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There is indisputable evidence that the environment, humans and wildlife are continuously exposed not to single but to multiple chemicals from different sources. Exposure to these mixtures can lead to combined risks not yet sufficiently addressed in any of the European chemical legislations. Under the REACH regulation for industrial chemicals, specific environmental mixture assessments are challenged by a lack of data on toxicity, use and exposures and the communication of data along the supply chain. Within the Chemicals Strategy for Sustainability the European Commission proposed to introduce (a) mixture allocation factor(s) (MAF) as regulatory management tool to reduce exposures, effects and potential risks of unintentional mixtures. The MAF is proposed to be applied as default value within the chemical safety assessments undertaken by companies under REACH. Here, we critically review the relevant literature discussing the conceptual background of the MAF and approaches to derive its magnitude. The analysis focuses on the environment and key issues for an implementation in regulatory practise together with remaining uncertainties and needs for possible ways forward. At this stage introducing a MAF in REACH Annex I appears the most pragmatic and immediately implementable measure to address risks from unintentional mixtures in the environment. A so-called MAFceiling appears as the preferred option of policy makers, since it would only affect relevant substances close to their respective risk threshold. While the magnitude of a MAF will be decided politically, the choice of methods and assumptions to derive its size should be clear and transparent, build on the available scientific evidence and take account for uncertainties. A MAF will be most effective reducing environmental releases and exposure levels if risk mitigation measures are implemented in practise. Its socioeconomic impacts and costs need to be assessed in a balanced way together with the benefits for the environment, society, and for companies—also in comparison to the efforts needed for specific mixture risk assessments. In the future and with the experiences gathered in practise, a discussion is needed on how to assess and regulate unintentional mixtures across different pieces of chemicals legislation to consider the true exposure situation and ensure harmonisation. [ABSTRACT FROM AUTHOR]

Co-exposure soil studies of pollutants are necessary for an appropriate ecological risk assessment. Here, we examined the effects of two-component mixtures of metal oxide nanoparticles (ZnO NPs or goethite NPs) with the insecticide chlorpyrifos (CPF) under laboratory conditions in short-term artificial soil assays using Eisenia andrei earthworms. We characterized NPs and their mixtures by scanning electron microscopy, atomic force microscopy, dynamic light scattering and zeta potential, and evaluated effects on metal accumulation, oxidative stress enzymes, and neurotoxicity related biomarkers in single and combined toxicity assays. Exposure to ZnO NPs increased Zn levels compared to control in single and combined exposure (ZnO NPs + CPF) at 72 h and 7 days, respectively. In contrast, there was no indication of Fe increase in organisms exposed to goethite NPs. One of the most notable effects on oxidative stress biomarkers was produced by single exposure to goethite NPs, showing that the worms were more sensitive to goethite NPs than to ZnO NPs. Acetylcholinesterase and carboxylesterase activities indicated that ZnO NPs alone were not neurotoxic to earthworms, but similar degrees of inhibition were observed after single CPF and ZnO NPs + CPF exposure. Differences between single and combined exposure were found for catalase and superoxide dismutase (goethite NPs) and for glutathione S-transferase (ZnO NPs) activities, mostly at 72 h. These findings suggest a necessity to evaluate mixtures of NPs with co-existing contaminants in soil, and that the nature of metal oxide NPs and exposure time are relevant factors to be considered when assessing combined toxicity, as it may have an impact on ecotoxicological risk assessment. [ABSTRACT FROM AUTHOR]

The co-occurrence of heavy metals and microplastics (MPs) is an emerging issue that has attracted considerable attention. However, the interaction of nickel oxide nanoparticle (nano-NiO) combined with MPs in soil was poorly researched. Here, experiments were conducted to study the influence of nano-NiO (200 mg/kg) and polyethylene (PE) MPs with different concentrations (0.1, 1, and 10%) and sizes (13, 50, and 500 µm) on earthworms for 28 days. Compared to control, the damage was induced by PE and nano-NiO, which was evaluated by biomarker Integrated Biomarker Response index: version 2 (IBRv2) based on six biomarkers including SOD, POD, CAT, MDA, AChE, Na+/K+-ATPase and cellulase. The majority of the chosen biomarkers showed significant but complicated responses with increasing contaminant concentrations after 28 days of exposure. Moreover, the joint effect was assessed as antagonism by the effect addition index (EAI). Overall, this work expands our understanding of the combined toxicity of PE and nano-NiO in soil ecosystems. [ABSTRACT FROM AUTHOR]

Individual typical endocrine-disrupting chemicals (EDCs), including organophosphate triesters (OPEs), parabens, triclosan (TCS), bisphenols, benzophenones (BPs), phthalates (PAEs), and synthetic phenolic antioxidants (SPAs), are associated with renal dysfunction. However, the combined effects and underlying mechanisms of mixed EDC exposure on renal function remain unclear. Two hundred ninety-nine adult participants were enrolled in the cross-sectional survey conducted in Guangzhou, China. Urinary levels of 7 OPEs, 6 parabens, TCS, 14 bisphenols, 8 BPs, 15 PAEs, 4 SPAs, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) were determined, and estimated glomerular filtration rate (eGFR) was served as the outcome index. We found elevated levels of diphenyl phosphate (DPP), bisphenol A (BPA), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-butyl phthalate (MBP) showed dose-responsive associations with eGFR decline, However, nonlinear associations were observed for bis(2-butoxyethyl) hydrogen phosphate (BBOEP), TCS, 4-hydroxybenzophenone (HBP), mono-n-pentyl phthalate (MnPP), and mono-benzyl phthalate (MBzP). The quantile-based g-computation model demonstrated that a quartile increase in the EDC mixture corresponded to a 0.383-SD decrease (95% CI − 0.658 ~ − 0.108, P = 0.007) in eGFR. Notably, BPA was identified as the primary contributor to this effect. Moreover, 8-OHdG mediated the eGFR decline associated with EDC mixtures with a mediation proportion of 25.49%. A sex-modified effect was also observed (P = 0.004), indicating that exposure to the mixture of EDC was linked to more pronounced renal dysfunction in females. Our novel findings suggest that exposure to a typical mixture of EDCs is associated with renal dysfunction in the general adult population of Southern China. Furthermore, 8-OHdG may play a role in the pathogenesis of EDC mixture-related renal dysfunction. [ABSTRACT FROM AUTHOR]

Co-exposure to multiple parasites can alter parasite success and host life history when compared to single infections. These infection outcomes can be affected by the order of parasite arrival, the host immune response, and the interspecific interactions among co-infecting parasites. In this study, we examined how the arrival order of two trematode parasites, Schistosoma mansoni and Echinostoma caproni, influenced parasite ecology and the life history of their snail host, Biomphalaria glabrata. Snail hosts were exposed to E. caproni cercariae before, with, and after their exposure to S. mansoni miracidia. We then measured the effects of this timing on infection prevalence, infection intensity of E. caproni metacercariae, and cercarial output of S. mansoni, as well as on snail reproduction and survival. Snails infected only with S. mansoni and snails exposed to E. caproni after S. mansoni both shed more cercariae than simultaneously exposed snails. Additionally, S. mansoni prevalence was lower in snails that were first exposed to E. caproni compared to snails that were exposed to E. caproni after S. mansoni. Moreover, snails exposed to E. caproni before S. mansoni did not differ in their survival compared to control snails, whereas simultaneously exposed snails and snails exposed to E. caproni after S. mansoni had lower survival than control snails. Combined, this prevalence and survival data suggest a potential protective role of early E. caproni exposure. The timing of E. caproni exposure impacts S. mansoni establishment and reproduction, but host survival patterns are likely driven by S. mansoni prevalence alone. [ABSTRACT FROM AUTHOR]

Bluetongue is an arthropod-borne viral infection that is notifiable in several countries and causes significant economic losses and major concerns for ruminant trade. In this study, we investigated bluetongue 1seroprevalence in the Campania region, southern Italy, in cattle and buffalo populations, and assessed which factors were correlated with a high risk of exposure. The infection was widespread, as evidenced by the high individual (43.6%) and herd prevalence (85.4%). The highest prevalence was found in adult animals. Among the climatic factors analyzed, average temperature played a prominent role, being capable of affecting the probability of being positive for this infection. Surprisingly, exposure to Schmallenberg virus did not predispose animals to be positive for bluetongue virus, even though these infections share the same vector (Culicoides). Our data, consistent with those in the literature, suggest the transversal spread of bluetongue virus in the Mediterranean area, and indicate a limited co-exposure rate between Bluetongue and Schmallenberg viruses. [ABSTRACT FROM AUTHOR]

