Synergistic interaction of co-exposure to humidifier disinfectant chemicals CMIT/MIT and PHMG in lung injury.

A number of biocidal disinfectant chemicals are used as household products to prevent spread of pathogens. People are commonly exposed to multiple chemicals through those disinfectants. However, effects of interactions (e.g., synergism) between disinfectants on human health outcomes have been rarely studied. In this study, we aimed to investigate associations of a mixture of chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) and polyhexamethylene guanidine (PHMG), which had been used as humidifier disinfectants (HDs) in South Korea, with HD-associated lung injury (HDLI) in a Korean population (n = 4058) with HD exposure through use of HD products. Exposure to HD was retrospectively assessed by an interview-based standardized survey, and HDLI was determined by clinical assessment. After adjusting for covariates, PHMG-specific exposure indices (e.g., amount of use, indoor air concentration, and weekly exposure level) were dose-dependently associated with HDLI (their odds ratios for the comparison of third tertile versus first tertile were 1.95, 1.77, and 2.16, respectively). CMIT/MIT exposure was not observed to have a significant association with HDLI in a single chemical exposure model; however, associations between PHMG exposure and HDLI were strengthened by co-exposure to CMIT/MIT in combined chemical exposure models, where synergistic interactions between CMIT/MIT use and PHMG indices (amount of use and weekly exposure level) were observed (p-interaction in additive scale: 0.02 and 0.03, respectively). Our findings imply that adverse effects of PHMG exposure on lung injury among HD users might be worsened by co-exposure to CMIT/MIT. Given that plenty of household products contain disinfectants on global markets, epidemiological and toxicological investigations are warranted on interaction effects of co-exposure to disinfectants.

Associations between serum perfluoroalkyl and polyfluoroalkyl concentrations and diabetes mellitus in the Korean general population: Insights from the Korean National Environmental Health Survey 2018-2020.

AIMS: Recent epidemiologic research has examined the relationship between perfluoroalkyl and polyfluoroalkyl substances (PFAS) and diabetes mellitus with inconclusive findings. In this cross-sectional study, we aimed to explore the association between serum PFAS concentrations and the prevalence of prediabetes and pre-diagnostic diabetes in the general Korean population as well as the combined effects of exposure to mixed PFAS compounds. METHODS: We analyzed data from participants aged ≥19 years enrolled in the Korean National Environmental Health Survey Cycle 4 (2018-2020). Individuals diagnosed with diabetes were excluded to minimize potential bias. We identified cases of pre-diagnostic diabetes based on the HbA1c level ≥6.5% and prediabetes as HbA1c levels of 5.7-6.49%. Serum concentrations of PFAS, including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDeA), perfluorohexane sulfonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS), were quantified using high-performance liquid chromatography-tandem mass spectrometry. Survey-weighted logistic regression models were used to assess the relationships between PFAS levels and diabetes risk, adjusting for covariates. Additionally, Bayesian kernel machine regression (BKMR) was used to investigate the combined effects of exposure to mixed PFAS compounds. RESULTS: In the study population excluding participants with diagnosed diabetes (n = 2709), the prevalence of pre-diagnostic diabetes and prediabetes was 4.8% and 30.1%, respectively. Significant positive associations were found between serum PFHxS and PFOS quartiles and pre-diagnostic diabetes risk. Likewise, among those without diagnosed or pre-diagnostic diabetes (n = 2579), the highest quartiles of PFDeA, PFHxS, and PFOS and the overall PFAS level were associated with an increased risk of prediabetes compared with the lowest quartiles. BKMR analysis revealed a significant positive association between overall serum PFAS level and prediabetes risk, which was most marked for PFOS. CONCLUSIONS: These findings highlight the potential health implications of PFAS exposure and prediabetes risk. Further research is needed to validate these associations and identify potential mechanistic pathways.

Elevated levels of serum per- and poly-fluoroalkyl substances (PFAS) in contact lens users of U.S. young adults.

