Benchmark Dose of Melamine Exposure for a Renal Injury Marker Mediated by Oxidative Stress: Examples in Patients with Urolithiasis and Occupational Workers.

Establishing a safe exposure level from epidemiological studies while providing direct hazard characterization in humans often faces uncertainty in causality, especially cross-sectional data. With advances in molecular epidemiology, it is reasonable to integrate identified intermediate biomarkers into health risk assessment. In this study, by considering the mediation of the oxidative stress marker malondialdehyde (MDA), we explored the exposure threshold of melamine on the early renal injury marker N-acetyl-ß-D glucosaminidase (NAG). The benchmark dose (BMD) was derived from model averaging of the composite direct effect of melamine exposure and the indirect effect through the mediation of MDA on NAG levels. As illustrative examples, we analyzed 309 adult patients with calcium urolithiasis and 80 occupational workers for the corresponding exposure thresholds. The derived threshold was subpopulation-dependent, with the one-sided lower bound BMDL10 for the patients with urolithiasis with (without) the mediator MDA for the patients with kidney stones and the occupational workers being 0.88 (0.96) µg/kg_bw/day and 22.82 (18.09) µg/kg_bw/day, respectively. The derived threshold levels, considering the oxidative stress marker MDA, were consistent with those without adjusting for the mediation effect. However, the study outcomes were further supported by the suggested mechanism pathway. The threshold for the patients with urolithiasis was up to two orders lower than the current tolerable daily intake level of 200 µg/kg_bw/day recommended by the WHO (EFSA).

Associations between long-term ambient PM2.5 exposure and the incidence of cardiopulmonary diseases and diabetes, attributable years lived with disability, and policy implication.

Long-term exposure to ambient PM2.5 is known associated with cardiovascular and respiratory health effects. However, the heterogeneous concentrationresponse function (CRF) between PM2.5 exposure across different concentration range and cardiopulmonary disease and diabetes mellitus (DM) incidence, and their implications on attributable years lived with disability (YLD) and regulation policy has not been well-studied. In this retrospective longitudinal cohort study, disease-free participants (approximately 170,000 individuals, aged ≥ 30 years) from the MJ Health Database were followed up (2007-2017) regarding incidents of coronary heart disease (CHD), ischemic stroke, chronic obstructive pulmonary disease (COPD), lower respiratory tract infections (LRIs), and DM. We used a time-dependent nonlinear weight-transformation Cox regression model for the CRF with an address-matched 3-year mean PM2.5 exposure estimate. Town/district-specific PM2.5-attributable YLD were calculated by multiplying the disease incidence rate, population attributable fraction, disability weight, and sex-age group specific subpopulation for each disease separately. The estimated CRFs for cardiopulmonary diseases were heterogeneously with the hazard ratios (HRs) increased rapidly for CHD and ischemic stroke at PM2.5 concentration lower than 10 µg/m3, whereas the HRs for DM (LRIs) increased with PM2.5 higher than 15 (20) µg/m3. Women had higher HRs for ischemic stroke and DM but not CHD. Relative to the lowest observed PM2.5 concentration of 6 µg/m3 of the study population, the PM2.5 level with an extra risk of 0.1 % (comparable to the disease incidence) for CHD, ischemic stroke, DM, and LRIs were 8.59, 11.85, 22.09, and 24.23 µg/m3, respectively. The associated attributable YLD decreased by 51.4 % with LRIs reduced most (83.6 %), followed by DM (63.7 %) as a result of PM2.5 concentration reduction from 26.10 to 16.82 µg/m3 during 2011-2019 in Taiwan. The proportion of YLD due to CHD and ischemic stroke remained dominant (56.4 %-69.9 %). The cost-benefit analysis for the tradeoff between avoidable YLD and mitigation cost suggested an optimal PM2.5 exposure level at 12 µg/m3. CRFs for cardiopulmonary diseases, attributable YLD, and regulation level, may vary depending on the national/regional background and spatial distribution of PM2.5 concentrations, as well as demographic characteristics.

Elafin as a Prognostic Marker in Esophageal Squamous Cell Carcinoma: A Pilot Study Using Three-Dimensional Imaging and Genomic Profiling.