The phenomenon of population aging has brought forth the challenge of frailty. Nevertheless, the contribution of environmental exposure to frailty remains ambiguous. Our objective was to investigate the association between phenols, phthalates (PAEs), and polycyclic aromatic hydrocarbons (PAHs) with frailty. We constructed a 48-item frailty index using data from the National Health and Nutrition Examination Survey (NHANES). The exposure levels of 20 organic contaminants were obtained from the survey circle between 2005 and 2016. The association between individual organic contaminants and the frailty index was assessed using negative binomial regression models. The combined effect of organic contaminants was examined using weighted quantile sum (WQS) regression. Dose–response patterns were modeled using generalized additive models (GAMs). Additionally, an interpretable machine learning approach was employed to develop a predictive model for the frailty index. A total of 1566 participants were included in the analysis. Positive associations were observed between exposure to MIB, P02, ECP, MBP, MHH, MOH, MZP, MC1, and P01 with the frailty index. WQS regression analysis revealed a significant increase in the frailty index with higher levels of the mixture of organic contaminants (aOR, 1.12; 95% CI, 1.05–1.20; p < 0.001), with MIB, ECP, COP, MBP, P02, and P01 identified as the major contributors. Dose–response relationships were observed between MIB, ECP, MBP, P02, and P01 exposure with an increased risk of frailty (both with p < 0.05). The developed predictive model based on organic contaminants exposure demonstrated high performance, with an R2 of 0.9634 and 0.9611 in the training and testing sets, respectively. Furthermore, the predictive model suggested potential synergistic effects in the MIB-MBP and P01-P02 pairs. Taken together, these findings suggest a significant association between exposure to phthalates and PAHs with an increased susceptibility to frailty. [ABSTRACT FROM AUTHOR]

Assessing the effects of heavy metals (HMs) on kidney stone is often limited to analyzing individual metal exposures, with studies on the effects of exposure to mixtures of HMs being scarce. To comprehensively evaluate the relationship between exposure to mixed HMs and kidney stones, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2007–2016, which included 7809 adults. We used multiple statistical methods, including multiple logistic regression models, weighted quantile sum (WQS) regression, quantile g-computation (qgcomp) and bayesian kernel machine regression (BKMR), to assess the association between single HM and mixed exposure to HMs and kidney stones. Firstly, in single exposure analysis, urinary cadmium (Cd) and cobalt (Co) demonstrated a positive association with the risk of kidney stones. Secondly, various other approaches consistently revealed that mixed exposure to HMs exhibited a positive association with kidney stone risk, primarily driven by Cd, Co, and barium (Ba) in urine, with these associations being particularly notable among the elderly population. Finally, both BKMR and survey-weighted generalized linear models consistently demonstrated a significant synergistic effect between urinary Co and urinary uranium (Ur) in elevating the risk of kidney stones. Overall, this study provides new epidemiological evidence that mixed exposure to HMs is associated with an increased risk of kidney stones. Further prospectively designed studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

People intake metals from their environment. This study investigated type 2 diabetes mellitus (T2DM) related to internal exposure to metals and attempted to identify possible biomarkers. A total of 734 Chinese adults were enrolled, and urinary levels of ten metals were measured. Multinomial logistic regression model was used to assess the association between metals and impaired fasting glucose (IFG) and T2DM. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction were used to explore the pathogenesis of T2DM related to metals. After adjustment, lead (Pb) was positively associated with IFG (odds ratio [OR] 1.31, 95% confidence interval [CI] 1.06–1.61) and T2DM (OR 1.41, 95% CI 1.01–1.98), but cobalt was negatively associated with IFG (OR 0.57, 95% CI 0.34–0.95). Transcriptome analysis showed 69 target genes involved in the Pb-target network of T2DM. GO enrichment indicated that the target genes are enriched mainly in the biological process category. KEGG enrichment indicated that Pb exposure leads to non-alcoholic fatty liver disease, lipid and atherosclerosis, and insulin resistance. Moreover, there is alteration of four key pathways, and six algorithms were used to identify 12 possible genes in T2DM related to Pb. SOD2 and ICAM1 show strong similarity in expression, suggesting a functional correlation between these key genes. This study reveals that SOD2 and ICAM1 may be potential targets of Pb exposure-induced T2DM and provides novel insight into the biological effects and underlying mechanism of T2DM related to internal exposure to metals in the Chinese population. [ABSTRACT FROM AUTHOR]

In the current study, we assessed the impact of DMA (dimethylarsinic acid) and MPs (microplastics) interactions in C. elegans over the course of five generations. We found that the redox state of the organisms changed over generations as a result of exposure to both pollutants. From the third generation onward, exposure to MPs reduced GST activity, indicating reduced detoxifying abilities of these organisms. Additionally, dimethylarsinic exposure decreased the growth of organisms in the second, fourth, and fifth generations. In comparison to isolated pollutants, the cumulative effects of co-exposure to DMA and MPs seem to have been more harmful to the organisms, as demonstrated by correlation analysis. These findings demonstrate that DMA, despite being considered less hazardous than its inorganic equivalents, can still have toxic effects on species at low concentrations and the presence of MPs, can worsen these effects. [ABSTRACT FROM AUTHOR]

Soil contamination by cadmium (Cd) and degradation by salinity are likely to become one of the most important problems hindering food production and human health. However, their combined effect on crops is still ambiguous. A hydroponic study was made to investigate the separate and combined exposure of 100 µM Cd and 150 µM NaCl on soybeans (Glycine max L.) growth, photosynthetic pigment, and antioxidant systems for 7 days. Both Cd and NaCl, applied separately decreased the seedlings growth, chlorophyll contents and caused oxidative stress. However, the toxic effects of salinity applied alone were more pronounced. Interestingly, combined exposure of Cd and NaCl induced higher decreases in all growth parameters and lipid peroxidation than single exposure suggesting synergistic effects. The results implicate that the phytotoxicity of both stressors can be associated with redox status imbalance. Our finding may provide insight into the physiological mechanisms of heavy metal exposure and salinity stress tolerance in soybeans and suggest that saline stress changes the effects of Cd toxicity on crops in Cd-salt-polluted soils. [ABSTRACT FROM AUTHOR]

Host–parasite interactions do not occur in a vacuum, but in connected multi-parasite networks that can result in co-exposures and coinfections of individual hosts. These can affect host health and disease ecology, including disease outbreaks. However, many host–parasite studies examine pairwise interactions, meaning we still lack a general understanding of the influence of co-exposures and coinfections. Using the bumble bee Bombus impatiens, we study the effects of larval exposure to a microsporidian Nosema bombi, implicated in bumble bee declines, and adult exposure to Israeli Acute Paralysis Virus (IAPV), an emerging infectious disease from honey bee parasite spillover. We hypothesize that infection outcomes will be modified by co-exposure or coinfection. Nosema bombi is a potentially severe, larval-infecting parasite, and we predict that prior exposure will result in decreased host resistance to adult IAPV infection. We predict double parasite exposure will also reduce host tolerance of infection, as measured by host survival. Although our larval Nosema exposure mostly did not result in viable infections, it partially reduced resistance to adult IAPV infection. Nosema exposure also negatively affected survival, potentially due to a cost of immunity in resisting the exposure. There was a significant negative effect of IAPV exposure on survivorship, but prior Nosema exposure did not alter this survival outcome, suggesting increased tolerance given the higher IAPV infections in the bees previously exposed to Nosema. These results again demonstrate that infection outcomes can be non-independent when multiple parasites are present, even when exposure to one parasite does not result in a substantial infection. [ABSTRACT FROM AUTHOR]

Layered double hydroxide (LDH) nanomaterials are utilized extensively in numerous fields because of their distinctive structural properties. It is critical to understand the environmental behavior and toxicological effects of LDHs to address potential concerns caused by their release into the environment. In this work, the toxicological effects of two typical LDHs (Mg-Al-LDH and Zn-Al-LDH) on freshwater green algae (Scenedesmus obliquus) and the main affecting factors were examined. The Zn-Al-LDH exhibited a stronger growth inhibition toxicity than the Mg-Al-LDH in terms of median effect concentration. This toxicity difference was connected to the stability of particle dispersion in water and the metallic composition of LDHs. The contribution of the dissolved metal ions to the overall toxicity of the LDHs was lower than that of their particulate forms. Moreover, the joint toxic action of different dissolved metal ions in each LDH belonged to additive effects. The Mg-Al-LDH induced a stronger oxidative stress effect in algal cells than the Zn-Al-LDH, and mitochondrion was the main site of LDH-induced production of reactive oxygen species. Scanning electron microscope observation indicated that both LDHs caused severe damage to the algal cell surface. At environmentally relevant concentrations, the LDHs exhibited joint toxic actions with two co-occurring contaminants (oxytetracycline and nano-titanium dioxide) on S. obliquus in an additive manner mainly. These findings emphasize the impacts of the intrinsic nature of LDHs, the aqueous stability of LDHs, and other environmental contaminants on their ecotoxicological effects. [ABSTRACT FROM AUTHOR]

