Human Risk Assessment Research Articles

Prediction of Maternal Hemorrhage Using Machine Learning: Retrospective Cohort Study

BackgroundPostpartum hemorrhage remains one of the largest causes of maternal morbidity and mortality in the United States.ObjectiveThe aim of this paper is to use machine learning techniques to identify patients at risk for postpartum hemorrhage at obstetric delivery.MethodsWomen aged 18 to 55 years delivering at a major academic center from July 2013 to October 2018 were included for analysis (N=30,867). A total of 497 variables were collected from the electronic medical record including the following: demographic information; obstetric, medical, surgical, and family history; vital signs; laboratory results; labor medication exposures; and delivery outcomes. Postpartum hemorrhage was defined as a blood loss of ≥1000 mL at the time of delivery, regardless of delivery method, with 2179 (7.1%) positive cases observed. Supervised learning with regression-, tree-, and kernel-based machine learning methods was used to create classification models based upon training (21,606/30,867, 70%) and validation (4630/30,867, 15%) cohorts. Models were tuned using feature selection algorithms and domain knowledge. An independent test cohort (4631/30,867, 15%) determined final performance by assessing for accuracy, area under the receiver operating curve (AUROC), and sensitivity for proper classification of postpartum hemorrhage. Separate models were created using all collected data versus models limited to data available prior to the second stage of labor or at the time of decision to proceed with cesarean delivery. Additional models examined patients by mode of delivery.ResultsGradient boosted decision trees achieved the best discrimination in the overall model. The model including all data mildly outperformed the second stage model (AUROC 0.979, 95% CI 0.971-0.986 vs AUROC 0.955, 95% CI 0.939-0.970). Optimal model accuracy was 98.1% with a sensitivity of 0.763 for positive prediction of postpartum hemorrhage. The second stage model achieved an accuracy of 98.0% with a sensitivity of 0.737. Other selected algorithms returned models that performed with decreased discrimination. Models stratified by mode of delivery achieved good to excellent discrimination but lacked the sensitivity necessary for clinical applicability.ConclusionsMachine learning methods can be used to identify women at risk for postpartum hemorrhage who may benefit from individualized preventative measures. Models limited to data available prior to delivery perform nearly as well as those with more complete data sets, supporting their potential utility in the clinical setting. Further work is necessary to create successful models based upon mode of delivery and to validate the findings of this study. An unbiased approach to hemorrhage risk prediction may be superior to human risk assessment and represents an area for future research.

Coal Miners and Lung Cancer: Can Mortality Studies Offer a Perspective on Rat Inhalation Studies of Poorly Soluble Low Toxicity Particles?

Inhalation studies involving laboratory rats exposed to poorly soluble particles (PSLTs), such as carbon black and titanium dioxide, among others, have led to the development of lung cancer in conditions characterized as lung overload. Lung overload has been described as a physiological state in which pulmonary clearance is impaired, particles are not effectively removed from the lungs and chronic inflammation develops, ultimately leading to tumor growth. Since lung tumors have not occurred under similar states of lung overload in other laboratory animal species, such as mice, hamsters and guinea pigs, the relevance of the rat as a model for human risk assessment has presented regulatory challenges. It has been suggested that coal workers' pneumoconiosis may reflect a human example of apparent “lung overload” of poorly soluble particles. In turn, studies of risk of lung cancer in coal miners may offer a valuable perspective for understanding the significance of rat inhalation studies of PSLTs on humans. This report addresses whether coal can be considered a PSLT based on its composition in contrast to carbon black and titanium dioxide. We also review cohort mortality studies and case-control studies of coal workers. We conclude that coal differs substantially from carbon black and titanium dioxide in its structure and composition. Carbon black, a manufactured product, is virtually pure carbon (upwards of 98%); TiO2 is also a manufactured product. Coal contains carcinogens such as crystalline silica, beryllium, cadmium and iron, among others; in addition, coal mining activities tend to occur in the presence of operating machinery in which diesel exhaust particles, a Type I Human carcinogen, may be present in the occupational environment. As a result of its composition and the environment in which coal mining occurs, it is scientifically inappropriate to consider coal a PSLT. Despite coal not being similar to carbon black or TiO2, through the use of a weight of evidence approach-considered the preferred method when evaluating disparate studies to assess risk- studies of coal-mine workers do not indicate a consistent increase in lung cancer risk. Slight elevations in SMR cannot lead to a reliable conclusion about an increased risk due to limitations in exposure assessment and control of inherent biases in case-control studies, most notably confounding and recall bias. In conclusion, the weight of the scientific literature suggests that coal mine dust is not a PSLT, and it does not increase lung cancer risk.