Esophageal cancers are globally the sixth deadliest malignancy, with limited curative options. The association of high serum elafin levels, a molecule produced by epithelial cells, with esophageal squamous cell carcinoma (ESCC) risk is established, but its link to poor ESCC prognosis remains unclear. To explore this question, we first used three-dimensional confocal imaging to create a model of the spatial distribution of elafin inside locoregional ESCC tissues. Then, after analyzing data obtained from whole-genome microarrays for ESCC cell lines and their more invasive sublines, we performed in vitro experiments using RNA sequencing to identify possible elafin-related pathways. Three-dimensional tissue imaging showed elafin distributed as an interweaved-like fibrous structure in the stroma of tissue obtained from patients with high serum levels of elafin and poorer prognoses. By contrast, the signal was confined inside or around the tumor nest in patients who had lower serum levels and better survival. The analysis of a TCGA dataset revealed that higher levels of elafin mRNA in stage I-IIIA ESCC patients were associated with shorter survival. The in vitro studies revealed that elafin promoted ESCC cell proliferation, migration, and invasion via the epithelial-mesenchymal transition pathway. Thus, elafin inhibition could potentially be used therapeutically to improve survival in patients with locoregional ESCC.

Sex-specific interactive effect of melamine and DEHP on a marker of early kidney damage in Taiwanese adults: A national population-based study from the Taiwan Biobank.

Taiwan had the high incidence of chronic kidney disease (CKD) worldwide. Our objective was to examine associations between daily exposure of phthalates and melamine, two common nephrotoxins, and kidney damage risk in a well-established nationwide cohort. Study subjects were from Taiwan Biobank (TWB) with existing data of questionnaire and biochemical examinations. Average daily intake (ADI) levels of melamine and seven parental phthalates, including DEHP (di-2-ethylhexylphthalate), DiBP (Dibutyl phthalate), DnBP (Di-n-butyl phthalate), BBzP (Butyl benzyl phthalate), DEP (Diethyl phthalate), and DMP (Dimethyl phthalate) were estimated using a creatinine excretion-based model from urine melamine and 10 phthalate metabolites. Urine microalbumin to creatinine ratio (ACR) was used to represent for the outcome of kidney damage. Two statistical strategies were used: First, a weighted quantile sum (WQS) regression model to select the most important exposure variables of ADI levels of phthalates and melamine associated with ACR; Second, to examine effects of those most important exposure variables on ACR in multivariable linear regression models. In total, 1153 eligible adults were left for analyses. Of them, 591 (51.3%) and 562 (48.7%) were men and women, respectively, with a median age of 49 years old. By WQS, a significant and positive association was found between ADI of melamine and phthalates and ACR (ß = 0.14, p = 0.002). ADI levels of melamine had the highest weight (0.57), followed by DEHP (0.13). Next, examining the two most important exposures in association with ACR, we found that the higher the melamine and DEHP intakes, the higher the ACR levels were found. An interaction effect was also found between melamine and DEHP intakes on urine ACR (p = 0.015). This result was more prominent in men (p = 0.008) than in women (p = 0.651). Environmental co-exposure of melamine and DEHP can potentially affect ACR in the community-dwelling Taiwanese adult population.

Burden of cardiovascular disease attributable to long-term exposure to ambient PM2.5 concentration and the cost-benefit analysis for the optimal control level.