Although existing epidemiological studies have reported the relationship between single polycyclic aromatic hydrocarbon (PAH) exposure and chronic obstructive pulmonary disease (COPD), little is known about the impact of PAH mixture exposure on COPD. Therefore, we aimed to evaluate the associations of single and mixed exposures to PAHs with COPD in US adults using data from NHANES 2013–2016 by fitting three statistical methods, including multiple logistic regression, Bayesian kernel machine regression (BKMR), and quantile-based g-computation (qgcomp) models. This study included 1836 participants aged 40 and older. Multiple logistic regression showed that 2-FLU, 1-PHE, 1-PYR, and 2&3-PHE increased the risk of COPD after adjusting for all covariates. The BKMR model identified positive trends between PAH mixture and the risk of COPD in all adults and males when all PAHs were at or above their 55th percentile compared to all PAHs at their 50th percentile. The qgcomp model suggested that PAH co-exposure increased the risk of COPD (OR:1.44, 95%CI:1.09, 1.90) when each quartile increased in PAH mixture concentration, with 2-FLU having the highest weight. The combined impact also be observed in men. In conclusion, PAHs co-exposure was associated with a higher risk of COPD, especially in males, with the positive impact of 2-FLU being the most important. [ABSTRACT FROM AUTHOR]

Metals play an important role in the development of diabetes mellitus (DM). The association of metals with diabetes among the Dong ethnicity in China remains poorly understood. The current study aimed to evaluate the association of single metal exposure and multi-metal co-exposure with DM risk. Urinary concentrations of arsenic, cadmium, chromium, copper, iron, lead, manganese, mercury, molybdenum, nickel, strontium, vanadium, and zinc were measured using inductively coupled plasma-mass spectrometry (ICP-MS) among 4479 Dong ethnic participants aged 30–79 years from the China Multi-Ethnic Cohort (CMEC) study. Based on tertiles, the metal exposure can be divided into three groups: low, middle, and high exposure. Multivariate logistic regression models and principal component analysis were performed to determine exposure to single-metal and multi-metal co-exposure in relation to DM. A decrease in risk of DM was associated with iron (OR = 0.78, 95% CI: 0.61–1.00 and 0.68, 0.53–0.88 for the middle and high vs. low) and strontium (OR = 0.87, 95% CI: 0.69–1.12 and 0.67, 0.51–0.86 for the middle and high vs. low), respectively. A principal component 3 (PC3) characterized by iron and strontium showed an inverse association with DM. A principal component 4 (PC4) characterized by manganese and lead positively associated with DM. Exposure to high concentrations of urinary iron and strontium may reduce the risk of diabetes mellitus. This study revealed an increase in the risk of diabetes mellitus by co-exposure to high concentrations of urinary manganese and lead. [ABSTRACT FROM AUTHOR]

Investigation of the effects of natural compounds in aquatic ecosystems on the modulation of toxicity of coexisting xenobiotics is important for realistic ecological risk assessments. We investigated the individual and interactive effects of sublethal cadmium (Cd) concentrations and environmentally realistic humic acid (HA) concentrations on several life-history characteristics of Moina macrocopa. Female individuals were exposed to Cd and HA for their entire lifespan from the neonatal stage. The survival and reproductive output were recorded daily, and the growth and swimming velocity were determined upon maturity. Cd at the tested concentrations in single treatments did not significantly affect the growth and lifespan. But 5 µg/l Cd significantly decreased the swimming velocities and reproduction. Greater than 20 mg/l HA in single treatments significantly increased the individuals' growth, reproduction, and lifespan. Swimming velocities were significantly increased at 10 mg/l HA in single treatments. In combined treatments, such beneficial effects on all life-history characteristics were still seen under the co-occurrence of 1 µg/l Cd, but with 5 µg/l Cd, those beneficial effects on life-history characteristics except for swimming velocities were not observed. These dissimilar responses of different life-history characteristics indicate energy tradeoffs for maintenance, reproduction, and longevity, upon exposure to stressors in M. macrocopa. [ABSTRACT FROM AUTHOR]

Telomere length (TL) is considered a marker of biological aging and lifetime health, and some epidemiological studies report that the environmental exposures may influence TL at birth. We aimed to investigate the associations between prenatal rare earth elements (REE) exposure and newborn TL. A total of 587 mother-newborn pairs were recruited during 2013 to 2015 in Wuhan, China. Maternal urinary concentrations of REE collected during three trimesters were measured by inductively coupled plasma mass spectrometry. Quantitative real-time polymerase chain reaction was used to measure relative cord blood TL. The trimester-specific associations between prenatal REE exposure and cord blood TL were evaluated using multiple informant models. Weighted quantile sum regression was used to estimate the mixture effect of urinary REE on cord blood TL. After adjustment for potential confounders, per doubling of urinary REE (Dy, Yb, Pr, Nd, and Tm) concentrations (μg/g creatinine) during the second trimester was respectively associated with 1.94% (95% CI 0.19%, 3.72%), 2.10% (95% CI 0.31%, 3.92%), 2.11% (95% CI 0.35%, 3.89%), 2.08% (95% CI 0.01%, 4.20%), and 1.38% (95% CI 0.09%, 2.70%) increase in cord blood TL. Furthermore, exposure to the mixture of REE during the second trimester was also significantly associated with increased cord blood TL (percent change 1.20%, 95% CI 0.30%, 2.11%). However, these associations were not statistically significant in the first and third trimesters. This study provides new evidence on the potential effect of prenatal REE exposure on the initial (newborn) setting of offspring's telomere biology. Further epidemiological studies are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Several nano-toxicological studies have assessed the prospective health risks of engineered nanostructures. Still, nanoscale ingredients from food products are not explored well, and only a few have attended to the possible effects of food additive-based nanoparticles in food. The physicochemical properties of food additives and their fate on human health are still unknown. To fill this knowledge gap, we examined the physicochemical characteristics of food product isolate E341/E551. Additionally, we assessed the consequence of these nanoscale E341 and E551 as co-exposure on human mesenchymal stem cells (hMSCs). The transmission electron microscope (TEM) images revealed that food product isolate (E341/E551) consists of nanoscale particles. The E551 and E341 have 20–50 nm and 70–200 nm diameters, respectively. Co-exposure of food additives SiO2 (E551) and Tricalcium phosphate (E341) effect on the cell viability, morphology, mitochondrial membrane potential, and reactive oxygen species (ROS) level of hMSCs were studied. The cell viability reduction, mitochondrial membrane potential loss, and ROS generation in E341/E551 co-exposed cells were observed. Our study suggests that E341/E551 co-exposure elevated the ROS level and mitochondrial membrane potential depletion at a high dose. The oxidative stress-related genes MDM3, TNFSF10, and POR have exhibited significant upregulation in the E341/E551 treatment group. These results conclude that long-term over-exposure to E341/E551 may be triggers health risks in a human. Further in vivo studies are required for food industry implications due to nanoscale ingredients in E341 and E551. [ABSTRACT FROM AUTHOR]

Populations in malaria endemic areas are frequently exposed to mycotoxin-contaminated diets. The possible toxicological outcome of co-exposure to dietary aflatoxin B1 (AFB1) and artemisinin-based combination therapy warrants investigation to ascertain amplification or attenuation of cellular injury. Here, we investigated the neurobehavioral and biochemical responses associated with co-exposure to anti-malarial drug coartem, an artemether-lumefantrine combination (5 mg/kg body weight, twice a day and 3 days per week) and AFB1 (35 and 70 µg/kg body weight) in rats. Motor deficits, locomotor incompetence, and anxiogenic-like behavior induced by low AFB1 dose were significantly (p < 0.05) assuaged by coartem but failed to rescue these behavioral abnormalities in high AFB1-dosed group. Coartem administration did not alter exploratory deficits typified by reduced track plot densities and greater heat map intensity in high AFB1-dosed animals. Furthermore, the reduction in cerebral and cerebellar acetylcholinesterase activity, anti-oxidant enzyme activities, and glutathione and thiol levels were markedly assuaged by coartem administration in low AFB1 group but not in high AFB1-dosed animals. The significant attenuation of cerebral and cerebellar oxidative stress indices namely reactive oxygen and nitrogen species, xanthine oxidase activity, and lipid peroxidation by coartem administration was evident in low AFB1 group but not high AFB1 dose. Although coartem administration abated nitric oxide level, activities of myeloperoxidase, caspase-9, and caspase-3 in animals exposed to both doses of AFB1, these indices were significantly higher than the control. Coartem administration ameliorated histopathological and mophometrical changes due to low AFB1 exposure but not in high AFB1 exposure. In conclusion, contrary to AFB1 alone, behavioral and biochemical responses were not altered in animals singly exposed to coartem. Co-exposure to coartem and AFB1 elicited no additional risk but partially lessened neurotoxicity associated with AFB1 exposure. [ABSTRACT FROM AUTHOR]

