological risks are relatively unknown. In this study, a series of chronic toxicity tests were conducted for these pharmaceuticals using algae, two cladocerans, and a fish. After a 21-d exposure to amoxicillin, enrofloxacin, and neomycin, no observed effect concentration (NOEC) for the reproduction of Daphnia magna was detected at 27.2, 3.3, and 0.15 mg/L, respectively. For the survival of juvenile Oryzias latipes following the 40-d exposure, NOEC was found at 21.8, 3.2, and 0.87 mg/L, respectively. Based on the results of the chronic toxicity tests and those reported in the literature, predicted no-effect concentrations (PNECs) were determined at 0.078, 4.9, and 3.0 µg/L for amoxicillin, enrofloxacin, and neomycin, respectively. Their hazard quotients (HQs) were less than 1 at their average levels of occurrence in ambient freshwater. However, HQs based on the maximum detected levels of amoxicillin and enrofloxacin were determined at 21.2 and 6.1, respectively, suggesting potential ecological risks. As the potential ecological risks of these veterinary pharmaceuticals at heavily contaminated sites cannot be ignored, hotspot delineation and its management are required.

Effects of 3,4-dichloroaniline (3,4-DCA) and 4,4'-methylenedianiline (4,4'-MDA) on sex hormone regulation and reproduction of adult zebrafish (Danio rerio).

3,4-dichloroaniline (3,4-DCA) and 4,4'-methylenedianiline (4,4'-MDA) have been widely used in manufacture of many industrial and consumer products, and hence often detected in aquatic environment. Reproductive toxicity of aniline and its derivatives in aquatic organisms has been suggested, however, knowledge on the endocrine disruption potentials and toxicological consequences of both anilines are not well understood, especially in fish. In this study, we aimed to understand the effects of 3,4-DCA and 4,4'-MDA on sex hormone regulation and reproduction of adult zebrafish (Danio rerio). Following 21 d exposure, significant decreases of the reproduction were observed at 0.38 mg/L 3,4-DCA, and 4.6 mg/L 4,4'-MDA. Moreover, plasma concentrations of testosterone (T) and 17ß-estradiol (E2) level were significantly decreased in both male and female fish following the exposure. The sex hormone changes could be explained by the regulatory changes of the genes along the hypothalamic-pituitary-gonadal (HPG) axis, including significant down-regulation of steroidogenic acute regulatory protein (star) and cytochrome P450 family 19 subfamily A (cyp19a) genes in the gonad. Moreover, inhibition of gonadotropin hormone signaling and prostaglandin-endoperoxide synthase 2 (ptgs2) gene expression were observed, suggesting potential disruption of oocyte maturation and ovulation by the exposure. Our observations indicate that 3,4-DCA and 4,4'-MDA can impair reproduction of zebrafish potentially through disruption of steroid hormone synthesis and ovulation.

Variability of urinary creatinine, specific gravity, and osmolality over the course of pregnancy: Implications in exposure assessment among pregnant women.

Due to dilution status of the urine, chemical concentrations measured in spot urine are frequently adjusted using correction factors, such as creatinine, specific gravity (SG), or osmolarity of the urine. Urinary correction factors, however, can be influenced dramatically by physiological changes such as pregnancy. Details about the variation of urine dilution over the course of pregnancy are not well characterized. In the present study, we investigated the variation of urine correction factors over time among the pregnant women of Korea (n = 69) and Thailand (n = 102). Creatinine, SG, and osmolality were determined in the urine samples obtained in each trimester of the participating women, and were compared by sampling time and by nationality. Implication of the variation in these correction factors was studied using phthalate metabolites measured in the urine samples as model chemicals. Urinary correction factors significantly varied across the trimesters especially in Korean pregnant women: urinary creatinine and osmolality were significantly lower in the third trimester (T3) urine than the first trimester (T1) urine. Urinary creatinine and SG of the T3 urine of Korean pregnant women were also significantly lower than those reported from the non-pregnant women who participated in Korean National Environmental Health Survey (KoNEHS) 2015-2017. Among Thai women, however, these correction factors were rather stable across the pregnancy. Differences in ethnicity, or in behavior such as water consumption amount may partly explain the differences. Temporal changes in these urine correction factors influenced the urinary phthalate metabolite concentrations adjusted for dilution, in both Korean and Thai pregnant women. The present observations show that the variations of urinary correction factors should be considered in exposure assessment of urinary chemicals for pregnant women, in order to circumvent potential bias due to physiological changes occurring during pregnancy, and to reduce errors in exposure classification and association.