Despite evidence indicating the presence of per- and poly-fluoroalkyl substances (PFAS) in contact lenses (CL), it remains unclear whether CL use increases PFAS exposure in the general population. We aimed to determine whether CL users have higher serum concentrations of PFAS than non-users, using data of 1660 adults aged 20-39 years participating in the National Health and Nutrition Examination Survey 1999-2000 and 2003-2008. We classified the individuals into CL users and non-users using the record of vision correction types during a vision test. Serum concentrations of six individual PFAS were measured, and the overall PFAS burden was calculated by item response theory scoring. Survey-weighted linear models were used to compare serum PFAS levels between CL users and non-users after adjusting for covariates. Distributions of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) concentrations were compared with reference values (e.g., human biomonitoring [HBM]-II values) indicating potential for adverse health effects. Survey-weighted linear models revealed that covariate-adjusted serum PFOA concentration was higher in CL users (geometric mean [GM]: 3.68 ng/mL; 95% CI: 3.00, 4.50) than in non-users (GM: 3.27 ng/mL; 95% CI: 2.81, 3.80; p = 0.02). Similarly, CL users had a significantly higher serum PFHxS concentration (GM: 1.58 ng/mL; 95% CI: 1.13, 2.20) than non-users (GM: 1.30 ng/mL; 95% CI: 1.10, 1.66; p = 0.03). CL users also had a significantly higher overall burden of PFAS than non-users. The differences in PFAS concentrations between CL users and non-users were more pronounced in females than in males. Moreover, a larger proportion of lens users (4.5%), compared to non-users (3.9%), had PFOA concentrations above the HBM-II, where adverse health effects are expected from PFOA exposure. This study suggests that CL use in general U.S. young adults may contribute significantly to PFAS body burden, which can potentially lead to public health problem.

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

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

Urinary concentrations of organophosphate esters and associated health outcomes in Korean firefighters.

Although firefighters are at an increased risk of occupational exposure to chemicals, such as flame retardants, research on the exposure of Korean firefighters to organophosphate esters (OPEs)-a group of emerging flame retardants-remains limited. Therefore, in the present study, OPE metabolite concentrations in the urine samples of 149 former and current Korean firefighters were measured. Based on the data obtained, the estimated daily intakes (EDIs) of OPEs were calculated. Subsequently, the association between the urinary concentrations of OPE metabolites and the potential determinants of OPE exposure and health outcomes (e.g., obesity and serum lipids) was investigated. We found that bis(1-chloro-2-propyl) phosphate (BCIPP) and bis(2-chloroethyl) phosphate (BCEP) were the most prevalent urinary OPE metabolites, with median concentrations of 2.33 and 1.80 ng/mL, respectively; these concentrations were higher than those reported previously in other countries, such as the USA and China. Moreover, their parent compounds-tris(1-chloro-2-propyl) phosphate (TCIPP) and tris(2-chloroethyl) phosphate (TCEP)-exhibited EDIs of 126 and 94.8 ng/kg bw/day, respectively. Unlike the high detection rate of bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) in other populations, its detection rate in this study was low (6.7%), suggesting regional differences in the exposure pattern of OPEs among countries. Furthermore, occupational characteristics, such as recent participation in firefighting activity, were identified as determinants of the urinary concentrations of OPE metabolites. Total OPE metabolites were inversely associated with body mass index and positively associated with high-density lipoprotein cholesterol. Overall, our findings demonstrate that Korean firefighters are highly exposed to several occupation-related OPEs. Further prospective studies will help elucidate the potential health implications of occupational exposure to OPEs among firefighters.

Association between environmental chemical exposure and albumin-to-creatinine ratio is modified by hypertension status in women of reproductive age.

Chemicals have been identified as a potential risk factor of renal dysfunction. However, studies that consider both multiple chemicals and non-chemical risk factors, such as hypertension, are rare. In this study, we assessed the associations between exposure to several chemicals, including major metals, phthalates, and phenolic compounds, and the albumin-to-creatinine ratio (ACR). A group of Korean adult women in reproductive age (n = 438, aged between 20 and 49 years), who had previously been studied for association of several organic chemicals, was chosen for this purpose. We constructed multivariable linear regression models for individual chemicals and weighted-quantile sum (WQS) mixtures, by hypertension status. Among the study population, approximately 8.5% of the participants exhibited micro/macro-albuminuria (ACR ≥30 mg/g), and 18.5% and 3.9% exhibited prehypertension and hypertension, respectively. Blood cadmium and lead levels showed a stronger association with ACR only among women with prehypertension or hypertension. Among organic chemicals, depending on the statistial model, benzophenone-1 (BP-1) and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) showed a significant association regardless of hypertension status, but most associations disappeared in the (pre)hypertensive group. These findings clearly indicate that hypertension status can modify and may potentiate the association of environmental chemicals with ACR. Our observations suggest that low-level environmental pollutant exposure may have potential adverse effects on kidney function among general adult women. Considering the prevalence of prehypertension in the general population, efforts to reduce exposure to cadmium and lead are necessary among adult women to minimize the risk of adverse kidney function.