Environmental exposure to fine particulate matter PM2.5 is known to be associated with many hazardous health effects, including cardiovascular diseases (CVDs). To reduce the related health burden, it is crucial that policy-makers throughout the world set regulation levels according to their own evidence-based study outcomes. However, there appears to be a lack of decision-making methods for the control level of PM2.5 based on the burden of disease. In this study, 117,882 CVD-free participants (≥30-years-old) of the MJ Health Database were followed-up (for a median of 9 years) between 2007 and 2017. Each participant's residential address was matched to the 3× 3 km grid PM2.5 concentration estimates with a 5-year average for long-term exposure. We used a time-dependent nonlinear weight-transformation Cox regression model for the concentration-response function (CRF) between exposure to PM2.5 and CVD incidence. Town/district-specific PM2.5-attributable years of life in disability (YLDs) in CVD incidence were calculated by using the relative risk (RR) of the PM2.5 concentration level relative to the reference level. A cost-benefit analysis was proposed by assessing the trade-off between the gain in avoidable YLDs (given a reference level at u and considering mitigation cost) versus the loss in unavoidable YLDs by not setting at the lowest observed health effect level u0. The CRF varied across different areas with dissimilar PM2.5 exposure ranges. Areas with low PM2.5 concentrations and population sizes provided crucial information for the CVD health effect at the lower end. Additionally, women and older participants were more susceptible. The avoided town/district-specific YLDs in CVD incidence due to lower RRs ranged from 0 to 3000 person-years comparing the PM2.5 concentration levels in 2019 with the levels in 2011. Based on the cost-benefit analysis, an annual PM2.5 concentration of 13 µg/m3 would be optimal, which provides a guideline for the updated regulation level (currently at 15 µg/m3). The proposed cost-benefit analysis method may be applied to other countries/regions for regulation levels that are most suitable for their air pollution status and population health.

Environmental melamine exposure and adverse kidney outcomes in patients with type 2 diabetes mellitus.

The impact of melamine exposure on kidney outcomes in type 2 diabetes mellitus (T2D) patients remains unclear. In this prospective cohort study, 561 T2D patients during October 2016 and June 2020 were enrolled and followed until December 2021. Baseline one-spot urinary corrected melamine levels were measured by LC-MS/MS. Average daily intake (ADI) of melamine represented environmental melamine exposure in daily life, and was estimated using urinary corrected melamine level by creatinine excretion (CE)-based model. Primary kidney outcomes were defined as doubling of serum creatinine levels or end stage kidney disease (ESKD), and secondary kidney outcomes included rapid decline in kidney function as estimated glomerular filtration rate (eGFR) decline >5 ml/min/1.73 m2/year. Baseline median urinary corrected melamine levels and estimated DI of melamine were 0.8 µg/mmol and 0.3 µg/kg/day in 561 T2D patients. During 3.7 years of follow-up, urinary corrected melamine level was positively correlated with reaching composite outcomes of either doubling of serum creation levels or ESKD and rapid decline in kidney function. Those with the highest quartile of urinary corrected melamine had 2.96-fold risk of composite outcomes of either doubling of serum creation levels or ESKD and 2.47-fold risk of eGFR decline >5 ml/min/1.73 m2/year. Estimated ADI of melamine also had significant correlation with adverse kidney outcomes. Furthermore, the positive relationship between melamine exposure and rapid decline in kidney function was only found in T2D patients with male, baseline eGFR ≥60 ml/min/1.73 m2 or glycated hemoglobin ≤7%. In conclusion, melamine exposure is significantly associated with adverse kidney outcomes in T2D patients, especially in those with male, well sugar control or good baseline kidney function.

Benchmark dose in the presence of coexposure to melamine and diethylhexyl phthalate and urinary renal injury markers in pregnant women.

Environmental exposures to mixtures of toxic chemicals have potential interaction effects that may lead to hazard index values exceeding one. However, current regulation levels, such as tolerable daily intake (TDI), are mostly based on experimental studies conducted with a single chemical compound. In this study, we assessed the relationships between melamine and di-(2-ethylhexyl) phthalate (DEHP) exposure and their coexposure with the early renal injury markers N-acetyl -D-glucosaminidase (NAG), albumin/creatinine ratio (ACR), and microalbuminuria in 1236 pregnant women. Various generalized linear models with interaction terms and Bayesian kernel machine regression models were used for the (co-)exposure response associations. We derived the benchmark dose (BMD) and the corresponding one-sided 95% confidence bound BMDL based on the estimated (covariate-adjusted) average daily intake of melamine and DEHP metabolites measured in spot urine of the women collected during the third trimester. Given a benchmark response of 0.1, the BMDL level of melamine (DEHP) exposure on NAG (ACR, microalbuminuria) was 2.67 (11.20, 4.45) µg/kg_bw/day, and it decreased to as low as 1.46 (3.83, 2.73) µg/kg_bw/day when considering coexposure to DEHP (melamine) up to the 90th percentile. Both the exposure threshold levels of melamine and DEHP for early renal injuries in pregnant women were several-fold to one order lower than the current recommended TDIs by the WHO and the US FDA and EPA and were even lower considering coexposure. Because of concurrent exposures in real-world environments, more stringent regulation levels are recommended in susceptible populations, such as pregnant women, due to potential synergistic mixture effects.

