Uncovering the impact of mega-scale shipbreaking yards on soil and crop quality in Bangladesh: A spatiotemporal dynamics and associated health risks of metal/loid contamination.

The uncontrolled release of harmful metal/loids from mega-scale shipbreaking activities in Bangladesh is a significant concern. This study investigated the impact of shipbreaking activities on soil and crop quality and human health in relation to metal/loid contamination. This work covered an area of 1221 km2 surrounding the shipbreaking yards in Chittagong during the wet and dry seasons between 2019 and 2020. Amongst the sixteen elements measured, the concentrations of Pb, Cd, As, V, Cr, Mn, Cu, Zn, Fe, Co, Ni, and Sn in the soil, rice, and vegetables from the four exposure sites were significantly higher compared to the control site in both seasons. Soil pollution indices indicated moderate to higher contamination levels of Pb, Zn, Cd, As, and Se in 30-50% of soil, supporting their accumulation in food crops. Source apportionment analysis identified uncontrolled shipwrecking operations as the primary anthropogenic activity mainly contributing to metal/loid pollution. Health risk analysis showed inorganic arsenic (estimated), Cd, and Pb in food crops could pose potential health threats to the general population. Spinach leaf and gourd were identified as the highest-risk contributing vegetables in the dry and wet seasons. These findings help to inform management strategies to protect agroecosystems and public health.

Relationships between growth indicators, liver and kidney function markers, and blood concentrations of essential and potentially toxic elements in environmentally exposed young children.

Environmental exposure to multiple metals and metalloids is widespread, leading to a global concern relating to the adverse health effects of mixed-metals exposure, especially in young children living around industrial areas. This study aimed to quantify the concentrations of essential and potentially toxic elements in blood and to examine the potential associations between multiple elements exposures, growth determinants, and liver and kidney function biomarkers in children living in several industrial areas in Dhaka, Bangladesh. The blood distribution of 20 trace elements As, Ag, Bi, Br, Cd, Co, Cr, Cu, I, Mn, Hg, Mo, Ni, Pb, Se, Sb, Tl, V, U, and Zn, growth determinants such as body mass index and body fats, blood pressure, liver and kidney injury biomarkers including serum alanine aminotransferase and alkaline phosphatase activities, serum calcium, and creatinine levels, blood urea nitrogen, and hemoglobin concentrations, and glomerular filtration rate were measured in 141 children, aged six to 16 years. Among these elements, blood concentrations of Ag, U, V, Cr, Cd, Sb, and Bi were measured below LOQs and excluded from subsequent statistical analysis. This comprehensive study revealed that blood concentrations of these elements in children, living in industrial areas, exceeded critical reference values to varying extents; elevated exposure to As, Pb, Br, Cu, and Se was found in children living in multiple industrial areas. A significant positive association between elevated blood Tl concentration and obesity (ß = 0.300, p = 0.007) and an inverse relationship between lower As concentration and underweight (ß = -0.351, p < 0.001) compared to healthy weight children indicate that chronic exposure to Tl and As may influence the metabolic burden and physical growth in children. Concentration-dependent positive associations were observed between the blood concentrations of Cu, Se, and Br and hepatic- and renal dysfunction biomarkers, an inverse association with blood Mo and I level, however, indicates an increased risk of Cu, Se, and Br-induced liver and kidney toxicity. Further in-depth studies are warranted to elucidate the underlying mechanisms of the observed associations. Regular biomonitoring of elemental exposures is also indispensable to regulate pollution in consideration of the long-term health effects of mixed-elements exposure in children.

Effect of basal metabolic rate on lifespan: a sex-specific Mendelian randomization study.