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

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

Zebrafish (Danio rerio) as a model organism for screening nephrotoxic chemicals and related mechanisms.

Because of essential role in homeostasis of the body fluid and excretion of wastes, kidney damage can lead to severe impacts on health and survival of humans. For most chemicals, nephrotoxic potentials and associated mechanisms are unclear. Hence, fast and sensitive screening measures for nephrotoxic chemicals are required. In this study, the utility of zebrafish (Danio rerio) was evaluated for the investigation of chemical-induced kidney toxicity and associated modes of toxicity, based on the literature review. Zebrafish has a well-understood biology, and many overlapping physiological characteristics with mammals. One such characteristic is its kidneys, of which histology and functions are similar to those of mammals, although unique differences of zebrafish kidneys, such as kidney marrow, should be noted. Moreover, the zebrafish kidney is simpler in structure and easy to observe. For these advantages, zebrafish has been increasingly used as an experimental model for screening nephrotoxicity of chemicals and for understanding related mechanisms. Multiple endpoints of zebrafish model, from functional level, i.e., glomerular filtration, to transcriptional changes of key genes, have been assessed to identify chemical-induced kidney toxicities, and to elucidate underlying mechanisms. The most frequently studied mechanisms of chemical-induced nephrotoxicity in zebrafish include oxidative stress, inflammation, DNA damage, apoptosis, fibrosis, and cell death. To date, several pharmaceuticals, oxidizing agents, natural products, biocides, alcohols, and consumer chemicals have been demonstrated to exert different types of kidney toxicities in zebrafish. The present review shows that zebrafish model can be efficiently employed for quick and reliable assessment of kidney damage potentials of chemicals, and related toxic mechanisms. The toxicological information obtained from this model can be utilized for identification of nephrotoxic chemicals and hence for protection of public health.

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

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

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.

Exposure to phthalates and environmental phenols in association with chronic kidney disease (CKD) among the general US population participating in multi-cycle NHANES (2005-2016).

Exposure to consumer chemicals has been associated with chronic kidney disease (CKD) among humans, but their associations with estimated glomerular filtration rate (eGFR) are inconsistent. Such observations may be due to potential bias caused by the method of urine dilution adjustment and lack of consideration for multiple chemical exposure in the association models. This study aimed to identify major urinary chemicals associated with CKD by applying an alternative adjustment method of urine dilution ('novel' covariate-adjusted creatinine adjustment vs 'traditional' creatinine adjustment) and with a mixture exposure concept in the association model. For this purpose, the adult participants of US National Health and Nutrition Examination Survey (NHANES) 2005-2016 (n = 9008) were used, and the associations of urinary exposure biomarkers of major consumer chemicals, e.g., phthalates, bisphenol A, benzophenone-3, and parabens, with CKD related parameters of eGFR and albumin-to-creatinine ratio (ACR), were assessed. The use of the novel covariate-adjusted creatinine standardization resulted in significant inverse associations with eGFR for most measured chemicals, unlike the results with the use of the conventional creatinine adjustment. Phthalate metabolites, such as monobutyl phthalate (MBP) and mono-benzyl phthalate (MBzP), were positively associated with ACR. Even in mixture exposure models using weighted quantile sum (WQS) regression, MBzP, metabolites of di-(2-ethylhexyl) phthalate (DEHP), and bisphenol A (BPA) were revealed as major drivers of the association with eGFR or ACR. Results of sensitivity analyses with the subpopulation with normal eGFR range (n = 7041) were generally similar. Our observation suggests that exposure to benzyl butyl phthalate (BBP), DEHP, and BPA may be responsible for declined eGFR and increased ACR even at the exposure levels occurring among general adults.

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.

Environment-Wide Association Study of CKD.