Uptake and metabolism of 14C-triclosan in celery under hydroponic system

As triclosan is used extensively as an antimicrobial agent, it inevitably enters agroecosystems, when sewage and treated wastewater are applied to agricultural fields. As a result, triclosan can be accumulated into crops and vegetables. Currently, limited information is available on the metabolism of triclosan in vegetables. In this study, the fate of 14C-triclosan in celery under a hydroponic system was investigated in a 30-day laboratory test. Most (97.7 %) of the 14C-triclosan accumulated in celery. The bioconcentration factors of triclosan were up to 3140 L kg−1 at day 30. The concentration of 14C-triclosan in roots (17.8 mg kg−1) was 57- and 127-fold higher than that in stems (0.31 mg kg−1) and leaves (0.14 mg kg−1), respectively, at day 30, suggesting a higher accumulation of triclosan in celery roots and negligible transport to stems and leaves. Moreover, triclosan, as well as its eight metabolites, was detected and identified in celery tissues and the growth medium using 14C-labelling and LC-Q-TOF-MS analysis methods. Phase I metabolites in the growth medium were from hydroxylation, dechlorination, nitration, and nitrosylation. Phase II metabolism was the major pathway in celery tissues. Monosaccharide, disaccharide, and sulfate conjugates of triclosan were putatively identified. The results represent an important step toward a better evaluation of the behavior of triclosan in vegetables, with notable implications for environmental and human risk assessments of triclosan.

Winter and spring variation in sources, chemical components and toxicological responses of urban air particulate matter samples in Guangzhou, China

The sources and chemical components of urban air particles exhibit seasonal variations that may affect their hazardousness to human health. Our aims were to investigate winter and spring variation in particulate matter (PM) sources, components and toxicological responses of different PM size fractions from samples collected in Guangzhou, China. Four size-segregated PM samples (PM10–2.5, PM2.5–1, PM1–0.2, and PM0.2) were collected separately during winter (December 2017 and January 2018) and spring (March 2018). All PM samples were analyzed for chemical components and characterized by source. RAW 264.7 macrophages were exposed to four doses of PM samples for 24 h. Cytotoxicity, oxidation, cell cycle, genotoxicity and inflammatory parameters were tested. PM concentrations were higher in the winter samples and caused more severe cytotoxicity and oxidative damage than to PM in the spring samples. PM in winter and spring led to increases in cell cycle and genotoxicity. The trends of size-segregated PM components were consistent in winter and spring samples. Metallic elements and PAHs were found in the largest concentrations in winter PM, but ions were found in the largest concentrations in spring PM. metallic elements, PAHs and ions in size-segregated PM samples were associated with most toxicological endpoints. Soil dust and biomass burning were the main sources of PM in winter, whereas traffic exhaust and biomass burning was the main source with of spring PM. Our results suggest that the composition of PM samples from Guangzhou differed during winter and spring, which led to strong variations in toxicological responses. The results demonstrate the importance of examining a different particle sizes, compositions and sources across different seasons, for human risk assessment.

Carcinogenicity of Poorly Soluble Low Toxicity Particles: Commentary on Epidemiology as a Risk Assessment "Reality Check".