Observationally, the association of basal metabolic rate (BMR) with mortality is mixed, although some ageing theories suggest that higher BMR should reduce lifespan. It remains unclear whether a causal association exists. In this one-sample Mendelian randomization study, we aimed to estimate the casual effect of BMR on parental attained age, a proxy for lifespan, using two-sample Mendelian randomization methods. We obtained genetic variants strongly (p-value < 5 × 10-8) and independently (r2 < 0.001) predicting BMR from the UK Biobank and applied them to a genome-wide association study of parental attained age based on the UK Biobank. We meta-analyzed genetic variant-specific Wald ratios using inverse-variance weighting with multiplicative random effects by sex, supplemented by sensitivity analysis. A total of 178 and 180 genetic variants predicting BMR in men and women were available for father's and mother's attained age, respectively. Genetically predicted BMR was inversely associated with father's and mother's attained age (years of life lost per unit increase in effect size of genetically predicted BMR, 0.46 and 1.36; 95% confidence interval 0.07-0.85 and 0.89-1.82), with a stronger association in women than men. In conclusion, higher BMR might reduce lifespan. The underlying pathways linking to major causes of death and relevant interventions warrant further investigation.

Clinical outcome of a quadrifocal (trifocal) intraocular lens in Chinese patients: prospective, observational case series.

PURPOSE: To report the visual outcomes and quality of vision and life after bilateral implantation of a single-piece trifocal intraocular lens (IOL) in Chinese patients. SETTING: Hong Kong Sanatorium & Hospital, Hong Kong, China. DESIGN: Prospective, observational case series. METHODS: Patients with bilateral implantation of AcrySof IQ PanOptix multifocal IOL were included. Distance, intermediate (60 cm), and near (40 cm) visual acuities (VAs) and contrast sensitivity (CS), defocus curve, preoperative higher-order aberration (HOA), dysphotopsia (0 to 5), satisfaction (1 to 5), spectacle independence, and quality of life were evaluated. The association between preoperative HOA and postoperative halos was also assessed. RESULTS: 54 eyes of 27 patients were included. The mean binocular distance, intermediate, and near uncorrected VA was -0.05 ± 0.06 (20/18), 0.06 ± 0.10 (20/23), and 0.04 ± 0.05 (20/22), respectively. No eyes lost more than 1 line of vision. Binocular CS was comparable with the monocular population norm of older adults. The defocus curve demonstrated that the binocular VA of 20/25 or better was achieved at a power of -3.00 to +0.50 diopters. The mean scores for halos, glare, and starbursts were 2.4 ± 1.4, 0.2 ± 0.8, and 1.4 ± 1.4 (of 5), respectively. The mean satisfaction score was 4.3 ± 0.7 (of 5). All the patients (100%) reported total spectacle independence. The mean vision-targeted composite score of the vision-related quality-of-life questionnaire was 97.2 ± 9.7 (of 100). Preoperative HOA was not associated with postoperative halos. CONCLUSIONS: Implantation of the trifocal IOL provided satisfactory visual outcomes and quality of vision and life, which resulted in a high rate of spectacle independence.

Genotoxicity assessment of per- and polyfluoroalkyl substances mixtures in human liver cells (HepG2).

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous, toxic, and persistent environmental chemicals of concern that have been widely detected in all environmental matrices including human biological fluids. Although humans are exposed to complex mixtures of PFAS, it remains uncertain whether the co-exposure to PFAS mixtures could induce genotoxic damage in humans. Hence, this study evaluated the combined genotoxicity of PFAS mixtures in a human cell line system. To assess the possible genotoxic damage caused by human exposure to PFAS and their mixtures, we investigated their potential to induce cytotoxicity (cell viability) and genotoxicity (DNA damage) in a human liver cell line (HepG2). The selected PFAS include perfluorononanoic acid (PFNA), perfluorooctane sulfonic acid (PFOS), perfluorodecanoic acid (PFDA), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonic acid (PFHxS). The interaction toxicities of these PFAS in binary mixtures were also determined using the additive index approach. The results revealed that exposure to PFNA, PFOS, PFDA, PFOA, and PFHxS singly and in binary mixtures induced a concentration-dependent decrease in cell viability. The additive index values indicated that the binary mixtures of PFOS + PFNA, PFOS + PFDA, and PFOS + PFOA displayed synergistic interaction, whereas the binary mixtures of PFOS + PFHxS, PFOA + PFNA, PFOA + PFDA, and PFOA + PFHxS behaved additively. Using the alkaline Comet assay, the potential of PFAS and their mixtures to induce DNA damage was evaluated based on a 1:1 ratio of the concentration of respective compounds required to produce a 1/10th of effective concentrations causing 50 % inhibition in cell viability (EC50). The results revealed that exposure to PFNA, PFOS, PFDA, PFOA, and PFHxS singly and in binary mixtures (PFOS + PFNA, PFOS + PFDA, PFOS + PFOA, PFOS + PFHxS, PFOA + PFNA, PFOA + PFDA, and PFOA + PFHxS) caused a moderate increase in cellular DNA damage, but no dose-response relationship was observed. Overall, this study indicates that the tested PFAS causes a concentration-dependent decrease in cell viability and only a modest increase in cellular DNA damage under these conditions.