Avatar-like body imaging of dermal exposure to melamine in factory workers analyzed by ambient mass spectrometry.

Ambient mass spectrometry thermal desorption-electrospray ionization/mass spectrometry (TD-ESI/MS) can rapidly identify chemicals without pretreatment of biological samples. This study used a rapid semi-quantitative TD-ESI/MS screening technique for the probe skin sampling of melamine workers occupationally exposed to different ambient melamine concentrations to create avatar-like body images, which were then used to study temporal and dynamic changes in nephrotoxic melamine exposure. We enrolled four voluntary melamine workers from one factory, each from one of four worksites. Melamine exposure was highest in manufacturing and molding, followed by grinding and polishing, packing, and administration, the lowest. Skin samples were collected Friday (end-of-shift) and Monday (pre-shift). Early morning one-spot urine samples were also collected right after skin sampling. 2198 probe skin samples were collected and subjected to semi-quantitative TD-ESI/MS analyses of melamine chemical within 40 h. After normalization, converted body image scores revealed exposure to be highest in the manufacturing worker on Friday and lowest in the administrative worker on Monday. The absolute differences (Friday minus Monday) of normalized body image scores were all significantly positive in each individual worker and across all four workers (permutation test, all p-values < 0.002). The slope estimates of the linear regression line between body image scores and urinary melamine levels were 0.81 (p-value = 0.008). We concluded that this fast and non-invasive technique can potentially be used to study temporal and dynamic changes in exposure to occupational hazards. A future study of developing an automatic and reproducible TD-ESI/MS sampling platform is needed.

Longitudinal changes in oxidative stress and early renal injury in children exposed to DEHP and melamine in the 2011 Taiwan food scandal.

In 2011, phthalates, mainly di-(2-ethylhexyl) phthalate (DEHP), were found to have been added to a variety of foods in Taiwan, increasing the risk of microalbuminuria in children. Exposure to melamine perhaps modifies that risk. This prospective cohort study investigates whether renal injury resulting from exposure to DEHP-tainted foods from the 2011 Taiwan Food Scandal is reversed over time. The temporal and interactive effects of past daily DEHP intake, current daily DEHP intake, and urinary melamine levels on oxidative stress and renal injury were also examined. Two hundred possibly DEHP-affected children (aged < 18 years) were enrolled in the first survey wave (August 2012-January 2013), with 170 and 159 children in the second (July 2014-February 2015) and third waves (May 2016-October 2016), respectively. The first wave comprised questionnaires that were used to collect information about possible past daily DEHP intake from DEHP-tainted foods. One-spot first morning urine samples were collected to measure melamine levels, phthalate metabolites, and markers indicating oxidative stress (malondialdehyde and 8-oxo-2'-deoxyguanosine), and renal injury (albumin/creatinine ratio (ACR) and N-acetyl-beta-D-glucosaminidase) in all three waves. Generalized estimating equation (GEE) modeling revealed that both past daily DEHP intake and time might affect urinary ACR. However, most interactions were negative and significant correlation was observed only during the second wave (P for interaction = 0.014) in the group with the highest past daily DEHP intake (>50 µg/kg/day). Urinary melamine levels were found to correlate significantly with both urinary ACR and oxidative stress markers. The highest impact associated with exposure to DEHP-tainted foods in increasing urinary ACR of children was observed during the first wave, and the effect may partially diminish over time. These results suggest that continuous monitoring of renal health and other long-term health consequences is required in individuals who were affected by the scandal in 2011.

Genetic Polymorphisms of MnSOD Modify the Impacts of Environmental Melamine on Oxidative Stress and Early Kidney Injury in Calcium Urolithiasis Patients.