Inhaled particles that are poorly soluble or insoluble and of low toxicity (“poorly soluble low toxicity” or “PSLT” particles), can accumulate in the lung and at lung overload levels induce lung cancers in rats. The question of whether PSLT particles increase lung cancer risk in humans is complicated by large differences between rats and humans and the relatively large particle doses administered in animal studies even when compared with heavy human occupational exposures. We review the findings of epidemiological studies on occupational exposure to each of three different PSLT particles (carbon black, talc and taconite). The epidemiological evidence indicates that at even very high occupational exposure levels at which non-malignant respiratory diseases including pneumoconiosis and even talcosis are observed, lung cancer risks appear not to be elevated. Although positive human cancer risks might be predicted based on extrapolation from overload doses in rats to relevant exposures in humans, the epidemiological “reality check” based on the three examples indicates that these PSLT particles are unlikely to increase lung cancer risk in humans even at high occupational levels of exposure. Therefore, we propose that careful evaluation of the epidemiological evidence can serve as a “reality check” for human risk assessment and help balance the risk evaluation process.

Evaluation of heavy metal contamination in copper mine tailing soils of Kitwe and Mufulira, Zambia, for reclamation prospects

Understanding the level of heavy metal contamination coupled with the assessment of environmental and human risks associated with mine waste dumpsites is an important step to initiating efficient measures for mine wasteland restoration, stabilization, and bioremediation. In the present study, concentration of the heavy metals; Copper (Cu), Cobalt (Co), Iron (Fe), Lead (Pb), Manganese (Mn), and Zinc (Zn) in soil from mine waste dumpsites around Kitwe (Sites: BM and TD26) and Mufulira (Site: TD10), Zambia, was assessed to determine the level of contamination, ecological risks, and progress made in reclamation. The mine waste dumpsites in the two towns are located in the vicinity of residential areas. Therefore, there is need to provide information for optimization of protocols for post-mining landscape in Zambia and elsewhere to limit soil, river, and groundwater contamination and to accelerate the restoration process . Mean values for soil pH, electrical conductivity, and organic matter varied between 5.9–8.4, 2534.8–538.6 μS/cm, and 0.90–2.75%, respectively. The mean concentrations of heavy metals of BM, TD26, and TD10 decreased in order of Fe > Cu > Co > Mn > Pb > Zn across all sites. However, the order of overall degree of heavy metal contamination computed using control soil as a baseline in BM, TD26, and TD10 was Cu > Co > Fe > Pb > Mn > Zn. The pollution load index was 0.355 at BM, 0.329 at TD26, and 0.189 at TD10, indicating high soil pollution at BM and TD26. The Potential Ecological Risk Index for all heavy metals tested at BM, TD26, and TD10 showed low ecological risk in the vicinity of the studied dumpsites. Furthermore, the present study also showed that the polluted soils around smelter sites and mine waste dumpsites are susceptible to dispersion by wind and water. Additionally, results from TD10 revealed that the initiated remediation of the tailings dam was somewhat successful. Finally, this study provided an updated status regarding the accumulation of heavy metals in mine waste dumpsites of Kitwe and Mufulira, Zambia and baseline information necessary to enhance post-mining landscape reclamation.