BACKGROUND AND OBJECTIVES: Exposure to environmental chemicals has been recognized as one of the possible contributors to CKD. We aimed to identify environmental chemicals that are associated with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed the data obtained from a total of 46,748 adults who participated in the National Health and Nutrition Examination Survey (1999-2016). Associations of chemicals measured in urine or blood (n=262) with albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g), reduced eGFR (<60 ml/min per 1.73 m2), and a composite of albuminuria or reduced eGFR were tested and validated using the environment-wide association study approach. RESULTS: Among 262 environmental chemicals, seven (3%) chemicals showed significant associations with increased risk of albuminuria, reduced eGFR, or the composite outcome. These chemicals included metals and other chemicals that have not previously been associated with CKD. Serum and urine cotinines, blood 2,5-dimethylfuran (a volatile organic compound), and blood cadmium were associated with albuminuria. Blood lead and cadmium were associated with reduced eGFR. Blood cadmium and lead and three volatile compounds (blood 2,5-dimethylfuran, blood furan, and urinary phenylglyoxylic acid) were associated with the composite outcome. A total of 23 chemicals, including serum perfluorooctanoic acid, seven urinary metals, three urinary arsenics, urinary nitrate and thiocyanate, three urinary polycyclic aromatic hydrocarbons, and seven volatile organic compounds, were associated with lower risks of one or more manifestations of CKD. CONCLUSIONS: A number of chemicals were identified as potential risk factors for CKD among the general population.

Human exposure to legacy and emerging flame retardants in indoor dust: A multiple-exposure assessment of PBDEs.

Human exposure to flame retardants (FRs) in indoor environments is a growing concern. In this study, the concentrations of polybrominated diphenyl ethers (PBDEs) and their alternatives, such as novel brominated flame retardants (NBFRs), dechlorane plus (DP), and organophosphate flame retardants (OPFRs), were measured in dust from indoor environments in Korea to investigate their occurrence, contamination profiles, and health risks. Legacy and emerging FRs were detected in dust samples, indicating widespread contamination of indoor environments. The concentrations of alternative FRs were higher in dust from offices compared with house dust, suggesting that office environments are major consumers of alternative FRs. Similar compositional profiles for indoor dust were found for PBDEs in different microenvironments and regions, while OPFR composition varied widely due to disparate applications. The estimated daily intakes of PBDEs, NBFRs, and OPFRs via dust ingestion were lower than the reference doses proposed by previous studies. A multiple-exposure assessment showed that dust ingestion was a major contributor to total PBDEs for toddlers and adults. However, major exposure pathways of BDEs 47 and 209 differed between toddlers and adults. Our study suggests that multiple exposure pathways should be considered in a comprehensive exposure assessment of PBDEs.

Urinary metabolites of organophosphate esters (OPEs) are associated with chronic kidney disease in the general US population, NHANES 2013-2014.

Organophosphate esters (OPEs) have been widely used in building materials and consumer products as flame retardants and plasticizers. In vitro studies have suggested adverse effects of OPEs on the kidney. Despite accumulating evidence indicating widespread exposure to OPEs, their association with renal function in humans has not been evaluated. This study aims to investigate the association between OPEs exposure and chronic kidney disease (CKD) among the general US adult population by employing data from the US National Health and Nutrition Examination Survey (NHANES) 2013-2014. Among 1578 adults who were not currently pregnant, the associations of the urinary OPE metabolites with two CKD-related parameters, i.e., estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR), and CKD were assessed. To account for urine dilution, in addition to conventional creatinine-adjustment, covariate-adjusted creatinine standardization, which controls for potential confounding by kidney function, was employed. Multi-pollutant models were also constructed to verify the associations observed in the models on individual OPE metabolites. The urinary bis(2-chloroethyl) phosphate (BCEP) level was negatively associated with eGFR only with the covariate-adjusted standardization method, but not with the conventional creatinine adjustment. In addition, both bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) and di-n-butyl phosphate (DNBP) were positively associated with the ACR, regardless of methods of urine dilution adjustment. These three compounds were also associated with CKD. Following adjusting urine dilution with the covariate-adjusted standardization method, the association became more evident. Moreover, similar results were observed in the secondary analysis with the multi-pollutant models. Among the US general population, several OPEs were identified as potential chemical determinants of CKD. Experimental studies are warranted to understand the potential mechanisms underlying this observation.