Background: Agricultural products are frequently co-contaminated by mycotoxins and pesticides. Most studies have only focused on the single toxicities of these chemicals, while their combined effects are neglected. Therefore, we investigated the combined toxic effects of T-2 toxin (T-2) and propiconazole (PRO) on zebrafish (Danio rerio). Results: Our data exhibited that T-2 had higher toxicity to embryonic fish (96-h LC50 value of 0.39 mg a.i. L−1) than PRO (96-h LC50 value of 17.16 mg a.i. L−1). The mixture of T-2 and PRO showed an acute synergistic effect on zebrafish. Meanwhile, indicators associated with oxidative stress (SOD, Mn-sod, and cat) displayed significant variations in most exposures to T-2 and PRO mixtures (MTP) compared with the single exposures. The expressions of apoptosis-related genes cas3 and cas9 were also substantially elevated in the high-dose MTP exposure compared with the corresponding T-2 exposure. Besides, the expressions of endocrine system-related genes (TRβ, tsh, crh, cyp19a, and vtg1) were markedly varied in most MTP exposures compared with the corresponding single exposures. Our present results suggested that the mixture of T-2 and PRO could cause enormous effects on oxidative stress, cellular apoptosis, and the hypothalamic–pituitary–thyroid/hypothalamic–pituitary–gonadal (HPG/HPT) axis of zebrafish. Conclusions: Our results provided new insights into the development of combined pollution standards for agricultural products. Taken together, the impact of the combined effects could be considered and regulated as priorities. [ABSTRACT FROM AUTHOR]

Co-exposure of widely used single-walled carbon nanotubes (SWCNTs) and ubiquitous cadmium (Cd) to humans through ambient air is unavoidable. Studies on joint toxicity of SWCNTs and Cd in human cells are scarce. We aimed to investigate the joint effects of SWCNTs and Cd in human lung epithelial (A549) cells. Results showed that SWCNTs were safe while Cd induce significant toxicity to A549 cells. Remarkably, Cd-induced cell viability reduction, lactate dehydrogenase leakage, cell cycle arrest, dysregulation of apoptotic gene (p53, bax, bcl-2, casp3, and casp9), and mitochondrial membrane potential depletion were significantly mitigated following SWCNTs co-exposure. Cd-induced intracellular level of reactive oxygen species, hydrogen peroxide, and lipid peroxidation were significantly attenuated by SWCNT co-exposure. Moreover, glutathione depletion and lower activity of antioxidant enzymes after Cd exposure were also effectively abrogated by co-exposure of SWCNTs. Inductively coupled plasma-mass spectrometry study indicated that higher adsorption of Cd on SCWNTs might decreased cellular uptake and the toxic potential of Cd in A549 cells. Our work warranted further research to explore the potential mechanism of joint effects of SWCNTs and Cd at in vivo levels. [ABSTRACT FROM AUTHOR]

Chronic exposure to environmental cadmium (Cd) and lead (Pb) may have adverse effects on the human health. In this study, we aimed to determine the primary and interactive effects of Cd and Pb exposure on liver function in residents near a mining and smelting area in northwestern China. A total of 451 subjects were recruited, from which blood samples were collected to determine the levels of Cd, Pb, and liver function indices. Additionally, the association between the levels of exposure markers and liver function indices was analysed. Cd and Pb levels were significantly higher in subjects living in the polluted area than in those living in the non-polluted reference area. The liver function levels of subjects in the polluted area were poor compared with those in the reference area. In addition, Cd and Pb levels in the blood were positively associated with gamma glutamyl transpeptidase (GGT) levels and negatively associated with direct bilirubin (DBil) levels. Cd and Pb may be risk factors for abnormal liver function. The risk of abnormal liver function was higher in subjects with moderate Cd and Pb levels, high Cd levels, high Pb levels, and high Cd and Pb levels than in those with low Cd and Pb levels. Our data show that exposure to Cd and/or Pb can cause abnormal liver function. Cd and Pb may have an antagonistic effect on liver function, and high Cd exposure alone has a more profound effect on abnormal liver function compared with co-exposure to Pb and Cd. [ABSTRACT FROM AUTHOR]

Arsenic (As), and fluoride (F−) are potent contaminants with established carcinogenic and non-carcinogenic impacts on the exposed populations globally. Despite elevated groundwater As and F− levels being reported from various regions of Pakistan no biomonitoring study has been reported yet to address the co-exposure impact of As and F− among school children. We aimed to investigate the effects of these two contaminants on dental fluorosis and intelligence quotient (IQ) along with the induction of oxidative stress in rural children under co-exposed conditions. A total of 148 children (5 to 16 years old) from the exposed and control group were recruited in the current study from endemic rural areas of Lahore and Kasur districts, Pakistan having elevated As and F− levels in drinking water than permissible limits. We monitored malondialdehyde and its probable association with antioxidants activity (SOD, CAT, and GR) as a biomarker of oxidative stress. GSTM1/T1 polymorphisms were measured to find the impact of As on health parameters. Mean urinary concentrations of As (2.70 vs. 0.016 µg/L, P < 0.000) and F− (3.27 vs. 0.24 mg/L, P < 0.000) as well as the frequency of dental fluorosis were found elevated among the exposed group. The cases of children with lower IQ were observed high in the exposed group. Additionally, lower concentrations of antioxidants (SOD, CAT, and GR) were found suggesting high susceptibility to F− toxicity. The findings suggest that F− accounted for high variations in health parameters of children under the co-exposure conditions with As. [ABSTRACT FROM AUTHOR]

In this study, we investigated the associations between cadmium (Cd) and lead (Pb) co-exposure, and serum ion levels in two populations living near a mining/smelting area and a nature reserve (control area), respectively. A total of 445 participants were included in this study. Their blood cadmium (BCd), blood lead (BPb), and serum ion levels were determined, and the association between exposure levels and serum ion levels was analyzed. The exposure levels of subjects living in the polluted area were significantly higher (p < 0.001). Lower levels of potassium, inorganic phosphorus, and iron were observed in subjects from the polluted area, whereas their sodium and chloride levels were higher (p < 0.01). The anion gap in their serum was also significantly lower. We observed positive dose–effect relationships between Cd and/or Pb exposure and serum sodium and chloride, and negative dose–effect relationships between Cd and/or Pb exposure and serum inorganic phosphorus, iron, as well as the anion gap. High Cd–Pb, high Cd, and high Pb exposure led to modification effects in potassium, calcium, inorganic phosphorus, and iron levels, and the anion gap. No synergistic effects were observed in our results. In conclusion, our data demonstrate that Cd and Pb exposure, alone or in combination, can lead to serum ion imbalances. [ABSTRACT FROM AUTHOR]

It is acknowledged that a variety of chemicals enter the environment and may cause joint effects. Chemicals regulated under the European Chemicals Regulation REACH are often part of formulated mixtures and during their processing and use in various products they can be jointly released via sewage treatment plants or diffuse sources, and may combine in the environment. One can differentiate between intentional mixtures, and unintentional mixtures. In contrast to other substance-oriented legislations, REACH contains no explicit requirements for an assessment of combined effects, exposures and risks of several components. Still, it requires ensuring the safe use of substances on their own, in mixtures, and in articles. The available options to address intentional as well as unintentional mixtures are presented and discussed with respect to their feasibility under REACH, considering the responsibilities, communication tasks and information availability of the different actors (registrants, downstream-user and authorities). Specific mixture assessments via component-based approaches require a comprehensive knowledge on substances properties, uses, fate and behaviour, and the composition of the mixture under consideration. This information is often not available to the responsible actor. In principle, intentional mixtures of known composition can be assessed by the downstream-user. But approaches have to be improved to ensure a transparent communication and sound mixture assessment. In contrast, unintentional mixtures appear to be better addressable via generic approaches such as a mixture allocation factor during the chemical safety assessment, although questions on the magnitude, implementation and legal mandates remain. Authorities can conduct specific mixture risk assessments in well-defined and prioritized cases, followed by subsequent regulatory measures. In order to address intentional and unintentional mixtures within the current REACH framework, legal mandates together with guidance for the different actors are needed. Furthermore, further data on mixture compositions, uses and co-exposures need to be made accessible via shared databases. [ABSTRACT FROM AUTHOR]

