Exposure characteristics and cumulative risk assessment of bisphenol A and its substitutes: the Taiwan environmental survey for toxicants 2013.

Introduction: Ever since the use of bisphenol A (BPA) has been restricted, concerns have been raised regarding the use of its substitutes, such as bisphenol S (BPS) and bisphenol F (BPF). Meanwhile, the EU European Food Safety Authority (EFSA) issued the new tolerable daily intake (TDI) after the latest re-risk assessment for BPA, which enforced the need for cumulative risk assessment in the population. This study was conducted to identify BPA and its substitute's exposure characteristics of the general Taiwanese population and estimate the cumulative risk of bisphenol exposure. Methods: Urine samples (N = 366 [adult, 271; minor, 95]) were collected from individuals who participated in the Taiwan Environmental Survey for Toxicants 2013. The samples were analyzed for BPA, BPS, and BPF through ultraperformance liquid chromatography-tandem mass spectrometry. Daily intake (DI) levels were calculated for each bisphenol. Hazard quotients (HQs) were calculated with the consideration of tolerable DI and a reference dose. Additionally, hazard index (HI; sum of HQs for each bisphenol) values were calculated. Results: Our study found that the median level of BPA was significantly higher in adults (9.63 µg/g creatinine) than in minors (6.63 µg/g creatinine) (p < 0.001). The DI of BPS was higher in female (0.69 ng/kg/day) than in male (0.49 ng/kg/day); however, the DIs of BPF and BPS were higher in boys (1.15 and 0.26 ng/kg/day, respectively) than in girls (0.57 and 0.20 ng/kg/day, respectively). Most HI values exceeded 1 (99% of the participants) after EFSA re-establish the TDI of BPA. Discussion: Our study revealed that the exposure profiles and risk of BPA and its substitute in Taiwanese varied by age and sex. Additionally, the exposure risk of BPA was deemed unacceptable in Taiwan according to new EFSA regulations, and food contamination could be the possible source of exposure. We suggest that the risk of exposure to BPA and its substitutes in most human biomonitoring studies should be reassessed based on new scientific evidence.

Usefulness of cone-beam computed tomography-reformatted epidurography in percutaneous epidural adhesiolysis: A pilot study.

BACKGROUND: Conventional epidurography (CE) is thought to have insufficient usefulness on percutaneous epidural adhesiolysis (PEA). We aimed to evaluate the association between the outcome of PEA and cone-beam computed tomography-reformatted epidurography (CBCT-RE). METHODS: After ethics board approval and written informed consent were obtained, we performed 30 PEA in 26 participants, and evaluated their post-PEA image findings. Two independent radiologists categorized and recorded the occurrence of contrast in the intracanal ventral and extraforaminal regions on CE, and in the dorsal canal (DC), ventral canal (VC), dorsal foramen (DF), and ventral foramen (VF) on CBCT-RE. Reproducibility was assessed using intraclass correlation coefficients (ICCs). Baseline characteristics along with contrast distribution patterns of CE and CBCT-RE were analyzed in terms of their association with symptom relief at 1 month after PEA. RESULTS: The rate of patients with symptoms relief >50% after PEA was 63.3%. The inter-reader agreement was higher for CBCT-RE (ICC = 0.955) than for CE (ICC = 0.793). Participants with contrast coexisting in VC and DF adjacent to the irritated nerve root on CBCT-RE ( p = 0.015) had a significantly better response after PEA than those without contrast at these locations on CBCT-RE, independent of baseline characteristics (adjusted odds ratio: 11.414 [ p = 0.012]). CONCLUSION: CBCT-RE with identifying contrast distribution patterns is useful for predicting outcome of PEA.

Associations between paraben exposure, thyroid capacity, homeostasis and pituitary thyrotropic function in the general Taiwanese: Taiwan Environmental Survey for Toxicants (TEST) 2013.

Several studies have suggested that some endocrine disruptors such as synthetic phenols, parabens and phthalates may disrupt thyroid hormone signaling and associated negative feed-backs with the central hypothalamic-pituitary-thyroid (HPT) axis. Therefore, we investigated urinary paraben and blood thyroid hormone levels in the Taiwanese population. Our sample comprised 264 adults (aged 18-97 years) and 75 minors (aged 7-17 years) from Taiwan Environmental Survey for Toxicants 2013. Urinary levels of methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), and butylparaben (BuP) were assessed. Hormones of particular interest include: thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4). We sought integrated parameters to describe the transfer of thyroid hormones in homeostatic models. The geometric mean urinary paraben levels of the adults were higher than those of the minors (adults vs. minors; MeP: 383 vs. 62.4 ng/mL; PrP: 109 vs. 8.00 ng/mL; EtP: 39.5 vs. 2.38 ng/mL, and BuP: 6.36 vs. 2.13 ng/mL). In the male adults, we discovered that 0.253% (p = 0.032), 0.256% (p = 0.041) and 0.257% (p = 0.037) decreases in the TSH, TSH/T4 and TSH/FreeT4 ratio was associated with 1% EtP increases, respectively. In the female minors, 0.093% (p = 0.044), 0.072% (p = 0.047) and 0.156 (p = 0.004) increases in the TSH ratios were associated with a 1% MeP, EtP and BuP increase, respectively. Moreover, 0.151% (p = 0.008) and 0.177% (p = 0.001) increases in TSH/T4 and TSH/free T4 ratios were associated with a BuP 1% increase, respectively. Finally, EtP was positively associated with SPINA-GT (ß: 15.66, p = 0.036) in the male adults. By contrast, EtP were positively associated with Jostel's TSH index and sTSHI (ß: 0.072, p = 0.049; ß: 0.107, p = 0.049) in the female minors. The Taiwanese population is commonly exposed to parabens, which can potentially lead to alteration of thyroid hormone homeostasis.