Environmental melamine exposure increases the risks of oxidative stress and early kidney injury. Manganese superoxide dismutase (MnSOD), glutathione peroxidase, and catalase can protect the kidneys against oxidative stress and maintain normal function. We evaluated whether their single-nucleotide polymorphisms (SNPs) could modify melamine's effects. A total of 302 patients diagnosed with calcium urolithiasis were enrolled. All patients provided one-spot overnight urine samples to measure their melamine levels, urinary biomarkers of oxidative stress and renal tubular injury. Median values were used to dichotomize levels into high and low. Subjects carrying the T allele of rs4880 and high melamine levels had 3.60 times greater risk of high malondialdehyde levels than those carrying the C allele of rs4880 and low melamine levels after adjustment. Subjects carrying the G allele of rs5746136 and high melamine levels had 1.73 times greater risk of high N-Acetyl-ß-d-glucosaminidase levels than those carrying the A allele of rs5746136 and low melamine levels. In conclusion, the SNPs of MnSOD, rs4880 and rs5746136, influence the risk of oxidative stress and renal tubular injury, respectively, in calcium urolithiasis patients. In the context of high urinary melamine levels, their effects on oxidative stress and renal tubular injury were further increased.

Identifying low-PM2.5 exposure commuting routes for cyclists through modeling with the random forest algorithm based on low-cost sensor measurements in three Asian cities.

Cyclists can be easily exposed to traffic-related pollutants due to riding on or close to the road during commuting in cities. PM2.5 has been identified as one of the major pollutants emitted by vehicles and associated with cardiopulmonary and respiratory diseases. As routing has been suggested to reduce the exposures for cyclists, in this study, PM2.5 was monitored with low-cost sensors during commuting periods to develop models for identifying low exposure routes in three Asian cities: Taipei, Osaka, and Seoul. The models for mapping the PM2.5 in the cities were developed by employing the random forest algorithm in a two-stage modeling approach. The land use features to explain spatial variation of PM2.5 were obtained from the open-source land use database, OpenStreetMap. The total length of the monitoring routes ranged from 101.36 to 148.22 km and the average PM2.5 ranged from 13.51 to 15.40 µg/m³ among the cities. The two-stage models had the standard k-fold cross-validation (CV) R2 of 0.93, 0.74, and 0.84 in Taipei, Osaka, and Seoul, respectively. To address spatial autocorrelation, a spatial cross-validation approach applying a distance restriction of 100 m between the model training and testing data was employed. The over-optimistic estimates on the predictions were thus prevented, showing model CV-R2 of 0.91, 0.67, and 0.78 respectively in Taipei, Osaka, and Seoul. The comparisons between the shortest-distance and lowest-exposure routes showed that the largest percentage of reduced averaged PM2.5 exposure could reach 32.1% with the distance increases by 37.8%. Given the findings in this study, routing behavior should be encouraged. With the daily commuting trips expanded, the cumulative effect may become significant on the chronic exposures over time. Therefore, a route planning tool for reducing the exposures shall be developed and promoted to the public.

Diminishment of Nrf2 Antioxidative Defense Aggravates Nephrotoxicity of Melamine and Oxalate Coexposure.

Chronic kidney disease (CKD) usually causes devastating healthy impacts on patients. However, the causes affecting the decline of kidney function are not fully revealed, especially the involvement of environmental pollutants. We have revealed that exposure to melamine, a ubiquitous chemical in daily life, is linked to adverse kidney outcomes. Hyperoxaluria that results from exposure to excessive oxalate, a potentially nephrotoxic terminal metabolite, is reportedly associated with CKD. Thus, we explored whether interaction of these two potential nephrotoxicants could enhance kidney injury. We established a renal proximal tubular HK-2 cell model and a Sprague-Dawley rat model of coexposure to melamine with sodium oxalate or hydroxy-L-proline to investigate the interacting adverse effects on kidneys. Melamine and oxalate coexposure enhanced the levels of reactive oxygen species, lipid peroxidation and oxidative DNA damage in the HK-2 cells and kidney tissues. The degrees of tubular cell apoptosis, tubular atrophy, and interstitial fibrosis were elevated under the coexposed condition, which may result from the diminishment of Nrf2 antioxidative capacity. To conclude, melamine and oxalate coexposure aggravates renal tubular injury via impairment of antioxidants. Accumulative harmful effects of exposure to multiple environmental nephrotoxicants should be carefully investigated in the etiology of CKD progression.

Melamine and oxalate coexposure induces early kidney tubular injury through mitochondrial aberrations and oxidative stress.