Effects of shipwrecks on spatiotemporal dynamics of metal/loids in sediments and seafood safety in the Bay of Bengal.

Metal/loid pollution from shipwrecking activities has drawn significant concern due to their persistent threat to the marine ecosystem and human health. We investigated the spatiotemporal distribution, pollution characteristics, risks, sources, and potential impact of metal/loids in the sediments and seafood in the Bay of Bengal at nearby open beaching shipwrecking yards in Bangladesh. We collected 78 sediments and 208 seafood samples from the exposed and control sites from 2018 to 2020 during the dry and wet seasons. The concentrations of 16 elements, including cadmium, arsenic, lead, chromium, manganese, copper, zinc, iron, tin, antimony, nickel, cobalt, molybdenum, vanadium, selenium, and thallium were measured using validated inductively coupled plasma-mass spectrometry (ICP-MS) methods. Based on the pollution indices (enrichment factor, geoaccumulation index, pollution index, and pollution load index), lead, arsenic, cadmium, selenium, copper, zinc, and tin from the dry season showed higher contaminations compared to the wet and their concentrations were increased from 2018 to 2020 with seasonal fluctuations. Sediment cadmium and arsenic posed relatively higher and moderate ecological risks. Health risk analysis indicated that lead, cadmium, and inorganic arsenic (estimated) in seafood species pose a possible health threat to the general population. Further, there were possible ecological and health risks for the metal/loids in combination based on the ecological risk index in sediment and the hazard index in seafood, respectively. Source apportionment suggested that anthropogenic activities through uncontrolled shipwrecking operations over the last four decades were the largest polluting dominator, contributing 55-77% of the metal/loid concentrations. Therefore, the data may inform mitigation strategies for emission control at the shipwrecking yards to protect marine ecosystems and their local population.

Toxicity assessment of historical aqueous film-forming foams (AFFFs) using cell-based assays.

Aqueous film-forming foam (AFFF) has historically contained high concentrations of long-chain per-and polyfluoroalkyl substances (PFAS), which have been linked with adverse health outcomes. However, the toxicity of historical AFFFs remains largely unknown, presenting uncertainties in their risk assessment. This study assessed the toxicity of historical AFFFs by exposing human liver cells (HepG2) to various dilutions of 3M Light Water AFFF or Ansulite AFFF (0.001%, 0.002%, 0.005%, 0.009%, 0.019%, 0.038%, 0.075%, 0.15%, and 0.3%) for 24 h. The effects of the two AFFF formulations on the cell viability, intracellular reactive oxygen species (ROS) production, Nrf2-ARE activity, and DNA damage were assessed by CellTiter 96® Aqueous One Solution Cell Proliferation Assay (MTS kit), dichlorofluorescein diacetate assay, luciferase assay, and alkaline Comet assay, respectively. The results revealed that the two brands of AFFFs tested were toxic to HepG2 cells at dilutions lower than the recommended 3% application formulation. Specifically, exposure to 3M Light Water AFFF or Ansulite AFFF induced a dilution-dependent decrease in cell viability, increased intracellular ROS production, and increased Nrf2-ARE activity. However, except for the highest concentration (lowest dilution) of 3M Light Water AFFF tested (0.038%.), both 3M Light Water AFFF and Ansulite AFFF did not significantly induce cellular DNA damage. Overall, 3M Light Water AFFF was more toxic than Ansulite AFFF. The findings from this study provided valuable in vitro toxicity data that may better inform the health risk assessment of these historical AFFFs.