Research on the Rescue Time of the Taiwan Marathon Emergency Medical Service System Between 2013 and 2021.

BACKGROUND: While there are several studies on marathon injuries worldwide, there are no related studies on the Taipei Marathon regarding the rescue time of onsite injury cases, the incidence of out-of-hospital cardiac arrest (OHCA) cases, and the success rate of recovery of spontaneous circulation (ROSC). This study aims to fill that gap. HYPOTHESIS: The rescue time onsite of contact injury cases was in the prime time for lifesaving. STUDY DESIGN: Descriptive epidemiological study. LEVEL OF EVIDENCE: Level 2c. METHODS: This is a retrospective study of numerical and timeflow data using descriptive statistics. Our data were obtained from records of the Taipei Marathon from 2013 to 2021. These included (1) notification data, (2) the time record of the emergency care personnel in contact with patients, (3) incidence of OHCA, (4) the success rate of ROSC, (5) the location of occurrence of OHCA, and (6) emergency medical service capacity and configuration. RESULTS: The average time taken for first contact was 1.56 minutes in OHCA cases, and the total incidence rate of OHCA in 9 years was 4 people per 100,000 people, with a 100% ROSC success rate. Further, the location of OHCA cases was mostly in Q4 of the race (66.67%), followed by Q3 (22.22%) and Q2 (1.11%). The average number of emergency care personnel per marathon was 78, spread across 6 rescue and 6 medical stations and equipped with 8 ambulances and 35 automated external defibrillators. CONCLUSION: Shortening the arrival time of medical personnel to the scene and implementing a complete chain of survival can improve survival rates. Other ways to provide faster and more timely emergency rescue services require further study. CLINICAL RELEVANCE: Contact with patients as soon as possible, timely implementation of cardiopulmonary resuscitation, and use of an automated external defibrillator are the basic requirements of the chain of survival theory.

Mediation effects of thyroid function in the associations between phthalate exposure and lipid metabolism in adults.

Phthalates are a group of industrial chemicals widely used in everyday products including cosmetics, food packaging and containers, plastics, and building materials. Previous studies have indicated that urinary phthalate metabolites are associated with metabolic effects including those on lipid metabolism, but the results are mixed. Furthermore, whether thyroid function mediates the association between phthalate exposure and lipid metabolism remains unclear. In the present study, we explored whether changes in thyroid function markers mediate the associations between phthalate exposure and lipid metabolism indicators in Taiwanese adults. The cross-sectional data were obtained from the Taiwan Environmental Survey for Toxicants conducted in 2013. Levels of 11 urinary phthalate metabolites, levels of 5 thyroid hormones, and 8 indicators of lipid metabolism were assessed in 222 Taiwanese adults. The relationships of urinary phthalate metabolite levels with serum thyroid hormone levels and lipid metabolism indicators were explored using multiple regression models. Mediation analysis was conducted to evaluate the role of thyroid function in the association between phthalate exposure and lipid metabolism. The metabolite of di(- 2-ethylhexyl) phthalate (∑DEHPm) exhibited a significant positive association with the lipid metabolite indicator of high-density lipoprotein cholesterol (HDL-C; ß = 0.059, 95% confidence interval [CI] = 0.009, 0.109) in adults, and the thyroid function indicator thyroxine (T4) had a significant negative association with the metabolite ∑DEHPm (ß = - 0.059, 95% CI = - 0.101, - 0.016) and a significant negative association with HDL-C (ß = - 0.284, 95% CI = - 0.440, - 0.128). The T4 indirect effect was 0.015 (95% CI = - 0.0087, 0.05), and the mediation effect was 32.2%. Our results support the assumption that exposure to phthalates influences the homeostasis of lipid metabolism by interfering with thyroid function.

Relationships among phthalate exposure, oxidative stress, and insulin resistance in young military soldiers: A cumulative risk assessment and mediation approach.