Exposure to melamine, which is ubiquitous in daily life, is linked to adverse kidney outcomes. The melamine tolerable daily intake in humans is based on the no-observed-effect-level (NOEL) established in a single-toxicant murine model. However, humans are often simultaneously exposed to multiple environmental nephrotoxicants. The NOEL of melamine during coexposure with other toxicants needs to be evaluated. Oxalate is a potentially nephrotoxic terminal metabolite, and hyperoxaluria is reportedly associated with chronic kidney disease. We explored whether these two potential nephrotoxicants can interact and enhance kidney injury. We established a Sprague-Dawley rat model of coexposure to the melamine NOEL (63 mg/kg/day) and 2% hydroxy-L-proline (HLP, an oxalate precursor) in drinking water to simulate human environmental melamine exposure. Melamine/oxalate coexposure increased proximal tubular cell mitochondrial reactive oxygen species levels, lipid peroxidation and oxidative DNA damage. The degrees of mitochondrial damage, tubular cell apoptosis, tubular atrophy, and interstitial fibrosis were elevated in coexposed rat kidneys. The evidence indicated that exposure to the melamine NOEL can cause renal tubular injury via oxidative stress and that this effect may be enhanced via interaction of melamine with other environmental factors, such as oxalate. Thus, melamine risk assessment and toxicity prevention should be conducted carefully in different susceptible populations.

Estimating monthly PM2.5 concentrations from satellite remote sensing data, meteorological variables, and land use data using ensemble statistical modeling and a random forest approach.

Fine particulate matter (PM2.5) is associated with various adverse health outcomes and poses serious concerns for public health. However, ground monitoring stations for PM2.5 measurements are mostly installed in population-dense or urban areas. Thus, satellite retrieved aerosol optical depth (AOD) data, which provide spatial and temporal surrogates of exposure, have become an important tool for PM2.5 estimates in a study area. In this study, we used AOD estimates of surface PM2.5 together with meteorological and land use variables to estimate monthly PM2.5 concentrations at a spatial resolution of 3 km2 over Taiwan Island from 2015 to 2019. An ensemble two-stage estimation procedure was proposed, with a generalized additive model (GAM) for temporal-trend removal in the first stage and a random forest model used to assess residual spatiotemporal variations in the second stage. We obtained a model-fitting R2 of 0.98 with a root mean square error (RMSE) of 1.40 µg/m3. The leave-one-out cross-validation (LOOCV) R2 with seasonal stratification was 0.82, and the RMSE was 3.85 µg/m3, whereas the R2 and RMSE obtained by using the pure random forest approach produced R2 and RMSE values of 0.74 and 4.60 µg/m3, respectively. The results indicated that the ensemble modeling approach had a higher predictive ability than the pure machine learning method and could provide reliable PM2.5 estimates over the entire island, which has complex terrain in terms of land use and topography.

Melamine exposure threshold in early chronic kidney disease patients - A benchmark dose approach.

Environmental melamine exposure has been associated with deteriorating kidney function in early-stage chronic kidney disease patients. In this study, a benchmark dose (BMD) approach was used to establish melamine exposure threshold in 293 patients with eGFR≥30 ml/min per 1.73 m2. The patients were enrolled 2006-2010 and followed-up for a median of 7.0 years to monitor kidney outcomes. Average daily intakes (AvDI) of melamine were estimated using one-spot urine samples collected at enrollment. BMDs and corresponding one-sided 95% lower bound (BMDLs) were derived using established dose-response models relating estimated AvDIs and dichotomous kidney outcomes: doubling of serum creatine levels, eGFR decreased > 3 ml/min per 1.73 m2 per year, and >30% decline in eGFR during the first 2 years. In addition, survival time to doubling of serum creatinine and eGFR decline over time were assessed as continuous endpoints. Given a benchmark response of 0.10, BMDLs ranged from 0.74 to 2.03 µg/kg_bw/day after Bayesian model averaging, a range one to two orders lower than the current WHO recommended tolerable daily intake of 200 µg/kg_bw/day and the US FDA's 63 µg/kg_bw/day. Our results suggest that early-stage CKD patients should strictly refrain from using melamine tableware and related melamine-made products.