EFSA International Workshop on RA of Combined Exposure to Multiple Chemicals

Human Risk Assessment (RA) of combined exposure to multiple chemicals follows the steps of RA namely problem formulation, exposure assessment, hazard assessment and risk characterisation. Over the last decade, scientific advisory bodies have published a range of harmonised guidance documents to provide practical approaches for risk assessors. These include the WHO, the US-EPA, the Joint Research Centre (JRC) of the European Commission, the OECD and the recent EFSA MIXTOX guidance document dealing with harmonised methodologies for the human health, animal health and ecological RA areas. On May 21st 2021, the Scientific Committee of EFSA published a draft guidance document on scientific criteria to group chemicals in assessment groups using hazard-driven criteria and prioritisation methods using exposure-driven and risk-based approaches. The latter guidance and future challenges were the topic of this international workshop which was held online in the afternoons of the 18th, 19th and 20st October 2021. First, a plenary session provided overviews of European and international activities in the field including WHO, OECD, US-EPA, JRC and EFSA. With a total of 118 participants including national and international scientific advisory bodies, academics and researchers, NGOs, industry, risk assessors, risk managers, four discussions groups were created for three break-out group sessions: 1) Hazard-driven criteria for grouping multiple chemicals into assessment groups; 2) Exposure-driven and risk-based criteria for the prioritisation of multiple chemicals 3) Data gaps and future challenges for human health and environmental RA of combined exposure to multiple chemicals to identify priority topics of international relevance and a way forward to address these topics. A final discussion and wrap-up session concluded the meeting. This event report provides a summary of the discussions together with conclusions and recommendations.

Carcinogenic and Human Risk Assessments, Trace Element Concentrations, Proximate Composition, and Liver Antioxidants of Three Commercial Tilapia Fish Species from Manzalah Wetland, Egypt

Carcinogenic and Human Risk Assessments, Trace Element Concentrations, Proximate Composition, and Liver Antioxidants of Three Commercial Tilapia Fish Species from Manzalah Wetland, Egypt

In-situ TD-GCMS measurements of oxidative products of monoterpenes at typical vaping temperatures: implications for inhalation exposure to vaping products

Vaping is gaining in popularity. However, there is still much that remains unknown about the potential risk and harms of vaping. Formation of oxidative products is one of such areas that are not well understood. In this study, we used an in-situ thermal desorption GC/MS method to investigate the formation of oxidative products of several monoterpenes at or below typical vaping temperatures. Among the five tested monoterpenes, the unchanged portion of the parent compound in the vapour varied from 97 to 98% for myrcene to 11–28% for terpinolene. The majority of formed oxidative products in the vapour have a molecular weight of 134 (loss of two hydrogens), 150 (insertion of one oxygen and loss of two hydrogen atoms) or 152 (insertion of one oxygen atom). Three products, likely to be p-(1-propenyl)-toluene, β-pinone and fenchol were also observed. This is the first in-situ thermal desorption GC/MS study to investigate the possible formation of oxidative products of monoterpenes, one of the major components in vaping liquids, at temperatures that are relevant to the vaping process. Although the toxicity of inhaling these oxidative products is not clear yet, allergic and irritation reactions associated with oxidized monoterpene oils are well documented. Therefore, potential adverse effects of inhaling these oxidative products during vaping could be investigated to help support human risk assessment.

Human risk assessment of 4-n-nonylphenol (4-n-NP) using physiologically based pharmacokinetic (PBPK) modeling: analysis of gender exposure differences and application to exposure analysis related to large exposure variability in population.

As a toxic substance, 4-n-nonylphenol (4-n-NP) or 4-nonylphenol (4-NP) is widely present in the environment. 4-n-NP is a single substance with a linear-alkyl side chain, but 4-NP usually refers to a random mixture containing various branched types. Unfortunately, human risk assessment and/or exposure level analysis for 4-n-NP (or 4-NP) were almost nonexistent, and related research was urgently needed. This study aimed to analyze the various exposures of 4-n-NP (or 4-NP) through development of a physiologically based-pharmacokinetic (PBPK) model considering gender difference in pharmacokinetics of 4-n-NP and its application to human risk assessment studies. A PBPK model was newly developed considering gender differences in 4-n-NP pharmacokinetics and applied to a human risk assessment for each gender. Exposure analysis was performed using a PBPK model that considered gender differences in 4-n-NP (or 4-NP) exposure and high variabilities in several countries. Furthermore, an extended application was attempted as a human risk assessment for random mixture 4-NP, which is difficult to accurately evaluate in reality. External-exposure and margin-of-safety estimated with the same internal exposure amount differed between genders, meaning the need for a differentiated risk assessment considering gender. Exposure analysis based on biomonitoring data confirmed large variability in exposure to 4-n-NP (or 4-NP) by country, group, and period. External-exposures estimated using PBPK model varied widely, ranging from 0.039 to 63.875mg/kg/day (for 4-n-NP or 4-NP). By country, 4-n-NP (or 4-NP) exposure was higher in females than in males and the margin-of-safety tended to be low. Overall, exposure to 4-n-NP (or 4-NP) in populations was largely not safe, suggesting need for ongoing management and monitoring. Considering low in vivo accumulation confirmed by PBPK model, risk reduction of 4-n-NP is possible by reducing its use.