BACKGROUND: Epidemiological studies concerning whether oxidative stress mediates phthalate exposure-insulin resistance (IR) associations in young adults are limited. Therefore, we investigated this potential mediation by using a cumulative risk approach involving daily intake (DI) and a hazard index (HIRfD). METHODS: The participants were 391 Taiwanese military personnel. This study measured their IR (as homeostatic model assessment of estimated IR [HOMA-IR]), levels of oxidative stress biomarkers (8-hydroxy-2-deoxyguanosine, 8-nitroguanine, 8-iso-prostaglandin F2α, and N-acetyl-S-[tetrahydro-5-hydroxy-2-pentyl-3-furanyl]-L-cysteine [HNE-MA]), the sum of these four biomarkers (ΣOS), and urinary phthalate metabolite concentrations. The HIRfD was estimated on the basis of urinary levels of phthalate metabolite, and the DI of five phthalates was determined: dimethyl phthalate, benzyl butyl phthalate (BBzP), diethyl phthalate, dibutyl phthalate (DBP), and di (2-ethylhexyl) phthalate (DEHP). Logistic regression models were employed to explore associations among DI, HIRfD, oxidative stress biomarkers, and HOMA-IR values. The role played by oxidative stress in the phthalate exposure-HOMA-IR association was determined using mediation analysis. RESULTS: We discovered positive associations between high DI of DBP, BBzP, and DEHP; high HIRfD; and high ΣOS. High ΣOS and HNE-MA were associated with a higher likelihood of a high HOMA-IR value. Mediation analysis indicated that high ΣOS and HNE-MA were significant mediators of the associations between phthalates and IR. CONCLUSION: Oxidative stress may partially mediate the phthalate-IR relationship in young adults.

Distinct Age-Specific Effects on Olfactory Associative Learning in C57BL/6 Substrains.

C57BL/6 is the most widely used mouse strain in the laboratories. Two substrains of C57BL/6, C57BL/6J (B6J), and C57BL/6N (B6N) are well-known backgrounds for genetic modification and have been shown difference in quite a few tests, including open field test, rotarod test, and Morris water maze. However, difference between these two substrains in olfaction-dependent behaviors remains unknown. Here, we used olfactory two-alternative choice task, which is modified to have two training stages, to evaluate animals' ability in instrumental learning and olfactory association. In the first (rule learning) stage, the mice were trained to use the operant chamber to collect water rewards. An odor cue was provided in the procedure, with no indication about reward locations. In the following (discrimination learning) stage, two odor cues were provided, with each indicating a specific water port. The animals were rewarded upon correct port choices following cue deliveries. We found that during young adulthood (7-10 weeks old), proportionally more B6J than B6N mice were able to pass rule learning (58.3% vs. 29.2%) and ultimately acquire this task (54.2% vs. 25%), with the two substrains showing similar pass rates in discrimination learning (92.9% vs. 85.7%). Surprisingly, at a more mature age (17 weeks old), this substrain difference disappeared. Mature B6N mice had a significant improvement in pass percentages of rule learning and overall task, whereas similar improvement was not observed in the B6J counterparts. Instead, mature B6J mice had an improved speed in rule learning and overall task. We further examined behavioral patterns of 8-week-old B6J and B6N mice in the olfactory habituation or dishabituation test. We observed normal olfactory habituation from subjects of both substrains, with the B6J mice exhibiting stronger investigative responses to newly presented odorants. These results reveal for the first time that B6J and B6N mice are different in acquisition processes of a behavioral task that requires instrumental learning and olfactory association, and that maturation appears to employ different effects on these two substrains during these processes. Furthermore, young adult B6J and B6N mice might be similar in olfactory habituation but different in the olfactory aspects of novelty seeking.

Food Processing and Phthalate Exposure: The Nutrition and Health Survey in Taiwan (1993-1996 and 2005-2008).

Background: Phthalates esters are widely used commercially and can leach from a food container or food packaging. Few studies have been conducted in Asia regarding food processed to varying levels and human phthalate exposure. This study aimed to evaluate the association between unprocessed and ultra-processed food intake and urinary phthalate metabolite levels in the Taiwanese adult population. Methods: A total of 516 participant data were extracted from the cross-sectional 1993-1996 and 2005-2008 Nutrition and Health Survey in Taiwan of those aged over 18 years, where urinary measures and one 24-h dietary recall were collected. Urinary concentrations of dimethyl phthalate, diethyl phthalate, dibutyl phthalate, butyl benzyl phthalate, and di-(2-ethylhexyl) phthalate metabolites including monomethyl phthalate, monoethyl phthalate (MEP), monobutyl phthalate (MBP), monobenzyl phthalate, mono-(2-ethylhexyl) phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, and mono-(2-ethyl-5-oxohexyl) phthalate were measured in spot urine samples. The NOVA food processing classification system was applied to divide all consumed foods into four mutually exclusive groups including unprocessed or minimally processed, processed culinary ingredients, processed and ultra-processed food. Generalized linear models were employed to examine the associations between the percentage quartiles (Qs) of unprocessed and ultra-processed foods in the total weight of food and the urinary phthalate metabolites. Results: Compared with participants in the lowest quartiles (Q1) of ultra-processed food intake, highest ultra-processed food intake (Q4) had 65.7% (95% confidence interval [CI]: 4.83, 162) higher urinary concentrations of MEP after adjusted for covariates. In contrast, the higher unprocessed food consumption was inversely associated with urinary concentrations of MEP and MBP (P for trend = 0.03). When compared to the lowest unprocessed food consumers (Q1), higher consumers (Q4) presented 38.6% (95% CI: -61.3, -2.59) lower MEP concentrations and 23.1% (95% CI: -38.5, -3.71) lower MBP concentrations. Conclusion: Ultra-processed food consumption was associated with increased concentrations of urinary MEP. Conversely, consuming unprocessed food was associated with lower concentrations of MEP and MBP in the Asian Taiwanese adult population.