The increasing use and disposal of plastics has become a persistent problem in the marine environment, calling for studies that refer to realistic scenarios to understand their effects on biota. Particularly, the understanding about the effects of co-exposure with nanoplastic particles and metals on aquatic organisms is still limited. The present work aimed to investigate the acute toxicity of amino-functionalized polystyrene nanoparticles (PS-NH2; 50 nm) as proxy for nanoplastics on brine shrimp Artemia franciscana larvae under different culture conditions and at different stages of development, as well as the combined effect with two reference toxicants — potassium dichromate (K2Cr2O7) and copper sulfate (CuSO4). Nauplii (instar II or III larval stages) were exposed to different concentrations of PS-NH2 (0.005 to 5 μg mL-1) for up to 48 h, with or without agitation in order to mimic a more realistic environmental scenario. Larval mobility and PS-NH2 accumulation were monitored under microscopy. PS-NH2 alone showed toxicity only at the highest concentration tested (5 μg mL-1) regardless the incubation method used (61.2 + 3.1% and 65.0 + 4.5% with and without agitation, respectively). Moreover, instar III stage was the most sensitive to PS-NH2 exposure (38.2% immobility in 24 h of exposure; 5 μg mL-1). Evidence of PS-NH2 retention in the gastrointestinal tract in a concentration- and time-dependent manner was also obtained. Mixtures of PS-NH2 (0.005 and 5 μg mL-1) with different concentrations of K2Cr2O7 increased the immobilization rate of the larvae after 48 h of exposure, when compared to the K2Cr2O7 alone. Similar results were observed for CuSO4 in the co-exposure conditions at different concentrations. However, exposing nauplii to a mixture of PS-NH2 (0.005 μg mL-1) and CuSO4 decreased immobilization rate, in comparison to the group exposed to CuSO4 alone. The present work highlights the potential risk posed by nanoplastics to zooplanktonic species through their interaction with other toxicants. [ABSTRACT FROM AUTHOR]

Although many studies have confirmed metabolic syndrome (MetS) is correlated with metal exposures, few studies have elucidated the associations of multiple metals with MetS risk. We aim to explore the relationship between serum 22 metals and MetS. We determined serum 22 metals using ICP-MS and used LASSO regression to select metals independently related with MetS to construct multiple-metals model. We further explored the dose-response relationship between positive metals and MetS by the restricted cubic spline regression. After screening by LASSO regression, serum 11 metals were selected to construct multiple-metals model in cross-sectional analysis, while 5 metals in longitudinal analysis. In the 11-metal model, only tin and zinc were associated with MetS in cross-sectional analysis (ORtin = 2.22, 95% CI:1.43, 3.45; ORzinc = 2.17, 95% CI: 1.42, 3.32; both Ptrend < 0.05). Besides, the same results were found in the 5-metal model in longitudinal analysis (HRtin = 1.66, 95% CI: 0.87, 3.17; HRzinc = 1.83, 95% CI: 1.07, 3.14; both Ptrend < 0.05). Moreover, there were positive linear relationships between serum tin and zinc concentrations and the increasing risk of MetS (both Poverall < 0.05, Pnon-linearity > 0.05). Furthermore, the interaction between high tin and high zinc was also associated with increasing MetS risk (Pinteraction < 0.05). We found that serum tin and zinc were independently and interactively associated with MetS in the southern Chinese men. Our results suggested that high tin and zinc may be the risk factors of MetS. [ABSTRACT FROM AUTHOR]

Data for 639 US children aged 3–11 years who participated in the National Health and Nutrition Examination Survey during 2013–2014 were analyzed by fitting regression models with log10-transformed values of blood lead and methyl and total mercury as dependent variables and log10-transformed values of perfluoroalkyl acids (PFAA) as one of the independent variables. PFAAs considered were 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MPAH), linear isomer of perfluorooctanoic acid (NPFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorohexane sulfonic acid (PFHxS), linear isomer of perfluorooctane sulfonic acid (NPFOS), and monomethyl branch isomer of perfluorooctane sulfonic acid (MPFOS). Adjusted regression slopes (β) indicating associations between the concentrations of PFAAs with blood lead and mercury were estimated. Statistically significant associations between concentrations of each PFAA and blood lead were observed. For 10% increases in concentrations of MPAH, NPFOA, PFNA, PFDA, PFHxS, NPFOS, and MPFOS, percent increases in the concentrations of blood lead were 0.45%, 1.59%, 0.78%, 0.32%, 0.65%, 1.32%, and 0.89% respectively. For 10% increases in concentrations of MPAH, PFNA, PFDA, and NPFOS, percent increases in the concentrations of total mercury in the blood were 1.62%, 1.44%, and 3.24% respectively. For 10% increases in concentrations of PFDA and NPFOS, percent increases in the concentrations of methyl mercury in the blood were 2.07% and 4.57% respectively. While concentrations of each of the seven PFAAs were positively associated with the concentrations of blood lead, concentrations of only PFDA and NPFOS were positively associated with increases in total and methyl mercury. PFAAs having positive associations with lead and mercury imply co-exposure and/or co-existence of high concentrations of PFAAs and lead/mercury. Since PFAAs as well as lead/mercury are known to be neurotoxic, nephrotoxic, and endocrine disruptors, their co-existence/co-exposure may lead to neurodevelopmental deficits that are additive/synergistic than neurodevelopmental deficits associated with exposures to PFAAs and lead/mercury alone. Future studies are needed to investigate additive/synergistic neurodevelopmental deficits associated with co-exposures to PFAAs and lead/mercury. [ABSTRACT FROM AUTHOR]

Recent attention has been focused on reproductive toxicity of nanoscale materials in combination with pre-existing environmental pollutants. Due to its unique characteristics, bismuth (III) oxide (Bi2O3) nanoparticles (BONPs) are being used in diverse fields including cosmetics and biomedicine. Benzo[a]pyrene (BaP) is a known endocrine disruptor that most common sources of BaP exposure to humans are cigarette smoke and well-cooked barbecued meat. Hence, joint exposure of BONPs and BaP in humans is common. There is scarcity of information on toxicity of BONPs in combination with BaP in human reproductive system. In this work, combined effects of BONPs and BaP in mouse spermatogonia (GC-1 spg) cells were assessed. Results showed that combined exposure of BONPs and BaP synergistically induced cell viability reduction, lactate dehydrogenase leakage, induction of caspases (-3 and -9) and mitochondrial membrane potential loss in GC-1 spg cells. Co-exposure of BONPs and BaP also synergistically induced production of pro-oxidants (reactive oxygen species and hydrogen peroxide) and reduction of antioxidants (glutathione and several antioxidant enzymes). Experiments with N-acetyl-cysteine (NAC, a reactive oxygen species scavenger) indicated that oxidative stress was a plausible mechanism of synergistic toxicity of BONPs and BaP in GC-1 spg cells. Present data could be helpful for future in vivo research and risk assessment of human reproductive system co-exposed to BONPs and BaP. [ABSTRACT FROM AUTHOR]

Background: Buprenorphine is a unique μ-opioid receptor partial agonist with avid receptor binding, nominal euphoric reward, and a ceiling effect on sedation and respiratory depression. Despite a pharmacologic profile that enhances safety, cases of fatal opioid overdose with buprenorphine on postmortem toxicology are reported, but details of these cases in the literature are limited. Methods: A retrospective review of opioid-involved drug overdose fatalities in Rhode Island (RI) from 2016 to 2018 using the RI Department of Health State Unintentional Drug Overdose Reporting System (SUDORS) database. Deaths with buprenorphine on toxicology testing versus opioid-involved overdose deaths without buprenorphine were compared to assess the type and number of co-exposures. Results: Of 534 opioid-involved deaths, 29 (5.4%) included buprenorphine and/or norbuprenorphine on toxicology. Most frequent co-exposures are as follows: fentanyl (75.9%), norfentanyl (72.4%), cocaine (41.4%), benzoylecgonine (41.4%), cannabinoids (31.0%), ethanol (31.0%), levamisole (31.0%), and free morphine (31.0%). An average number of co-exposures for fatalities with buprenorphine were 9.24 versus 6.68 in those without buprenorphine. In one case buprenorphine was the only drug listed to cause death; all other fatalities with buprenorphine on toxicology reported additional drugs contributing to death. Conclusion: Decedents with buprenorphine detected on toxicology testing commonly had documented polysubstance use. Although data are limited, buprenorphine may provide some risk mitigation against full agonist opioid overdose including fentanyl. Further work should explore the use of postmortem concentrations of buprenorphine, norbuprenorphine, and other opioid metabolites to determine the role of buprenorphine in fatal overdose pharmacology. [ABSTRACT FROM AUTHOR]

The worldwide contamination of waters by microplastics is an emerging health and environmental issue. Despite being relatively inert, microplastics may adsorb and carry other aquatic pollutants such as heavy metals. Adsorption of heavy metals onto microplastics is a spontaneous process controlled by the microplastic surface. Marine microplastics have been well discussed, yet there are actually a few reviews on microplastics in freshwater. Here, we review microplastic contamination in freshwater systems with focus on adsorption of heavy metals. We present microplastic abundance, distribution, impact of microplastic size, affinity for heavy metals and combined toxic effects of the co-occurrence of microplastic and heavy metals. Remarkably, the concentration of metals on polystyrene and polyvinyl chloride was 800 times higher than in the surrounding environment. Combined toxic effects include endocrine disrupting and reduced predatory behavior of aquatic carnivores. [ABSTRACT FROM AUTHOR]