Metal(loid) flux change in Dongting Lake due to the operation of Three Gorges Dam, China.

A drastic decrease in the suspended sediment of Dongting Lake (DTL) has been observed due to Three Gorges Dam (TGD) impoundment operation since 2003. However, the relationship between sediment loads and metal fluxes has not been studied. This study comprehensively analyzed the content characteristics of seven metal(loid)s (As, Cd, Cr, Cu, Hg, Pb, and Zn) in the surface sediment of DTL from 2000 to 2019. The period of 2005-2009 corresponded to a metal(loid) enrichment stage in the sediment of DTL. The metal(loid) cumulative input of DTL from 2000 to 2019 reached 153 × 103 t, and the increasing rate was gradually diminished because of TGD operation, while the metal(loid) cumulative output reached 132 × 103 t. Undergoing an input-output state transition, the metal(loid) cumulative deposition of DTL in 2019 was only 42% of its peak in 2007. Especially, the metal(loid) fluxes of DTL all became negative for the first time in 2006. It is worth noting that Cd in DTL has shifted to a net export during the study period. Finally, the assessment results of pollution, risk, and toxicity indicated that metal(loid) effects on sediment quality were weakening in recent years. This study confirmed that DTL has shifted from metal(loid) deposition to export, providing new information for future DTL management options.

Concentrations of essential and toxic elements and health risk assessment in brown rice from Qatari market.

Twenty-two brown rice varieties available in the Qatari market were analyzed for essential and toxic elements by ICP-MS. Found concentrations (µg/kg) were: As: 171 ± 78 (62-343), Cd: 42 ± 60 (4-253), Cr: 515 ± 69 (401-639), Pb: 6 ± 7 ( 1 in million, may possibly be > 1 in 10,000 based on conservatively high brown rice consumption rates of 200 g/d or 400 g/d in Qatar. These elevated risks may be applicable to specific population subgroups with diabetic conditions who consume only brown rice. Non-cancer risks are mainly derived from Mn, V, Se, and Cd with a hazard index > 1 from some brown rice samples.

Effect of time since primary laser-assisted in situ keratomileusis on flap relift success and epithelial ingrowth risk.

PURPOSE: To assess the association of time since primary laser-assisted in situ keratomileusis (LASIK) with flap relift success and risk for epithelial ingrowth (EI) in eyes undergoing flap relift after primary LASIK. SETTING: Hong Kong Sanatorium & Hospital, Hong Kong Special Administrative Region. DESIGN: Retrospective observational case series. METHODS: 73 eyes with flaps relifted for refractive enhancement LASIK were included. Main outcome measures included rate of relift success and EI; associations of time since primary LASIK, sex, age at relift, year of relift, and flap creation method in primary LASIK with relift success and EI. RESULTS: Of the 73 eyes included, relifting was successful in 71 eyes (97.3%). Among the successfully relifted eyes, 12 (16.9%) developed EI, of which 3 (4.2%) were clinically significant. No eyes lost more than 1 line of corrected distance visual acuity. The time since primary LASIK (up to 22 years), sex, age at relift, year of relift, and flap creation method in primary LASIK were not associated with relift success or EI. CONCLUSIONS: With the described surgical technique, flaps could be successfully relifted without much difficulty up to 22 years after primary LASIK with a low incidence of EI.

Combined effects of mixed per- and polyfluoroalkyl substances on the Nrf2-ARE pathway in ARE reporter-HepG2 cells.