Association between ambient temperature and cognitive function in a community-dwelling elderly population: a repeated measurement study.

OBJECTIVES: Evidence on the associations between short-term and long-term air temperature exposure and cognitive function in older adults, particularly those in Asia, is limited. We explored the relationships of short-term and long-term air temperature exposure with cognitive function in Taiwanese older adults through a repeated measures survey. DESIGN AND SETTING: We used data the ongoing Taiwan Longitudinal Study on Aging, a multiple-wave nationwide survey. PARTICIPANTS: We identified 1956, 1700, 1248 and 876 older adults in 1996, 1999, 2003 and 2007, respectively. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants' cognitive function assessment was based on the Short Portable Mental Status Questionnaire. We calculated the temperature moving average (TMA) for temperature exposure windows between 1993 and 2007 using data from air quality monitoring stations, depending on the administrative zone of each participant's residence. Generalised linear mixed models were used to examine the effects of short-term and long-term temperature changes on cognitive function. RESULTS: Short-term and long-term temperature exposure was significantly and positively associated with moderate-to-severe cognitive impairment, with the greatest increase in ORs found for 3-year TMAs (OR 1.247; 95% CI 1.107 to 1.404). The higher the quintiles of temperature exposure were, the higher were the ORs. The strongest association found was in long-term TMA exposure (OR 3.674; 95% CI 2.103 to 6.417) after covariates were controlled for. CONCLUSIONS: The risk of mild cognitive impairment increased with ambient temperature in community-dwelling older adults in Taiwan.

Human biomonitoring reference values and characteristics of Phthalate exposure in the general population of Taiwan: Taiwan Environmental Survey for Toxicants 2013-2016.

Since a 2011 incident involving phthalate-tainted food, Taiwanese people have become concerned with food quality, and they are still being exposed to certain levels of phthalates. However, no nationwide human biomonitoring survey had been conducted to gather information on levels or reference values (RVs) of phthalates in the Taiwanese population. We aimed to establish the urinary levels and RVs of phthalate metabolites and identify exposure characteristics among Taiwan's population. We enrolled 1857 participants 7 years of age and older from the Taiwan Environmental Survey for Toxicants (TESTs) conducted during 2013-2016. Levels of 11 phthalate metabolites in each participant's urine samples were determined using liquid chromatography-tandem mass spectrometry. For all phthalate metabolites except for mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), and mono-ethylhexyl phthalate (MEHP), urinary median levels were significantly higher in the 7-17-year old group than in the ≧18-year-old group. For most phthalate metabolites and in the general population, the geometric mean decreased with increasing age. Median levels of MEP (19.55 µg/L), mono-benzyl phthalate (MBzP) (2.11 µg/L), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) (22.82 µg/L), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEOHP) (16.08 µg/L), ΣDibutyl phthalate metabolites (ΣDBPm) (0.17 nmol/mL), Σdi-(2-ethylhexyl) phthalate metabolites (ΣDEHPm) (0.29 nmol/mL) were higher in participants from central Taiwan than those from other areas. The median level of DBP (ΣDBPm: 0.20 nmol/mL) was significantly higher in participants from harbor areas than those from other urbanization groups. The RV of the 95 percentile (P95) for phthalate metabolites in the 7-17/≧18-year-old groups were 185.95/208.19 µg/L for MMP, 198.46/265.81 µg/L for MEP, 119.85/69.99 µg/L for mono-isononyl phthalate (MiBP), 165.19/204.32 µg/L for Mono-n-butyl phthalate (MnBP), 15.61/11.73 µg/L for MBzP, 62.09/59.23 µg/L for MEHP, 149.70/69.66 µg/L for MEHHP, 112.06/35.07 µg/L for MEOHP, 195.20/93.83 µg/L for mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), 45.66/27.69 µg/L for mono-(2-carboxymethylhexyl) phthalate (MCMHP), and 9.09/12.13 µg/L for mono-iso-nonyl phthalate (MiNP). We concluded that phthalate exposure of the general population in Taiwan varies by sex, age, region, and urbanization level. Exposure by the 7-17-year-old group to DMP, DBP, and DEHP in Taiwan remains higher than that of youth from other countries. RV of phthalate metabolites in Taiwan were established in the current study.