Endocrine disruption by several aniline derivatives and related mechanisms in a human adrenal H295R cell line and adult male zebrafish.

Aniline and aniline derivatives have been widely used in the production of pesticides, pharmaceuticals, cosmetic, dyes, rubber, and adhesives products. These chemicals can easily be released into the environment through industrial and municipal discharges or as degradation byproducts. Several studies have suggested that aniline and some of its derivatives could cause reproductive toxicity in aquatic organisms. However, knowledge on the endocrine disruption potentials of these chemicals is limited only to aniline and associated mechanisms are rarely investigated. The objective of this study was to investigate the potential of major aniline derivatives, i.e., 3,4-dichloroaniline (3,4-DCA), 1-naphthylamine (1-NPA), and 4,4'-methylenedianiline (4,4'-MDA), to disrupt sex steroid production and other biological processes. For this purpose, the human adrenal H295R cell line and adult male zebrafish (Danio rerio) were used. In the H295R cell line, all tested aniline derivatives decreased testosterone (T) levels. Regulatory changes of several steroidogenic genes, i.e., down-regulation of StAR or CYP17 genes, and up-regulation of CYP19A, observed in the H295R cells could explain the sex hormone disruption. In male zebrafish, generally similar directions of changes, i.e., decreases in T levels and increased E2/T ratios, were observed. Again, down-regulation of key steroidogenic genes such as cyp17 or 3ß-hsd, but slight up-regulation of cyp19a gene observed in the fish could explain the sex hormone changes. The results of our study demonstrate that all tested aniline derivatives could influence steroidogenesis and disrupt sex hormone balance toward reduced androgenicity. Consequences of anti-androgenicity following long-term exposure warrant further investigation.

Urinary metabolites of dibutyl phthalate and benzophenone-3 are potential chemical risk factors of chronic kidney function markers among healthy women.

Chronic kidney disease (CKD) is a global health threat of growing concern. Recently, exposure to endocrine disrupting compounds (EDCs) such as phthalates and bisphenol A has been suggested as a risk factor for CKD. However, most epidemiological studies have focused on a limited number of urinary chemicals. This study aimed to identify chemical determinants of the urinary albumin-to-creatinine ratio (ACR), which is a kidney function marker, among multiple major EDCs including phthalate metabolites, bisphenols, and benzophenones in a Korean female population (20-45 years old, n = 441). First, the creatinine-adjusted urinary concentration of each urinary chemical was associated with ACR in a linear regression model (single-pollutant model). Then, compounds with a significant association with ACR in the single-pollutant model were added in a multi-pollutant model and evaluated for their association with ACR. Moreover, to prevent potential reverse causality due to impaired kidney function, quartile analyses were performed for the subjects with healthy renal function (ACR < 9.71 mg/g). In addition to creatinine adjustment, the statistical analysis was also conducted with specific gravity-adjusted concentrations of urinary chemicals, and the results were compared. Several compounds measured in the urine showed a significant association with ACR in the single-pollutant model. In the multi-pollutant model, however, only monobutyl phthalate and benzophenone-1, which are metabolites of dibutyl phthalate and benzophenone-3, respectively, showed significant positive associations. The association of these chemicals remained significant in a couple of the sensitivity analyses with a different adjustment of urine dilution and in a subpopulation with normal ACR. In conclusion, among dozens of urinary chemicals, monobutyl phthalate and benzophenone-1 consistently showed a strong association with urinary ACR. Confirmation of our observation in other human populations and experimental studies is warranted.

Pharmaceutical residues in streams near concentrated animal feeding operations of Korea - Occurrences and associated ecological risks.