Widespread application of titanium dioxide nanoparticles (nTiO2) and ubiquitous cadmium (Cd) pollution may increase their chance of co-existence in the natural environment. Toxicological information on co-exposure of nTiO2 and Cd in mammalian models is largely lacking. Hence, we studied the combined effects of nTiO2 and Cd in human liver (HepG2) and breast cancer (MCF-7) cells. We observed that nTiO2 did not produce toxicity to HepG2 and MCF-7 cells. However, moderate concentration of Cd exposure caused cytotoxicity to both cells. Interestingly, non-cytotoxic concentration of nTiO2 effectively enhanced the oxidative stress response of Cd indicated by pro-oxidants generation (reactive oxygen species, hydrogen peroxide, and lipid peroxidation) and antioxidants depletion (glutathione level and glutathione reductase, superoxide dismutase, and catalase enzymes). Moreover, nTiO2 potentiated the Cd-induced apoptosis in both cells suggested by altered expression of p53, bax, and bcl-2 genes along with low mitochondrial membrane potential. Cellular uptake results demonstrated that nTiO2 facilitates the internalization of Cd into the cells. Overall, this study demonstrated that non-cytotoxic concentration of nTiO2 enhanced the toxicological potential of Cd in human cells. Therefore, more attention should be paid on the combine effects of nTiO2 and Cd on human health. [ABSTRACT FROM AUTHOR]

In this study, the immature mice were taken to assess the potential neurological toxicity of lead (Pb) and di (n-butyl) phthalates (DBP) combination exposure. Mouse administration with DBP combination with Pb exhibited longer escape latency and lower average number of crossing of the platform. Pb content in the tissues was increased, especially in the brain, after Pb exposure as compared to those without Pb exposure. The alterations of oxidative damages in tissues (MDA and SOD) and biochemical indicators in the brain (AChE, TNOS, and iNOS) were observed, as well as the synergistic effect of joint exposure. Expressions of apoptosis-related protein (bax/bcl-2 ratio and caspase-3) were significantly increased in the hippocampus, while the bcl-2 was remarkably decreased and no significant differences were observed on the bax. The results suggested that the possible mechanisms for the learning and memory ability impairments were as follows: Firstly, the combination exposure induced the occurrence of lipid peroxidation in the brain, leading to damage to the brain cells. Secondly, it destroyed the normal metabolic balance of ACh, causing nerve damage in mice. Thirdly, it induced apoptosis in mouse hippocampal cells. The overall findings revealed that Pb and DBP co-exposure greatly influenced the developmental nervous system and accompanied with synergistic toxic effect. [ABSTRACT FROM AUTHOR]

Cutaneous exposure to carcinogenic polycyclic aromatic hydrocarbons (PAH) occurs frequently in the industrialized workplace. In the present study, we addressed this topic in a series of experiments using human skin explants and organic extracts of relevant industrial products. PAH mixtures were applied topically in volumes containing either 10 or 1 nmol B[a]P. We first observed that although mixtures were very efficient at inducing expression of CYP450 1A1, 1A2, and 1B1, formation of adducts of PAH metabolites to DNA, like those of benzo[a]pyrene diol epoxide (BPDE), was drastically reduced as the complexity of the surrounding matrix increased. Interestingly, observation of a nonlinear, dose-dependent response with the least complex mixture suggested the existence of a threshold for this inhibitory effect. We then investigated the impact of simulated sunlight (SSL) on the effects of PAH in skin. SSL was found to decrease the expression of CYP450 genes when applied either after or more efficiently before PAH treatment. Accordingly, the level of DNA-BPDE adducts was reduced in skin samples exposed to both PAH and SSL. The main conclusion of our work is that both increasing chemical complexity of the mixtures and co-exposure to UV radiation decreased the production of adducts between DNA and PAH metabolites. Such results must be taken into account in risk management. [ABSTRACT FROM AUTHOR]

An unsafe level of manganese (Mn) was detected in the drinking water in some arsenic (As)-contaminated areas in Bangladesh. Mn is an essential trace element; however, the intake of a higher level of Mn through the drinking water is associated with the development of toxicity in humans. This study was designed to evaluate the effects of As and Mn co-exposure on neurobehavioral and biochemical alterations in a mouse model. Sodium arsenite (10 mg/kg body weight) and manganese chloride tetrahydrate (10 mg/kg body weight) were given to mice individually and in combination with drinking water for 90 days. Results showed that individual As and Mn exposure as well as co-exposure of As and Mn significantly (p < 0.05) reduced the percent of time spent in the open arms when compared with that of control mice. In addition, percent of time spent in open arms significantly (p < 0.05) increased in co-exposed mice compared with As exposure in elevated plus maze (42.05 ± 1.10 versus 38.94 ± 0.66). In the Morris water maze test, the mean time latency to find the platform was longer in metal-treated mice in comparison to that of control mice (p < 0.05). Importantly, the co-exposed group had shorter time when compared with the As-exposed group during the training periods (p < 0.05). Moreover, co-exposed mice stayed significantly (p < 0.05) more time in the target quadrant in the probe trial in comparison with that of As-exposed mice (27.25 ± 1.21 versus 23.83 ± 0.87 s) but less time than control mice (27.25 ± 1.21 versus 43.17 ± 1.49 s). In addition, a significant (p < 0.05) alteration of biochemical parameters such as ALT, AST, ALP, BChE, and SOD as well as urea and creatinine levels were noted in the As-exposed group compared with the control group and Mn significantly (p < 0.05) attenuated the effects of As in co-exposed mice. Therefore, the results of this study suggest that As and Mn may have some antagonistic effect and Mn could attenuate the As-induced neurobehavioral and biochemical alterations in co-exposed mice. [ABSTRACT FROM AUTHOR]

Exposure to environmental endocrine disruptors (EEDs) has been linked to adverse health outcomes. The vast majority of studies examined one class of EEDs at a time but humans often are exposed to multiple EEDs at the same time. It is, therefore, important to know the co-exposure status of multiple EEDs in an individual, to preclude and control for potential confounding effects posed by co-exposed EEDs. This study examined the concentrations of seven classes of EEDs in the US population utilizing the data from the National Health and Nutrition Examination Survey (NHANES), 2009–2014 survey cycles. We applied linear correlation and cluster analysis to characterize the correlation profile and cluster patterns of these EEDs. We found that EEDs with a similar structure are often highly correlated. Among between-class correlations, mercury and perfluoroalkyl substances (PFAS) and cadmium and polycyclic aromatic hydrocarbons (PAHs) were two significantly correlated EEDs. In epidemiologic studies, measurement and control for co-exposure to pollutants, especially those with similar biological effects, are critical when attempting to make causal inferences. Appropriate statistical methods to handle within- and between-class correlations are needed. [ABSTRACT FROM AUTHOR]

Deoxynivalenol (DON), nivalenol (NIV), T-2 toxin (T2), fumonisin B1 (FB1), zearalenone (ZEA), and moniliformin (MON) mycotoxins are common food and feed contaminants produced by Fusarium spp. However, while they are usually found to co-occur in a large range of commodities, only few data are available on mycotoxin co-exposure effects and cellular response mechanisms. In this study, the individual and combined toxic effects of these fusariotoxins were evaluated on the THP-1 human immune cell line as major fusariotoxins are mostly potent immunomodulators. In particular, four relevant fusariotoxin mixtures, namely DON-MON, DON-FB1, DON-ZEA, and NIV-T2, were studied using several parameters including cell viability as well as the expression of cell surface markers and the main mitogen-activated protein kinases (MAPKs). After 48 h exposure, a reduction of cell viability in a dose-dependent manner was observed for T2, the most cytotoxic mycotoxin, followed by NIV, DON, MON, FB1, and ZEA. Regarding mycotoxin mixtures, they mainly showed antagonism on cell viability reduction. Interestingly, at concentrations inhibiting 50% of cell viability, most viable cells exhibited surface marker loss and thus became potentially non-functional. In addition, during the first 18 h of exposure, the effects of mycotoxin mixtures on early cell apoptosis and necrosis were found to be different from those induced by the toxins alone. At the molecular level, after 1 h exposure of individual and combined mycotoxins, the three main MAPK signaling pathways (p38, SAPK/JNK, and ERK1/2) were activated, highlighting a fast reaction of the exposed cells even at low cytotoxicity levels. [ABSTRACT FROM AUTHOR]