Mediation effects of thyroid function in the associations between phthalate exposure and glucose metabolism in adults.

The mediating influence of thyroid function on the association of phthalate exposure with glucose metabolism, including insulin resistance, remains unclear. We explored the mediating influence of thyroid hormone levels on the phthalate exposure-insulin resistance association. This cross-sectional study of 217 Taiwanese adults assessed insulin resistance (Homeostatic Model Assessment for Insulin Resistance, HOMA-IR scores) and the levels of 11 urinary phthalate metabolites and 5 thyroid hormones. Multiple regression models were used to analyze the associations among serum thyroid hormone levels, urinary phthalate metabolite levels, and HOMA-IR scores. The mediation analysis assessed the influence of thyroid function on the phthalate exposure-HOMA-IR association. Our data indicated urinary mono-ethylhexyl phthalate (MEHP) levels was negatively associated with free thyroxine (T4) (ß = -0.018; 95% confidence interval [CI]: -0.031, -0.005) and positively associated with HOMA-IR scores (ß = 0.051, 95% CI: 0.012, 0.090). The study also revealed urinary mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) levels was negatively associated with free T4 (ß = -0.036, 95% CI: -0.056, -0.017) and HOMA-IR (ß = 0.070, 95% CI: 0.013, 0.126). Free T4 and HOMA-IR had a negative association (ß = -0.757, 95% CI: -1.122, -0.392). In the mediation analysis, free T4 mediated 24% and 35% of the associations of urinary MEHP and MEOHP with HOMA-IR, respectively. Our findings revealed the mediating role of thyroid function in the phthalate exposure-glucose metabolism association in adults.

Associations Between Symptoms of Depression and Air Pollutant Exposure Among Older Adults: Results From the Taiwan Longitudinal Study on Aging (TLSA).

Background: Little epidemiological research has investigated the associations of air pollutant exposure over various time windows with older adults' symptoms of depression. This study aimed to analyze the relationships of long- and short-term ambient air pollution exposure (to coarse particulate matter, O3, SO2, CO, and NOx) with depressive symptoms in a sample of community-dwelling older adults. Methods: A sample of older adults (n = 1,956) was recruited from a nationally representative multiple-wave study (Taiwan Longitudinal Study on Aging). Between 1996 and 2007, four waves of surveys investigated depressive symptoms by using the 10-item Center for Epidemiologic Studies Depression questionnaire. We approximated air pollutant concentrations from 1995 to 2007 by using daily concentration data for five air pollutants at air quality monitoring stations in the administrative zone of participants' residences. after adjusting for covariates, we applied generalized linear mixed models to analyze associations for different exposure windows (7-, 14-, 21-, 30-, 60-, 90-, and 180-day and 1-year moving averages). Results: In a one-pollutant model, long- and short-term exposure to CO and NOx was associated with heightened risks of depressive symptoms; the odds ratio and corresponding 95% confidence interval for each interquartile range (IQR) increment in CO at 7-, 14-, 21-, 30-, 60-, 90-, and 180-day and 1-year moving averages were 1.232 (1.116, 1.361), 1.237 (1.136, 1.348), 1.216 (1.128, 1.311), 1.231 (1.133, 1.338), 1.224 (1.124, 1.332), 1.192 (1.106, 1.285), 1.228 (1.122, 1.344), and 1.180 (1.102, 1.265), respectively. Those for each IQR increment in NOx were 1.312 (1.158, 1.488), 1.274 (1.162, 1.398), 1.295 (1.178, 1.432), 1.310 (1.186, 1.447), 1.345 (1.209, 1.496), 1.348 (1.210, 1.501), 1.324 (1.192, 1.471), and 1.219 (1.130, 1.314), respectively. The exposure to PM10, O3, and SO2 over various windows were not significant. In the two-pollutant model, only the associations of NOx exposure with depressive symptoms remained robust after adjustment for any other pollutant. Conclusions: Exposure to traffic-associated air pollutants could increase depression risks among older adults.

Urinary phthalate metabolites are associated with biomarkers of DNA damage and lipid peroxidation in pregnant women - Tainan Birth Cohort Study (TBCS).

Phthalate exposure and oxidative stress have been linked to adverse reproductive outcomes in experimental studies, whereas no clear line has been drawn for human, especially in pregnant women. This study explored relationships between urinary phthalate metabolites and biomarkers of lipid peroxidation and oxidative and nitrosative DNA damage. Measurements from 97 Taiwanese pregnant women were taken at three different times during second and third trimesters. Five oxidative/nitrosative stress biomarkers - 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-nitroguanine (8-NO2Gua), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA), 8-isoprostaglandin F2α (8-isoPF2α), and malondialdehyde (MDA), and 11 phthalate metabolites were measured in urine samples. Linear regressions in each visit and linear mixed-model regressions were fitted to estimate percent changes in oxidative/nitrosative stress biomarkers resulting from inter-tertile increase of phthalate metabolite level and the cumulative concentrations of di (2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate. The highest urine concentrations of phthalate metabolites and the greatest number of significant positive associations between phthalate metabolites and oxidative/nitrosative stress biomarkers were observed in the third visit and in repeated measurements analysis, respectively. Of the biomarkers related to DNA damage, 8-OHdG (25.4% inter-tertile increase for mono-iso-butyl phthalate) was more sensitive to phthalate exposure than 8-NO2Gua. Among the biomarkers of lipid peroxidation, HNE-MA (61.2% inter-tertile increase for sum of DEHP metabolites) was more sensitive than 8-isoPF2α and MDA. Our findings support the hypothesis that pregnant phthalate exposure increases the oxidative stress biomarkers of DNA damage and lipid peroxidation. Future research may elucidate the mediating roles of oxidative/nitrosative stress biomarkers in the link between phthalate exposure and adverse reproductive outcomes.