Concentrated animal feeding operations (CAFOs) have been suggested to be the most significant source of pharmaceutical release into the environment. However, limited information is available on the occurrence of veterinary pharmaceutical residues and the associated ecological risks to the aquatic environment near CAFO areas. In this study, ten commonly used veterinary antibiotics, including sulfonamides, tetracyclines, and cephalosporins, along with three analgesics, were measured in water samples collected from the streams that run near two CAFOs in Korea in 2013 (n = 16) and 2014 (n = 10). In addition, the associated ecological risks were estimated by calculating risk quotient. The pharmaceuticals were detected in a higher amount in the samples collected downstream from the CAFO than in those collected upstream. Acetaminophen, sulfamethazine, sulfathiazole, and oxytetracycline were detected at maximum concentrations of 38.8 µg/L, 21.3 µg/L, 17.4 µg/L, and 16.9 µg/L, respectively. Relatively higher concentrations of pharmaceuticals were observed in locations adjacent to the CAFO and the downstream area, suggesting the influence of the CAFO. Except for acetaminophen, lower concentrations of the target pharmaceuticals were detected in the samples collected during the high-flow season. The concentrations of most of the target pharmaceuticals exceeded the risk quotient of one, suggesting potential ecological effects in the areas affected by CAFOs. Our observations show that the water environment near a CAFO could be heavily affected by veterinary pharmaceuticals and analgesic drugs that are also frequently used among humans. Hence, the ecological consequences of pharmaceutical residues in the water bodies near CAFOs warrant further investigation.

Perfluoroalkyl acids in serum of Korean children: Occurrences, related sources, and associated health outcomes.

Perfluoroalkyl acids (PFAAs) have been widely used in human environment, and their exposure among general population has been frequently reported. However, extent of PFAAs exposure and their potential effects among children are not well characterized. In this study, children of between 3 and 18 years of age (n = 150) were recruited in Seoul and Gyeonggi, Korea, and the serum levels of 16 PFAAs along with lipids and thyroid hormones were measured. Questionnaire survey was conducted for dietary and behavioral characteristics of the children. Among the measured PFAAs, PFOA, PFNA, PFHxS, and PFOS were detected in all the samples, and PFUnDA and PFDA were detected in over 75% of the samples. PFOS was detected at the highest concentration with a median of 5.68 ng/mL. PFUnDA was detected at higher levels (median of 0.652 ng/mL) compared to those reported for children in USA. Serum PFAA levels were not different by sex among the children of <10 years of age, but in older children, those of boys are significantly higher than girls. Physiological characteristics like menstruation may explain lower PFAAs levels of the girls. In addition, breastmilk consumption, fish/shellfish consumption, non-stick frying pan use, and waterproof cloth use were identified as potential sources of PFAAs exposure. Serum PFUnDA level was positively associated with total cholesterol and low-density lipoprotein level of the children. PFNA was positively associated with free T4 level. High levels of PFUnDA among children and its association with serum lipids warrant replication and confirmation in other populations and/or supports by experimental studies.

Differential micronucleus frequency in isogenic human cells deficient in DNA repair pathways is a valuable indicator for evaluating genotoxic agents and their genotoxic mechanisms.

The micronucleus (MN) test has become an attractive tool both for evaluating the genotoxicity of test chemicals because of its ability to detect clastogenic and aneugenic events and for its convenience. As the MN assay has been mostly performed using only DNA repair-proficient mammalian cells, we believed that the comparison of the MN frequency between DNA repair-proficient and -deficient human cells may be an excellent indicator for detecting the genotoxic potential of test chemicals and for understanding their mode of action. To address this issue, the following five genes encoding DNA-damage-response (DDR) factors were disrupted in the TK6 B cell line, a human cell line widely used for the MN test: FANCD2, DNA polymerase ζ (REV3), XRCC1, RAD54, and/or LIG4. Using these isogenic TK6 cell lines, the MN test was conducted for four widely-used DNA-damaging agents: methyl methanesulfonate (MMS), hydrogen peroxide (H2 O2 ), γ-rays, and mitomycin C (MMC). The frequency of micronuclei in the double strand break repair-deficient RAD54-/- /LIG4-/- cells after exposure to γ-rays, H2 O2 , MMS and MMC was 6.2-7.5 times higher than that of parental wild-type TK6 cells. The percentages of cells exhibiting micronuclei in the base excision repair- and single strand break repair-deficient XRCC1-/- cells after exposure to H2 O2 , MMC and MMS were all ∼5 times higher than those of wild-type cells. In summary, a supplementary MN assay using the combination of RAD54-/- /LIG4-/- , XRCC1-/- and wild-type TK6 cells is a promising method for detecting the genotoxic potential of test chemicals and their mode of action. Environ. Mol. Mutagen., 2018. © 2018 Wiley Periodicals, Inc.