Projection of future temperature extremes, related mortality, and adaptation due to climate and population changes in Taiwan.

BACKGROUND: Extreme temperature events have been observed to appear more frequently and with greater intensity in Taiwan in recent decades due to climate change, following the global trend. Projections of temperature extremes across different climate zones and their impacts on related mortality and adaptation have not been well studied. METHODS: We projected site-specific future temperature extremes by statistical downscaling of 8 global climate models followed by Bayesian model averaging from 2021 to 2060 across Taiwan under the representative concentration pathway (RCP) scenarios RCP2.6, RCP4.5, and RCP8.5. We then calculated the attributable mortality (AM) in 6 municipalities and in the eastern area by multiplying the city/county- and degree-specific relative risk of mortality according to the future population projections. We estimated the degree of adaptation to heat by slope reduction of the projected AM to be comparable with that in 2018. RESULTS: The annual number of hot days with mean temperatures over 30 °C was predicted to have a substantial 2- to 5-fold increase throughout the residential areas of Taiwan by the end of 2060 under RCP8.5, whereas the decrease in cold days was less substantial. The decrease in cold-related mortality below 15 °C was projected to outweigh heat-related mortality for the next two decades, and then heat-related mortality was predicted to drastically increase and cross over cold-related mortality, surpassing it from 2045 to 2055. Adjusting for future population size, the percentage increase in heat-related deaths per 100,000 people could increase by more than 10-fold under the worst scenario (RCP8.5), especially for those over 65 years old. The heat-related impacts will be most severe in southern Taiwan, which has a tropical climate. There is a very high demand for heat-adaptation prior to 2050 under all RCP scenarios. CONCLUSIONS: Spatiotemporal variations in AM in cities in different climate zones are projected in Taiwan and are expected to have a net negative effect in the near future before shifting to a net positive effect from 2045 to 2055. However, there is an overall positive and increasing trend of net effect for elderly individuals under all the emission scenarios. Active adaptation plans need to be well developed to face future challenges due to climate change, especially for the elderly population in central and southern Taiwan.

A probabilistic approach for benchmark dose of melamine exposure for a marker of early renal dysfunction in patients with calcium urolithiasis.

Environmental exposure to melamine has been associated with early renal injury in urolithiasis patients even when urinary concentrations of melamine are low. The aim of this study was to derive a benchmark dose (BMD) for melamine for urolithiasis patients. To do this, one-spot urine sample from 309 participants was obtained to measure urinary melamine and N-acetyl ß-D-glucosaminidase (NAG), an early renal damage biomarker. The participants were then classified into four exposure groups based on the outcomes of melamine tableware usage questionnaire. A beta distribution of urinary excretion fraction for each group was assumed to estimate their average daily intakes (AvDIs) of melamine. The BMD and the corresponding one-sided 95% lower bound (BMDL) was then derived based on Bayesian model averaging of alternative regression models between the participants' NAG levels and their estimated AvDIs, adjusting for age, gender, and other covariates. Bayesian Markov chain Monte Carlo simulations were used for all the estimates. With a benchmark response of 0.10, the simulated BMDL of 4.89 µg/kg-bw/day for melamine exposure threshold was much lower than the WHO's current recommended tolerable daily intake of 200 µg/kg_bw/day and the US FDA's 63 µg/kg_bw/day. The current regulation level of melamine might not safeguard urolithiasis patients from further deterioration of renal function.

The sex-specific association of phthalate exposure with DNA methylation and characteristics of body fat in children.