Immunomodulation and exposure to per- and polyfluoroalkyl substances: an overview of the current evidence from animal and human studies.

Per- and polyfluoroalkyl substances (PFAS) have been widely used and represent a class of environmental persistent chemicals. An association of a reduction of vaccination efficacy with PFAS serum levels in humans was used by the European Food Safety Authority as a key effect for PFAS risk assessment. The data support for using this association is reviewed by a critical analysis of the respective human epidemiology and the available animal studies on the immunomodulation of PFAS. Based on an analysis of the available human epidemiology, the overall level of evidence regarding associations between PFAS serum levels and reduced antibody response remains weak. Absence of anassociation between an increase in clinical infections and PFAS serum levels and the limited understanding of the importance of antibody levels as an isolated data point further support this conclusion. Animal toxicity studies with PFAS focusing on immunomodulation also provide only limited support for immunomodulation as an important endpoint in PFAS toxicity. While immunomodulation is observed after PFAS administration, generally at blood concentrations several orders of magnitude above those seen in environmentally exposed humans, the relevance of these observation is hampered by the high doses required to influence immune endpoints, the limited number of endpoints assessed, and inconsistent results. The limitations of the current database on associations of human PFAS exposures outlined here indicate that more evidence is required to select immunomodulation as a critical endpoint for human PFAS risk assessment.

Candidate City Human Rights Proposals for the 2026 World Cup: The Promise of a Positive Legacy

Since 2017, the Fédération Internationale de Football Association (FIFA) has incorporated human rights risk assessments into its bidding requirements for major events, beginning with the competition to host the 2026 FIFA Men’s World Cup.1 This process began at a time of increased scrutiny on the impact of major events and greater focus on the applicability of the UN Guiding Principles on Business and Human Rights (UNGPs) to sport. In 2014, the Centre for Sport and Human Rights’ founding Chair Mary Robinson, together with John Ruggie (author of the UNGPs), wrote to FIFA in their respective capacities as Patron and Chair of the Institute for Human Rights and Business (IHRB) to stress the need for ‘sustained due diligence […] with respect to decisions about host nations and how major sporting events are planned and implemented’.2 Following recommendations set forth in the letter, expanded upon in Ruggie’s 2016 report ‘For the Game, For the World’, FIFA introduced robust bidding requirements that any country or region wishing to bid to host a World Cup will have to conduct a human rights risk assessment and outline how they intend to mitigate each of the risks identified.3 These requirements are designed to align the World Cup bidding process with the UNGPs.

Pollution and risk assessment of heavy metals in water, sediment and fish (Clarias gariepinus) in a fish farm cluster in Niger Delta region, Nigeria.