The waste management occupational environment is recognized by the simultaneous presence of several substances and biologic agents. Therefore, workers are exposed simultaneously to multiple contaminants. Occupational exposure to aflatoxin B1 in one Portuguese waste sorting plant was already reported. However, besides this mycotoxin, data regarding fungal contamination showed that exposure to other mycotoxins could be expected. A study was developed to analyze if exposure to other mycotoxins besides aflatoxin B1 was occurring in the workers from the waste sorting plant previously assessed and to discuss how these findings need to be considered in the risk assessment process. In addition to aflatoxin B1 detected previously by ELISA, two additional mycotoxins and one mycotoxin degradation product were detected and quantified by a multi-mycotoxin HPLC-MS/MS approach: Enniatin B and ochratoxin A as well as 2’R-ochratoxin A. Besides the confirmation of co-exposure to several mycotoxins, results probably indicate different exposure routes for the mycotoxins reported. [ABSTRACT FROM AUTHOR]

This study investigated the transformation of triclosan (TCS) following co-exposure to UV irradiation and ClO2. Special attention was given to understand the influencing of water quality parameters and toxicity changes during the co-exposure process. The results show that the co-exposure process prompted TCS elimination quickly and effectively, with more than 99% of TCS degraded under the experimental conditions. The molar yield ratios of 2,4-dichlorophenol/TCS (2,4-DCP/TCS) were calculated to be 35.81-74.49%; however, the by-product of 2,8-dichlorodibenzop-dioxin (2,8-Cl2DD) was not detected. The TCS degradation was sensitive to ClO2 dosage, pH, H2O2, and natural organic matter (NOM), but not to the carbonate (CO32−) concentration. Neutral and slightly alkaline condition were favorable to TCS elimination. The TCS removal rate increased from 85.33 to 99.75% when the ClO2 concentration increased from 0.25 to 1.5 mg L−1. TCS degradation can be promoted at low NOM level (1, 3, and 5 mg L−1), whereas was inhibited at high NOM concentrations of 7 and 9 mg L−1. While adding H2O2, the degradation rate of TCS increased with increasing H2O2 concentration from 1 to 3 mg L−1; however, too low or overdosed H2O2 (0.5 and 5 mg L−1) hindered TCS degradation. Based on the results of a microtox bioassay, the toxicity did not change following the co-exposure process. [ABSTRACT FROM AUTHOR]

Arsenic (As) toxicity has caused an environmental tragedy affecting millions of people in the world. Little is known about the toxic effects of As on neurobehavioral and biochemical changes in vivo. Along this line of metal toxicity, co-exposure of lead (Pb) could aggravate the situation in the host. The present study was designed to explore the combined effects of As and Pb on behavioral changes like anxiety, spatial memory and learning impairment, and blood indices related to organ dysfunction. Exposure of mice to As (10 mg/kg body weight), Pb (10 mg/kg body weight), and As + Pb via drinking water significantly decreased the time spent exploring the open arms while it increased the time spent in the closed arms compared to control mice in the elevated plus maze. The mean latency time of the control group to find the platform decreased significantly during the learning for 7 days compared to all three treated groups in the Morris water maze test, and the As-exposed group spent significantly less time in the desired quadrant as compared to the control group in the probe trial. Both metals posed an anxiety-like behavior and deficits in spatial memory and learning, and also altered blood indices related to liver and kidney dysfunction, and a combined exposure of these metals inhibited the individual accumulation of As and Pb. Taken together, these data suggest that As has more toxic effects on neurobehavioral and biochemical changes than Pb, and there may be antagonism in the effects and accumulation between these two toxicants. [ABSTRACT FROM AUTHOR]

Both ultrafine particles (UFP) and polycyclic aromatic hydrocarbons (PAHs) are widely present in the environment, thus increasing their chances of exposure to human in the daily life. However, the study on the combined toxicity of UFP and PAHs on respiratory system is still limited. In this study, we examined the potential interactive effects of silica nanoparticles (SiNPs) and benzo[a]pyrene (B[a]P) in bronchial epithelial cells (BEAS-2B). Cells were exposed to SiNPs and B[a]P alone or in combination for 24 h. Co-exposure to SiNPs and B[a]P enhanced the malondialdehyde (MDA) contents and reduced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities significantly, while the reactive oxygen species (ROS) generation had a slight increase in the exposed groups compared to the control but not statistically significant. Cell cycle arrest induced by the co-exposure showed a significant percentage increase in G2/M phase cells and a decrease in G0/G1 phase cells. In addition, there was a significant increase in BEAS-2B cells multinucleation as well as DNA damage. Cellular apoptosis was markedly increased even at the low-level co-exposure. Our results suggest that co-exposure to SiNPs and B[a]P exerts synergistic and additive cytotoxic and genotoxic effects. [ABSTRACT FROM AUTHOR]

The purpose of present study was to determine the sub-acute toxicity effects of diazinon on the gill and intestine tissues histopathology of common carp ( Cyprinus carpio) in exposure to TiO NPs. In this study, common carp (length: 21 ± 1.3 cm; weight: 11 ± 1.1 g) were assigned randomly to 12 experimental groups (15 each) and exposed to three non-lethal concentration of TiO NPs, two non-lethal concentrations of diazinon, and six mixture concentrations of diazinon and TiO NPs, as well a control group for a period of 14 days. For studies of classic histological, the samples of gill and intestine organs were prepared and stained by hematoxylin-eosin and, finally, was imagined by light microscopy. Compared to the control group, gill and intestine tissues of common carp in treatment groups, TiO, diazinon, and a mixture of TiO and diazinon, showed higher histopathological alterations. The most commonly observed alterations in gill were hyperplasia, fusion of lamellae, aneurism, and necrosis. Common alterations in intestine were degeneration, increase in the number of goblet cells, increase in the number of lymphocyte, vacuolation, and necrosis and erosion. In conclusion, this research suggested that the coexistence toxicity of diazinon and TiO NPs on the gill and intestine histopathology of common carp was higher than the diazinon and TiO NPs alone. [ABSTRACT FROM AUTHOR]

Honeybee exposure to pesticides is widely accepted, but the role they play in impacting bee health remains controversial. The development of risk assessment procedures is notably a difficult task due to the variability of responses observed for a single pesticide at a specific dose. Indeed, honeybees, during most of their lifetime, are exposed to fluctuating environmental conditions (e.g., pathogen pressure, resource availability, climatic conditions) and can go through important physiological changes within a few days (e.g., behavioral maturation) or even a day (e.g., circadian clock), which are all factors that can affect the bee response to pesticides. Integrating the range of variability in conditions experienced by bees is relevant to honeybee toxicology and will contribute to a better assessment of their susceptibility to pesticides. The aim of this review is therefore to provide empirical evidence of how co-exposure to stressors, and environmental and endogenous factors modulate the honeybee response to pesticide. [ABSTRACT FROM AUTHOR]

The study aimed to assess the genotoxic potential of silica-coated iron oxide nanoparticle functionalized with dithiocarbamate groups (IONP, 100 nm) in vitro exposure alone or its interference with mercury (Hg) co-exposure in the blood of European eel ( Anguilla anguilla L.) by evaluating 8-hydroxy-2′-deoxyguanosine (8-OHdG), lipid peroxidation (LPO), and erythrocytic nuclear abnormalities (ENA). Four groups were made: (i) 2 × 10 erythrocytes + Roswell Park Memorial Institute-1640 (RPMI-1640) (control), (ii) 2 × 10 erythrocytes + IONP (2.5 mg L), (iii) 2 × 10 erythrocytes + Hg (50 μg L), and (iv) 2 × 10 erythrocytes + IONP + Hg. Blood plasma was also processed following the previous exposure conditions. Samplings were performed at 0, 2, 4, 8, 16, 24, 48, and 72 h of exposure. The results revealed significant ENA increases at both early (2, 4, 8) and late (16, 24, 48, 72) hours of exposure to IONP alone. However, IONP exposure combined with Hg co-exposure revealed no ENA increase at 2 h, suggesting that IONP-Hg complex formation is efficient to eliminate the DNA damage induced by individual exposure to IONP or Hg at early hours. Hence, the initial occurrence of antagonism between IONP and Hg was perceptible; however, at late hours of exposure, IONP was unable to mitigate the mercury-accrued negative impacts. Plasma exposure to IONP alone displayed a significant increase in 8-OHdG levels at 2 and 48 h of exposure. However, IONP in combination with Hg co-exposure revealed an increase in 8-OHdG levels at all the exposure length (except 16 h), suggesting that both IONP and Hg independently oxidized DNA. In addition, an additive effect on 8-OHdG levels at both early and late hours, and on LPO only at late hours (except 24 h), suggested that DNA is more susceptible to peroxidative damage than lipid. [ABSTRACT FROM AUTHOR]