Although the Nrf2-ARE pathway plays a critical role in cellular protection against toxicity and oxidative stress from environmental chemical stressors, the association between exposure to per- and polyfluoroalkyl substances (PFAS) mixtures and the changes of Nrf2-ARE pathway remains largely unexplored. This study evaluated the potential of PFAS to induce the Nrf2-ARE pathway as individual compounds and as binary, ternary, and multicomponent mixtures in the ARE reporter-HepG2 cells and compared the mixture toxicity data to the predictions by concentration addition (CA) model. The toxicological interactions between PFAS mixture components were also determined by the model deviation ratio (MDR) between the CA predicted and mixture toxicity values. The induction of the Nrf2-ARE pathway was quantified using the luciferase system, and the endpoint assessed was the concentration that induced an induction ratio (IR) of 1.5 (ECIR1.5). The results showed that exposures to both individual and mixed PFAS induced the Nrf2-ARE pathway in ARE reporter-HepG2 cells. Based on the MDRs, the combinations with PFOS showed synergistic interactive effects, while the combinations with PFOA showed additive effects. These results indicate that the CA model underestimated the mixture toxicity of PFAS with PFOS co-exposures and may have health risk assessment implications.

Effect of Basal Metabolic Rate on Cancer: A Mendelian Randomization Study.

Background: Basal metabolic rate is associated with cancer, but these observations are open to confounding. Limited evidence from Mendelian randomization studies exists, with inconclusive results. Moreover, whether basal metabolic rate has a similar role in cancer for men and women independent of insulin-like growth factor 1 increasing cancer risk has not been investigated. Methods: We conducted a two-sample Mendelian randomization study using summary data from the UK Biobank to estimate the causal effect of basal metabolic rate on cancer. Overall and sex-specific analysis and multiple sensitivity analyses were performed including multivariable Mendelian randomization to control for insulin-like growth factor 1. Results: We obtained 782 genetic variants strongly (p-value < 5 × 10-8) and independently (r 2 < 0.01) predicting basal metabolic rate. Genetically predicted higher basal metabolic rate was associated with an increase in cancer risk overall (odds ratio, 1.06; 95% confidence interval, 1.02-1.10) with similar estimates by sex (odds ratio for men, 1.07; 95% confidence interval, 1.002-1.14; odds ratio for women, 1.06; 95% confidence interval, 0.995-1.12). Sensitivity analyses including adjustment for insulin-like growth factor 1 showed directionally consistent results. Conclusion: Higher basal metabolic rate might increase cancer risk. Basal metabolic rate as a potential modifiable target of cancer prevention warrants further study.

Assessment methodology applied to arsenic pollution in lake sediments combining static and dynamic processes.

The fraction transformation from stable to mobile forms in sediments is continuous, slow, and spontaneous chain reactions causing static risks to the aquatic system. However, this process may change into abrupt, rapid, and dynamic paths when certain physicochemical conditions changed. Using the Delayed Geochemical Hazard (DGH) model, comprehensive methods combing both static and dynamic risk assessment were therefore conducted to evaluate the aforementioned processes. By applying these methods, arsenic (As) pollution in surface sediments of the Baiyangdian Lake (BYD Lake) was investigated thoroughly as a case study area. The results showed that the total As concentrations in those sediment samples ranged from 4.87 to 17.94 mg/kg, with an average of 8.75 mg/kg. In a fraction, Fe and Mn were observed to pose effects on the surface-adsorbed (AsS) and residual fractions (AsR) with the coefficient analysis. The static risk assessment showed that both the contamination and ecological risk are at a low level in the total content but a low to moderate risk in the fraction. The dynamic risk assessment posted the potential transformation paths of As in the sediments, indicating a trend of potential DGH burst in 45.24%-78.57% of the BYD Lake. In summary, this study provides a methodology for the risk assessment of arsenic that may extend to other heavy metal(loid)s combining static and dynamic processes in sediments.

Evaluation of the individual and combined toxicity of perfluoroalkyl substances to human liver cells using biomarkers of oxidative stress.