Mediating role of oxidative/nitrosative stress biomarkers in the associations between phthalate exposure and thyroid function in Taiwanese adults.

Phthalate exposure was shown to alter thyroid function, however it is unclear, whether oxidative and nitrosative stress explains the intermediate biological mechanism. This study aimed to investigate the associations between phthalate exposure, oxidative/nitrosative stress, and thyroid function in adults, and to examine the mediating role of oxidative/nitrosative stress in the associations between phthalate exposure and thyroid function. Levels of eleven urinary phthalate metabolites, three urinary biomarkers of oxidative/nitrosative stress (malondialdehyde [MDA], 8-OHdG, and 8-NO2Gua) and five serum thyroid hormones (thyroxine [T4], free T4, triiodothyronine, thyroid-stimulating hormone, and thyroxine-binding globulin) were measured in 266 Taiwanese adults. Cross-sectional associations between phthalate metabolites, biomarkers of oxidative/ nitrosative stress and thyroid hormones were analyzed using multivariate regression models. Mediation analysis was conducted to assess the role of oxidative/nitrosative stress in the associations between phthalate metabolites and thyroid hormone levels. Sum of di-(2-ethylhexyl) phthalate (DEHP) metabolites was positively associated with MDA (ßT1-T2 = 0.253, 95%CI [0.060, 0.447]; ß â‰§ T2 = 0.317, 95% CI [0.098, 0.536]; Ptrend = 0.005) and 8-NO2Gua (ßT1-T2 = -0.010, 95%CI [-0.138, 0.118]; ß â‰§ T2 = 0.144, 95% CI [-0.001, 0.289]; Ptrend = 0.045). Mono-n-butyl phthalate (MnBP) was positively associated with 8-NO2Gua (ßT1-T2 = 0.201, 95% CI [0.078, -0.324]; ß â‰§ T2 = 0.161, 95% CI [0.031, -0.292]; Ptrend = 0.018). T4 was negatively associated with MDA (ßT1-T2 =  -0.027, 95% CI [-0.088, 0.0034]; ß≧T2 = -0.094, 95% CI [-0.161, -0.028]; Ptrend = 0.005) and 8-NO2Gua (ßT1-T2 = -0.068, 95% CI [-0.127, -0.010]; ß≧T2 = -0.125, 95% CI [-0.184, -0.066]; Ptrend < 0.001). Free T4 was positively associated with MDA (Ptrend = 0.047) and with 8-NO2Gua (Ptrend < 0.001). 8-NO2Gua mediated 11% of the association between the sum of DEHP metabolites and T4, and 17% of the association between MnBP and free T4. These results suggest that phthalate exposure may influence thyroid hormone levels through induced oxidative/nitrosative stress.

Phthalate exposure increased the risk of early renal impairment in Taiwanese without type 2 diabetes mellitus.

Studies have suggested that phthalates may be a risk factor for microalbuminuria, whereas little is known regarding their nephrotoxic effects on adults. We enrolled 311 participants (≥18 y, N = 241; <18 y, N = 70) who provided questionnaire information as well as blood and urine samples from a nationally cross-sectional study. Urinary phthalate metabolites were analyzed through liquid chromatography-tandem mass spectrometry. From the renal function index, we measured the serum level of blood urea nitrogen (BUN), and the urinary levels of microalbumin, albumin, protein and creatinine. We used multiple logistic regressions and a cumulative risk assessment of renal effect to evaluate the relationship between phthalate exposure and renal function in our participants. We aimed to assess the relationship between phthalate exposure and renal function including serum level of BUN, and urinary levels of microalbumin, albumin, protein, and creatinine in 311 participants (≥18 y, N = 241; <18 y, N = 70) from a population-based study. The multiple logistic regression showed that the adjusted odds ratio of the highest tertile of estimated di-2-ethylhexyl phthalate (DEHP) daily intake in participants ≥18 y for early renal impairment (microalbumin >1.9 mg/dL) was 9.40 times higher (95% confidence interval = 1.67-52.84) than the lowest tertile. The cumulative hazard index of phthalate-induced nephrotoxicity (HInephro) was significantly positively associated with microalbumin (ß: 0.98, P < 0.001), BUN (ß: 0.19, P = 0.002), and urine protein (ß: 0.75, P = 0.001) in participants ≥18 y without type 2 diabetes mellitus after adjusting for confounding factors, but not in those <18 y. Our findings suggest that daily exposure to DEHP and its metabolites were significantly positively associated with an increased risk of higher microalbumin in Taiwanese ≥18 y. Comprehensive or mechanistic studies are required to elucidate these associations.