The present study assessed the association between phthalate exposure and mitochondrial DNA (mtDNA) polymerase γ (POLG) methylation along with the potential effect on the characteristics of body fat in children. A total of 152 children were enrolled. The urinary concentrations of phthalate metabolites were measured using ultraperformance liquid chromatography-tandem mass spectrometry. Genomic DNA was extracted from the buffy coat, and bisulfite-treated DNA was subjected to a pyrosequencing assay. In total, 17 CpG sites in the exon 2 region of POLG were included in the analysis. A multivariable regression model was applied to determine whether characteristics of body fat were associated with phthalate exposure and methylation of POLG. After adjustment for covariates, male children with a ten-fold increase in mono-methyl phthalate (MMP) or mono-benzyl phthalate (MBzP) concentrations had significantly higher measurements for total body fat (MMP: ß = 6.47%; MBzP: ß = 3.54%), and trunk fat (MMP: ß = 6.67%; MBzP: ß = 3.90%). Male children who had hypermethylation at the 2nd CpG site in exon 2 of POLG also had high measurements for BMI (ß = 1.66 kg/m2), waist (ß = 4.49 cm) and hip (ß = 4.81 cm) circumference, total body fat (ß = 5.48%), and trunk fat (ß = 6.21%). A dose-response relationship existed between methylation at the 2nd CpG site in exon 2 of POLG and characteristics of body fat (p for trend<0.01). This study suggested that male children who are exposed to phthalic acid esters have high body weight, BMI, and body and trunk fat percentages. Methylation of the exon 2 region of POLG is a possible mechanism behind the causal effect of endocrine-disrupting substances.

Phthalate exposure and prostate cancer in a population-based nested case-control study.

BACKGROUND: Phthalic acid esters are established as endocrine disruptors. The study aimed to evaluate the association between urinary phthalate metabolites and prostate cancer occurrence. METHODS: The study was based on the Taiwan Community-Based Cancer Screening Program, which was set up in 1991-1992 and followed periodically. By 2010, 80 incident prostate cancer cases were identified in the 12,020 men. For each case, 2 controls were randomly selected, matched by age (±3 years), urine collection date (±3 months), and residential township. Frequently used phthalate metabolites from the urine samples were quantified by liquid chromatography/electrospray ionization tandem mass spectrometry. Logistic regression was conducted to assess the association between the exposure levels and prostate cancer occurrence. RESULTS: Exposure to di (2-ethylhexyl), butyl-benzyl and di-isobutyl phthalates (DEHP, BBzP, DiBP) was positively associated with prostate cancer in men with waist circumference (WC) ≥90 cm but not in the leans. Odds ratio for the DEHP metabolite summary score (upper tertile compared to the rest) and prostate cancer were 7.76 (95% CI = 1.95-30.9) for WC ≥ 90 cm. CONCLUSIONS: DEHP, BBzP, and DiBP exposure were associated with prostate cancer occurrence in abdominally obese men. The main limitation remains the lack of mechanistic experiments and comparable toxicological data.

Effects of Apparent Temperature on the Incidence of Ventricular Tachyarrhythmias in Patients With an Implantable Cardioverter-Defibrillator: Differential Association Between Patients With and Without Electrical Storm.

Background: Electrical storm (ES) has profound psychological effects and is associated with a higher mortality in patients with implantable cardioverter-defibrillator (ICD). Assessing the incidence and features of ES, is vital. Previous studies have shown winter peaks for ventricular tachyarrhythmia (VTA) in ICD patients. However, the effects of heat with a high relative humidity remain unclear. Thus, this study aimed to assess the nonlinear and lagged effects of apparent temperature [or heat index (HI)] on VTA among patients with and without ES after ICD implantation. Methods: Of 626 consecutive patients who had ICDs implanted from January 2004 to June 2017 at our hospital, 172 who experienced sustained VTAs in ICD recording were analyzed, and their clinical records were abstracted to assess the association between VTA incidence and HI by time-stratified case-crossover analysis. Cubic splines were used for the nonlinear effect of HI, with adjustment for air pollutant concentrations. Results: A significant seasonal effect for ES patients was noted. Apparent temperature, but not ambient temperature, was associated with VTA occurrences. The low and high HI thresholds for VTA incidence were <15° and >30°C, respectively, with a percentage change in odds ratios of 1.06 and 0.37, respectively, per 1°C. Lagged effects could only be demonstrated in ES patients, which lasted longer for low HI (in the next 4 days) than high HI (in the next 1 day). Conclusion: VTA occurrence in ICD patients was strongly associated with low HI and moderately associated with high HI. Lagged effects of HI on VTA were noted in patients with ES. Furthermore, patients with ES were more vulnerable to heat stress than those without ES. Patients with ICD implantation, particularly in those with ES, should avoid exposure to low and high HI to reduce the risk of VTAs, improve quality of life and possibly reduce mortality.