Although human exposure is to mixtures of per- and polyfluoroalkyl substances (PFAS), their combined effects and underlying mechanisms remain largely unknown. In this study, the combined effects of PFAS was investigated by treating human liver cells (HepG2) with various concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (PFDA), perfluorononanoic acid (PFNA), and perfluorohexanoic acid (PFHxS) individually or in binary combinations (PFOS + PFOA, PFOS + PFDA, PFOS + PFNA, PFOS + PFHxS, PFOA + PFDA, PFOA + PFNA, and PFOA + PFHxS) for 24 h using an orthogonal design. The individual and binary combination effects of PFAS on the cytotoxicity, intracellular reactive oxygen species (ROS) production, and glutathione (GSH) levels were determined by MTS assay, dichlorofluorescein diacetate assay, and GSH-Glo™ Glutathione assay, respectively. The results showed that exposure to PFOA, PFOS, PFDA, PFNA, and PFHxS individually and in binary combinations caused concentration-dependent cytotoxicity to HepG2 cells. Also, intracellular ROS production was not significantly induced in both the individual and co-treatment groups, indicating that ROS production may not be likely influencing the combined cytotoxicity of PFAS to HepG2 cells. However, the depletion of the intracellular glutathione levels was correlated with cytotoxicity. Moreover, the factorial analysis results showed no significant interactive effects between PFOS + PFOA, PFOS + PFDA, PFOS + PFNA, PFOS + PFHxS, PFOA + PFDA, PFOA + PFNA, and PFOA + PFHxS. Taken together, the results showed that both individual and combined PFAS could induce concentration-dependent cytotoxicity and depletion of GSH levels, but could not induce significant increases in ROS production at the concentration range tested. Overall, these results provided valuable toxicological data on the combined effects of mixed PFAS that may help to better assess their human health risk.

Development and Validation of an ICP-MS Method and Its Application to Determine Multiple Trace Elements in Small Volumes of Whole Blood and Plasma.

Essential and nonessential element concentrations in human blood provide important information on the nutritional status of individuals and can assist in the screening or diagnosis of certain disorders and their association with other causative factors. A simple and sensitive method, suitable for use with small sample volumes, for quantification of multiple trace element concentrations in whole blood and plasma has been developed using inductively coupled plasma-mass spectrometry. Method validation was performed using standard reference materials of whole blood and serum using varying sample treatments with nitric acid, water and hydrogen peroxide. The method was applied to quantify the trace element concentrations in whole blood and plasma samples (0.1 mL) from 50 adult blood donors in Queensland. The whole blood sample (5 mL) was collected in Vacutainer tubes with K2EDTA as anticoagulant. The developed method was able to quantify, in blood and plasma samples over a wide range of concentrations, several essential elements: cobalt, copper, zinc, iron, manganese and selenium; the nutritionally probably essential elements vanadium and strontium; and nonessential elements including lead, cadmium, arsenic, caesium, barium, thallium and uranium. Significant differences (P < 0.0001) were observed between whole blood and plasma concentrations for 13 elements; 5 of the measured elements, cobalt (0.49 vs. 0.36 µg/L), copper (1.0 vs. 0.75 mg/L), strontium (28 vs. 16 µg/L), barium (1.5 vs. 0.64 µg/L) and thallium (0.06 vs. 0.03 µg/L), had higher mean concentrations in plasma than in blood. Whole blood concentrations of nine trace elements were significantly correlated (P < 0.0001) with plasma concentrations. The distribution of the trace elements between human blood and plasma varied considerably for the different elements. These results indicate that, using a small sample volume, this assay is suitable for the evaluation of nutritional status as well as in monitoring human toxic elemental exposures.

Assessment of human health risk due to lead in urban park soils using in vitro methods.

Beijing parks always have a large flow of local residents and tourists, and the soil Pb could threaten human health by incidental ingestion. Soil samples from eleven parks in Beijing were collected to assess the human health risk associated with Pb. Lead bioaccessibility in these parks ranged from 3.2 ± 0.4% to 12.1 ± 0.5% in the physiologically based extraction test (PBET) gastric phase and increased when approaching the city center. The chemical forms and soil properties (Fe, organic matter, and grain size) were important factors affecting the soil Pb bioaccessibility. The geo-accumulation index of Beihai Park (BH, near the city center) reached 1.3 ± 0.1 indicating moderate contamination. Lead health risk to children in BH should be of concern though its hazard quotient was below one. Results obtained from the Diffusive Gradients in Thin-films (DGT)-induced fluxes in the soils (DIFS) model showed that Pb-release in some parks farther from the city center was a "partially sustained case" (Rdiff < R < 0.95) indicating that soil particles could partially replenish effective Pb to the soil solution. A relatively higher desorption rate constant (k1) and shorter characteristic response time (Tc) were also found in these parks, indicating non-negligible release risk. Soil Pb based on the PBET method and DIFS model could provide a reliable reference to park managers for the health risk management of Pb pollution.