The study determined the following heavy metals: cadmium (Cd), chromium (Cr), copper (Cu), manganese (Mn), lead (Pb) and zinc (Zn) concentrations in surface water and in fish pond (water, sediments and farmed fish (Clarias gariepinus)) from a fish farm cluster with the view of assessing its pollution level and associated human health exposure risk to these heavy metals through fish consumption. Samples were digested with aqua regia and metal concentrations were determined with an atomic absorption spectrophotometer equipped with an air acetylene flame. Mean concentrations of the heavy metals (ppm) in surface and pond water ranged as follows: cadmium (below detection limit (bdl): 0.298); chromium (bdl: 0.257); copper (bdl: 0.067); manganese (bdl: 0.163); lead (bdl: 0.736) and zinc (bdl: 0.078) while in sediment, the ranges (mg/kg dry weight) were as follows: cadmium (1.156-3.329); chromium (9.439-14.373); copper (26.710-121.819); manganese (3.143-37.202); lead (0.340-1.537) and zinc (87.681-371.060). The mean concentrations of the metals in surface water were significantly different (p < 0.05) from those in sediment in all the sampling sites. The mean metal concentrations (mg/kg dry weight) in C. gariepnus were in the following ranges: cadmium (0.733-1.405); chromium (0.593-1.692); copper (175.882-245.321); manganese (bdl: 3.326); lead (0.221-0.263) and zinc (248.191-292.333). Some of the heavy metal concentrations obtained in water, sediment and catfish analyzed were above the permissible limit set by some National (DPR) and International organisations (WHO, FEPA and FAO). The pollution studies showed that lead, cadmium and chromium contaminated the surface water samples. Sediment from all sites showed low to considerable contamination by the heavy metals. The human exposure risk assessment of the metals showed that the total hazard index was less than one which indicates no probable adverse health effect from the consumption of fish from the ponds, although this case is different for Pb since there is no estimation of oral reference dose (RfDo) for lead according to EPA.

Comparative evaluation of three methylene dianiline isomers in the bacterial reverse mutation assay, the in vitro gene mutation test, and the in vitro chromosomal aberration test.

4,4'-MDA is classified as a genotoxic carcinogen based on numerous in vitro and animal data. The consequential assumption that a safe threshold does not exist is not only applied to 4,4'-MDA but also to its structural isomers and impurities 2,2'- and 2,4'-MDA in the absence of substance-specific data. This constitutes a problem in human risk assessments for all three substances as the inherent risks of 2,2'- and 2,4'-MDA and their contribution as impurities to that of 4,4'-MDA are essentially unknown. A comparative in vitro genotoxicity dataset consisting of the bacterial reverse mutation (Ames) test and the chromosomal aberration test in human lymphocytes (both performed according to the current OECD Guidelines) was generated for all three isomers. Furthermore, an in vitro gene mutation test in Chinese hamster ovary (CHO) cells (HPRT locus assay) was conducted with 2,4'-MDA. The results indicate differences regarding the genotoxic mechanism and potential, respectively, between the three structures and suggest that the no-threshold assumption for 4,4'-MDA may not be appropriate for 2,2'- and 2,4'-MDA.

Accumulation, environmental risk characteristics and associated driving mechanisms of potential toxicity elements in roadside soils across China

Roadside soils may be affected by potential toxicity elements (TPEs) from vehicles; however, pollution status, ecological and health risks of PTEs in roadside soils were rarely reported on national scale. In this study, a dataset of PTEs in roadside soils was compiled based on the literatures published in 2000–2021, and then pollution level, ecological and health risks of PTEs were evaluated using geochemical accumulation index (Igeo), potential ecological risk index (ER), and human risk assessment coupled with Monte Carlo simulation. Driving factors of PTE accumulation in soils were determined by Geo-detector method. Results indicated that Cd exhibited moderate pollution and considerable ecological risk with the highest Igeo of 1.25 and ER of 100.1, respectively. Vehicle ownership (VP) and precipitation (PP) significantly affected accumulation of PTEs, with q values of 0.209 and 0.191 (P < 0.05), respectively. VP paired with PP enhanced nonlinearly PTE accumulation (q = 0.77). Only 6.89% and 1.54% of non-carcinogenic risks for children and adolescent exceeded the threshold of 1, respectively, whereas 93.11%, 95.67%, 58.80% and 58.14% of carcinogenic risks for senior, adults, adolescent, and children surpassed 1E−06, respectively. The results of this study provided valuable implication for managers to design effective strategies for pollution prevent and risk control.