Objectives: Due to incomplete curing and material degradation, cells in the oral cavity may be exposed to monomers and filler particles from dental composite fillings. The objective of the present study was to investigate if combined exposures to particles and a methacrylate monomer from composite fillings resulted in additive effects on the macrophage immune response. Material and methods: Two filler particles, Nanosilica (12 nm) and Quartz (1 μm), were studied at concentrations 0.5-4 μg/cm, while the methacrylate monomer triethyleneglycol dimethacrylate (TEGDMA) was applied at 5 and 50 μM. RAW 264.7 macrophages were exposed to monomers and/or particles for 24 h, with a subsequent 24 h combined exposure to monomers and/or particles and the bacterial factor lipopolysaccharide (LPS) to stimulate an immune response. Release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were measured as well as the cellular viability. Results: Co-exposure to Nanosilica and Quartz resulted in an additive attenuation of the LPS-induced IL-1β release. Moreover, co-exposure to TEGDMA and both types of filler particles also resulted in an additive attenuation, although with a weak synergistic trend. The cellular viability and TNF-α release were not significantly affected by the exposures. Conclusion: The present findings emphasize the necessity of considering effects of combined exposure to dental degradation products in future risk assessments. Clinical relevance: Attenuated cytokine release could have implications for the macrophage immune response and result in impaired bacterial clearance. Further studies are necessary to determine implications for formation of dental biofilms and caries development. [ABSTRACT FROM AUTHOR]

It has been shown that cadmium and fluoride may both have adverse effects on liver and kidney functions, but most studies focus on a single agent. In this study, we observed the effects of cadmium and fluoride on liver and kidney functions using a rat model. Total of 24 Sprague-Dawley male rats were divided into four groups, one control group and three exposure groups that were given cadmium (50 mg/L) and fluoride (100 mg/L) alone or in combination via drinking water. At the 12th week, urine, blood, and kidney tissues were collected. Aspartate transaminase, alanine transaminase (ALT), urinary β-microglobulin, and albumin were determined. Contents of malondialdehyde (MDA) and superoxide dismutase (SOD) in liver and kidney homogenates were measured to evaluate oxidative stress. There was a significant increase in serum ALT and urinary β-microglobulin of rats in exposure groups compared with control. Serum ALT and urinary β-microglobulin of rats exposed to cadmium and fluoride in combination was significantly higher than those treated with cadmium alone and fluoride alone. SOD declined significantly and MDA increased in combination group compared with control and those treated with cadmium and fluoride alone. Cadmium and fluoride co-exposure increase the liver and kidney damage compared with that exposed to cadmium or fluoride alone. [ABSTRACT FROM AUTHOR]

Technetium-99 (Tc) was used as an isotope tracer to study the biodistribution of oxidized multi-walled carbon nanotubes (oMWCNTs) and /or graphene oxide nanoplatelets (GONP) after intravenous administration (i.v.). The authors also investigated the histological impact of non-radiolabeled oMWCNT or GONP as they passed through systemic circulation and their excretion pathways in comparison to co-exposure groups of both (oMWCNTs and GONP). Results indicated that oMWCNTs were mainly excreted through feces rather than urine. From the blood, oMWCNTs first entered the stomach, then intestines via chyme, and were finally excreted in feces. GONP also followed this pathway, but could also be excreted through urine when co-exposed with oMWCNTs. In summary, the biodistribution patterns and excretion rates of the nanomaterials in vivo depended on their composition and chemical modifications. A new mechanism is proposed to explain how chemical modification groups affect the behavior of nanomaterials in vivo. The behavior and fate of GONP depended strongly on oMWCNTs in mice in vivo, but the GONP did not affect deeply biodistribution and excretion pattern of oMWCNTs in co-exposure. [ABSTRACT FROM AUTHOR]

Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are environmentally persistent neurodevelopmental toxicants. The primary source of human exposure is the consumption of contaminated fish, seafood and marine mammals. However, little is known about the molecular mechanisms of MeHg and PCB toxicities and interactions between these contaminants. We investigated the functional profiles of differently expressed genes in the brains of offspring mice perinatally exposed to MeHg and/or PCBs to elucidate how these contaminants interact with each other. Pregnant mice (C57BL/6) were divided into four groups by exposure: (1) vehicle control, (2) MeHg alone, (3) PCBs alone, (4) MeHg + PCBs. Gene expression analysis of the brains of offspring mice was carried out with 4 × 44 K whole mouse genome’s microarrays (Agilent) on postnatal day 1. The gene expression pattern of the MeHg exposure-group differed from that of the PCB-exposure group. The MeHg + PCB group expressed a larger number of genes, most of which were not expressed in the MeHg group or PCB group. It was revealed that gene expression was greatly increased, and the most altered genes were found with co-exposure. The genes were related to the functional categories of development, inflammation, calcium ion homeostasis, signal transduction, the ubiquitin–proteasome pathway and detoxication. The ubiquitin–proteasome system and detoxication categories might function for protection against the toxicity induced by co-exposure to MeHg and PCBs. These results suggest that co-exposure does not simply exacerbate the toxicity of MeHg alone or PCB alone, but stimulates a protection system. [ABSTRACT FROM AUTHOR]

Arsenic is a known global groundwater contaminant, while malathion is one of the most widely used pesticides in agriculture and public health practices in the world. Here, we investigated whether repeated exposure to arsenic at the groundwater contamination levels and to malathion at sublethal levels exerts adverse effects on the hepatic drug-metabolizing system in rats, and whether concurrent exposure is more hazardous than the single agent. Male Wistar rats were exposed daily to 4 or 40 ppm of arsenic via drinking water, 50 or 500 ppm of malathion-mixed feed and in a similar fashion co-exposed to 4 ppm of arsenic and 50 ppm of malathion or 40 ppm of arsenic and 500 ppm of malathion for 28 days. At term, toxicity was assessed by evaluating changes in body weight, liver weight, levels of cytochrome P450 (CYP), cytochrome b 5 and microsomal and cytosolic proteins, and activities of aminopyrine- N-demethylase (ANDM), aniline- P-hydroxylase (APH), glutathione- S-transferase (GST) and uridine diphosphate glucuronosyltransferase (UGT) in liver. Arsenic and malathion alone did not alter body weight and liver weight, but these were significantly decreased in both the co-exposed groups. These treatments decreased the activities of ANDM and APH and the levels of liver microsomal and cytosolic proteins, increased GST activity and had no effect on UGT activity. The effects of exposure to low-dose and high-dose combinations on the activities of either phase I or phase II drug-metabolizing enzymes and protein content were mostly similar to that produced by the respective low and high dose of either arsenic or malathion, except APH activity. The effect of arsenic (40 ppm) on APH activity was partially, but significantly, inhibited by malathion (500 ppm). Results indicate that the body or liver weights and the biochemical parameters were differentially affected in male rats following concurrent subacute exposure to arsenic and malathion, with the co-exposure appearing more hazardous to physical variables based on body or liver weights whilst producing biochemical changes comparable to those caused by the individual agents. From these findings, no specific toxicological interaction between arsenic and malathion can be conclusively generalized. [ABSTRACT FROM AUTHOR]

We previously showed that maternal exposure to nicotine, alone or in combination with chlorpyrifos, caused an increase in glial fibrillary acidic protein (GFAP) immunostaining in the CA1 subfield of hippocampus and cerebellum in postnatal day (PND) 30 offspring. In the present study, PND 60 offspring were evaluated for histopathological and cholinergic effects following maternal exposure to nicotine and chlorpyrifos, alone and in combination. Timed-pregnant Sprague-Dawley rats (300–350 g) were treated daily with nicotine (1 mg/kg, s.c., in normal saline) or chlorpyrifos (0.1 mg/kg, dermal, in ethanol) or a combination of nicotine and chlorpyrifos from gestational days (GD) 4 to 20. Control animals were treated with saline and ethanol. On PND 60, the offspring were evaluated for cholinergic changes and pathological effects. Plasma butyrylcholinesterase (BChE) activity in the female offspring from chlorpyrifos treated mothers showed a significant increase (~183% of control). Male offspring from mothers treated with either chlorpyrifos or nicotine alone showed a significant increase in the acetylcholinesterase (AChE) activity in the brainstem while female offspring from mothers treated with either nicotine or a combination of nicotine and chlorpyrifos showed a significant increase (~134 and 126% of control, respectively) in AChE activity in the brainstem. No significant changes were observed in the ligand binding densities for α4β2 and α7 nicotinic acetylcholine receptors in the cortex. Histopathological evaluation using cresyl violet staining showed a significant decrease in surviving Purkinje neurons in the cerebellum of the offspring from nicotine treated mothers. An increase in GFAP immunostaining in cerebellar white matter was observed in the offspring from the mothers treated with nicotine. These results suggest that maternal exposure to real-life levels of nicotine and/or chlorpyrifos causes differential regulation of brainstem AChE activity. Also, nicotine caused a decrease in the surviving neurons and an increased expression of GFAP in cerebellar white matter of the offspring on PND 60. These changes can lead to long-term neurological adverse health effects later in life. [ABSTRACT FROM AUTHOR]