Air Pollution Exposure and Cognitive Function in Taiwanese Older Adults: A Repeated Measurement Study.

Studies related to air pollution exposure and neurocognitive disorders, specifically cognitive impairment, among older adults are limited. We investigated the association between short-term and long-term exposure to ambient air pollution (i.e., particulate matter with an aerodynamic diameter of <10 µm and ozone) and the effects of their interaction on cognitive function in a community-dwelling, free-living elderly population. Study participants were in a multiple-wave representative sample, namely the Taiwan Longitudinal Study on Aging (n = 2241). In four surveys between 1996 and 2007, their cognitive function was assessed using the Short Portable Mental Status Questionnaire (SPMSQ). We estimated air pollution from 1993 to 2007, including daily concentrations of PM10 and O3 from air quality monitoring stations, based on the administrative zone of each participant's residence. Generalized linear mixed models were used to examine these associations after adjusting for covariates. We found that long-term exposure to PM10 and O3 was significantly associated with cognitive impairment (OR = 1.094, 95% CI: 1.020, 1.174 for PM10; OR = 1.878, 95% CI: 1.363, 2.560 for O3). The joint effect of exposure to PM10 and O3 was associated with cognitive impairment (p < 0.001). Co-exposure to ambient PM10 and O3 may deteriorate cognitive function in older adults.

Changes in insulin resistance mediate the associations between phthalate exposure and metabolic syndrome.

BACKGROUND: Information on the relationships between phthalate exposure, insulin resistance, and metabolic syndrome (MetS) in younger adults is limited. It is still unclear whether changes in insulin resistance represent an intermediate biological mechanism linking phthalate exposure and MetS. OBJECTIVE: To investigate the associations between cumulative risk of phthalates (such as daily intake [DI] and hazard index [HI]), insulin resistance, and MetS in younger adults and to examine the mediating role of insulin resistance in the associations between phthalate exposure and MetS. METHODS: Urinary phthalate metabolite levels, insulin resistance (by using the Homeostatic Model Assessment of estimated Insulin Resistance [HOMA-IR]), and MetS status were determined in 435 military personnel in Taiwan. We estimated the DI of five phthalates: dimethyl phthalate (DMP), diethyl phthalate, dibutyl phthalate, benzyl butyl phthalate (BBzP), and di (2-ethylhexyl) phthalate and the HI based on urinary phthalate metabolite levels. Cross-sectional associations between DI and HI, HOMA-IR, and the indicators of MetS were explored using logistic regression models. Mediation analysis was conducted to assess the role of insulin resistance in the associations between phthalate exposure and MetS. RESULTS: Higher DIDMP was associated with an increased odds of high HOMA-IR and MetS (odds ratio [OR], 1.686; 95% confidence interval [CI], 1.079-2.634 for high HOMA-IR; OR, 2.329; 95% CI, 1.263-4.295 for MetS). The mediation analysis indicated that 43% of the association between higher DIDMP and MetS was mediated by HOMA-IR. Higher DIBBzP and HI were associated with an increased odds of abdominal obesity (OR, 1.816; 95% CI, 1.180-2.797 for the high DIBBzP group; OR, 1.700, 95% CI, 1.105-2.614 for the high HI groups). CONCLUSIONS: Exposure to environmental phthalates may be positively associated with insulin resistance and MetS. Insulin resistance may mediate these associations between exposure to certain phthalates and MetS.

Prenatal and childhood exposure to phthalate diesters and neurobehavioral development in a 15-year follow-up birth cohort study.

OBJECTIVE: Longitudinal studies on neurobehavioral development in relation to prenatal and postnatal exposure to phthalates in school-age children and adolescents are limited. We investigated the association of prenatal and childhood phthalate exposure with the development of behavioral syndromes in 8-14-year-old children. METHOD: We recruited 430 pregnant women from 2000 to 2001 and followed their children at the ages of 2, 5, 8, 11, and 14 years, yielding 153 mother-child pairs in total. Urine samples from pregnant women in the third trimester and from children at 2-8 years of age were analyzed for the concentrations of seven urinary phthalate metabolites: monomethyl phthalate, monoethyl phthalate, monobutyl phthalate, monobenzyl phthalate (MBzP), and three di(2-ethylhexyl) phthalate (DEHP) metabolites, namely mono-2-ethylhexyl phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate, and mono(2-ethyl-5-oxohexyl) phthalate. Behavioral syndromes in children aged 8-14 years were assessed using the Child Behavior Checklist. We constructed mixed models to examine these associations after adjustments for potential covariates. RESULTS: Maternal urinary MEHP levels were associated with higher scores for internalizing problems (ß = 0.028, 95% confidence interval [CI]: 0.0004, 0.055) and externalizing problems (ß = 0.040, 95% CI: 0.013, 0.066). Associations of the maternal urinary sum of DEHP metabolite levels with delinquent behavior scores and externalizing problems scores were positive (ß = 0.035, 95% CI: 0.013, 0.057 for delinquent behavior; ß = 0.026, 95% CI: 0.001, 0.050 for externalizing problems). Furthermore, children's urinary MBzP levels were associated with higher scores for social problems (ß = 0.018, 95% CI: 0.001, 0.035). Similar patterns were observed for borderline and clinical ranges. CONCLUSION: Early-life exposure to phthalates may influence behavioral syndrome development in children. Future studies are needed to replicate these findings, and efforts to reduce exposures to phthalates during critical early life stages may be warranted.