An in vitro approach to determine the human relevance of anti-spermatogenic effects of 4-methylmorpholine 4-oxide, monohydrate (NMMO) in rat reproductive toxicity studies

Reduced sperm counts have been observed in male rats in an extended one generation reproductive toxicity study (EOGRTS, OECD 443) following repeated administration of 300 mg/kg/day N-Methylmorpholine N-oxide (NMMO). However, no adverse effects on reproductive organs have been reported in studies conducted with NMMO, and the mode of action (MOA) for the effects of NMMO on spermatogenesis is unknown, which complicates the interpretation of these data for human risk assessment. Here, a New Approach Method (NAM) strategy was used to evaluate NMMO MOA and compare interspecies susceptibility for anti-spermatogenic effects using organotypic in vitro assays combined with in vitro metabolism and in vitro to in vivo extrapolation (IVIVE) biokinetic modeling to compare predicted oral equivalent doses (OEDs) in human and rat. Dose-response data were collected in isolated germ cells and in an ex vivo seminiferous tubule model that recapitulates the interaction between the somatic environment and differentiating germ cells to account for potential direct and indirect effects on germ cells. With regard to direct spermatogenic effects, the human isolated germ cell model showed no toxicity at doses ≤300 μM (OED ≤ 86 mg/kg/day). With regard to indirect effects, the rat ex vivo model demonstrated dose-dependent decreases in secondary spermatocyte populations at OEDs ≥89 mg/kg/day, and reduced expression of RNAs specific to several stages of spermatogenesis (spermatogonia, pachytene spermatocytes, round spermatids) at OED = 267 mg/kg/day, consistent with in vivo observations. In contrast, the monkey ex vivo model did not show dose-dependent decreases in these same RNAs, and often demonstrated increased trends instead. These studies demonstrate clear quantitative and qualitative differences in the rat and primate response to NMMO. Furthermore, effects observed in the rat in vitro culture were not observed in the monkey at concentrations equivalent to in vivo doses of up to 1376 mg/kg/day, which is higher than the in vivo dose limit in the EOGRT study, indicating that the isolated findings on spermatogenesis in the rat studies are not likely to be relevant to humans.

Quantitative risk assessment of two successive landslide dams in 2018 in the Jinsha River, China

Two large successive co-site landslide dams blocked the Jinsha River in the Sichuan Province of China in 2018. A quantitative risk analysis was carried out to quantify potential human and economic losses resulting from the failure of these dams, especially the interaction between the co-site landslide dams, and to further investigate the influence of digging a diversion channel on risk mitigation. Flood routing for three scenarios (i.e. after the first dam formation, when the second landslide mass was added, and with a diversion channel after failures) were simulated using HEC-RAS. The human and economic losses were evaluated using a human risk assessment model together with empirical formulations. The results show that the risk of breaching floods had increased significantly after the second co-site landslide dam formation on the pre-existing loose deposits of the first dam. This amplification effect of outburst floods was so great that the peak outflow resulting from the breaching of the second landslide dams was more important, leading to greater economic losses than those resulting from the breaching of the first dam. However, the expected loss of life caused by the breach of the two landslide dams appeared small because of the sufficient time lag provided by the long distance between the residential area and the dam site. The simulations also outline the importance of the diversion channel in decreasing the peak outflow rate and hence downstream risks. A parametric analysis shows that a deep channel with a moderate longitudinal gradient can significantly decrease the peak outflow discharge at the dam site. Flood intensity and risks to downstream towns did not change because of the relatively small attenuation rate of the peak outflow rate. However, a shorter height of the residual dam can be obtained by optimizing the diversion channel, and the amplification effects of such co-site dam can be significantly reduced in the future.

Application of the Adverse Outcome Pathway Concept to In Vitro Nephrotoxicity Assessment: Kidney Injury due to Receptor-Mediated Endocytosis and Lysosomal Overload as a Case Study.