Assessing the human health risks of per- and polyfluoroalkyl substances: A need for greater focus on their interactions as mixtures.

Humans are exposed to complex mixtures of per- and polyfluoroalkyl substances (PFAS). However, human health risk assessment of PFAS currently relies on animal toxicity data derived from individual substance exposure, which may not adequately predict the risk from combined exposure due to possible interactions that can influence the overall risk. Long-chain perfluoroalkyl acids (PFAAs), particularly perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are recognised as global emerging contaminants of concern due to their ubiquitous distribution in all environmental media, wildlife, and humans, persistency, bioaccumulative-, toxic-, and human health-risk potentials. This article reviews the current understanding of the human health risks associated with PFAS exposure focusing on more recent toxicological and epidemiological studies from 2010 to 2020. The existing information on PFAA mixtures was also reviewed in an attempt to highlight the need for greater focus on their potential interactions as mixtures within the class of these chemicals. A growing number of toxicological studies have indicated several adverse health outcomes of PFAA exposure, including developmental and reproductive toxicity, neurotoxicity, hepatotoxicity, genotoxicity, immunotoxicity, thyroid disruption, and carcinogenicity. Epidemiological findings further support some of these adverse human health outcomes. However, the mechanisms underlying these adverse effects are not well defined. A few in vitro studies focusing on PFAA mixtures revealed that these compounds may act additively or interact synergistically/antagonistically depending on the species, dose level, dose ratio, and mixture components. Hence, the combined effects or potential interactions of PFAS mixtures should be considered and integrated into toxicity assessment to obtain a realistic and more refined human health risk assessment.

Effect of Glucagon on Ischemic Heart Disease and Its Risk Factors: A Mendelian Randomization Study.

CONTEXT: Glucagon acts reciprocally with insulin to regular blood glucose. However, the effect of glucagon on cardiovascular disease has not been widely studied. It has been suggested that insulin may increase the risk of ischemic heart disease. OBJECTIVE: To investigate whether glucagon, the main counteracting hormone of insulin, plays a role in development of ischemic heart disease. DESIGN, SETTING, AND PARTICIPANTS: In this 2-sample Mendelian randomization study, we estimated the causal effect of glucagon on ischemic heart disease and its risk factors using the inverse-variance weighted method with multiplicative random effects and multiple sensitivity analyses. Genetic associations with glucagon and ischemic heart disease and its risk factors, including type 2 diabetes and fasting insulin, were obtained from publicly available genome-wide association studies. MAIN OUTCOME MEASURE: Odds ratio for ischemic heart disease and its risk factors per 1 standard deviation change in genetically predicted glucagon. RESULTS: Twenty-four single-nucleotide polymorphisms strongly (P < 5 × 10-6) and independently (r2 < 0.05) predicting glucagon were obtained. Genetically predicted higher glucagon was associated with an increased risk of ischemic heart disease (inverse-variance weighted odds ratio, 1.03; 95% confidence interval, 1.0003-1.05) but not with type 2 diabetes (inverse-variance weighted odds ratio, 0.998, 95% confidence interval, 0.97-1.03), log-transformed fasting insulin (inverse-variance weighted beta, 0.002, 95% confidence interval, -0.01 to 0.01), other glycemic traits, blood pressure, reticulocyte, or lipids. CONCLUSION: Glucagon might have an adverse impact on ischemic heart disease. Relevance of the underlying pathway to existing and potential interventions should be investigated.