Increased risk of phthalates exposure for recurrent pregnancy loss in reproductive-aged women.

Recurrent pregnancy loss (RPL) is the termination of pregnancies, usually before 20 weeks of gestation, and is defined as the loss of two or more pregnancies. In Taiwan, after 2011 di-2-ethylhexyl phthalate (DEHP) exposure episode, more reproductive-aged women still expose to high levels of DEHP and di-butyl phthalate (DBP) than have women of other age groups. Phthalates might be involved in the RPL pathogenesis. This study assessed the association of phthalate exposure with RPL risk in reproductive-aged Taiwanese women. This study recruited 103 patients diagnosed by a physician with RPL of unknown etiology and 76 controls from the Department of Obstetrics and Gynecology at a medical center in southern Taiwan between August 2013 and August 2017. Urine samples were analyzed for 11 phthalate metabolites through liquid chromatography-tandem mass spectrometry; subsequently, principal component analysis (PCA) and hierarchical clustering analysis were performed to determine the main sources of phthalate exposure. Finally, multivariate logistic regression was used to determine the RPL risk. The creatinine-unadjusted median levels of mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP) in RPL/control were 9.8/5.3, 27.2/13.1, 11.4/8.1, and 12.9/9.5 ng/mL, respectively; furthermore, ΣDBPm and ΣDEHPm in RPL/control were 0.18/0.10 and 0.15/0.12 nmol/mL, respectively. PCA revealed three primary components of phthalate exposure: diethyl phthalates (DEP), DEHP, and DBP. Plastic food container use and medication were identified as the main phthalate exposure sources. After adjustment for potential confounding factors (urinary creatinine, age, age at menarche, education, and plastic food container use), we found that the urinary level of ΣDBPm was significantly associated with elevated risk for RPL (OR = 2.85, p = 0.045). Our findings supported the hypothesis that exposure to phthalates increases RPL risk. The development of a strategy to reduce phthalate exposure among reproductive-aged women should be emphasized.

Longitudinal assessment of prenatal phthalate exposure on serum and cord thyroid hormones homeostasis during pregnancy - Tainan birth cohort study (TBCS).

An increasing number of studies have revealed that phthalate exposure alters thyroid hormone homeostasis in the general population, but there is insufficient evidence of the effect of longitudinal maternal phthalate exposure on maternal and fetal thyroid hormones during pregnancy. We longitudinally assessed the effect of prenatal phthalate exposure in pregnant women on umbilical cord and maternal thyroid hormones at three trimesters during pregnancy. We recruited 98 pregnant women and collected urine and blood samples at three trimesters in an obstetrics clinic in Southern Taiwan from 2013 to 2014. We analyzed the concentrations of 11 urinary phthalate metabolites, including monoethylhexyl phthalate, mono-(2-ethyl-5-oxo-hexyl) phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-n-butyl phthalate, monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP), using online liquid chromatography-tandem mass spectrometry. The cord and maternal serum levels of thyroxine (T4), free T4, triiodothyronine (T3), thyroid-stimulating hormone (TSH), and thyroxine-binding globulin were measured using an electrochemiluminescence immunoassay. A mixed-model analysis was utilized to assess the effect of longitudinal phthalate exposure on thyroid hormones and adjusted for significant covariates. We found that urinary MiBP (ß=-0.065, 95% confidence interval (CI): -0.124, -0.005), and MEOHP (ß=-0.083, 95% CI: -0.157, -0.009) were significantly negatively associated with serum TSH. Urinary MECPP was inversely related to serum T3 (ß=-0.027, 95% CI: -0.047, -0.006). Urinary MEP (ß=0.014, 95% CI: -0.001, 0.028) and MiBP (ß=0.033, 95% CI: 0.018, 0.049) were positively related to free T4. We found that cord serum T3 (ß=0.067, 95% CI: 0.003, 0.131) and free T4 (ß=0.031, 95% CI: 0.001, 0.062) levels had significant positive associations with maternal ΣDBPm levels at the second trimester. We concluded that different phthalates exposure windows during gestation may alter cord and serum thyroid hormone homoeostasis.