Application of adverse outcome pathways (AOP) and integration of quantitative in vitro to in vivo extrapolation (QIVIVE) may support the paradigm shift in toxicity testing to move from apical endpoints in test animals to more mechanism-based in vitro assays. Here, we developed an AOP of proximal tubule injury linking a molecular initiating event (MIE) to a cascade of key events (KEs) leading to lysosomal overload and ultimately to cell death. This AOP was used as a case study to adopt the AOP concept for systemic toxicity testing and risk assessment based on in vitro data. In this AOP, nephrotoxicity is thought to result from receptor-mediated endocytosis (MIE) of the chemical stressor, disturbance of lysosomal function (KE1), and lysosomal disruption (KE2) associated with release of reactive oxygen species and cytotoxic lysosomal enzymes that induce cell death (KE3). Based on this mechanistic framework, in vitro readouts reflecting each KE were identified. Utilizing polymyxin antibiotics as chemical stressors for this AOP, the dose-response for each in vitro endpoint was recorded in proximal tubule cells from rat (NRK-52E) and human (RPTEC/TERT1) in order to (1) experimentally support the sequence of key events (KEs), to (2) establish quantitative relationships between KEs as a basis for prediction of downstream KEs based on in vitro data reflecting early KEs and to (3) derive suitable in vitro points of departure for human risk assessment. Time-resolved analysis was used to support the temporal sequence of events within this AOP. Quantitative response-response relationships between KEs established from in vitro data on polymyxin B were successfully used to predict in vitro toxicity of other polymyxin derivatives. Finally, a physiologically based kinetic (PBK) model was utilized to transform in vitro effect concentrations to a human equivalent dose for polymyxin B. The predicted in vivo effective doses were in the range of therapeutic doses known to be associated with a risk for nephrotoxicity. Taken together, these data provide proof-of-concept for the feasibility of in vitro based risk assessment through integration of mechanistic endpoints and reverse toxicokinetic modelling.

Heavy Metals Contaminants in Watercress (Nasturtium officinale R. BR.): Toxicity and Risk Assessment for Humans along the Swat River Basin, Khyber Pakhtunkhwa, Pakistan

This research aimed to investigate the bioaccumulation and health risk associated with absorption of the selected heavy metals (HMs) i.e., lead (Pb), cadmium (Cd), zinc (Zn), and copper (Cu) in a wild leafy vegetable Nasturtium officinale that grows along the Swat River in swampy areas. The areas were categorized using the ecological risk index (RI), which indicates how heavy metal concentrations in soil and plants change over time. The bioaccumulation factor was greater than that at the 400 ≤ RI sites, indicating a probable health risk of these metals from N. officinale consumption. Furthermore, the health risk index for Cd and Pb was more significant, i.e., greater than one in the majority of the samples, indicating health concerns associated with consuming N. officinale from the study site. However, Zn and Cu levels were lower than the nutritionally needed levels, raising the risk of deficiency in the population. Plants cultivated in Pb and Cd-polluted sites were nutrient deficient in Cu and Zn. Intake of such plants can expose people to HM contamination and nutritional deficiencies. The results concluded that the plants accumulated significant HM contents and may have health concerns but are safe for consumption in children and adults.

Modified DLLME-SFO approach for evaluation of multiclass agrochemicals and its associated risk assessment: Soil, Saccharum officinarum and Jaggery

Pesticides have drawn attention due to their presence in various matrices and thus its after-effects in the environment and human body via various pathways. The use of agrochemicals by farmers in developing countries up-surged because of their low cost that results in increased production of crops. In the present study, a modified DLLME-SFO method was developed, optimized, and validated in soil, sugarcane, and jaggery. The developed method provides recoveries between 59.5- 109.48% and RSD less than 10% for all the analytes. The current study focuses on associated human dietary risk assessment on consumption of raw sugarcane and jaggery poses major threat to children and supports the concept that risk is age-dependent. In chronic exposure, pesticides detected were alachlor and heptachlor that have the potential of causing cancer. The risk to the soil ecology is within the acceptable range indicating the direct application of pesticides to crops rather than soil.